June 2015

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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • June 2015 • Vol. 10, No. 6

Tips for encouraging healthy lifestyles in breast cancer patients.........

5

Prehab Offers Faster Track to Recovery From Ca Treatment

Strategies to reduce bloodstream infections in oncology patients ..........

6

T

CURRENT PRACTICE

SOLID TUMORS Strong evidence supports early docetaxel in patients with advanced/metastatic prostate cancer ................... 12

HEMATOLOGIC DISEASE Report From AACR Meeting: The risks and benefits of blinatumomab in clinical practice ................... 16 Clinical Conundrums ........

18

by the

numbers Nivolumab vs vs. docetaxel in second-line treatment of advanced or metastatic squamous NSCLC Nivolumab

Docetaxel

10 9

see PREHABILITATION, N page 8

9.2

6.0

Median OS

3.5

Melanoma cells. Two multicenter trials show checkpoint inhibitors are not interchangeable in melanoma; story on page 10.

More Evidence Shows Aspirin May Lower Risk for GI Cancers

How I Manage Early-Stage Hodgkin Lymphoma

Philadelphia—Use of two or more 325-mg doses of aspirin weekly for 16 years or longer is associated with a modest overall reduction in cancer risk, mainly from fewer gastrointestinal (GI) malignancies, according to two studies that prospectively followed more than

arly-stage classical Hodgkin lymphoma (cHL) is a highly curable disease. Outcomes are favorable with either chemotherapy alone or combined modality therapy (CMT). Recently, interim positron emission tomography (PET)-computed tomography

Months

8

o speed your patient’s recovery from a difficult course of cancer treatment, start rehabilitation even before surgery, chemotherapy or radiation begins. That’s the message from Oncology Rehab Partners, whose nationally recognized STAR (Survivorship Training and Rehabilitation) Program has certified nearly 200 cancer rehabilitation programs at more than 400 sites nationwide.

This complementary approach to rehabilitation, dubbed “prehab” by STAR Program creator Julie Silver, MD, isn’t entirely new. For years, some

2.8

Median PFS

E

Trusted to take a bite out of G-CSF acquisition costs* X® has gai aine ned d >3 >34% 4% sha h re of the US short-acting G-CS GCSF F ho hosp spit ital al mar arke kett in its first 17 montths1 Indication » GRAN GR ANIX X is a leukocyte growth factor indicated for red duction in the duration of se evere neu utropenia in pa ati t ents with nonmyeloid malignancies receiving myelosuppressive anticancer drugs asso ociated with a c inically significant incidence of febrile neutropenia. cl

NOW Available

Important Safety Information »

Splenic rupture: Splenic rupture, includingEssential fatal casess, can occur following the administra ation of human ™ GRANIX and evalluate for an enlarged spleen granulocyte colony-stimulating factors (hG-CSFs).

Disccontinue Oncology or splenic rupture in patients who report upper abdom minal or shoulder pain after receivin ng GRANIX.

See what’s new inside!

Please see reverse side for additional Important Safe ety Information and brief summary y Essential Oncology of Full Prescribing Information on page adjacent to our ad inside. essentialoncology.com *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products a as of March 2015. WAC represents pub blished catalo ogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

65 Cancer Types

Important Safety Information (continued) » Acute respiratory distress syn y drom me (A (ARD RD DS) S): ARD DS ca an oc occu cu ur in n pat atie ient ie ntts rece rece re ceiv ivin iv ing in g hG hG-C -C CSF SFs. s. Eva valu luat ate e pa pati tien ents ts who dev evel elop op fev ever er and lung infilt ltrates or o fi f lg gra r sttim im) m) In nje ject ctio ct ion, io n, for ARD RDS. S. Diissco c nttin inue u GRA ue ANI NIX X in pat atie ent ntss wi with th ARD DS. S respiratory distress after receiiving GRANIX® (tbo» Allergic reactions: Serio iouss aller e gicc re reac a tiion ons, s, inc nclu lu udi ding ng ana naph phyl ph ylax yl a iss, ca ax can n oc occu curr in pat cu atie ient ntss re rece ceiv ivin ing g hG hG-- CSF SFs. Reactions can n occur on initial exposure.

Permanently disc s ontinue GR G AN NIX X in n pa p ti t en nts witth se seri riou ri ouss al ou alle lerg le r ic rea rg eact c io ct onss. Do D not adm dmin inisste terr GR GRAN ANIX IX to patien e ts with a history of serious allergic reactions to filgrastim or o peg egfilgra rastim m. » Use in pat atie entss wi with h sicckl k e ce c lll dis isea ease ea se:: Sev se ever e e an er and d so s me meti time m s fa me fata tall si sick ckle le cel ell cr crisses e can a occur in n patie ents with sickle cell disease receiving hG-CSFs. C nsid Co der the he pot o en nti t al a rissks and ben e ef efit itss prrio it iorr to t the adm d in inis istr trat atio ion n of GRA RANI NIX X in n patients with sickle ce ell disease. Discontinue GRANIX in patients unde un derg goi o ng g a sic ickl kle kl e ce cellll cri risi sis. si s s. » Ca Capi p ll l ar ary y le eak syn yndr drom dr ome om e (C (CLS LS): LS ) CL ): C S ca can n occu occurr in pat atie ient ntss rece c ivving hG-CSFss and is characterized by hypotension, hypoalbuminemia, edema and hemo he moco mo conc co ncen nc entr en trat tr atio at ion. io n. Epi piso sode so dess va de vary r in fr ry f eq equ uency, sev uenc ever erit ity and ma ay be life-threatening if treatment is de elayed. Patients who develop symptoms of CLS shou sh ould ou ld be cl clos osel os elyy mo el moni n to ni ore ed an and d re rece ceiv ive e st sta anda dard rd sym ympt ptomatic treatment, which may include a need for intensive care. » Po Pote tent te ntia nt iall fo ia forr tu tumo morr grow mo gro gr ow w th sti timu mula lato tory y eff ffec e ts on malignant cells: The granulocyte colony-stimulatting factor (G-CSF) receptor, through which GRANIX acts ac ts,, ha ts hass be been en fou ound nd on tu tumo mor ce cellll lin ness. The e po poss s ibility that GRANIX acts as a growth factor for any tu umor type, including myeloid malignancies and myel my elod el odys od yspl ys plas pl asia as ia a, di dise se eas ases es for whi h ch GRA ANI N X is not o approved, cannot be excluded. » Mo Most st com ommo m n tr mo t ea e tm tmen entt-em emer e ge gent nt adv d errse reacttion: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the rec ecom o me om mend nded ed dos o e wiith an incidence e of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Plea Pl ease ea se see bri r ef sum umma mary ry of Fu Full l Prescribing g Information on page adjacent to our ad inside.

Refere Ref erence ere er nce ce:: 1.

1. Th Thi h s info nformatio tion n is an an esti stimat m e deri erived ve frrom the t use of information under license from the following IMS Health Information Service: IMS National Sales Perspective, GRANIX micrograms by non-federal hospit hos pi al pit a cha ch nne nnel Marc arch h 2015 2 15.. IMS IMS exp expres ressly sly re eserves ves alll righ ghts, including rights of copying, distribution, and republication (micrograms calculated as eaches x strength).

©2015 Cep ©2015 Cephal ha on, In I c., c a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All r ight ghtss rese eserved. d GRX GRX-40 40679 May 2015.

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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • June 2015 • Vol. 10, No. 6

Tips for encouraging healthy lifestyles in breast cancer patients.........

5

Prehab Offers Faster Track to Recovery From Ca Treatment

Strategies to reduce bloodstream infections in oncology patients ..........

6

T

CURRENT PRACTICE

SOLID TUMORS Strong evidence supports early docetaxel in patients with advanced/metastatic prostate cancer ................... 12

HEMATOLOGIC DISEASE Report From AACR Meeting: The risks and benefits of blinatumomab in clinical practice ................... 16 Clinical Conundrums ........

18

by the

numbers Nivolumab vs vs. docetaxel in second-line treatment of advanced or metastatic squamous NSCLC Nivolumab

Docetaxel

10 9 8

Months

7 6 5 4 3 2 1

9.2

6.0

3.5

2.8

0

Median OS

Median PFS

Based on data from Phase III CheckMate 017 study (ASCO abstract 8009) released May 13, 2015.

o speed your patient’s recovery from a difficult course of cancer treatment, start rehabilitation even before surgery, chemotherapy or radiation begins. That’s the message from Oncology Rehab Partners, whose nationally recognized STAR (Survivorship Training and Rehabilitation) Program has certified nearly 200 cancer rehabilitation programs at more than 400 sites nationwide.

This complementary approach to rehabilitation, dubbed “prehab” by STAR Program creator Julie Silver, MD, isn’t entirely new. For years, some see PREHABILITATION, N page 8

Melanoma cells. Two multicenter trials show checkpoint inhibitors are not interchangeable in melanoma; story on page 10.

More Evidence Shows Aspirin May Lower Risk for GI Cancers

How I Manage Early-Stage Hodgkin Lymphoma

Philadelphia—Use of two or more 325-mg doses of aspirin weekly for 16 years or longer is associated with a modest overall reduction in cancer risk, mainly from fewer gastrointestinal (GI) malignancies, according to two studies that prospectively followed more than 130,000 health care professionals. No protective relationship was observed between aspirin use and breast, lung and advanced prostate cancers.

“The association of aspirin use with reduced cancer risk was similar for women and men and did not vary by race, history of diabetes, family history of cancer, body mass index, smoking history, or regular use of [nonsteroidal anti-inflammatory drugs] or

arly-stage classical Hodgkin lymphoma (cHL) is a highly curable disease. Outcomes are favorable with either chemotherapy alone or combined modality therapy (CMT). Recently, interim positron emission tomography (PET)-computed tomography (CT) has been used to guide the decision regarding consolidative radiation therapy (RT), with many clinicians omitting RT in PET-negative patients. Bulky early-stage disease remains a challenge. Presenta- Nancy L. Bartlett, MD tion with bulky disease is most common in young women, in whom the use of mediastinal RT increases the risk for secondary breast cancer. Identifying more effective systemic therapies with limited late effects remains a priority for these patients.

see ASPIRIN, N page 11

E

see EARLY-STAGE HL, page 14

Essential Oncology™

NOW Available Colorectal Cancer Shahab U. Ahmed, MD Cathy Eng, MD To download the Essential Oncology app go to: essentialoncology.com

65 Cancer Types

Trusted to take a bite out * of G-CSF acquisition costs GRANIX X® has gained >3 34% share of the t US short-actting G-CSF hospita al marrket in its first 17 monthss1 » A 71% red duction in duration of severe e neutrropenia vs placebo (1.1 days vs 3.8 days, p<0.000 01)2 – Efficacy was evaluated in a mu ultinattional, m multi ltice t center, random mizzed e , co c ntrolllled ed d, Ph P a asse IIIII st stu udy of che h mo moth th her erap apyap y-na naïv ïve e pati patien ents ts V bo olu us))/d /doc occet etax axel ax el (75 mg/ g/m m2)2 with high h-risk breast cancer re eceivin ng doxo orubicin n (60 mg/m2 IV » The safetyy of GRANIX was esttab blish hed in 3 Ph Phasse II III trria alss, wi with th 680 80 pat atie ie ent ntss re recce ceivin ceiv ivving g ch hem emo othera othe rapy py for eithe herr br breast cancer,, lung cance er, or non-Hodgkin lyym mpho oma ma (NH NH HL)2 » Offering a prese entatio i n fo for se elf--a adm dmin nisstr trat atio at io on

Indication » GRAN GRANIX X is a le eukkoc o yt yte e gr grow owth ow th fa acto ac t r indi to d ca cate ted te d fo forr re redu duct ctio ion n in the durat atio ion of severe neutropeniia in patients with nonmyeloid malilign ma g a gn an nci c es es rec ecei eivi ei ving vi ng mye yelo losu lo supp pre r sssive an anti tica canc ncer er dru rugs gs ass ssoc o ia ated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Sp Sple leni le nicc ru ni upt ptur ure: ur e: Spl e: p en e ic rup uptu turre e, in incl clu udin ng fatal ca c ses, can occur following the administration of human granulocyte colonystim st imul im ulat ul atin at ing in g fa fact c or ct o s (h ( GG-CS CSFs Fs). ). Dis isco ont ntinue GRANIX and evaluate for an enlarged spleen or splen nic rupture in patients who repo re port po rt upp pper abd b om omin inal al or sh s ou ould der pain a after receiving GRANIX. » Ac Acut ute ut e re resp spiirrat sp ator orry di dist stre ress ss syn y drom me (A ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and an d lu lung ng g inf n ililtr trat ates es or re resp spir irat atory distresss after receiving GRANIX, for ARDS. Discontinue GRANIX in n patients with ARDS. » Al Alle lerg le rgic ic react eactio ionss: Ser eriouss allerrgic reactions, including anaphylaxis, can occur in patients receivving hG-CSFs. Reactions can occu oc cu ur on ini niti tial al exp xpos o urre. Perrma anently discontinue GRANIX in patients with serious allergic reacctions. Do not administer GRAN GR ANIX IX to pa pati tien ents t wit ith h a hi h st sto oryy of se erious allergic reactions to filgrastim or pegfilgrastim. » Us U e in pattie ient ntss wi with th sickl kle ce c ll diseasse: Severe and sometimes fatal sickle cell crises can occurr in patients with sickle cellll dis ce isea easse s rec ecei eivi ving n hG-CSFs F . Consid der the p potential risks and benefits prior p to the administrattion of GRANIX in patients with sick si ckle le cel elll di dise seas ase. e Dissco c ntinue GRANIX X in patients undergoing a sickle cell crisis. » Capi Capilllar ary y le leak ak syndr d ome (CLS):: CLS ca an occur in patients receiving hG-CSFs and is characte erize ed by hypotension, hypo hy poal albu b mi m ne emi mia, ede ema and h hemoco oncentration. Episodes vary in frequency, severity and may be life-threatening if treatment is del elay ayed ed d. Pati t ents who develo op symp ptoms of CLS should be closely monitored and receive sta andard symptomatic treatmen e t, whic wh ich h ma mayy includ de a need for in ntensive e care. » Pote Po ent ntia al for tumor growth stim mulatory effects on malignant cells: The granulocyte colony-stim mulating factor (G-CSF) receptor, thro th roug gh wh which GR RANIX X acts, hass been found f on tumor cell lines. The possibility that GRANIX act c s as a growth factorr for any tumor type ty p , in nclu u uding myeloi myeloid o d maligna ancies and myelodysplasia, diseases for which GRANIX is not apprroved, cannot be excluded. »M Most s com mmon treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in n pattientss treated wi w th GRANIX X at the e recommended dose with an incidence of at least 1% or greater and tw wo times more freq fr e ue ent n than in the placebo gro oup wa as bone pain.

