Cancer Therapy Advisor November/December 2018 Issue by Haymarket Media

NOVEMBER/DECEMBER 2018 | VOL 5, ISSUE 2

34 FEATURE

Societies Weigh In on Medicare Advantage Step Therapy Medical societies have called for the reversal of a policy that allows step therapy under Medicare Advantage. 28 EXPERT PERSPECTIVE

Identifying Gene Variants Involved in Radiotherapy Toxicity Risk 37 IN THE CLINIC

Bowel Preparation for Colorectal Cancer Screening: Improving Outcomes 37 TREATMENT REGIMENS

Breast Cancer (Invasive) ï&#x201A;&#x201E; Non-Hodgkin Lymphoma: Diffuse Large B-Cell Lymphoma

39 VIEWPOINT Expansion Cohort Trials Expected to Modernize Oncology Studies

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Liquid Biopsy May Predict Response to Therapy in DLBCL Novel Approaches for the Treatment of PCNSL Next-Gen ADCs: An Option for Non-Hodgkin Lymphoma and Myeloma?

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Liquid Biopsy May 15 Predict Response to Therapy in DLBCL

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Approaches for 24 Novel the Treatment of PCNSL ADCs: An Option 26 Next-Gen for Non-Hodgkin Lymphoma

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Cancer Therapy Advisor (ISSN 2375-558X), November/December 2018, Volume 5, Number 2. Published 6 times annually by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales &amp; Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). Standard Postage paid at Orem, UT. Postmaster: Send changes of address to Cancer Therapy Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Unless otherwise indicated, persons appearing in photographs are not the actual individuals m entioned in the articles. They appear for illustrative purposes only.

CONTENTS 10 LATEST NEWS

Recent headlines in oncology research and practice. 28 EXPERT PERSPECTIVE

Identifying Gene Variants Involved in Radiotherapy Toxicity Risk Benjamin Smith, MD

34 FEATURE

Societies Weigh In on Medicare Advantage Step Therapy Bryant Furlow

4 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2018 | CancerTherapyAdvisor.com

Editorial and Business Staff Managing Editor, Haymarket Oncology Lauren Burke Oncology Editor Randi Hernandez

Group Art Director, Medical Communications Jennifer Dvoretz Graphic Designer Vivian Chang Production Manager Brian Wask; (646) 638-6066 Vice President, Sales & Business Development Scott Bugni; (917) 882-0658; scott.bugni@haymarketmedia.com Account Manager Henry Amato; (646) 638-6096; henry.amato@haymarketmedia.com Manager, Multi-Channel Business Development Marc A. DiBartolomeo; (609) 417-0628; marc.dibartolomeo@ haymarketmedia.com VP, Content; Medical Communications Kathleen Tulley President, Medical Communications Michael Graziani Chief Executive Officer Lee Maniscalco

Editorial Advisory Board Barbara Ann Burtness, MD

Yale Cancer Center  New Haven, CT

IN THE CLINIC

Bowel Preparation for Colorectal Cancer Screening: Improving Outcomes C. Andrew Kistler, MD, PharmD

Steven J. Cohen, MD Thomas Jefferson University Hospital  Philadelphia, PA

E. David Crawford, MD University of Colorado, Denver  Aurora, CO

Isabel Cunningham, MD

Columbia University College of Physicians & Surgery  New York, NY

VIEWPOINT

Expansion Cohort Trials Expected to Modernize Oncology Studies Leah Lawrence

Don S. Dizon, MD, FACP Lifespan Cancer Institute  Providence, RI

Jeffrey M. Farma, MD Fox Chase Cancer Center  Philadelphia, PA

Neal D. Shore, MD, FACS Atlantic Urology Clinics  Myrtle Beach, SC

TREATMENT REGIMENS 41

Breast Cancer (Invasive)