Plea Pl e se e see e brief summary of Fulll Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. *Ba Base sed d on o who ole lesa ale e acquisiition n cost (WA AC) of all short-acting G-CSF products as of March 2015. WAC represents pub blished catalogue or list prices and mayy no ma nott re repr pre e en es nt actual tra ans nsactional p prices. Ple ease contact your supplier for actual prices. ease prices R fe Re fere renc nces es: 1. Th Thiss inf nfo orma mati tion n iss an a estim mate de derived from the use of information under license from the following IMS S Health Information Service: IMS Nati Na t on ti onal al Sal ales es Per ersp spec ecti tive ve, GR GRAN ANIX X mic i rro ogr g ams byy non-federal hospital channel March 2015. IMS expressly reserves all rights, including right h s of copying, d st di stri ribu b ti bu t on on, an nd re epu publ b ic icat atio on (m mic icro rogr gram ams ca alcul ullate ed as eaches x strrength). 2. GRANIX® (tbo-filgrastim) Inje j ction Presccribing Information. North Wales, PA A: Teva Te va Pha harm rmac a euti ac eutica cals ls;; 20 2014 14..

©2015 ©201 5 Ce Ceph phal alon on,, In Inc. c , a wh w olllyy-o -owned e sub u sidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered t ad tr adem emar arkk of Tev eva a Ph Phar arma m ce ceut utic iccal a Ind ndustrries Ltd. All rights reserved. GRX-40681 May 2015.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

More Exact Med Reconciliation Crucial for Cancer Patients M

edication reconciliation can be frustrating, but it is crucial, especially when the patient is an older one on multiple medications for several comorbidities.

Medication reconciliation is so important because physicians often are unaware of all the medications a patient is taking, which can result in unnecessary additional prescriptions, nonprescription medications and potential drug–drug interactions that cause

unexpected adverse effects (AEs).

When a cancer diagnosis is thrown into the mix, the drug–drug interactions can become even more complex.

“This is a vulnerable population,” said Andrew Chapman, DO, the co-director of the Multidisciplinary Senior Adult Oncology Center clinic at Thomas Jefferson University, in Philadelphia. “Theyy are prescribed complicated medical regimens that have a real risk of interfering with their cancer care.”

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,ië À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À iÊ[see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

A new study that evaluated available screening tools for determining if and when older people with cancer

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

are taking too many medications found that a more comprehensive medication assessment and monitoring survey is needed to improve treatment for this patient population ((J Clin Oncol 2015;33[13]:1453-1459, PMID: 25800766).

“There is still a lot we don’t know about the impact of excessive and potentially inappropriate medication use for senior adults with cancer, specifically in terms of whether and how increased pill burdens might lead to compromised cancer management plans,” said Ginah Nightingale, PharmD, BCOP, an assistant professor in the Department of Pharmacy Practice at Jefferson School of Pharmacy.

As part of a multidisciplinary clinic in which older cancer patients are seen by a team including a medical oncologist, geriatrician, clinical pharmacist, social worker and dietician, Drs. Chapman and Nightingale and their colleagues looked at the drug regimens of 234 such patients. Using three standard evaluation tool surveys— the Beers Criteria list, the Screening Tool of Older Persons’ Prescriptions (STOPP) survey and the Healthcare Effectiveness Data and Information Set (HEDIS) criteria, which were designed to identify medications with a higher risk for causing AEs in older adults—they found that the association with potentially inappropriate medications (PIM) increased with the number of comorbid conditions requiring medication ((P=0.005) and the number of medications the patients were taking ((P<0.001).

Of the 234 cancer patients evaluated, 43% were taking more than 10 concurrent medications, and the prevalence of polypharmacy, excessive polypharmacy and PIM use was 41% (n=96), 43% (n=101) and 51% (n=119), respectively, the investigators found.

“It’s difficult for an able-bodied adult to keep track of the dosing schedules and appropriate administration of 10 medications, much less for a senior who may have underlying functional or cognitive impairment,” Dr. Nightingale said. “This study is meant to give us a baseline, a sense of the landscape, and the risks involved in this population of cancer patients.”

Now that they established a baseline, the investigators plan to develop a tool that combines the available assessments and considers cancer diagnosis, prognosis and cancer-related therapy to minimize the use of inappropriate medications in the elderly population.

In the meantime, they recommend that comprehensive medication assessments and monitoring plans be implemented and completed routinely for all patients.

—Clinical Oncology News Staff

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Breast Cancer Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Hematologic Malignancies

Betty Ferrell, RN, PhD

Joseph P. DeMarco, PhD

Cancer Treatment Centers of America Zion, IL

City of Hope National Medical Center Duarte, CA

Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD

Michele Neskey, MMSc, PA-C

Paul J. Ford, PhD

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

University of Texas, MD Anderson Cancer Center Houston, TX

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Harry Erba, MD, PhD University of Alabama Birmingham, AL

Mayo Clinic Rochester, MN

Richard Stone, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Cathy Eng, MD

Saad Z. Usmani, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Levine Cancer Institute Charlotte, NC

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

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CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

Six Oncology Agents Gain Accelerated Approval in 12 Months Philadelphia—Blinatumomab is one of six cancer drugs that have emerged from the FDA’s breakthrough therapy designation to reach clinical practice over the past 12 months. Based on a session dedicated to breakthrough therapies at the 2015 annual meeting of the American Association for Cancer Research (AACR), the regulatory process is simply accelerated but not necessarily truncated.

The review timeline for blinatumomab (Blincyto, Onyx), for example, was a mere 75 days. “However, the review team consisted of almost 40 agency personnel, half of whom were primary discipline reviewers, so although the review was quick, it was thorough,” maintained Donna Przepiorka, MD, PhD, an FDA medical officer who provided a detailed explanation of the approval process for this agent at the AACR meeting.

FDA representatives invited to recount the review process for the other breakthrough agents during the meeting made similar remarks. In addition to blinatumomab, the agents approved under the accelerated process program include ibrutinib (Imbruvica, Pharmacyclics), idelalisib (Zydelig, Gilead), nivolumab (Opdivo, Bristol-Myers Squibb), palbociclib (Ibrance, Pfizer) and pembrolizumab (Keytruda, Merck) (Table).

The major criterion for breakthrough designation is substantial improvement

over existing therapies in a clinically important outcome measure for a lifethreatening disease, according to Amy E. McKee, MD, the FDA’s lead medical officer. This no doubt explains why almost half of the 270 Breakthrough Drug Applications and the majority of the more than 75 breakthrough designation requests granted since the initiation of the program in 2012 have been in oncology.

For each of the recently approved breakthrough drugs, FDA officers provided a clear rationale, but the complexity of the process could not be missed. In addition to the fact that the term “substantial improvement” can be vague when the end point does not include survival and the results include life-threatening toxicities, there also can be debate about the unmet need that is being addressed.

Ian Krop, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute, in Boston, outlined this debate briefly in an expert view of the role of palbociclib.

After a review of the approval process

by Julia A. Beaver, MD, an FDA medical officer, Dr. Krop noted that some oncologists expressed concern that early approval of palbociclib may have

inhibited clinical development of other options for estrogen receptor–positive/ HER2-negative breast cancer.

In a further elaboration of the decision process in the discussion that followed Dr. Krop’s remarks, FDA representatives asserted that this concern was not overlooked. The decision to move forward was taken after determining that alternative agents did not match the benefits

of palbociclib. However, the comment and the response underscored the multiple difficulties and concerns faced by regulators when performing an accelerated review.

—Ted Bosworth Dr. Krop reported financial relationships with Genentech, Lilly and Novartis.

Dr. Beaver reported no relevant financial relationships.

Table. Agents Granted Accelerated Approval Indications in Past Year Agent

Pharmacology

Indication(s) Approved Under Accelerated Processa

Blinatumomab (Blincyto, Onyx)

Monoclonal antibody

Ph-negative relapsed or refractory precursor B-cell ALL

Ibrutinib (Imbruvica, Pharmacyclics)

BTK inhibitor

CLL, Waldenstrom macroglobulinemia

Idelalisib (Zydelig, Gilead)

P13K inhibitor

Relapsed FL, relapsed SLL

Nivolumab (Opdivo, Bristol-Myers Squibb)

PD-1 blocking antibody

Metastatic melanoma

Palbociclib (Ibrance, Pfizer)

CDK4/CDK6 inhibitor

Metastatic ER-positive and HER2-negative breast cancer

Pembrolizumab (Keytruda, Merck)

PD-1 blocking antibody

Metastatic melanoma

ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; ER, estrogen receptor; FL, follicular B-cell non-Hodgkin lymphoma; Ph, Philadelphia chromosome; SLL, small lymphocytic lymphoma a Idelalisib also is approved for CLL; ibrutinib also is approved for mantle cell lymphoma; nivolumab also iss approved app oved for o metastatic etastat c squamous squa ous non-small o s a ce cell lung u g ca cancer. ce e

Encouraging Healthy Lifestyles in Breast Cancer Patients San Antonio—A low-fat diet does not improve survival in women with breast cancer, according to results from the Women’s Intervention Nutrition Study (WINS). The researchers said that because numerous studies have tied excess weight and weight gain to poorer breast cancer outcomes, patient interventions should focus on weight loss and physical activity instead of a low-fat diet.

Starting in 1984, WINS enrolled 2,437 women with early breast cancer who had received primary surgery, with or without radiation, plus adjuvant systemic therapy. To be included, a woman’s dietary fat intake had to be more than 20% of daily calories. Within a year from breast cancer surgery, women were randomized to a control group or to a dietary intervention that reduced fat intake from an average of about 30% of daily calories at baseline to 20%. The intervention lasted for an average of five years.

Lead investigator Rowan Chlebowski, MD, PhD, a medical oncologist at Harbor-UCLA Medical Center, in Los Angeles, who presented the study at

‘Sometimes, clinicians don’t know what to say, so they don’t bring it up at all. You need to have a conversation with the patient. What is your activity level? What are you doing for exercise?

If you don’t talk about it, you will never be able to counsel patients.’

—Tara Sanft, MD the San Antonio Breast Cancer Symposium (SABCS; abstract S5-08), said that with a follow-up of 20 years, there was no difference in survival between the two groups. (An exploratory analysis showed that the intervention improved survival in women who were both estrogen receptor–positive and progesterone receptor–positive, but Dr. Chlebowski said further analysis is needed to determine whether this post-hoc analysis should spur a randomized clinical trial.)

“Given emerging evidence over the last 20 years, future lifestyle interventions should best target weight loss/ maintenance and increased physical

activity,” he said.

Numerous reports have shown that obesity is associated with an increased risk for various cancers, that weight gain after a breast cancer diagnosis is associated with an increase in recurrence, and that exercise can protect against breast cancer recurrence ((Br J Cancer 2011;105[S1]:s52-s73; PMID: 22048034; J Clin Oncol 2012;30:3697-3704; PMID: 23008316; Epidemiology 2012;23[2]:320327; PMID: 22317813). One study showed that for every 11 pounds gained in the five years after a breast cancer diagnosis, women experienced a 13% increase in breast cancer–specific

mortality ((P=0.01) (Cancer Epidemiol Biomarkers Prev 2009;18[5]:1403-1409; PMID: 19366908).

The first thing that clinicians should do to encourage patients with breast cancer to make healthy lifestyle choices that will reduce their risk for cancer recurrence is to talk about it, according to Tara Sanft, MD, the medical director of adult survivorship for the Yale Cancer Center Survivorship Clinic, in New Haven, Conn. “Sometimes, clinicians don’t know what to say, so they don’t bring it up at all. You need to have a conversation with the patient.

What is your activity level? What are you doing for exercise? If you don’t talk about it, you will never be able to counsel patients,” she said.

She informs her patients about the cancer survivor recommendations from the American Cancer Society (ACS), including 150 minutes of exercise per week. “I discuss strategies for getting the 150 minutes in. That might include walking 30 minutes per day, five days a week, but if see LIFESTYLES, S page 9

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CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

Standardization Lessens CRBSIs in Oncology Patients Long Beach, Calif.—In patients receiving cancer treatment and home total parenteral nutrition (TPN), the risk for catheter-related bloodstream infections (CRBSI) can be reduced significantly by a standardized management approach, according to a recent study.

“Home parenteral nutrition has gotten a bad reputation, mainly because

national clinical director of gastroenterology, nutrition and metabolic support at Cancer Treatment Centers of America (CTCA), Midwestern Regional Medical Center, in Zion, Ill. The study, which was presented at the American Society for Parenteral and Enteral Nutrition’s Clinical Nutrition Week (poster M9), assessed the

‘Home parenteral nutrition has gotten a bad reputation, mainly beause of a high incidence of catheter-related infection, but this study shows we can significantly reduce that risk.’

—Pankaj Vashi, MD of a high incidence of catheter-related infection, but this study shows we can significantly reduce that risk,” said lead researcher Pankaj Vashi, MD, the

efficacy of an intensive education and compliance effort—in which patients received detailed pre-discharge teaching by a team of nurses, dieticians and

a dedicated case manager before going home with parenteral nutrition—and

a standardized home catheter maintenance protocol.

Latest Findings on Vitamin D and Cancer Link LONG BEACH, CALIF.—Is it time to add vitamin D supplements to the home infusion regimens of some cancer patients?

Some practitioners have already taken this step, based on the substance’s ability to inhibit apoptosis, inflammation and other processes linked to cancer, not to mention data showing a beneficial effect on survival. But the results of recent studies in patients with various types of cancer are mixed. Two new studies presented at Clinical Nutrition Week, sponsored by the American Society for Parenteral and Enteral Nutrition, have cast doubt on the need for the supplement in patients with prostate cancer or lung cancer, but studies in patients with colorectal cancer and follicular lymphoma indicate that low vitamin D levels lead to poorer outcomes.

In the first study (poster M10), 125 patients with newly diagnosed stage IV prostate cancer underwent a baseline serum evaluation of vitamin D (25-hydroxyvitamin D) levels before receiving treatment between January 2008 and December 2011.

At the time of diagnosis, vitamin D levels were deemed deficient (<20 ng/mL) in 25.6% of patients, insufficient (20-32 ng/mL) in 39.2% and sufficient (>32 ng/mL) in 35.2%. Patients were followed prospectively until May 2014, and all were alive at least 60 days after serum collection.