Non-Hodgkin Lymphoma: Diffuse Large B-Cell Lymphoma

Mark A. Socinski, MD Florida Hospital Cancer Institute  Orlando, FL

Mario Sznol, MD Yale Cancer Center  New Haven, CT

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LATEST NEWS

First-Line Nivolumab +/- Ipilimumab Continues to Show Durable Survival Benefits in Advanced Melanoma A 4-year update demonstrates that nivolumab plus ipilimumab or nivolumab monotherapy for the treatment of newly diagnosed advanced melanoma results in a durable survival benefit compared with ipilimumab alone. These findings were included in ananalysis of the CheckMate067 trial (ClinicalTrials.gov Identifier: NCT01844505) that was presented at the 2018 ESMO Congress in Munich, Germany, and simultaneously published in Lancet Oncology.1,2 Previously reported results from CheckMate067 demonstrated that the first-line combination of nivolumab and ipilimumab or nivolumab alone substantially improved objective response rate, progression-free survival (PFS), and overall survival (OS) compared with ipilimumab for advanced melanoma. This analysis provides updated 4-year data with a database lock of May 10, 2018. The phase 3 CheckMate067 trial randomly assigned 945 patients with previously untreated, unresectable, stage III or IV melanoma with known BRAF status to receive nivolumab plus ipilimumab, nivolumab plus placebo, or ipilimumab plus placebo. The coprimary endpoints were PFS and OS. Combination therapy or nivolumab plus placebo continued to show improved survival outcomes compared with ipilimumab plus placebo with a minimum follow-up of 48 months among the intention-to-treat population. The median OS was still not reached for nivolumab plus ipilimumab (95% CI, 38.2 months-not reached; (95% CI, 16.9-24.6) with ipilimumab (hazard ratio [HR], 0.54; 95% CI, 0.44-0.67; P < .0001) and was 36.9 months (95% CI, 28.3 months-not reached) with nivolumab (HR, 0.65; 95% CI, 0.53-0.79; P < .0001) compared with 19.9 months. PFS was also prolonged with the combination, with a median of 11.5 months (95% CI, 8.7-19.3 months; HR, 0.42; 95% CI, 0.35-0.51; P , .0001) and a median of 6.9 months (95% CI, 5.1-10.2 months) with nivolumab (HR, 0.53; 95% CI, 0.44-0.64; P < .0001) compared with 2.9 months (95% CI, 2.8-3.2 months) with ipilimumab. Treatment-related adverse events (TRAEs) occurred most frequently in the combination nivolumab plus ipilimumab arm among patients who received at least 1 dose of treatment. The rate of grade 3/4 TRAEs was 59%, 22%, and 28% in the combination, nivolumab, and ipilimumab arms, respectively. The most common grade 3 TRAEs was diarrhea with the combination or nivolumab groups and colitis in the ipilimumab group. Elevated lipase was the most common grade 4 TRAE in all groups. Serious adverse events were not evaluated in this analysis. There were 4 treatment-related deaths, 2 of which occurred in the combination arm as a result of cardiomyopathy and liver necrosis, 1 in the nivolumab arm due to neutropenia, and 1 in the ipilimumab arm due to colon perforation. None of these deaths occurred since the 3-year update. The authors concluded that this analysis shows “a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.”

Disclosure: Research for this study was funded by Bristol-Myers Squibb.

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Further Development of Hsp90 Inhibitor in NSCLC Remains Uncertain More than one-third of patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ins20) treated with the Hsp90 inhibitor luminespib achieved stable disease or better for longer than 3 months, according to a recent study.1 These results suggest that luminespib may be active for this patient subgroup, which generally has disease that is refractory to first- or second-generation EGFR inhibitors. In the phase 2 study, 29 patients with stage IV NSCLC with EGFR ins20 were assigned to receive a standard starting dose of luminespib 70 mg/m2 weekly. All patients had been treated with at least 1 therapy prior to enrollment in the study. In the overall intent-to-treat population, the overall response rate was 17%; all responses were partial responses. Stable disease lasting longer than 3 months was achieved in 6 patients. This translated into an effectiveness of 38%. Two patients were later found to be EGFR ins20-negative, and these 2 patients both had stable disease lasting less than 3 months. When these 2 patients were excluded from the analysis, the overall response rate was 19% with a target rate of effectiveness of 41%. The median progression-free survival was 2.8 months and the median overall survival was 9.9 months. When the 2 EGFR ins20-negative patients were excluded, this increased to 3.3 months and 12.8 months, respectively. The most common treatment-related adverse events were diarrhea (83%), visual changes (76%), and fatigue (45%). In December 2014, Novartis announced it would cease further development of the luminespib program, and as a result, the drug’s codeveloper, Vernalis plc, gained back the rights to the drug. Ligand Pharmaceuticals announced on October 10, 2018, the acquisition of Vernalis, which will now operate as a subsidiary of Ligand.2 “The development of luminespib was halted during the conduct of our study and the trial had to be stopped prematurely when all available drug supply expired in February 2017,” the researchers noted. “This highlights a major limitation of our current system of drug development, and the need for innovative strategies to provide ongoing treatment to responding patients when drug supplies are limited.” The authors noted that other targeted therapies for lung cancers harboring EGFR ins20 mutations — specifically, tyrosine kinase inhibitors (TKIs) — are under development at other pharmaceutical companies, including Spectrum Pharmaceuticals, Inc’s poziotinib, currently in phase 2 studies (ClinicalTrials.gov Identifier: NCT03066206); TAK-788 from Ariad Pharmaceuticals/Takeda (ClinicalTrials.gov Identifier: NCT02716116), now in an ongoing phase 1 study; and the currently recruiting phase 2 study on

osimertinib that is being run by the National Cancer Institute (ClinicalTrials.gov Identifier: NCT03191149). “We are optimistic that one or more of these new drugs will lead to both activity and a tolerable toxicity profile, with eventual regulatory approval in this underserved patient population,” the authors of the study wrote about the TKIs in the pipeline. “Nevertheless, we see a role for further study of luminespib or other hsp90 inhibitors, which act by a different mechanism than TKIs and could potentially benefit patients who do not respond to or become resistant to other novel therapies.” Disclosure: The original study was funded by Novartis Pharmaceuticals Corporation. For a full list of disclosures, please refer to the original study.

Organic Food Consumption Linked to Lower Cancer Risk, But Further Study Needed A large, prospective study in French adults showed that individuals who consumed organic foods at a higher frequency had a lower risk of canceroverall (ClinicalTrials. gov Identifier: NCT03335644). The study findings were published online October 22, 2018, in JAMA Internal Medicine.1 To conduct the study, researchers recruited French adult volunteers to complete online questionnaires. Participants were asked about their consumption frequency of organic foods for 16 products. This information was then used to generate an organic food score on a 0- to 32-point scale. Information was also collected on a variety of potentially confounding variables, including occupational status, monthly household income, physical activity, and smoking status. A total of 68,946 participants were included in the analysis. Participants had an average age of 44.2 years at baseline and 78% were female. At follow-up, 1340 individuals had cancer. The most common types were breast cancer (459 individuals), prostate cancer (180 individuals), skin cancer (135 individuals), colorectal cancer (99 individuals), non-Hodgkin lymphoma (47 individuals), and other lymphomas (15 individuals). After controlling for a variety of confounding variables, researchers found that high organic food scores were correlated to a reduced risk of cancer overall (P = .001), with an absolute reduction in risk of 0.6%. The study authors acknowledged in the article that although they accounted for a “wide range” of covariates, “the observed associations may have been influenced by residual confounding.”

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LATEST NEWS

Transplant May Be a Valid Treatment Option for Older Patients with Myeloma Certain older patients with multiple myeloma could benefit from undergoing autologous stem cell transplantation (ASCT), according to a recent study. These older patients had similar disease response and survival as younger patients undergoing the same type of transplant. In addition, older patients who underwent ASCT had superior survival compared with nontransplanted older patients, both for overall survival (59 months vs 30 months, respectively; P = .037) and event-free survival (45 months vs 27 months, respectively; P = .014). The retrospective study compared 132 patients with newly diagnosed myeloma (103 patients aged 65 years or younger; 29 patients older than 65 years) who underwent transplant with a group of 23 similar nontransplanted patients aged 65 years to 70 years. Conditioning was 200 mg/m2 melphalan for younger patients and half of the older patients; the other half of older patients had conditioning with 140 mg/m2 melphalan. Compared with patients aged younger than 65, older patients had no increased transplant-related myelotoxicity and nonhematopoietic toxicity. However, among the half of older patients conditioned with melphalan 200 mg/m2, there was a higher need for transfusional support and more days on intravenous antibiotics. In addition, preconditioning with 200 mg/m2 melphalan resulted in significantly increased mucositis (P = .028), increased need for transfusional support, and more days on IV antibiotics (P = .019) compared with older patients preconditioned with a lower dose of melphalan. According to the researchers, despite the higher rate of complications seen with 200 mg/m2 melphalan, the complications were “manageable” with current supportive standard of care. “Taking into account that optimal management of multiple

myeloma is vital for patient outcome, age should not be considered a major obstacle to transplantation,” the researchers wrote. “Eligibility should be based on biological fitness and comorbidities, ideally through geriatric assessment tools and comorbidity scores to avoid subjectivity, which was also an important limitation when analyzing our elderly patients.”

Efforts Made in the 1960s to Curb Smoking Will Have Effects Well Into Future Tobacco control efforts implemented in the mid-1960s should continue to reduce lung cancer rates and mortality until 2065, according to a study — published in Annals of Internal Medicine — that used comparative modeling to predict tobacco use.1 “Our analyses indicate that maintaining existing tobacco control efforts will result in considerable reductions in the lung cancer burden in the United States,” researchers wrote. The researchers developed 4 independent models of the natural history of lung cancer to project mortality rates for men and women from 1964 — when the Surgeon General’s Report on smoking and health was published — until the year 2065. The models used US data on smoking from 1964 to 2015 and on lung cancer mortality from 1969 to 2010. All of the models accurately predicted observed trends in lung cancer mortality that occurred from 1969 to 2010. Using status quo trend scenarios, the models projected continued decreases in lung cancer mortality rates from 2015 to 2065. Specifically, age-adjusted lung cancer mortality was projected to decrease by almost 80% from 2015 to 2065. Additionally, despite population growth and an aging population, the annual number of lung cancer deaths was projected to decrease by 63% from 135,000 per year to 50,000 per year. The researchers noted that despite these reductions in mortality, models projected about 4.4 million deaths due to lung cancer will still occur in the 50-year span from 2015 to 2065. The majority of these deaths will likely be in ever-smokers, showing a need for additional screening efforts. “We note that, although lung cancer screening is now being slowly adopted, changes to it could not only reduce lung cancer deaths but could also increase smoking cessation rates if support for quitting is combined with screening at the point of care,” the researchers wrote. ■

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“Further prospective studies using accurate exposure data are necessary to confirm these results and should integrate a large number of individuals,” the study authors wrote. “Although our findings need to be confirmed, promoting organic food consumption in the general population could be a promising preventive strategy against cancer.” Interestingly, the clinical trial identifier in the current study was linked to another prospective study that was published earlier this year, which demonstrated that a 10% increase in the proportion of ultra-processed foods in the diet was associated with a significant increase (of greater than 10%) in the risks of both overall cancer and breast cancer.