At the time of the analysis, 39.2% of patients had died and there was no association between the pretreatment vitamin D levels and overall survival (OS). The study was published online in PLoS One on March 16.

Other recent studies examining the relationship between vitamin D levels and prostate cancer have found conflicting results. One study, originally published in 2012 and presented at the American Chemical Society y meeting in March, evaluated the effect of vitamin D on 37 men undergoing elective

prostatectomies. The investigators found that a supplemental dose of 4,000 IU per day could slow or reverse the progression of low-grade prostate tumors (J Clin Endocrinol Metab 2012;97[7]:2315– 2324, PMID: 22508710). Dr. Bruce Hollis, PhD, a professor at the Medical University of South Carolina and one of the investigators involved with the study, said that a randomized controlled trial is underway to confirm the findings.

However, a retrospective large cohort study examined 518 fatal cases and 2,986 controls to assess the relationship between fatal prostate cancer, circulating vitamin D and common variations in key vitamin D–related genes, and found no statistically significant relationship (Cancerr 2015 Mar 2 [Epub ahead of print], PMID: 25731953).

In the other study presented at Clinical Nutrition Week, 270 patients with newly diagnosed stage III/ IV non-small cell lung cancer (NSCLC) underwent a vitamin D evaluation before receiving any treatment between January 2008 and December 2010 (poster M11). Investigators followed patients prospectively until July 2014. Almost 80% of the patients had stage IV disease at diagnosis. Adenocarcinoma (73.3%) and squamous cell carcinoma (21.9%) were the two most common histologic subtypes. At the time of diagnosis, 43.7% of patients were classified as deficient in vitamin D, 31.5% were deemed insufficient and 24.8% were classified as sufficient. At the time of the analysis, 91.1% of patients had died, and the researchers found no association between vitamin D status and OS. Pankaj Vashi, MD, the national clinical director of gastroenterology, nutrition and metabolic support at Cancer Treatment Centers of America, Midwestern Regional Medical Center, Zion, Ill., who was involved with both studies presented at Clinical Nutrition Week, said that “when a patient comes in with advanced lung or prostate cancer, whatever damage has been done is already done; trying to actively correct vitamin D levels might not make sense” based on the new data.

However, Kimmie Ng, MD, MPH, who was involved with a recent study of vitamin D supplementation in patients with colorectal cancer (CRC) that found positive results, said, “Although the advanced nature of

the cancer could have played a role in the lung cancer study, it is not a likely explanation for the results of the prostate study, [because] the median survival of those patients was long, at 40 to 50 months. It is also possible,” she added, “that the role of vitamin D is different in lung and prostate cancers than it is in colorectal cancer.”

Dr. Ng, a physician at Dana-Farber Cancer Institute, in Boston, and her colleagues conducted a study of 1,043 patients with metastatic CRC that demonstrated that higher pretreatment levels of vitamin D are associated with markedly improved progression-free survival and OS in patients receiving treatment (2015 Gastrointestinal Cancers Symposium, abstract 507).

Further commenting on the prostate and lung cancer studies presented at Clinical Nutrition Week, Dr. Ng said the two new studies were well conducted, but she pointed out they had very small patient numbers. “Therefore,” she said, “I am not surprised that they were unable to find an association between 25(OH)D [25-hydroxyvitamin D] levels and survival.”

Dr. Ng noted that although CRC is certainly the cancer with the strongest consistent data in support of a relationship between vitamin D status and outcome, studies are still needed to establish a cause-effect relationship. A randomized, doubleblind, Phase II trial of vitamin D in metastatic CRC is underway. “It’s too early to recommend vitamin D as a treatment, but since there are standard guidelines to replete to greater than 20 ng/mL for bone health, that is what I do with my [colorectal cancer] patients,” Dr. Ng said.

Similarly, Dr. Vashi said that while cause-and-effect, concrete evidence is lacking, he provides supplemental vitamin D to all patients with early-stage cancer who are deficient in vitamin D. He said, “I strongly believe that a normal vitamin D level, overall, may have some impact in patients in whom we can cure, that we can prevent them from getting a recurrence.”

—K.O. Drs. Vashi and Ng reported no relevant financial conflicts of interest.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

The 241 adult oncology patients in the study received home TPN from Coram CVS/specialty infusions services and active treatment at CTCA from Jan. 1, 2012 to Dec. 31, 2013.

The first two days of infusion were done at the hospital, during which patients were given verbal instruction, written educational material and DVDs. “We have them watch an educational DVD while they are getting their infusion, ask them if they have any questions, and then they go home with the DVD,” Dr. Vashi said. “Before they go home, we ask our patients to go over all the steps, starting from how they are going to handle the TPN bags (refrigerate them, keep them away from other food), to how they are going to add the nutrients to the bags/wash their hands, etc. Then a home health nurse goes to the patient’s home for the first couple of days and shows the patient how to do it.

By then, the patient has usually become quite familiar with the process and can follow the protocol very strictly.”

susceptible to CRBSI when receiving treatment and/or parenteral nutrition.

Up to 63% of patients undergoing home TPN have at least one CRBSI in a year ((Aliment Pharmacol Therr 2006;24[8]:12311240, PMID: 17014582). Moreover, the infections can have a two-pronged negative effect: They are associated with high morbidity and mortality and they come with a steep price tag, between $25,000 and $45,000 per infection (Clin Infect Dis 2011;52[9]:e162-e193, PMID: 21460264).

Dr. Vashi said the low infection rates in his study should reassure clinicians who want to recommend TPN, which

can be very valuable. Malnutrition is common in patients with cancer and is associated with reduced quality of life (QoL), increased incidence of complications, decreased efficacy of treatment and reduced life expectancy. TPN can diminish some of these problems and has been shown to significantly improve QoL, even in certain advanced cancer patients (BMC ( Cancer 2014;14:593, PMID: 25128023).

“The results of this study are significant because the cost of CRBSIs is so high, the infections require hospitalization and can lead to mortality, and the drugs used for treatment are

expensive,” said Robert Ignoffo, PharmD, a professor of clinical pharmacy at Touro University California and a clinical professor emeritus at the University of California, San Francisco, who was not involved with the study. “Anytime you can standardize a prophylactic treatment, it leads to optimal control of the problem.” He urged providers to “promote the use of standardized catheter care protocol.”

—Kate O’Rourke Drs. Vashi and Ignoffo reported no relevant financial conflicts of interest.

CTCA® FORUM 2015

Cancer Treatment Centers of America®

SYMPOSIUM

Strict Aseptic Techniques The catheter care protocol included a strict aseptic flushing and dressing change procedure; weekly sterile dressing changes with use of ChloraPrep (CareFusion); and the application of MicroClave connectors (ICU Medical) and SwabCaps (Excelsior Medical) on all lumens that were not in use. The home health nurse performed a weekly assessment that provided details about the patients’ clinical status and compliance with catheter care and TPN, as well as the catheter status.

The most common malignancies were stage III/IV colorectal, pancreatic and gynecologic cancers, and the average length of therapy was 70 days.

The bulk of patients had an implanted port (51%) or a peripherally inserted central line (46%), with only 3% having a tunneled catheter.

The investigators found an incidence of CRBSIs of 0.47 per 1,000 catheter-days.

This rate is higher than an Italian study that showed a rate of 0.35 per 1,000 catheter-days with an “optimally managed” TPN program ((J Parenter Enteral Nutr 2013;37[3]:375-383, PMID: 23002096), but significantly lower than many reports in the literature. For example, in a study of patients with a variety of diseases, including HIV, cancer and heart disease, who were receiving home infusion therapy, rates of CRBSI varied from 0.16 to 6.77 per 1,000 catheter-days, depending on risk factors ((Ann Intern Med d 1999;131[5]:340347, PMID: 10475886), Dr. Vashi said. In another study, the CRBSI rate was 4.49 per 1,000 catheter-days in pediatric hematology/oncology patients admitted to a hospital (J ( Microbiol Immunol Infect 2014.pii:S1684-1182[14]00164-9, PMID: 25311403).

Cancer patients, who are often immunocompromised, are particularly

Advances & Controversies in Gynecologic Oncology Friday, July 24, 2015 8:00 AM to 5:15 PM Radisson Blu Aqua Hotel Chicago, Illinois REGISTER NOW AT ctcaforumgynonc.org Participants in this CME program will be invited to share their perspectives and clinical experience surrounding evolving management strategies to improve outcomes in patients with gynecologic cancer.

PROGRAM CHAIRS Giuseppe Del Priore, MD, MPH National Director, Gynecologic Oncology Cancer Treatment Centers of America Newnan, Georgia Maurie Markman, MD President of Medicine and Science Cancer Treatment Centers of America Philadelphia, Pennsylvania

CME Credits will be available.

Complimentary for gynecologic and medical oncology fellows. #CTCAForum Jointly provided by Dannemiller and Athena Education Group.

Dannemiller and Athena Education Group gratefully acknowledge an educational grant from Cancer Treatment Centers of America® in support of this continuing medical education activity.

© 2015 Rising Tide

Faculty Peter Argenta, MD William A. Cliby, MD Robert L. Coleman, MD David M. Gershenson, MD Maurie Markman, MD

Daniela Matei, MD Julian Clifford Schink, MD William Small, MD Jason D. Wright, MD

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PREHABILITATION continued from page 1

cancer specialists have been advising their patients to prepare for surgery with a supervised physical conditioning program.

But the STAR Program prehabilitation takes a uniquely comprehensive approach that is multimodal and targeted to the specific type of cancer and course of treatment, according to Dr. Silver, an associate professor of physical medicine and rehabilitation at Harvard Medical School, in Boston, and herself a cancer survivor.

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

cessation to happen very quickly,” Dr. Silver noted. “Smoking has been shown to increase postoperative infections, and it appears that being off cigarettes for any length of time prior to surgery is better than being on them.”

The complement of prehab approaches is very targeted, Dr. Silver said. “It’s about driving specific outcomes in that particular cancer population, so we must anticipate the outcomes that that population has. For example, we know that women with breast cancer have specific problems with their arms, shoulders and chests after surgery, whereas head and neck cancer patients

‘…waiting to do rehab after we have completely squeezed all the life force out of the patient doesn’t make any sense.

It was intuitive to me that it was a very good idea if we got into the preventing disability game instead of recovering from disability game.’

—Barry Brooks, MD “Most of the studies that existed on prehabilitation in cancer were exercisebased,” she said in an interview. “One of the things that researchers started looking at was the question of, if we take someone who is older and largely sedentary, with multiple comorbidities, and we encourage them to be physically active right before surgery, do we need to do anything else to support them?”

The answer, perhaps not surprisingly, was yes. “There were some studies suggesting that increasing energy expenditure right before cancer treatment didn’t lead to patients doing as well as expected,” she explained. “We needed to give them more in the way of nutritional support, stress reduction and targeted exercise.”

Early data suggest that this “bundled” approach is effective. In a study published last October, colorectal cancer patients who took part in a prehab program that included regular aerobic exercise and strength training, a personalized nutrition program and protein supplementation, and guided relaxation, performed better on the sixminute walk test both before and after surgery than patients who received only standard postsurgical rehabilitation (Anesthesiology ( 2014;121[5]:937947, PMID: 25076007).

STAR prehab has five key components: • General exercise; • Targeted exercise depending on the patient population and diagnosis; • Nutritional interventions designed to support specific outcomes, tailored by diagnosis and patient; • Stress reduction; • Smoking cessation.

“We’re trying to drive smoking

have difficulties with swallowing and turning their heads.”

Prehab also is focused particularly on patients facing a relatively arduous course of treatment: a major surgery and/or a significant course of chemotherapy or radiation. “You probably don’t need prehab to get ready to remove a skin cancer on your arm,” said Barry Brooks, MD, a hematologist-oncologist with Texas Oncology, in Dallas, and an early adopter of prehab.

“But if you’re going to undergo a radical mastectomy, chemo, surgery, radiation, and all this is going to take six to eight months, waiting to do rehab after we have completely squeezed all the life force out of the patient doesn’t make any sense. It was intuitive to me that it was a very good idea if we got into the

preventing disability game instead of recovering from disability game.”

Lung Cancer Is a Good Starting Point Dr. Silver encouraged cancer centers and hospitals that are considering the launch of a STAR prehab program to start with lung cancer, because of the potential impact. “These patients are so deconditioned, and they have big surgeries ... the results we’re seeing with the STAR Program are very exciting.”

Mary Washington Healthcare, a regional medical system in Virginia, began implementing the five-point STAR prehab program for lung cancer patients in October 2013. A year later, an internal retrospective review found that the average hospital length of stay (LOS) for lung cancer prehab patients had decreased by 40% relative to the national average, from five days to three days.

“We’ve seen very significant improvements,” thoracic surgeon Timothy Sherwood, MD, in Fredericksburg, Va., told Clinical Oncology News. “Each patient is his or her own control. We haven’t done matching of patients who don’t undergo prehab, but compared to our general historical database, we do see improvements in length of stay as well as a decreased risk for requiring inpatient rehabilitation.”

Some oncologists may worry that implementing a prehab program could delay the course of a patient’s treatment, but Dr. Silver said that a great deal of progress can be made during the days and weeks that a patient is going through diagnosis, staging and treatment planning. “We have this period of time before acute cancer treatment starts where we can try to help improve outcomes. We want to make the most of that time.”

An additional benefit is that prehab helps patients feel they are engaged in their own care and recovery during the emotionally overwhelming weeks after

Breast cancer patient undergoing prehabilitation before her surgery, chemotherapy and radiation treatments at Medical City Dallas Hospital.

they know they have cancer but before anything is done to actively treat it.

“It’s like when you know a hurricane is coming,” Dr. Brooks said. “They are fearful of the upcoming treatment, and when you get them involved in something like physical therapy, occupational therapy and managing their nutrition, they have a sense of active engagement and they don’t feel so powerless.”

“In talking to patients about these ideas, it’s like a light bulb goes off in their heads: ‘Of course I want to be in the best shape I can be for surgery!’” said Andrea McKee, MD, an oncologist at the Lahey Hospital and Medical Center, in Burlington, Mass., which is implementing the STAR lung cancer prehab protocols.

Medicare’s recent decision to cover computed tomography screening for lung cancer in people aged 55 to 77 years with a long-term smoking history is likely to dramatically increase the number of candidates for lung cancer treatment prehab, Dr. McKee predicted. “Very soon, as many as 10 million people will be accessing screening. At our institution, we’ve screened over 3,000 patients and detected 51 lung cancers, and 75% have been stage 1 and treated surgically.

That’s a lot of surgery for small lung cancers, and this is where I think pulmonary prehab is going to fit in perfectly.”