LATEST NEWS

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Bortezomib-Based Frontline Therapy Boosts Survival in Mantle Cell Lymphoma In transplant-ineligible patients with previously untreated mantle cell lymphoma, frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) showed better survival compared with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The results of LYM-3002, a randomized phase 3 clinical trial (ClinicalTrials.gov Identifier: NCT00722137), were reported in The Lancet Oncology. A total of 487 participants were enrolled in the LYM-3002 trial between 2008 and 2011 across 128 centers in 28 countries. Eligible participants had treatment-naive stage II to stage IV mantle cell lymphoma and were ineligible for bone marrow transplantation. Patients were randomized in a 1:1 fashion to receive either 6 or 8 cycles (cycles of 21 days each) of VR-CAP or R-CHOP. For the follow-up analysis, 268 participants were included (140 participants from the VR-CAP arm and 128 from the R-CHOP arm). At a median follow-up of 82 months, participants who received VR-CAP had a nearly 35-month longer median overall survival than those who received R-CHOP (90.7 months vs 55.7 months; hazard ration [HR] = 0.66; P = .001). In the VR-CAP arm, 42% of participants (103 of 243) had died by the time of analysis, whereas 57% (138 of 244) in the R-CHOP arm had died. As for safety, 3 new adverse events were seen. In the R-CHOP arm, 1 patient had grade 2 pneumonia. In the VR-CAP arm, 1 patient had grade 4 lung adenocarcinoma and 1 patient had grade 4 gastric cancer. “This follow-up study showed that replacement of vincristine with bortezomib in the R-CHOP regimen (ie, VR-CAP) significantly improved median overall survival in previously untreated patients with mantle cell lymphoma,” the study authors wrote. “Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma.” Disclosure: This study was funded by Janssen Research & Development. For a full list of disclosures, please refer to the original study.

Brentuximab Vedotin Combo Active in Older Patients With Hodgkin Lymphoma For older patients with Hodgkin lymphoma with previously untreated disease, the addition of brentuximab vedotin (Bv) before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) showed survival benefit and favorable safety in a phase II trial (ClinicalTrials.gov Identifier: NCT01476410). Trial results were published online September 4, 2018, in the Journal of Clinical Oncology.

A total of 48 participants with previously untreated Hodgkin lymphoma (stage II-IV) were enrolled between 2012 and 2016 in the single-arm, open-label trial. All participants were aged 60 years or older with a median age of 69. Participants received 2 lead-in doses of Bv (1.8 mg/kg once every 3 weeks) followed by 6 cycles of AVD chemotherapy and then 4 consolidation doses of Bv in responding patients. About half (52%) of participants completed all treatment cycles; 73% of participants received at least 1 Bv consolidation dose. For participants who completed all treatment cycles, the

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LATEST NEWS

median Cumulative Illness Rating Scale for Geriatrics was 4 points lower than for patients who did not (4 vs 8; P = .03). For the intent-to-treat population (48 participants), the 2-year event-free survival rate was 80% (95% CI, 65%-89%), the 2-year progression-free survival was 84% (95% CI, 69%-92%), and 2-year overall survival was 93% (95% CI, 80%-98%). In total, 20 of 48 patients (42%) reported a grade 3 or 4 adverse event, with the most common being neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%). One-third of participants had grade 2 peripheral neuropathy, which for most participants, was reversible. “Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes,” the study authors wrote.

Despite a focus on a modified Fc region, phase 1 trials showed that the immune-related events associated with administration of tislelizumab were “consistent with previous reports of other PD-1 antibodies for the treatment of cHL.” The data from this study will be combined with additional follow-up data and included in BeiGene’s biologics license application with the China Food and Drug Administration later this year. Final results will be presented at an upcoming medical conference.

Preliminary Topline Results for Tislelizumab in Classical Hodgkin Lymphoma

The US Food and Drug Administration (FDA) approved mogamulizumab-kpkc (Poteligeo) intravenous (IV) injection for the treatment of adult patients with relapsed/refractory (R/R) mycosis fungoides (MF) or Sézary syndrome (SS) previously treated with at least 1 systemic therapy, according to a news release. Approval for mogamulizumab — a humanized monoclonal antibody that targets CC chemokine receptor type 4 (CCR4) — provides a new treatment option for patients with MF and marks the first FDA-approved therapy for SS. MF and SS are difficult-to-treat subtypes of cutaneous T-cell lymphoma (CTCL), a class of non-Hodgkin lymphoma that affects the skin. The FDA based its approval on data of the MAVORIC phase 3 (ClinicalTrials.gov Identifier: NCT01728805), in which researchers randomly assigned 372 patients with MF or SS to IV mogamulizumab 1 mg/kg weekly for 4 weeks then every other week thereafter or oral vorinostat 400 mg daily. Results showed that patients in the mogamulizumab arm had a progression-free survival (PFS) of 7.6 months (95% CI, 5.6-10.2) vs 3.1 months (95% CI, 2.8-4.0) in the vorinostat arm (hazard ratio [HR], 0.53; 95% CI, 0.41-0.69; P < .001). The overall response rate was 28% and 5% for the mogamulizumab and vorinostat arms, respectively (P < .001). The most frequently reported adverse events associated with mogamulizumab were diarrhea, fatigue, infusion-related reactions, musculoskeletal pain, rash, and upper respiratory tract infection. Serious treatment warnings included the risk of autoimmune problems, dermatologic toxicity, infusion reactions, and stem cell transplant complications. ■

Positive topline results from a pivotal phase 2 trial of tislelizumab (an antibody-based PD-1 inhibitor) that included patients with relapsed/refractory classical Hodgkin lymphoma (cHL) were recently released by BeiGene, in collaboration with Celgene. Tislelizumab was tested in a single-arm trial of 70 Chinese patients with relapsed/refractory cHL who had either failed or were ineligible for autologous stem cell transplantation. The overall response rate was 73%, with a 50% complete response, and the median duration of response had not been reached by study completion. The antibody is also being examined as a treatment for “nonsmall cell lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma; as well as [in] two global phase 2 trials in patients with previously treated hepatocellular carcinoma or with R/R mature T-and NK-cell lymphomas, and an additional pivotal phase 2 trial in China in urothelial cancer.” Though there are numerous checkpoint inhibitors already on the market, with many others also in developmental phases, BeiGene noted in a release that tislelizumab is different in that it has an Fc region engineered specifically to “minimize potentially negative interactions with other immune cells, based on preclinical data.” The Fc region of an antibody has an intracellular domain that may mediate some signaling to a variety of other immune cells. The signaling of these other types of cells is what is responsible for various immune responses — such as release of inflammation mediators, B-cell activation, endocytosis, phagocytosis, and cytotoxic attack — that patients may experience as adverse effects.