Integrated, Evidence-Based Approach

Patient with stage 4 bladder cancer working with Medical City Dallas Hospital’s prehabilitation staff.

Every STAR prehab program is developed by an interdisciplinary team of professionals trained in cancer rehabilitation using evidence-based information. The team consists of core rehabilitation professionals such as physiatrists, physical therapists, occupational therapists, speech therapists and mental health professionals, as well as oncologists, nurses, dieticians and patient navigators. “You also have to have the full

SOLID TUMORS

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LIFESTYLES continued from page 5

that is not going to work, maybe it is 10 minutes on your way to and from work, seven days a week,” Dr. Sanft said. To encourage a plant-based diet, she provides patients with “Catch a Rainbow” materials that encourage meals to involve a rainbow of colors. “Making sure you are eating a variety of colors every time you eat, is a very simple thing to do, and it can be very effective if you embrace it,” Dr. Sanft noted. “Some patients will tell me, ‘I realized that I was eating all white food, noodles and potatoes.’ Sometimes just being aware that you need more green or yellow or red on your plate can get a patient to eat a better, healthier plant-based diet.”

© Learning ZoneXpress • www.learningzonexpress.com

LIVESTRONG at the YMCA, a free, 12-week exercise program for adult cancer survivors, can be appealing for some individuals, whereas others may choose to exercise individually. “I tell my patients to move more,” Dr. Sanft said.

“It doesn’t have to be dedicated, working-up-a-sweat exercise. It can be taking several small short walks throughout the day or just not having a lot of sitting time. There is a growing body of evidence to suggest that sedentary time itself is a predictor of poor outcomes in cancer patients. ‘Move more’ is a very

easy motto to remember and can be individualized to each survivor.”

Jennifer Klemp, PhD, MPH, the director of the Cancer Survivorship Center at the University of Kansas Cancer Center, in Kansas City, said she provides similar basic recommendations on diet and exercise to all of her patients. Partnering with a national nonprofit called Back in the Swing, clinicians at her center helped to produce the “Back in the Swing Cookbook,” that provides breast cancer survivors with evidence-based information on diet and exercise, lifestyle, and how to live your “survivorship plan” every day.

“I tell patients, if you are already doing exercise, keep that up. If you are not, we want you to keep moving and take some steps in that direction. On days you don’t feel well, take a break,” Dr. Klemp said, adding that she gives patients permission to take days off, because some women think that if they don’t exercise regularly, then why do it at all. Referrals to community exercise programs and suggestions for individual exercise are helpful. For women who are overweight, her center recommends staying weight stable during treatment and weight loss once treatment is completed.

According to Dr. Klemp, reframing diet and exercise as a component of a treatment plan can spark motivation.

“A lot of our patients are on extended hormonal therapy for five or 10 years, so I try to frame it as, ‘you need to think of diet and exercise as a prescription,’” Dr. Klemp said. “It doesn’t mean you

Exercise Eases Chemotherapy Burden For Breast Ca Patients in Dutch Study

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omen undergoing chemotherapy for breast cancer who participated in regular exercise regimens experienced significantly less nausea and vomiting, fatigue, pain and loss of fitness than a control group undergoing usual care, according to a new Dutch study published in the Journal of Clinical Oncology (2015 Apr 27. [Epub ahead of print]).

The trial, conducted at the Netherlands Cancer Institute, in Amsterdam, randomized 230 breast cancer patients into three groups: a moderate-to-high intensity, resistance and aerobic exercise program (OnTrack), with two 50-minute workout sessions per week directly supervised by a trained physical therapist along with encouragement to exercise at least five days a week; a low-intensity home-based exercise program (OncoMove), coached by a nurse or nurse practitioner; and a usual care group that followed no exercise program.

Both exercise groups experienced fewer side effects from chemotherapy than the control group, and were able to return to work earlier and for more hours per week. But the higher-intensity, supervised group also required fewer dose adjustments to their chemotherapy than either the home-based exercise or the control groups. Only 12% of the OnTrack group required changes to their chemotherapy dosing, compared with 34% of the control group.

“We would recommend that women who are able and willing to participate be offered a supervised, moderate- to high-intensity exercise program during adjuvant chemotherapy,” wrote investigator Hanna van Waart, a PhD student at the institute.

“A lot of people are very excited about this study,” said Julie Silver, MD, an associate professor at Harvard Medical School and co-founder of Oncology Rehab Partners (see related story on pages 1 and 8). “Studies like this help us better understand where to put our resources. It’s important to note that some exercise, even if it’s a lower-intensity program and home-based rather than supervised, is likely better than none, but I think the very important finding is that higher-intensity, supervised exercise had the biggest impact, especially on chemotherapy tolerance. This is an important contribution as we seek to better define what high-quality cancer care looks like. We should be very focused on improving patient outcomes, improving the patient care experience and improving health-related quality of life.”

Although women on the higher-intensity, supervised exercise regimen better tolerated chemotherapy and required fewer dose adjustments than the other two groups, these results don’t address the efficacy of their treatment, said study coauthor Neil Aaronson, PhD, the head of the Department of Psychosocial Research, Division of Psychosocial Research and Epidemiology at the institute. “More research is needed [to determine] the relationship between the exact chemotherapy dosage received and long-term survival and the chance of recurrence before we can say anything about the positive effect of exercise on clinical outcomes.”

—Gina Shaw

have to like it, because a lot of people don’t like exercise, but we know the benefits of exercise. You take this pill every day to keep you breast cancer– free, and you need to think about diet and exercise as another thing that can hopefully do the same.”

Another tactic for increasing a healthy lifestyle is to keep repeating the diet and exercise message to patients. “You can talk to your patients until you are blue in the face, but they have to be ready for change. That is why it is important

to have multiple checkpoints, because it might be the right day with the right provider who says something that really triggers change for the patient,” Dr. Klemp said. “For example, I have been getting a lot of referrals from our radiation oncologist who is very pro-lifestyle. She is the tipping point for some.”

—Kate O’Rourke Drs. Chlebowski, Klemp and Sanft reported no relevant financial relationships.

CURRENT PRACTICE

support of hospital administrators to really drive the integration of a service line,” Dr. Silver said.

Prehab is medical care and, generally, should be covered by health insurance, Dr. Silver said. “It has to be appropriately implemented, and it must be offered by clinicians,” she cautioned. “For example, prehab exercise prescribed by a physical therapist would be covered, but not exercise supervised by a fitness professional.”

Integrating all of the prehab

components into one comprehensive program is key to its adoption. “Anytime you can make a treatment protocol or program easier for the patient and the clinician, utilization is better and compliance is better. Any type of rehabilitation program can be challenging to get ... going because of human nature and inertia,” Dr. Sherwood said. “But the STAR Program environment is very conducive to getting patients moving forward.”

The integrated STAR Program

approach to prehab is most advanced for lung cancer, but the potential benefits are obvious for many cancers, Dr. Brooks said. “People with head and neck cancer often lose rotary function after treatment. While you can help them deal with their new limited range of motion with things like car adaptations, the ideal way to handle it is to prevent it entirely with early range of motion work to prevent the loss of rotation. We can prepare patients for the

rigors of rectal surgery with smoking cessation, optimization of their medical status and getting them active. Even for patients with bone tumors, major losses of bone and even amputations, we can get them stronger and make sure they’re in optimal shape for that.

In so many of these diagnoses, we can improve outcomes with preparation and giving patients goals.”

—Gina Shaw

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CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

Checkpoint Inhibitors Not Interchangeable in Melanoma Philadelphia—In a newly completed head-to-head Phase III comparison, the anti–PD-L1 antibody pembrolizumab provided an overall survival (OS) advantage over the anti–CTLA-4 antibody ipilimumab in patients with advanced melanoma. Along with a separate randomized trial, which found that combining ipilimumab with the anti–PD-L1 antibody nivolumab produced longer progression-free survival (PFS) than ipilimumab alone, the data are helping to define optimal use of checkpoint inhibitors.

According to its indication, pembrolizumab (Keytruda, Merck) should follow ipilimumab (Yervoy, Bristol-Myers Squibb) in the treatment of unresectable, metastatic melanoma, but new data challenge this. In the KEYNOTE 006 trial, presented at the 2015 annual meeting of the American Association for Cancer Research (AACR), both of two study doses of pembrolizumab provided better OS, PFS and objective response rates (ORR) than ipilimumab (abstract CT 101). Pembrolizumab also was generally better tolerated.

“Our study shows the superiority of pembrolizumab over ipilimumab as firstline therapy for the treatment of patients with advanced melanoma,” maintained Antoni Ribas, MD, PhD, the director of the Tumor Immunology Program at UCLA’s Jonsson Comprehensive Cancer Center, in Los Angeles. He presented data that also were published simultaneously online in The New England Journal of Medicine (2015 Apr 19. [Epub ahead of print]).

In the Merck-funded KEYNOTE 006 trial, 834 patients with advanced melanoma were randomized to one of three groups: 3 mg/kg of ipilimumab every three weeks, 10 mg/kg of pembrolizumab every two weeks, or 10 mg/kg of pembrolizumab every three weeks. OS and PFS were both primary end points.

For OS, the hazard ratio (HR) for the every-two-week regimen of pembrolizumab relative to ipilimumab was 0.63 (95% confidence interval [CI], 0.47-0.83; P<0.0005), documenting a nearly 40% improvement in this outcome. The advantage of the every-three-week regimen of pembrolizumab was similar (HR, 0.69; 95% CI, 0.52-0.90; P=0.0036). The estimated 12-month survival rates for everytwo-week pembrolizumab, every-threeweek pembrolizumab and ipilimumab were 74.1%, 68.4% and 58.2%, respectively.

Similarly, at six months, the PFS rates for two- and three-week pembrolizumab (47.3% and 46.4%, respectively) were nearly double those of ipilimumab (26.5%).

ORRs for the two-week regimen of pembrolizumab, three-week regimen of pembrolizumab and ipilimumab were 33.7%, 32.9%, and 11.9%, respectively. Complete responses (CR) were achieved in 5%, 6.1% and 1.4% of patients, respectively.

An evaluation of response by patient and tumor characteristics supported an advantage for pembrolizumab over ipilimumab for almost all stratifications.

The possible exceptions were patients with tumors negative for PD-L1. For these patients (18%), there was little or no apparent advantage observed for OS, although a favorable trend persisted for PFS. Additionally, patients with mutant (MT) anti-BRAF F status tumors appeared to derive less benefit than those with BRAF F wild-type (WT) tumors, although OS and PFS trended in a favorable direction for both groups.

Overall, safety analyses suggested that pembrolizumab was better tolerated. Grade 3 or higher adverse events (AEs) were observed in 19.9% of those randomized to ipilimumab, versus 13.3% of those randomized to the every-twoweek pembrolizumab and 10.1% of

those randomized to every-three-week pembrolizumab. Colitis, the most common grade 3 or higher AE for all treatment arms, was observed in 7% of those receiving ipilimumab versus 1.4% and 2.5% of those receiving the two- and three-week regimens of pembrolizumab, respectively.

Commenting on the results of the study as the AACR-invited discussant, Jedd D. Wolchok, MD, PhD, the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center, in New York City, called the data “impressive,” although he cautioned that there is much more to learn as these treatments are employed with other options. “The OS advantage of pembrolizumab is interesting but will be more fully interpretable once data is available on what treatments are received post progression,” Dr. Wolchok said.

Checkpoint Inhibitor Plus Immunostimulatory Agent Passes Initial Safety Test PHILADELPHIA—An early-phase clinical trial has generated evidence that a checkpoint inhibitor can be safely combined with an immunostimulatory agent in patients with advanced melanoma.

It is widely theorized that stimulating the immune system may be essential to realize the full potential of checkpoint inhibitors, which have produced dramatic responses in advanced melanoma and other cancers but only in a relatively limited proportion of patients.

The study, presented at the 2015 annual meeting of the American Association for Cancer Research (AACR), showed that combining an immunostimulatory anti-CD antibody called CP-870,893 with an anti–CTLA-4 checkpoint antibody called tremelimumab (AstraZeneca) was well tolerated and active (abstract 6398), according to the lead investigator, David L. Bajor, MD, an instructor in the Division of Hematology/Oncology at the University of Pennsylvania, in Philadelphia. The immunostimulatory agent was administered every three weeks and the checkpoint inhibitor every 12 weeks, both intravenously.

Although the main focus of this study was tolerability, substantial evidence of activity was shown. Even with a dose-escalation design that required conservative initial doses, the objective response rate in 24 patients with advanced metastatic melanoma was 27.3%. It included two complete responses (9.1%). A variety of biomarkers of immune activation, such as an increase in activated CD8-positive cells, were consistent with immunostimulation.

As for tolerability, the adverse events were manageable, according to the investigators. Dose-limiting toxicities suspected of being treatment-related included colitis, hypophysitis and uveitis. Most patients (79.2%) developed cytokine-release syndrome within 24 hours of initiating the immunostimulatory agent, but it was grade 2 or less and readily and rapidly resolved with supportive care. The estimated maximum tolerated doses were 0.2 mg/kg of the immunostimulatory agent and 10 mg/kg of the checkpoint inhibitor.

Checkpoint proteins expressed on the surface of tumor cells, such as CTLA-4, inhibit the T-cell response and commonly are characterized as brakes on the immune system. Inhibiting these checkpoints with monoclonal antibodies has proven to be highly effective in a subset of patients with advanced melanoma. However, removing the brake appears to be insufficient in many individuals. This underlies the theoretical benefits of adding a therapy that boosts the immune response.

“There was real concern that stimulating the immune system while cutting the brakes with checkpoint inhibition could lead to increased incidence or severity of immune side effects,” Dr. Bajor said, “but we did not see this.”

—T.B. Dr. Bajor reported no relevant financial relationships.

The study was funded by the National Cancer Institute and an alliance between Pfizer and the University of Pennsylvania.

In a separate study that evaluated nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab relative to ipilimumab alone, the primary end point was ORR, but an advantage also was seen for PFS (abstract 4214). During this Phase II randomized placebo-controlled trial (CA209-069), funded by Bristol-Myers Squibb., 134 treatmentnaive patients with advanced melanoma were randomized in a 2:1 ratio to receive 3 mg/kg of ipilimumab every three weeks for four doses followed by 1 mg/kg of nivolumab or placebo.

Response rates were stratified by BRAF WT or BRAF V600 MT tumor status.