FDA Approves Mogamulizumab-kpkc for Rare Subtypes of Non-Hodgkin Lymphoma

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VIEWPOINT

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Liquid Biopsy May Predict Response to Therapy in DLBCL CHRISTINA BENNETT, MS

Circulating tumor DNA levels measured as early as 3 weeks post-therapy may provide clues about long-term outcomes in this lymphoma subtype.

irculating tumor DNA (ctDNA) levels before and during treatment can predict how a patient with diffuse large B-cell lymphoma (DLBCL) responds to standard therapy, according to a study recently published in the Journal of Clinical Oncology.1 The study suggests that long-term outcomes can be predicted as early as 3 weeks after the initiation of drug therapy. “In diffuse large B-cell lymphoma, we don’t have a great way of being able to tell if someone isn’t going to do as well after they’ve received treatment,” Sarah Rutherford, MD, oncologist at Weill Cornell Medicine and New YorkPresbyterian Hospital in New York, New York, told Cancer Therapy Advisor; she was not involved in the study. About one-third of patients with DLBCL do not respond to currently available treatments. “This research is striking because it [shows] a new method of trying to figure out and differentiate between which patients will do well with the frontline therapy versus which won’t do as well.” To conduct the study, researchers measured ctDNA levels in blood samples from 217 participants with DLBCL. The participants were from 6 academic cancer centers; 3 in the United States and 3 in Europe. The patients were retrospectively recruited from studies done at these centers between 1999 and 2016. Patient blood samples had been taken during that time period, but were later centrally analyzed at Stanford University in California. For the purpose of analysis,

participants were split into validation set 1 (144 patients) and validation set 2 (73 patients). Most participants had received treatment in the frontline setting; only 36 patients (25%) in set 1 had received salvage treatment. Before therapy, 98% of participants had detectable ctDNA levels. A threshold of 2.5 log hGE/mL of ctDNA was established to categorize pretreatment ctDNA levels as high or low. In validation set 1, participants with high pretreatment ctDNA levels were associated with worse event-free survival (EFS) at 24 months compared with patients with low levels (P < .001). Pretreatment ctDNA levels, however, did not show a statistically significant association with overall response rate (P = .07). As a result, researchers explored ctDNA dynamics, and were able to identify 2 thresholds that were predictive of response during therapy. The first was a 2-log drop in ctDNA by the start of cycle 2 of therapy, defined as early molecular response (EMR). The second was a 2.5-log drop in ctDNA by the start of cycle 3 of therapy, defined as major molecular response (MMR). Researchers found that patients who responded to treatment had a larger decline in ctDNA after 1 cycle of therapy (or 3 weeks) than patients who did not respond. The correlation was independent of line or type of therapy. Patients who achieved EMR or MMR had better EFS than patients who did not, a trend seen in both validation sets. However, EMR and MMR were associated with overall survival only in validation set 1. Continued on page 27

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FEATURE

Novel Approaches for the Treatment of PCNSL

ALEXANDER M. CASTELLINO, PhD

rimary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma with an annual estimated incidence of 0.48 per 100,000Â person-years.1 It accounts for approximately 3% of all CNS tumors and develops within the brain, spinal cord, eye, or leptomeninges.2 According to the National Comprehensive Cancer Network, systemic therapy with high-dose methotrexate is the most effective agent to treat primary brain lymphoma, and it is commonly used in combination with drugs such as vincristine, procarbazine, cytarabine, rituximab, or ifosfamide.2 Induction chemotherapy is typically followed by consolidation whole-brain radiation therapy to maximize response

ÂŠ PONGMOJI / GETTY IMAGES

Approaches being investigated are based on the mutational landscape and signaling pathways that are extant in the disease. and improve outcomes.2 Treatment options that include nonmyeloablative chemotherapy and high-dose chemotherapy along with stem cell transplantation are based on center expertise and patient eligibility.3 Currently, no targeted or immunotherapeutic agents are approved for the treatment of PCNSL. A review published in Blood highlights new approaches that are being investigated to treat PCNSL based on the mutational landscape and signaling pathways that are extant in the disease.3 Bruton Tyrosine Kinase Inhibition in PCNSL Targeting Bruton tyrosine kinase (BTK) with ibrutinib is supported by insights into its biology, especially regarding B-cell receptor signaling dependency, the authors reasoned. They observed that most studies with this drug were not

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comparative, with meaningful responses for lymphoma regression observed in 50% of patients and overall response rates of 77% observed in patients with relapsed/refractory (r/r) PCNSL. The review summarized findings from the French LYSARC group, which conducted a multicenter, single-arm study in 52 patients with r/r PCNSL. An interim analysis reported complete responses (CR) in 10 (19%) patients and partial responses (PR) in 16 (31%) patients. In this study, 32 of 52 patients (62%) stopped treatment, mainly due to disease progression. In addition to the known toxicities of ibrutinib, two cases of pulmonary Aspergillus infection (one being fatal) were also reported.3 Another study highlighted was a nonrandomized, single center, dose-escalation study of single-agent ibrutinib in r/r PCNSL (13 patients) and secondary

FEATURE CNS lymphoma (7 patients). In the PCNSL cohort, the objective response rate was 77% (CR: 5; PR: 5). The study reported a median progression-free survival (PFS) of 4.6 months and a median overall survival (OS) of 15 months.5 The review noted that responses seen in PCNSL with ibrutinib were higher than those seen outside the CNS in r/r diffuse large B-cell lymphomas. But the nondurable remissions and the incidence of Aspergillus infection with ibrutinib in PCNSL require further investigation.3 Noting that a protocol that combined ibrutinib with immune poly-chemotherapy called DA-TEDDI-R (temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab, and intrathecal cytarabine) was associated with a high 17% treatment-related mortality in a relatively young cohort of patients, it was suggested that investigating combinations of ibrutinib should be restricted to chemotherapy agents that have shown efficacy and safety in this setting.6 mTOR and PI3K Inhibition Molecules targeting the phosphoinositide 3-kinase (PI3K)-related kinase family, which regulate cell growth and proliferation, have also been studied in the r/r PCNSL setting. One such molecule is temsirolimus, which inhibits the mammalian target of rapamycin (mTOR). Based on preclinical evidence and activity seen in small single-arm studies, the review highlights data with temsirolimus in r/r PCNSL. Temsirolimus was studied in 37 patients who were given a weekly dose of 25 mg or 75 mg. An overall response rate of 54% was reported, with 8 patients showing complete or unconfirmed CR and 12 patients achieving PR. Median PFS was 2.1 months and median OS was 3.7 months. Adverse events included hyperglycemia, bone marrow suppression,

infections, and fatigue. Treatment-related mortality was 13.5%.7 Although close to half of the patients achieved remission, median PFS was short and treatment-associated toxicities were substantial, the review noted.3

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with novel agents are far from being considered precision medicine for PCNSL,” they noted. In addition, they suggested that trials be designed to test: • New combination and sequences;

Similar to diffuse large B-cell lymphoma, monotherapy with novel agents is unlikely to provide a cure for patients with PCNSL. Another molecule, buparlisib, a panPI3K inhibitor, was reported to show suboptimal results in 4 patients enrolled in a phase 2 study of r/r PCNSL.8 Immunomodulating Agents Immunomodulating agents such as lenalidomide have been approved to treat several hematologic malignancies. The French REVRI study investigated the combination of lenalidomide and rituximab in patients with r/r PCNSL. This single-arm trial enrolled 50 patients, including those with ocular lymphoma. Patients achieving at least a PR with lenalidomide/rituximab induction received lenalidomide as maintenance therapy. With a median follow up of 9 months, median PFS was 8.1 months and median OS was 15.3 months.9 The reviewers noted that, although associated with a response rate of 63% in r/r PCNSL, durable remissions were limited with the combination in this prospective study.3

• The possibility of a chemotherapy-free option in induction and maintenance for achieving long-term remission; and • Efficacy in specific patient populations (eg, early- vs late-relapse patients); • An approach based on chimeric antigen receptors. “Patients with r/r PCNSL and those not tolerating aggressive chemotherapy urgently require new approaches to improve their still-dismal prognosis,” the reviewers concluded.”3 ■ References

1. Olson JE et al. Cancer. 2002;95(7):1504-1510. 2. NCCN Clinical Practice Guidelines. Central nervous system cancers. Version 1.2018. http://nccn.org. Updated March 20, 2018. Accessed July 18, 2018. 3. Illerhaus G et al. Blood. doi: 10.1182/blood2018-01-791558 4. Choquet S et al. Blood. 2016;128(22):784. 5. Grommes C et al. Cancer Discov. 2017; 7(9):1018-1029. 6. Lionakis MS et al. Cancer Cell. 2017; 31(6):833-843.e5.

Suggestions for the Future The reviewers argued that similar to diffuse large B-cell lymphoma, monotherapy with novel agents is not likely to provide a potential cure for patients with PCNSL. “Current treatment strategies

7. Korfel A et al. J Clin Oncol. 2016; 34(15):1757-1763. 8. Grommes C et al. Ann Oncol. 2016;27 (suppl_6):103-113. 9. Ghesquieres H et al. Blood. 2016;128(22): 785 LP-785.

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FOCUS LYMPHOMA

VIEWPOINT

Next-Gen ADCs: An Option for NonHodgkin Lymphoma and Myeloma? BRYANT FURLOW

The Leukemia & Lymphoma Society partnered with Sutro Biopharma to test the safety of the investigational CD74-targeting antibody-drug conjugate STRO-001 for 2 blood cancers.

he Leukemia & Lymphoma Society (LLS) and Sutro Biopharma have partnered for a phase 1 clinical study of the firm’s firstin-class, CD74-targeting antibody-drug conjugates (ADC) STRO-001 against refractory and/or relapsed non-Hodgkin lymphoma and multiple myeloma. CD74 is highly expressed on the surface of malignant B cells. Were it to prove safe and effective, STRO-001 could represent a much-needed treatment for patients whose current options are limited. ADCs use engineered antibodies to target cancer cell surface proteins for delivery of a chemotherapy warhead, maximizing doses delivered to tumors while sparing surrounding tissues. Each ADC molecule contains a monoclonal antibody, a cytotoxic payload, and a covalent linker attaching these units.1,2 Early ADC development was challenging, beset by imprecise antibody-drug conjugation, unreliable targeting, off-target effects, and disappointing outcomes during clinical testing.1,2 Gemtuzumab ozogamicin, a CD33directed ADC, was approved for treating acute myeloid leukemia (AML) until 2010, when it was voluntarily taken off the market following clinical trial evidence of increased patient mortality and the determination that there was no benefit from treatment with the drug compared with conventional therapies. In 2017, the product returned to the market with a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population.