For BRAF F WT, the ORR was 59.7% with the combination versus 10.8% with ipilimumab alone. For BRAF F MT, the ORRs were 43.5% and 0%, respectively, reported F. Stephen Hodi, MD, the director of the Center of Immuno-Oncology at Dana-Farber Cancer Institute, in Boston. CR was achieved in 16.7% and 17.4% of those receiving the combination in the BRAF WT and MT groups, respectively, but in none of those receiving ipilimumab alone.

These translated into a large PFS advantage. For patients with BRAF F WT tumors, the median PFS has not been reached in the combination group versus 4.4 months with ipilimumab alone (HR, 0.40; P=0.001). For those with BRAF F MT tumors, median PFS was 7.4 months in the combination group and 2.7 months with ipilimumab alone (HR, 0.33; no P value due to small sample).

Highly durable responses persisted in a subgroup of both study arms but were far more common among those receiving the combination. Some responses are ongoing more than nine months after the last dose.

“Having both drugs appears to kickstart something in the immune system that is synergistic,” Dr. Hodi reported. Although he acknowledged that more patients on the combination of nivolumab and ipilimumab had a grade 3 or higher adverse event (54% vs. 24%), he concluded that the greater activity of the combination “appears to provide a favorable risk–benefit profile” for the combination overall.

Commenting on both studies, Louis M. Weiner, MD, the director of Georgetown University’s Lombardi Comprehensive Cancer Center, in Washington, D.C., characterized the activity of checkpoint inhibitors as “revolutionary.” He suggested that the incremental progress with checkpoint inhibitors presented at AACR has “profound implications” for control of melanoma as well as other cancers.

—Ted Bosworth Dr. Ribas reported a financial relationship with Merck. Drs. Wolchok, Hodi and Weiner reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

ASPIRIN continued from page 1

multivitamins,” reported Yin Cao, ScD, MPH, a research fellow in the Department of Nutrition at the Harvard School of Public Health, in Boston.

Presenting these data at the 2015 annual meeting of the American Association for Cancer Research (AACR; abstract 876), Dr. Cao noted that multiple case– control studies have previously associated aspirin with a reduction in cancer risk, particularly GI cancers, but the findings of this study are strengthened by the prospective collection of data and the large population sample.

“Previous studies of aspirin and cancer have been limited in terms of their size, length of follow-up or ability to examine aspirin use in the context of other lifestyle factors,” Dr. Cao said.

The current study used data from 82,600 women in the Nurses’ Health Study, established in 1980, and 47,651 men in the Health Professionals Follow-up Study, initiated in 1986. For both studies, participants have been providing detailed information about a broad range of lifestyle factors and health. Over 32 years of follow-up to date, 27,985 cancer cases were documented.

The overall cancer risk was 5% lower (relative risk [RR], 0.95; 95% confidence interval [CI], 0.93-0.98) in regular users of aspirin, defined as those taking at least 325 mg of aspirin twice weekly, compared with non-regular users. However, the risk reduction appeared to be limited to GI cancers, including a 25% decrease in colorectal cancer (CRC), a 14% decrease in gastroesophageal cancer and a 20% reduction in GI cancers overall. The risk reduction became nonsignificant when GI cancers were excluded (hazard ratio, 0.98; 95% CI, 0.99-1.01). The protection from cancer was no longer evident four years after aspirin use was discontinued.

Although the reduction in cancer risk with aspirin use joins strong evidence of protection against cardiovascular disease, aspirin use is also associated with GI bleeding. As a result, a calculation of the benefit-to-risk ratio is likely to vary for each individual, observed Andrew T. Chan, MD, MPH, the director of the Gastroenterology Training Program at Massachusetts General Hospital, in Boston.

However, Dr. Chan, who delivered a plenary talk on aspirin chemoprevention at the AACR annual meeting and co-authored this study, suggested that the greatest benefit from aspirin for some individuals is likely to be cancer prevention.

These data “strengthen the case for further research into defining subsets of the populations that may obtain preferential benefit from regular aspirin use,” Dr. Chan said. He observed that calculations that take into account genetic susceptibilities to the diseases prevented and complications caused by aspirin

are likely to offer the best opportunity to provide clinical benefit.

To that end, a recent study by the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) evaluated use of aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and single-nucleotide polymorphisms (SNPs) related to the risk for CRC to identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention (JAMA ( 2015;313[11]:1133-1142, PMID: 25781442).

Hongmei Nan, MD, PhD, from Indiana

University Melvin and Bren Simon Cancer Center, in Indianapolis, and her colleagues in the CCFR and GECCO evaluated 8,634 CRC cases and 8,553 matched controls using data from five case–control and five cohort studies conducted across the United States, Canada, Australia and Germany in patients of European descent.

The investigators found that compared with non-regular use, regular use of aspirin and/or NSAIDs was associated with reduced risk for CRC (38% vs.

28%; P=6.2×10−28). However, they found some differences in risk based on genetic variants. Looking at the SNP rs2965667

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located near the MGST1 gene on chromosome 12, they found that individuals with the TT genotype who regularly took aspirin and/or NSAIDs had a lower risk for CRC (28% vs. 38%; P=7.7×10−333), but those with rare (4%) TA or AA genotypes had a higher risk (35% vs. 29%; P=0.002). Looking at the SNP rs16973225 located near the IL166 gene on chromosome 15, they found that individuals with AA genotype who took aspirin or see ASPIRIN, N page 12

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Jerald Radich, MD Paul Richardson, MD Richard Riedel, MD Ravi Salgia, MD, PhD John Sweetenham, MD Everett Vokes, MD Anas Younes, MD

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CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

Advanced/Metastatic Prostate Cancer

Docetaxel Given With Hormonal Therapy Ups Survival Results from large STAMPEDE trial support earlier findings Orlando, Fla.—Although the ECOG3805 (CHAARTED) and French GETUG-15 (GETUG) trials had different patient populations and yielded slightly different results, a review of these trials presented at the 2015 Genitourinary Cancers Symposium indicated that for appropriate patients with metastatic prostate cancer, clinicians could administer docetaxel concurrently with hormone therapy.

Now, new results from the large STAMPEDE trial presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) showed that men with advanced or metastatic prostate cancer who received docetaxel plus standard therapy had a median survival 10 months longer than those who received only standard therapy.

“We hope our findings will encourage doctors to offer docetaxel to men newly diagnosed with metastatic prostate cancer, if they are healthy enough for chemotherapy,” said STAMPEDE lead investigator, Nicholas David James, MD, PhD, in a statement on the findings released before the ASCO meeting. “Men with locally advanced, non-metastatic prostate cancer may also consider docetaxel as part of up-front therapy, as it clearly delays relapse,” noted Dr. James, the director of the Cancer Research Unit at the University of Warwick, in the United Kingdom.

Markedly Improved OS With Docetaxel in STAMPEDE The STAMPEDE investigators reported that docetaxel plus standard therapy improved overall survival (OS) over that seen with the standard of care (SOC) alone and over that seen with zoledronic acid plus SOC. In this, the largest randomized trial of prostate cancer treatment ever conducted, the investigators evaluated 2,962 hormone-naive men who were assigned to SOC, SOC plus docetaxel for six cycles, SOC plus zoledronic acid for two years, or SOC plus both docetaxel and zoledronic acid. Under the trial design, SOC could change for the continuously recruiting control arm as treatment patterns changed. SOC was at least three years of androgen deprivation therapy (ADT), with local radiation when appropriate.

ASPIRIN continued from page 11

NSAIDs regularly had a lower risk for CRC (28% vs. 38%; P=1.9×10−300), but patients with the less common (9%) AC or CC genotypes had no reduced CRC risk when taking the drugs (36% vs. 39%; P=0.76).

Approximately 60% of the patients had metastatic prostate cancer and the rest had high-risk, locally advanced non-metastatic disease.

The investigators found that at a median follow-up of 42 months, 948 men had died. The median OS was 77 months in the docetaxel arm and 67 months in the SOC arm, with a relative improvement of 24%. For patients with metastatic disease, the median OS was 65 months in the docetaxel arm and 43 months in the SOC arm. Docetaxel also extended the time to relapse by 38% overall. There was no significant difference in OS between the SOC and the SOC plus zoledronic acid arms.

Furthermore, there was no additional benefit from adding zoledronic acid to the combination of SOC and docetaxel.

Although docetaxel was associated with some additional toxicity compared with SOC alone, the side effects were manageable, according to the investigators.

Commenting on the STAMPEDE findings released before the meeting, Evan Y. Yu, MD, an associate professor of medicine at Washington University School of Medicine and an associate member at the Fred Hutchinson Cancer Research Center, in Seattle, said “there are many unanswered questions from STAMPEDE and, hopefully, we will see some of those results at ASCO.” These include the toxicity data from docetaxel, the breakout of the survival curves from the metastatic population and the localized disease population and specifics about SOC. “Since flexibility was allowed, we need to see how much therapy SOC really received. We know that intermittent ADT is not non-inferior to continuous ADT. In both CHAARTED and GETUG, continuous ADT lifelong was mandated. If that isn’t the case in STAMPEDE, the control arm might do worse.”

just be seeing less docetaxel.”

According to Dr. Yu, these PK differences may explain some of the greater hematologic toxicity in the hormone-sensitive state and also the survival benefit observed in castration-sensitive compared with castration-resistant trials.

However, questions remain. When did patients start docetaxel relative to ADT in GETUG versus CHAARTED? How many patients were not castrated prior to starting docetaxel in each trial? Finally, perhaps most importantly, how much granulocyte colony-stimulating factor (G-CSF) was used in each trial?

While Dr. Yu recognized that practicing clinicians may consider waiting until after one to two months of ADT or until castrate testosterone levels have been reached before starting docetaxel, he cautioned that a reduction in toxicity could be associated with a decrease in the drug’s benefit. “Maybe we could just use G-CSF for the first couple of cycles until the patients are castrated,” he suggested as an alternative treatment to improve safety.

Dr. Yu concluded his talk by recommending the enrollment of both low- and high-volume/risk patients into the next wave of clinical trials because, as he put it, “we’re not curing these patients yet.”

Daniel W. Lin, MD, the chief of urologic oncology at the University of Washington Medical Center, in Seattle, said, “We used to wait until hormonal therapy failed before we prescribed docetaxel.

Now we know that even early on, if they have metastatic disease—especially highvolume, aggressive metastatic disease— we can start hormonal therapy right away with docetaxel, and there does seem to be some benefit. ... I think that all markers are pointing now toward the use of docetaxel for high-volume, early metastatic hormone-sensitive patients … and I think this could change guidelines.”

The two previous trials reporting results on using docetaxel in the hormone-naive metastatic setting— CHAARTED in the United States and GETUG-15 in France and Belgium—were smaller trials that showed conflicting results: CHAARTED, reported at ASCO 2014, showed a statistically significant survival advantage; GETUG did not but

did show a nonsignificant trend for a survival benefit.

Reviewing these studies at the ASCO Genitourinary meeting, Dr. Yu said the schema for both trials featured patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to receive ADT plus docetaxel or ADT alone, with OS as the primary end point.

OS did not differ between the trials, but Dr. Yu outlined some key distinctions: There were differences in the risk definitions used in the trials, the total population was smaller in GETUG, the median number of docetaxel cycles was greater in GETUG, prognostic criteria were better for patients in GETUG, and discontinuations related to toxicity occurred more frequently in GETUG. According to Dr. Yu, the major question is whether or not to treat low-volume/risk disease with docetaxel using the CHAARTED definition. “The data are really immature,” he said, “so we don’t know yet. If you see the number of deaths, most of them were in the highvolume disease groups, not the low-volume groups. There is potential to expose patients to excess toxicity and risk.”

However, he also noted the benefits of adding docetaxel. “CHAARTED was powered for the primary end point of survival difference in the overall patient population, not in a subgroup, and there was a 39% reduction in the risk of death. And a 13-month median survival benefit is still quite impressive for any oncology trial.”

Although Dr. Yu acknowledged the difficulty in interpreting toxicity data with incomplete information on growth factors and prophylactic antibiotics, he supported the surprising hypothesis that docetaxel may be more toxic in mHSPC. Citing a study from Johns Hopkins, he proposed that docetaxel’s pharmacokinetics (PK) differ between castrated and noncastrated patient groups (J ( Clin Oncol 2010;28[30];4562-4567, PMID: 20855838). “In patients who were castrated,” Dr. Yu said, “there was 100% greater increase in clearance of docetaxel, with a twofold reduction in AUC [area under the curve] …. If you have more docetaxel in the liver and more clearance, patients with castration-resistant disease might

A study presented at ASCO 2015 (abstract e12594) found that in patients with a PIK3CA mutant gene on chromosome 3 seemed to gain enhanced protection against CRC by taking aspirin after diagnosis compared with those with the wild type gene (HR, 0.71; P=0.04). An earlier study also had similar findings.

((N Engl J Med d 2012;367[17]:1596-1606, PMID: 23094721). In that study, among patients who regularly took aspirin after their diagnosis, those with mutated-PIK3CA CRC had improved CRC-specific survival ((P<0.001), whereas patients with wild-type PIK3CA did not ((P=0.76).

The precise mechanisms that might

associate these variants with CRC risk and aspirin or NSAID use remain unclear.

But the CCFR and GECCO investigators suggested that validation of their recent “findings in additional populations may facilitate targeted colorectal cancer prevention strategies.”

—Ted Bosworth and Sarah Tilyou

CHAARTED and GETUG Review

—Chase Doyle and Sarah Tilyou The STAMPEDE study received funding and support from sources including Astellas, Janssen, Novartis, Pfizer and Sanofi-Aventis.

Dr. Yu reported relationships with Amgen, Bayer, Bristol-Myers Squibb, Dendreon, Janssen, Medivation and Sanofi. Dr. Lin reported no relevant financial relationships.

Brief Summary (cont’d) In the phase 3 study of VELCADE® (bortezomib) administered intravenously vs dexamethasone in relapsed multiple myeloma, the most commonly reported adverse reactions (>20%) were nausea (52% vs 9%), diarrhea (52% vs 11%), fatigue (39% vs 25%), peripheral neuropathies (35% vs 4%), thrombocytopenia (33% vs 3%), constipation (30% vs 8%), vomiting (29% vs 3%), and anorexia (21% vs 2%). The most commonly reported serious adverse reactions were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each) in the VELCADE treatment group and pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each) in the dexamethasone treatment group.

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups.

The most commonly reported adverse reactions (≥10%) in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

In a single-arm, open-label study of retreatment with intravenous VELCADE in relapsed multiple myeloma, the most common adverse drug reaction was thrombocytopenia, which occurred in 52% of patients (grade ≥3: 24%).

Peripheral neuropathy was experienced by 28% of patients (grade ≥3: 6%). The incidence of serious adverse reactions was 12.3%; the most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each).