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The CD30-targeting ADC brentuximab vedotin is a treatment for relapsed or refractory Hodgkin lymphoma, systemic anaplastic large cell lymphoma, relapsed primary cutaneous anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides. The CD22-targeting ADC inotuzumab ozogamicin is used in the management of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). “First-generation ADCs are limited by the fact that they are structurally heterogeneous populations in which the position and number of conjugated linkers and warheads vary significantly,” noted Lee Greenberger, PhD, chief scientific officer at the LLS. But Dr Greenberger believes next-generation ADCs like STRO-001 are more attractive candidate treatments because of technological advances that make site-specific conjugation techniques less heterogeneous. “CD74 is a protein highly expressed in B-cell malignancies such as multiple myeloma and lymphoma,” Dr Greenberger said. “STRO-001 consists of a single predominant conjugated species with a drug-antibody ratio of 2.” Sutro’s cell-free XpressCF™ and XpressCF+™ conjugation platforms separate protein-generating cellular components into an extract that contains “all the necessary biochemical components for energy production, transcription and translation, and can be used to support cell-free biochemical protein synthesis by the addition of the specific DNA sequence for the desired protein,” Dr Greenberger explained.

VIEWPOINT STRO-001 has the potential to help patients with diverse blood cancers, Dr Greenberger noted. It is the first ADC for which the LLS has offered funding through its Therapy Acceleration Program (TAP). The company’s preclinical cell line and xenograft research suggested that STRO001 is highly specific to CD74 and confirmed the high expression levels of CD74 on myeloma and lymphoma tumor cells.

Hope Comprehensive Cancer Center in Duarte, California; the Medical College of Wisconsin in Milwaukee; Texas Oncology in Austin; the Rocky Mountain Cancer Centers in Aurora, Colorado; and at Virginia Cancer Specialists in Fairfax. The hope is that next-generation ADCs will limit off-tumor-target activity and its resulting side effects. STRO-001 is just one of many ADCs

STRO-001 is the first antibody-drug conjugate for which the LLS has offered funding through its Therapy Acceleration Program.

FOCUS LYMPHOMA

The LLS has invested $150 million in its TAP since it was started in 2007 to hasten the development of promising treatments, Dr Greenberger said. The program has been highly effective in accelerating new blood cancer therapies to patients, including CD19-targeting chimeric antigen receptor T-cell (CART) immunotherapy for several types of large B-cell lymphomas (YescartaTM) and a liposomal formulation of cytotoxic drugs for AML (VyxeosTM), both approved by the US Food and Drug Administration in 2017. STRO-001 is the first ADC in LLS’s TAP portfolio. ■ References

1. Corraliza-Gorjón I, Somovilla-Crespo B, Santamaria S, Garcia-Sanz JA, Kremer L. New strategies using antibody combinations

The clinical trial team started enrolling patients with multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma in the phase 1 safety and tolerability study in April 2018, at the City of

under development for the treatment of B-cell malignancies. Dozens of other phase 1 and phase 2 clinical trials are underway, testing ADC monotherapies and combination regimens of ADCs plus immune checkpoint inhibitors.2

Liquid Biopsy Viewpoint

response and PET/CT scan had further improved outcomes. “Both ctDNA and [PET/CT] scans have some information, but when you put them together, you get to be a little bit smarter [than if you were] using each one in isolation,” concluded Dr Alizadeh. Studies are currently underway to determine whether ctDNA is also prognostic for patients receiving chimeric antigen receptor T-cell therapy, such as tisagenlecleucel, which gained US Food and Drug Administration approval for relapsed/ refractory DLBCL in May 2018. The researchers of the current study are also planning a clinical trial to evaluate the clinical utility of the study results, but exactly what questions the trial will be designed to answer has not yet been

Continued from page 15

The ctDNA dynamics after treatment initiation were “much more predictive” than pretreatment ctDNA levels, co-senior author Ash Alizadeh, MD, PhD, associate professor of medicine at Stanford University, told Cancer Therapy Advisor. A multivariate analysis showed that ctDNA dynamics were independent of other prognostic factors, including International Prognostic Index and interim positron emission tomography/computed tomography (PET/CT) scan. Also, when ctDNA dynamics were combined with interim PET/CT scans, prognostic ability strengthened: Patients who achieved a promising molecular

to increase cancer treatment effectiveness.