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2.

Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum)) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers:: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use:: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment:: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered

after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment:: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes:: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

OVERDOSAGE: There is no known specific antidote for VELCADE overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia. In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given.

PATIENT COUNSELING INFORMATION Advise patients to contact their physicians if they experience the following symptoms: Dehydration/Hypotension, such as dizziness, light-headedness or fainting spells, or muscle cramps.

Cardiac:: swelling of feet, ankles, or legs, or other heart-related problems.

Respiratory:: shortness of breath, cough, or other lung problems.

Hepatic:: jaundice or right upper abdominal pain.

Dermal:: rash, severe injection-site reactions, or skin pain. Discuss the option for antiviral prophylaxis for herpes virus infection.

Peripheral Neuropathy and Nervous System, such as new or worsening tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs. Advise patients to contact their physicians if they experience symptoms possibly indicative of PRES or PML such as convulsion, persistent headache, reduced eyesight, blurred vision, confusion, lethargy, altered ability to think, or difficulty walking.

Other:: increase in blood pressure, bleeding, fever, constipation, or decreased appetite.

In addition, counsel patients on the following: Pregnancy/Nursing:: Advise patients to use effective contraceptive measures to prevent pregnancy during treatment with VELCADE. Instruct them to report pregnancy to their physicians immediately. Advise patients that they should not receive VELCADE while pregnant or breast-feeding. If a patient wishes to restart breast-feeding after treatment, she should be advised to discuss the appropriate timing with her physician.

Concomitant Medications:: Advise patients to speak with their physicians about any other medication they are currently taking.

Diabetic Patients:: Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level.

Ability to Drive or Operate Machinery or Impairment of Mental Ability: Advise patients not to drive or operate machinery if they experience fatigue, dizziness, syncope, or orthostatic/postural hypotension.

Please see full Prescribing Information for VELCADE at VELCADE-hcp.com.

Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited.

Other trademarks are the property of their respective owners.

Copyright © 2014, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in the USA USO/BOR/14/0015

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How I Manage ...

EARLY-STAGE HL continued from page 1

Nancy L. Bartlett, MD Professor of Medicine Koman Chair in Medical Oncology Washington University School of Medicine

What are the major differences between different prognostic models in early-stage cHL, and which one do you prefer in your practice?

Multiple prognostic models have been proposed for use in early-stage cHL. Unfortunately, the lack of an international consensus complicates both the design and interpretation of clinical trials in early-stage cHL. The terms favorable and unfavorable are used widely but are not strictly defined. Historically, adult US cooperative group trials have divided early-stage patients into 2 groups, those with bulky disease and those with nonbulky disease, with bulky defined as a mediastinal mass ratio (MMR) greater than 0.33 or a mass greater than 10 cm. Outside the United States, most centers generally employ either the German Hodgkin Study Group (GHSG) model or the European Organisation for Research and Treatment of Cancer (EORTC) model. Patients with any of the following features are considered unfavorable according to the GHSG model: more than 2 nodal sites of disease, extranodal disease, an MMR greater than 0.33, an

erythrocyte sedimentation rate (ESR) of at least 50 if there are no B symptoms, and an ESR at least 30 if there are B symptoms.1 Although the EORTC unfavorable category also incorporates an MMR greater than 0.33, an ESR of at least 50 if there are no B symptoms, and an ESR of at least 30 if there are B symptoms, unlike the GHSG, more than than 3 involved sites are considered unfavorable, and age at least 50 years is included in lieu of extranodal disease.2 In the National Cancer Institute of Canada (NCIC) trial of chemotherapy alone versus CMT in nonbulky early-stage cHL, the unfavorable, nonbulky cohort was defined as patients with at least one poor-risk feature including age at least 40 years, ESR of at least 50, more than 3 sites of disease, or mixed cellularity or lymphocyte-depleted histology.3,4 When using the results of a clinical trial to render standard-of-care treatment decisions for patients, it is critical to understand the trial eligibility criteria regarding risk factors and to follow these criteria in practice. An important example is application of the GHSG Hodgkin lymphoma (HD)10 and HD11 results for patients with early-stage cHL when considering CMT.5,6 The HD10 trial, which included only patients with favorable disease by the GHSG prognostic model, concluded that 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and 20 Gy of involved-field radiation therapy (IFRT) were adequate.6 However, the results of HD11 showed that patients with any unfavorable features were inadequately treated with 4 cycles of ABVD plus 20 Gy IFRT and, therefore, ABVD ×4 cycles plus 30 Gy of

Ongoing Clinical Trials in Early-Stage HL Phase II Trial of Response-Adapted Therapy Based on Positron Emission Tomography (PET) for Bulky Stage I and Stage II Classical Hodgkin Lymphoma (HL)

http://clinicaltrials.gov/ show/NCT01118026

A Phase 2 Open-label Study of Brentuximab Vedotin in Front-line Therapy of Hodgkin Lymphoma (HL) in Adults Age 60 and Above

http://clinicaltrials.gov/ show/NCT01716806

LCCC 1115: Pilot Feasibility Trial of Induction Chemotherapy With ABVD Followed by Brentuximab Vedotin (SGN-35) Consolidation in Patients With Previously Untreated Non-Bulky Stage I or II Hodgkin Lymphoma

http://clinicaltrials.gov/ show/NCT01578967

IFRT was recommended for these patients.5 In practice, I have seen the 2 + 20 approach applied to patients who did not meet the eligibility criteria of HD10, most commonly because they had more than 2 nodal sites of disease. Although in many cases this may be adequate treatment, it would be considered nonstandard in this setting.

In summary, none of the current clinical prognostic factor models for earlystage cHL are adequate to define the patients at highest risk for relapse who may benefit from alternative approaches.

Currently, I use only disease bulk to guide treatment decisions. An important goal is to identify new biomarkers that enhance prognostic models in early-stage cHL.

What is the best front-line therapy for favorable and unfavorable early-stage cHL? The options for nonbulky early-stage cHL include 3 to 6 cycles of ABVD alone or CMT with 2 to 4 cycles of ABVD followed by 20 to 30 Gy of IFRT. If CMT is selected, the number of cycles of

At a Glance • When using the results of a clinical trial to render standard of care treatment decisions for patients with early-stage cHL, it is critical to understand the trial eligibility criteria regarding risk factors and to follow these criteria in practice.

• None of the current clinical prognostic factor models for early-stage cHL are adequate to define the patients at highest risk for relapse who may benefit from alternative approaches.

• In younger patients with both favorable- and unfavorable-risk non-bulky cHL, I prefer ABVD alone, given the lack of a survival advantage with CMT and the risk for serious late effects.

• For patients with early-stage bulky cHL, as defined by the MMR >0.33 or a 10-cm mass, CMT remains the standard of care.

• Studies are ongoing to determine if the use of the interim PET-CT also can identify the subset of patients with bulky early-stage cHL who might safely forego consolidative RT. • Several studies demonstrated that PET-CT is superior to CT for the initial staging of cHL, with PET-CT upstaging approximately 10% to 20% of patients and downstaging 5% or less.

• The International Conference on Malignant Lymphomas Imaging Working Group recently published a comprehensive consensus paper on the role of imaging in the staging and response assessment of lymphoma including cHL.

chemotherapy and the dose of RT depend on risk stratification according to the GHSG prognostic index, as described above.5,6 For older patients (definitely over age 60 years and perhaps even over 50 years), I often recommend CMT for several reasons. First, age is a poor prognostic feature in most series and is associated with increased risk for relapse.

Second, although the absolute risk for a second cancer increases with age, the relative risk compared with age-matched controls is significantly less than for younger patients and may not have the same implications. Also, chemotherapy is more likely to be compromised in older patients due to comorbidities, particularly preexisting cardiopulmonary disease.

And finally, salvage of older patients who relapse may be more challenging. The risks for autologous hematopoietic cell transplant, especially in patients with underlying comorbidities, may be higher in older patients, suggesting that perhaps the front-line treatment associated with the lowest chance of relapse may be preferred. The one exception to recommending CMT in older patients might be patients with an extensive smoking history, in whom the risk for lung cancer following RT would be significant.7 In younger patients with both favorable and unfavorable non-bulky cHL, I prefer ABVD alone, given the lack of a survival advantage with CMT and the risk for serious late effects. Before the introduction of the interim PET-CT, I recommended 6 cycles of ABVD without RT for earlystage nonbulky cHL. However, preliminary results of recent studies incorporating interim PET have shown that 90% of patients with a negative interim PET are cured with 3 to 4 cycles of ABVD alone.8,9 The very high overall survival (OS) rates (>95%), despite a small increase in the recurrence rate when RT is omitted, justifies avoiding RT in the majority of patients with early-stage nonbulky cHL, regardless of initial risk profile.8 For patients with bulky cHL as defined by an MMR greater than 0.33 or a 10-cm mass, CMT remains the standard of care. An ongoing, Phase II cooperative group study, led by the Alliance for

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CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

Clinical Trials in Oncology, is evaluating the outcome of 6 cycles of ABVD alone for patients with bulky early-stage cHL and a negative interim PET. Historically, approximately 80% of patients with bulky early-stage cHL are cured with CMT.10

Several studies now support the conclusion that the majority of patients with early-stage, nonbulky cHL can be cured with chemotherapy.3,4,8,9 We have long known that CMT holds a modest advantage over chemotherapy alone, with several older studies showing a 5% to 10% improvement in progression-free survival (PFS). However, the addition of RT is not associated with an OS advantage. In 2012, the NCIC published the results of a randomized trial involving 405 patients with nonbulky, newly diagnosed earlystage cHL.4 Patients were randomized to ABVD alone versus extended-field RT with or without ABVD, depending on risk factors. Although the 12-year PFS was superior in the RT arm (92% vs 87%; P=0.05), patients receiving RT had an inferior 12-year OS (87% vs 94%; P=0.05) compared with those receiving chemotherapy alone (Figure). Importantly, the subset of patients (39%) in the ABVDalone arm who achieved a complete remission (by CT) after 2 cycles of ABVD, had a 94% 12-year PFS with a total of 4 cycles of ABVD. Two more recent studies, described in more detail below, randomized patients with early-stage nonbulky cHL and a negative PET-CT to consolidative IFRT versus observation after 2 to 3 cycles of ABVD.8,9 Although both studies confirmed a small improvement in PFS with the addition of RT, approximately 90% of patients in the observation arm were cured with chemotherapy alone.

In conclusion, the majority of patients with early-stage nonbulky cHL can be cured with chemotherapy alone. Studies are ongoing to determine if the use of the interim PET-CT also can identify the subset of patients with bulky early-stage cHL who might safely forego consolidative RT.

What are some of the pressing questions in the management of early-stage HL? In an era of limited resources, efforts to investigate options for optimizing therapy in early-stage cHL may be hampered by both the relatively favorable prognosis and the low disease incidence. Large studies are required to find meaningful differences in treatment approaches. However, the young median age of patients with cHL, the cost of premature cancer-related mortality, and the long-term complications of therapy warrant continued efforts to improve outcomes and minimize late effects.11 First and foremost is identifying reproducible biomarkers to differentiate patients at higher risk for relapse and

ABVD alone

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Can patients with early-stage disease be cured without RT?

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167 163

124 126

76 75

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Figure. Kaplan–Meier estimates of OS and freedom from disease progression.

ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; HR, hazard ratio; OS, overall survival; RT, radiation therapy Based on reference 4, with permission from Massachusetts Medical Society.

to serve as surrogate end points. Several candidate biomarkers have shown promise, but none have been tested prospectively. For example, tumor-associated macrophages, detected by CD68 and CD163 immunohistochemical staining, are associated with an inferior outcome in patients with cHL, including those with early-stage cHL.12-14 Recently, a 23-gene outcome predictor was developed that may identify, independently of clinical prognostic factors and CD68, patients with advanced-stage cHL who are at increased risk for death. 15 Ideally, this gene expression profile also will be applicable to patients with early-stage cHL. Incorporation of these potential biomarkers into all future clinical trials will be critical to confirm their value prospectively.

Another critical question is how to optimize therapy for the subset of early-stage

cHL patients with bulky disease, a presentation most common in young women with mediastinal involvement. The current standard of care dictates CMT, with RT often encompassing major portions of the heart and medial breasts. Late effects are dominated by cardiovascular toxicity and breast cancer in this population.16,17 Attempts to minimize the field and exposure to normal structures are limited by the disease location. The development of more effective drug regimens in combination with the use of interim PET may obviate the need for RT in the majority of these patients. Incorporating new agents, such as the antibody-drug conjugate brentuximab vedotin (BV; Adcetris, Seattle Genetics), into first-line therapy for this subset of early-stage patients is particularly appealing.18 Additionally, identifying appropriate screening and long-term follow-up for patients with early-stage cHL

treated with CMT also may help to maximize long-term outcomes.

Finally, with new less-toxic agents showing promise in patients with relapsed cHL, new approaches may be feasible in early-stage cHL.19,20 In patients with the most favorable risk, there could be a role for minimizing not only RT but also conventional chemotherapy, without sacrificing the excellent outcomes seen with current approaches. Rational designs incorporating BV and the programmed cell death 1 (PD-1) inhibitors (pembrolizumab [Keytruda, Merck] and nivolumab [Opdivo, BristolMyers Squibb]) into first-line therapy are appealing.

Is a bone marrow biopsy indicated for PET-confirmed early-stage HL? The need for a bone marrow (BM) biopsy has long been questioned in the routine evaluation of patients with earlystage cHL. Several older studies, which relied solely on CT staging, showed the incidence of BM involvement in patients deemed to have stage I or II disease by routine imaging to be less than 5%. Once the standard treatment of early-stage cHL changed to include chemotherapy for all patients, identifying the rare early-stage patient with BM involvement became even less germane. In 2012, El-Galaly et al published results of a retrospective study of 454 patients with newly diagnosed cHL staged with both a PET-CT and BM biopsy.21 Among the 265 patients with stage I or II disease based on PET-CT staging, none had a positive BM biopsy. This study confirms that there is no indication for a BM biopsy in PET-CT–confirmed early-stage cHL. The 2014 Lugano criteria for lymphoma staging and response evaluation conclude that if a PET-CT is performed, a BM biopsy is no longer required for the routine evaluation of patients with cHL.22

What is the role of PET scan in early-stage HL? The International Conference on Malignant Lymphomas Imaging Working Group recently published a comprehensive consensus paper on the role of imaging in the staging and response assessment of lymphoma, including cHL.23 Several studies demonstrated that PET-CT is superior to CT for the initial staging of cHL, with PET-CT upstaging approximately 10% to 20% of patients and downstaging 5% or less.24,25 Consequently, PET-CT should be considered the standard of care for all patients with newly diagnosed cHL. As described earlier, defining the role of interim PET-CT has been the objective of multiple clinical trials in early-stage cHL over the past decade.26 The initial hope was that interim PET-CT after 2 to 3 cycles of chemotherapy would identify the group of see EARLY-STAGE HL, page 16

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Report From AACR:

Risks and Benefits of Blinatumomab in Clinical Practice Philadelphia—The recently approved monoclonal antibody blinatumomab has the potential to save lives in B-cell malignancies, but, like many therapies in oncology, it has a narrow therapeutic window. An expert offering practical advice indicated that knowing the potential risks may not be the same as developing specific strategies to manage these risks in advance of the first infusion.

“Blinatumomab was pushed through a

rapid approval process, which is fantastic, but that means that not many centers and not many people have had hands-on experience,” cautioned Susan R. Rheingold, MD, the medical director of the outpatient oncology program at Children’s Hospital of Philadelphia (see related story on accelerated approvals, page 5). In a session during the 2015 annual meeting of the American Association for Cancer Research (AACR), Dr.

Rheingold outlined risk management strategies from her own experience.

Regulatory approval for blinatumomab (Blincyto, Onyx Pharmaceuticals), granted for the treatment of Philadelphia chromosome–negative (Ph–) relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL), came in December 2014, just six months after the FDA granted the agent a breakthrough designation. Both

EARLY-STAGE HL

subset for consideration of treatment intensification.

with early-stage Hodgkin’s lymphoma.

N Engl J Med. 2010;363(7):640-652, PMID: 20818855.

continued from page 15

patients who were most likely to benefit from RT, sparing the majority of patients the potential late effects of RT. The results of the RAPID trial showed that for the 75% of patients with a negative PETCT after 3 cycles of ABVD (Deauville score 1-2), the 3-year PFS was 90.8% (95% confidence interval [CI], 86.9%-94.8%) for those not receiving RT compared with 94.6% (95% CI, 91.5%-97.7%) for those receiving RT, with 3-year OS rates of 99% and 97%, respectively.8 The EORTC H10 trial, designed to evaluate the use of interim PET-CT results to dictate consolidative RT in early-stage cHL, closed prematurely due to a planned interim analysis that showed the omission of RT was not noninferior to CMT for patients with an early negative PET-CT.9 Importantly, despite the statistically significant inferior outcomes in the non-RT arms, the results were excellent in all groups with 1-year PFS rates of 94.9% (non-RT) versus 100% (RT) in the favorable subgroup ( =0.017) and 94.7% (non-RT) versus (P 97.3% (RT) for the patients deemed unfavorable at study entry ((P=0.026). These studies demonstrate that even with the use of interim PET-CT, there remains a statistically significant improvement in PFS in PET-negative disease with the use of consolidative RT. Research evaluating additional PETCT parameters, such as delta standardized uptake value (SUV) or change in total lesion glycolysis (TLG), may prove to be more predictive than the current qualitative Deauville score. Additionally, a recent prospective study evaluating the value of a post-cycle 1 PET-CT in 126 patients (68 stage I-II), showed a 2-year PFS of 98.3% for patients who were PETCT–negative following 1 cycle of chemotherapy compared with 38.5% for those who were PET-CT–positive.277 The results for the stage I to IIA patients were 100% and 50% for patients with a negative and positive post-cycle 1 PET-CT, respectively. Perhaps this earlier time point may provide a more useful separation of patients and identify the highest-risk

Conclusion For most patients with nonbulky earlystage cHL, chemotherapy alone represents the best approach to maximize long-term survival and minimize late effects. Identification and elimination of any unnecessary therapy associated with late effects remains an important goal, especially in children and young adults.

Additional studies, evaluating regimens incorporating new agents such as brentuximab vedotin, pembrolizumab, and nivolumab in place of RT, are warranted, particularly in bulky early-stage cHL. Support for Dr. Bartlett’s work was provided, in part, by the Foundation for Barnes-Jewish Hospital.

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the designation and the approval were based on a single-arm trial, according to Donna Przepiorka, MD, PhD, a medical officer with the FDA, who recounted this history at the AACR meeting.

The data showed that the objective response, the primary criterion considered by the FDA, was “clearly better” than that observed up to then with alternatives.

Noting that numerous Phase III trials

Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood.

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18. Younes A, Connors JM, Park SI, et al.

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19. Ansell SM, Lesokhin AM, Borrello I, et al.

PD-1 Blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319, PMID: 25482239.

20. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol.

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21. El-Galaly TC, d’Amore F, Mylam KJ, et al.

Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol.

2012;30(36):4508-4514, PMID: 231550698.

22. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano Classification. J Clin Oncol.

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12. Greaves P, Clear A, Coutinho R, et al.

Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. J Clin Oncol. 2013;31(2):256-262, PMID: 23045593.

23. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048-3058, PMID: 25113771.

13. Tan KL, Scott DW, Hong F, et al. Tumorassociated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood. 2012;120(16):3280-3287, PMID: 22948049.

24. Hutchings M, Loft A, Hansen M, et al. Position emission tomography with or without computed tomography in the primary staging of Hodgkin’s lymphoma. Haematologica.

2006;91(4):482-489, PMID: 16585015.

14. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875-885, PMID: 20220182.

15. Scott DW, Chan FC, Hong F, et al. Gene expression-based model using formalinfixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013; 31(6):692-700, PMID: 23182984.

16. Swerdlow AJ, Cooke R, Bates A, et al. Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in England and Wales: a National Cohort Study.

J Clin Oncol. 2012;30(22):2745-2752, PMID: 22734026.

17. Galper SL, Yu JB, Mauch PM, et al.

25. Elstrom RL, Leonard JP, Coleman M, Brown RKJ. Combined PET and low-dose, noncontrast CT scanning obviates the need for additional diagnostic contrast-enhanced CT scans in patients undergoing staging or restaging for lymphoma. Ann Oncol.

2008;19(10):1770-1773, PMID: 18550578.

26. Gallamini A, Kostakoglu L. Interim FDGPET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood.

2012;120(25):4913-4920, PMID: 22932799.

27. Hutchings M, Kostakoglu L, Zaucha JM, et al. In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J Clin Oncol.

2014;32(25):2705-2711, PMID: 25071108.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

are ongoing and have the potential to expand the indications for blinatumomab, which targets the CD19 antigen on B cells, Dr. Rheingold provided insight on how to mitigate risks in clinical practice. Her focus was on cytokine release syndrome (CRS) and neurologic toxicities, both of which are listed in black box warnings and are included in the Risk Evaluation and Mitigation Strategies (REMS) program for this agent.

Of these, CRS is the most likely to be life-threatening, according to Dr. Rheingold. It can develop within hours of the first dose. When it is severe, symptoms can include hypotension, fluid overload and capillary leak, with an onset resembling that of a rapid-onset inflammatory process. The problem is that “this looks like a lot of other things that can occur in a refractory ALL patient, such as sepsis and tumor lysis syndrome.” There is no definitive diagnostic test for CRS, but Dr. Rheingold suggested several steps that may help in modifying its effects.

One of these is considering cytoreductive therapy when the disease burden is substantial. Premedication with dexamethasone is included in the blinatumomab labeling, but Dr. Rheingold explained that CRS risk correlates with both disease burden and a high white blood cell count. She suggested reducing disease burden with a relatively well-tolerated chemotherapy such as vincristine and a steroid or oral chemotherapy before initiating blinatumomab treatment.

Dr. Rheingold also recommended a baseline ferritin in advance of the first blinatumomab dose. A precipitous ferritin increase in patients with inflammatory symptoms can be useful for drawing attention to CRS as the likely cause.

She also advised clinicians to consider in advance how to obtain cytokine levels in a timely fashion. Many laboratories are not equipped to provide results rapidly enough to direct patient care.

To manage CRS if it occurs, Dr. Rheingold recommended the interleukin-6 receptor inhibitor tocilizumab, advising clinicians to verify that they have access to this agent in advance.

Although control of CRS is an off-label use for this anti-inflammatory agent, she recounted dramatic clinical recoveries even in very severe cases after this drug was administered.

According to Dr. Rheingold, neurotoxicity, although more difficult to avoid, has typically been self-limited in the clinical experience to date. The incidence of a grade 3 or higher neurotoxicity, manifested by seizures, encephalopathy and aphasia, has been about 15% in the clinical studies, but Dr. Rheingold cautioned that patients with a history of seizures or other central nervous system (CNS) events have been excluded from trials.

“One concern is that with more use of blinatumomab in patients not necessarily screened for prior CNS problems,

these rates may go up, and we will see more cases in which they do not resolve spontaneously,” Dr. Rheingold said.

Dr. Rheingold paid special attention to her experience with blinatumomab in children. She noted that although rates of neurotoxicity have been lower in the pediatric population, they can still be a burden for families even after they have been reassured that these complications resolve. “Parents do not like watching their children have these kinds of CNS events,” Dr. Rheingold said. As a result, neurotoxicity, after CRS, is often one of the most challenging complications on a

list that includes headache, febrile neutropenia, nausea, edema, dyspnea and abnormal liver function tests.

Vigilance for toxicities should be particularly pronounced at the initiation of the drug. “All initial infusions should start in the hospital,” according to Dr. Rheingold. “This cannot be overemphasized. When patients get sick, they get sick quickly.” Moreover, “it is important that you have a good ICU available if the situation deteriorates,” she added.

The approval of blinatumomab was based on compelling evidence of a favorable benefit–risk ratio, according to Dr.

17

Przepiorka. Although she acknowledged that the toxicities are significant, she stressed that durable remissions of comparable quality have not been routinely achieved with other options. According to Dr. Rheingold, expanded indications seem likely, but she emphasized that managing adverse events is crucial to realizing the potential benefits.

—Ted Bosworth Dr. Rheingold reported a financial relationship with Novartis. Dr. Przepiorka reported no relevant financial relationships.

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014

Expiration Date: November 11, 2015

Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia.

2 Describe the comorbidities and causes commonly associated with hyponatremia and their significance in treatment.

3 Summarize current evidence and best practices in the management of hyponatremia.

4 Explain how to mitigate adverse events secondary to treatment of hyponatremia.

5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

18

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

Clinical Conundrums Updates in Hematology from d Blood NEJM, JCO and

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

QUESTIONS

3. Vitamin D levels do not influence outcomes of patients with follicular lymphoma (FL) who are treated with chemoimmunotherapy (CIT). True or false?

4. Translocation t(11;14) is associated

Prepared by

Syed A. Abutalib, MD

from salvage therapy. True or false?

Primum non nocere. (First, do no harm.)

Hodgkin lymphoma (HL) and negative positron emission tomography (PET) scanning after 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) had good prognosis even without further therapy. True or false?

with adverse outcome in patients with newly diagnosed amyloid light-chain amyloidosis treated with bortezomibbased regimens. True or false?

5. Relapsed and refractory myeloma

is defined as progression on therapy in patients who achieve minor response (MR) or better, or who progress within 60 days of their last therapy. True or false?

7.

Suppression of uninvolved immunoglobulins (Igs) is not associated with progression to multiple myeloma (MM) in patients with smoldering MM (SMM).

True or false?

8. Bisphosphonates (pamidronate or

zoledronic acid) administered using the MM dosing schedule are not recommended for patients with SMM. True or false?

9. Ibrutinib can be safely combined

with bendamustine and rituximab (Rituxan, Genentech) (BR), or fludarabine, cyclophosphamide, and rituximab (FCR) in the setting of relapsed and refractory CLL and small lymphocytic lymphoma (SLL). True or false?

2. In a study published in the Journal 6. Selinexor (Karyopharm) is effec- 10. Obinutuzumab (Gazyva, Genen-

1. In a study published in The New

of Clinical Oncologyy (JCO), patients with chronic lymphocytic leukemia (CLL) who relapsed after allogeneic hematopoietic cell transplant (allo-HCT) did not benefit

tive in acquired resistance to ibrutinib (Imbruvica, Pharmacyclics) and is synergistic with ibrutinib in CLL. True or false?

tech) is a type 2, glycoengineered, antiCD20 antibody recently approved for use with chlorambucil for the initial therapy of CLL. True or false?

ANSWERS

years, the adjusted PFS and OS hazard ratios (HRs) for the SWOG cohort were 1.97 (95% CI, 1.10-3.53) and 4.16 (95% CI, 1.66-10.44), respectively, for the 15% who were vitamin D–deficient (<20 ng/mL).

After a median follow-up of 6.6 years, the adjusted PFS and OS HRs for the LYSA cohort were 1.50 (95% CI, 0.93-2.42) and 1.92 (95% CI, 0.72-5.13), respectively, for the 25% of patients who were considered vitamin D–deficient (<10 ng/mL). Further investigation is needed to determine the effects of vitamin D supplementation in this setting.

Rajkumar SV, Harousseau JL, Durie B, et al.

Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1.

Blood. 2011;117(18):4691-4695, PMID: 21292775.

myeloma (idiopathic Bence Jones proteinuria): a retrospective cohort study. Lancet Haematol.

2014;1(1):e28-e36, PMID: 25530988.

England Journal of Medicine, patients with newly diagnosed stage IA or IIA

1. True. A total of 571 patients under-

went PET scanning after 3 cycles of ABVD. The PET findings were negative in 426 of these patients (74.6%); 420 patients were randomly assigned to a study group: 209 to radiotherapy and 211 to no further therapy. At a median of 60 months of follow-up, there were 8 instances of disease progression with radiotherapy, and 8 patients had died; there were 20 instances of progression in the group with no further therapy, and 4 patients had died. The 3-year progression-free survival (PFS) rate was 94.6% (95% confidence interval [CI], 91.5%-97.7%) in the radiotherapy group and 90.8% (95% CI, 86.9%-94.8%) in the group that received no further therapy, with an absolute risk difference of –3.8 percentage points (95% CI, –8.8 to 1.3).

Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med. 2015;372(17): 1598-1607, PMID: 25901426.

2. False. The prognosis of patients

with CLL who progress after allo-HCT is not necessarily poor. Retrospective analysis showed 2- and 5-year survival rates of 67% and 38%. Patients who developed acute or chronic graft-versushost disease had a longer overall survival (OS; P=0.05).

Rozovski U, Benjamini O, Jain P, et al. Outcomes of patients with chronic lymphocytic leukemia and Richter’s transformation after transplantation failure. J Clin Oncol. 2015;33(14):1557-1563, PMID: 25847930.

3. False. Prospective analysis of newly

diagnosed patients with FL treated in the SWOG (S9800, S9911, or S0016) and Lymphoma Study Association (LYSA) PRIMA trials evaluated vitamin D levels and outcomes. After a median follow-up of 5.4

Kelly JL, Salles G, Goldman B, et al. Low serum vitamin D levels are associated with inferior survival in follicular lymphoma: a prospective evaluation in SWOG and LYSA studies. J Clin Oncol.

2015;33(13):1482-1490, PMID: 25823738.

4. True. The presence of transloca-

tion t(11;14) was associated with inferior hematologic event-free survival versus its absence (median, 3.4 vs 8.8 mo, respectively; P=0.002), OS (median, 8.7 vs 40.7 mo, respectively; P=0.05), and remission rate (at least very good partial remission; 23% vs 47%, respectively; P=0.02). After backward variable selection, the final multivariable model was validated in a consecutive series of 32 patients treated with bortezomib (Velcade, Millennium), cyclophosphamide, and dexamethasone. The MM high-risk fluorescence in situ hybridization aberrations t(4;14), t(14;16), del(17p) and gain of 1q21 conferred no adverse prognosis in this group.

Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol. 2015;33(12):1371-1378, PMID: 25779559.

5. True. Patients who never achieve

at least MR to initial induction therapy and progress on therapy are defined as primary refractory myeloma.

6. True.

Despite the therapeutic efficacy of ibrutinib in CLL, complete responses are infrequent, and acquired resistance to Bruton tyrosine kinase inhibition is being observed in an increasing number of patients. Combination regimens that increase the frequency of complete remissions (CRs), accelerate the time to remission, and overcome single-agent resistance are of considerable interest. One such agent of interest is selinexor, an orally bioavailable selective inhibitor of nuclear export. The study is the first report describing the combined activity of ibrutinib and selinexor in CLL, which warrants evaluation in clinical trials.

Hing ZA, Mantel R, Beckwith KA, et al.

Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood. 2015;125(20): 3128-3132, PMID: 25838351.

7. False. In a Mayo Clinic study of 276

patients with SMM, immunoparesis was a significant risk factor for progression to MM or a related disorder. The median time to progression was 159 months in patients with normal levels of uninvolved Ig, 89 months in those with a reduction in 1 isotype, and 32 months in patients with a reduction in 2 isotypes of uninvolved Ig ((P=0.001). Suppression of uninvolved Ig has also been found to be a risk factor for progression in lightchain SMM. Kyle RA, Remstein ED, Therneau TM, et al.

Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-2590, PMID: 17582068.

Kyle RA, Larson DR, Therneau TM et al. Clinical course of light-chain smouldering multiple

8.

True. Once-yearly bisphosphonate used for the treatment of osteoporosis is appropriate. More frequent dosing of every 3 to 4 months can be considered for selected high-risk SMM patients.

Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma Blood.

2015;125(20):3069-3075, PMID: 25838344.

9. True. The overall response rate

(ORR) with BR-ibrutinib (n=30) was 93.3%, including 16.7% CRs initially, which increased to 40% during the extension period. Including one patient with partial response with lymphocytosis, the best ORR was 96.7%. All 3 patients treated with ibrutinib-FCR achieved CR. The investigators of this multicenter Phase Ib study conclude that the combination of ibrutinib with CIT should be considered, given the likely enhanced efficacy seen without significantly increased toxicity.

Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125(19):29152922, PMID: 25755291.

10. True. In the Phase III random-

ized trial, treatment with obinutuzumab-chlorambucil (G-Clb), compared with rituximab-chlorambucil (R-Clb), resulted in prolongation of PFS (HR, 0.39; 95% CI, 0.31-0.49; P<0.001) and higher rates of CR (20.7% vs 7.0%).

With longer follow-up, a higher rate of eradication of minimal residual disease was observed with G-Clb compared with R-Clb. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110, PMID: 24401022.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2015 • CLINICALONCOLOGY.COM

19

For the full chapter,

The following is an excerpt from

Multiple Myeloma

GO HERE: essentialoncology.com

Renju Raj, MD, and Parameswaran Hari, MD Medical College of Wisconsin, Milwaukee, Wisconsin

Step 1: Go to Consider comorbidities, renal function, age, risk status, supportive care

essentialoncology.com in your browser* and register. * Explorer 11 and any recent versions of Chrome, Firefox, Opera and Safari.

Available clinical trial/transplant referral to check eligibility/supportive care

Step 2: Touch

, middle icon located at the bottom of your screen.

Patient has poor performance status and likely is not a transplant candidate

Patient is a candidate for aggressive therapy

Novel agent–based induction to establish response

Novel agent doublet/triplet

Step 3: Touch

Dose adjustment for toxicity Stem cell collection

‘Add to Home Screen.’

Continuous therapy until relapse

auto-HCT up-front vs later

Step 4: Touch ‘Add’ at the top.

Now you have Essential Oncology™ saved as an app on your home screen to access quickly & easily!

Consolidation/maintenance based on risk profile

Figure 1. Initial therapy considerations.

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BRIEF SUMMARY VOTRIENT® ((pazopanib)) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food ((at least 1 hour before or 2 hours after a meal)) [[see Clinical Pharmacology ((12.3)) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology ((12.3)) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability. Hepatic p Impairment: p No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [[see Use in Specific Populations (8.6)) and Clinical Pharmacology ((12.3)) of full prescribing information]]. Concomitant Strongg CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin)) increases pazopanib concentrations and should be avoided.

Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg.

Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions ((7.1)) and Clinical Pharmacology (12.3) of full prescribing information]]. Concomitant Strongg CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers ((e.g., rifampin)) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases ((ALT, AST)) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations ((8.5)] ) . Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in )]. In the ranthe first 18 weeks)) [[see Dosage and Administration ((2.2)] domized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the groups receiving VOTRIENT and placebo, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% ((5/290)) of patients on VOTRIENT and 1% ((2/145)) on placebo. Two-tenths percent of the patients ((2/977)) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver )]. tests weekly for 8 weeks [[see Dosage and Administration ((2.2)] Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect ((unconjugated)) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [[see Clinical Pharmacology (12.5) of full prescribing information]]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken ). with caution and close monitoring [see Drug Interactions ((7.4)] Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [[see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation ((≥500 msec)) was identified on routine electrocardiogram monitoring in 2% ((11/558)) of patients. Torsades de pointes occurred in <1% ((2/977)) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% ((3/290)) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec.

None of the 145 patients who received placebo on the trial had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium)) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction

( (LVEF) ) and congestive heart failure have occurred. In the overall safety population for RCC ((N=586), ) cardiac dysfunction was observed in 0.6% ((4/586)) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 13% ((47/362)) of patients on VOTRIENT compared with 11% ((42/369)) of patients on sunitinib. Congestive heart failure occurred in 0.5% of patients on each arm. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment)) [see Warnings and Precautions ((5.10)] ) . Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% ((5/586)) in the RCC trials.

In the randomized RCC trial, 13% ((37/290)) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis ((2%), ) hemoptysis (2%), ( ) and rectal hemorrhage (1%). ( ) Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent ((4/290) of patients treated with VOTRIENT died from hemorrhage compared with no ((0/145)) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% ((2/586)) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% ((2/586)) of patients in the RCC trials. In the randomized RCC trial, 2% ((5/290)) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus ((PE)) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy ((TMA), ) including thrombotic thrombocytopenic purpura (TTP) ( ) and hemolytic uremic syndrome ((HUS)) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% ((2/586)) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome ((RPLS)) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). ) Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration ((2.2)] )]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% ((19/290)) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% ((27/290)) of patients receiving VOTRIENT and in no patients receiving placebo.

In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes )]. 5.14 despite dose reductions [[see Dosage and Administration ((2.2)] Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other

Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals.

VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger ( )]. 5.17 than 2 years of age [[see Use in Specific Populations (8.4)] Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [[see Warnings and Precautions ((5.15.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.1) ( ) of full prescribing information]. The median duration of treatment was 7.4 months ((range 0 to 23)) for patients who received VOTRIENT and 3.8 months ((range 0 to 22)) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC Who Received VOTRIENT VOTRIENT Placebo (N = 290) (N = 145) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Adverse % % % % % % Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia ((4% versus <1%), ) facial edema ((1% versus 0%), ) palmarplantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms. Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC Who Received VOTRIENT and More Commonly (≥5%) in Patients Who Received VOTRIENT Versus Placebo VOTRIENT Placebo (N = 290) (N = 145) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Parameters % % % % % % Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose increased 41 <1 0 33 1 0 Total bilirubin increased 36 3 <1 10 1 <1 Phosphorus decreased 34 4 0 11 0 0 Sodium decreased 31 4 1 24 4 0 Magnesium decreased 26 <1 1 14 0 0 Glucose decreased 17 0 <1 3 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase p Elevations: In a singlearm RCC trial, increases in lipase values were observed for 27% ((48/181)) of patients. Elevations in lipase as an adverse reaction were reported for 4% ((10/225)) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% ((4/586)) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: y In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs ((<60 beats per minute)) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Eye y Disorders: Retinal detachment/tear. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 ((e.g., ketoconazole, ritonavir, clarithromycin)) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology ((12.3)) of full prescribing information]]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [[see Dosage and Administration (2.2)] ( )]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations.

Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs that Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or BCRP should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [[see Clinical Pharmacology (12.3) ( ) of full prescribing information]]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [[see Clinical Pharmacology ((12.3)) of full prescribing information]]. 7.4 Effect of Concomitant Use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions ((5.1)] )]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs that Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor ((PPI), ) decreased the exposure of pazopanib by approximately 40% ((AUC and Cmax). ) Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [[see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day ((approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), ) while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at Day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from Day 9 through Day 14 postpartum (preweaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day ((approximately 0.07 times the human clinical exposure based on AUC). ) Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day ((approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks.

Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning Day 21 postpartum (post-weaning).

In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals.

There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions ((5.16)] )]. 8.5 Geriatric Use: In pooled clinical trials with VOTRIENT, 30% (618/2080) of patients were aged >65 years.

Patients aged >65 years had an increase in ALT elevations of >3 X ULN compared to patients aged <65 years ((23% versus 18%)) [[see Warnings and Precautions ((5.1)] )]. In clinical trials with VOTRIENT for the treatment of RCC, 33% ((196/582)) of patients were aged ≥65 years.

No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value)) was 200 mg per day ((N=11). ) The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment ((creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity ((Grade 3 fatigue)) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted.

However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day ((approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans.

In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day ((approximately 0.4 times the human clinical exposure based on AUC). ) Total litter resorption was seen at 300 mg/kg/day ((approximately 0.8 times the human clinical exposure based on AUC). Postimplantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day ((approximately 0.3 times the human clinical exposure based on AUC).

Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks ((approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively).

Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks ((approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day ((approximately 0.35 times the human clinical exposure based on AUC); ) atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests ((ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9.

Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away.

• Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications.

• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure.

• Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding.

• Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis.

• Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs.

• Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS ((headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting.

• GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula.

• VEGFR inhibitors such as VOTRIENT may impair wound healing.

Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery.

• Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment.

• Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection.

• Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.

• Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.

• Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709 ©2015, the GSK group of companies. All rights reserved.

Revised: 4/2015 VTR:14BRS Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

VOTRIENT T® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2 12 10

VOTRIENT Placebo

11.1

MONTHS

9.2

MONTHS

7.4

Months

8 6 4

MONTHS

4.2

4.2

MONTHS

2.8

MONTHS

MONTHS

2 0

HR 0.46; 95% CI 0.34-0.62 (P<0.001) All patients

HR 0.40; 95% CI 0.27-0.60 (P<0.001) First-line patients

HR 0.54; 95% CI 0.35-0.84 (P<0.001) Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145).

The study included first-line patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. CHF occurred in 0.5% of patients on each arm.

Monitor blood pressure (BP), and manage promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and reinitiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of CHF. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure.

• Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal (GI) hemorrhage in the past 6 months.

• Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events. Do not use VOTRIENT in patients who have had an arterial thromboembolic event in the past 6 months.

• Venous Thromboembolic Events (VTEs): VTEs have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms.

• Thrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.

• GI Perforation and Fistula: In RCC trials, GI perforation or fistula was reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events, and monitor for signs and symptoms.

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension (HTN): HTN, including hypertensive crisis, has occurred in clinical trials. HTN occurs early in the course of treatment (approximately 40% of cases occurred by Day 9, and 90% of cases occurred in the first 18 weeks). BP should be well controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased BP promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT, as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if HTN is severe and persistent despite antihypertensive therapy and dose

reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of HTN. • Wound Healing: VOTRIENT may impair wound healing.

Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence.

• Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo.

Monitoring of thyroid function tests is recommended.

• Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein at baseline and periodically as clinically indicated. Interrupt treatment for 24-hour urine protein *3 grams, and discontinue for repeat episodes despite dose reductions.

• Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation

Once-daily oral dosing1

VOTRIENT: Summary of serious and common adverse reactions1

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure

• Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm

• If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced

• Most common adverse reactions (*20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting

• No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9.

Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications fi based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

Pazopanib (VOTRIENT®) has a Category 1 recommendation as a first-line therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or Stage IV unresectable RCC of predominant clear cell histology. NCCN Guidelines® also include therapies other than pazopanib (VOTRIENT®) as first-line options.3

Important Safety Information for VOTRIENT (cont’d) during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their health care provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

• Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients.

In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

• Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax.

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm.

• Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases

concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

Concomitant treatment with strong inhibitors of P-glycoprotein (PgP) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insuffificient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

Please see additional Important Safety Information for VOTRIENT on adjacent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

• Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on VOTRIENT. The VOTRIENT dose was reduced for 36% of patients.

The most common adverse reactions (*20%) for VOTRIENT vs placebo were diarrhea (52% vs 9%), HTN (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

Laboratory abnormalities occurring in >10% of patients and more commonly (*5%) in patients taking VOTRIENT vs placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%).

References: 1. VOTRIENT® (pazopanib) Tablets [package insert].

Research Triangle Park, NC: GSK; 2015. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer v3.2015. ©National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed April 13, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org.

NATIONAL COMPREHENSIVE CANCER NETWORKK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

VOTRIENT.com/HCP/aRCC

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2015 Novartis

5/15

VRT-1114203

EFFICACY LIGHTS THE WAY

FDA-approved for treatment of advanced RCC since 2009

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1* *Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of VOTRIENT in first-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT® (pazopanib) tablets WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

• Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed.

Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions].

Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

• QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease.

Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (eg, calcium, magnesium, potassium) within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

EFFICACY LIGHTS THE WAY