Front Immunol. 2017;8:1804. 2. Herrera AF, Molina A. Investigational antibody–drug conjugates for treatment of B-lineage malignancies. Clin Lymphoma

Myeloma Leuk. 2018;18(7):452-468.

determined. “As with any clinical study that involves many centers, there are lots of opinions about how that should shake out,” said Dr Alizadeh. “We’re trying to work through that right now.” ■ Disclosures: Dr Alizadeh disclosed financial relationships with CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/ Genentech, and Gilead Sciences. He also reported patent filings on ctDNA detection assigned to Stanford University. Reference

1. Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma [published online August 20, 2018]. J Clin

Oncol. doi: 10.1200/JCO. 2018.78.5246

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EXPERT PERSPECTIVE

Identifying Gene Variants Involved in Radiotherapy Toxicity Risk Genomics could inform whether a patient should undergo implant reconstruction or autologous tissue-based reconstruction. BRYANT FURLOW

Benjamin Smith, MD Title Associate Professor

Affiliation University of Texas MD Anderson Cancer Center

Expertise Breast Cancer Radiation Treatment

dentifying gene variants that modulate the risk of cancer toxicities due to radiotherapy would help to better stratify risk and tailor treatment plans to individual patients. Associate Professor Benjamin Smith, MD, and colleagues at the University of Texas MD Anderson Cancer Center in Houston, Texas, published findings in JAMA Oncology from the first prospective validation of a radiotherapy toxicity biomarker, the C-509T variant allele, which is found in the promoter region of the transforming growth factor gene TGFB1.1 Cancer Therapy Advisor asked Dr Smith about the findings and their implications for clinical practice. CANCER THERAPY ADVISOR (CTA): The field of radiosensitivity

and radiotoxicity genomics, or ‘radiogenomics’, has been growing. Why did radiation oncologists begin to suspect a strong genetic basis for radiation toxicities? DR SMITH: Generally, if you have 2

patients with the same tumor type, body type, and radiation plan, 1 might come in to follow-up appointments and you can’t even tell they’ve undergone radiation — while the other will have a lot of side effects. That led people to ask what’s driving those differences.

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At a fundamental level, we know radiotherapy can treat cancer only because normal, healthy cells have this amazing machinery handed down from bacterial ancestors to repair the damage caused by radiation. This machinery stems from the need for bacteria to repair damage caused not only by ionizing radiation but also, more generally, by oxidative stress in the environment. Because radiation works by causing oxidative stress, these pathways prove to be very effective in promoting repair of radiation damage in normal cells. However, given underlying genetic diversity, it is certainly biologically plausible that cells, and, accordingly, people, would manifest variation in the ability to heal from radiation damage, and that this variation would have a genetic component. CTA: Why did your team decide to validate this gene variant, C-509T, in particular? DR SMITH: We decided in 2010, as we put together a grant, to incorporate a translational end point. The literature at that time wasn’t terribly illuminating, but some research had suggested that this variant in the promotor region for the TGF beta-1 gene might affect radiation toxicity risk. The underlying mechanism was thought to be that patients with this variant secrete higher levels of TGF-beta, which has long been thought to be one of the cytokines,

EXPERT PERSPECTIVE or signaling molecules, that promote fibroblasts to lay down collagen. So, it was reasonable to hypothesize these patients might experience more fibrosis after radiotherapy. CTA: You found that 3 years after

treatment, approximately 14% of C-509T–positive women experienced post-radiation breast fibrosis, compared with 4% C-509T–negative women. What else did you find? DR SMITH: We’d previously concluded from the study that a shorter, hypofractionated 4-week course of whole-breast radiation is not inferior to a 6-week regimen. [In this analysis, we] also found that 3-year fibrosis was predicted by this allele and also by [a] poor postoperative cosmetic outcome. I had not anticipated that. CTA: Why do you think poor healing was associated with fibrosis? DR SMITH: If your breast does not heal well after surgery, that could indicate that you won’t heal well from radiation either. It might also be the case that a breast that healed poorly from surgery does not respond well to radiotherapy. One hit from surgery and a second hit from radiotherapy, yielding more scarring. In an exploratory analysis, we also found a trend that patients with this variant allele were reporting more shoulder stiffness 3 years after radiation. That’s pretty interesting because we usually tell our patients that with whole-breast radiation alone, we don’t anticipate much shoulder stiffness. But there was this small group of patients who did experience it, and that was associated with this allele. I posit that they have more scarring, which can occur in the pectoralis muscle.

CTA: What variables did your team include in the multivariate analysis, to correct for potentially confounding factors? DR SMITH: We included everything we could easily measure as candidate covariables: age, race, surgery type, chemotherapy history, tumor stage, tumor ER/PR/HER2 status. But only 2 variables were significant in the multivariate analysis: adverse postoperative cosmetic outcome and the C-509T allele. We forced study arm [hypofractionated or conventionally-fractionated radiotherapy] into the model but it was not significant and did not interact with the allele. CTA: So, C-509T status did not predict a woman’s response to the different radiotherapy regimens. That being the case, what are the clinical implications of your findings? How might C-509T status inform clinical decision-making? DR SMITH: I think the most immediate implication is determining which patients we can safely receive a tumor-bed radiation boost without increasing the risk of

very likely to experience fibrosis (4% in our study). I think it’s reasonable to take it a step further and say, we know the boost is the key reason patients experience fibrosis in the first place, so if you have that allele and get the boost, that will increase your risk substantially. So, you have to weigh a very small 1% to 3% 10-year incremental benefit in tumor control versus a potentially meaningful increase in the risk of fibrosis, specifically in the patients with the variant allele. I think that information could be very helpful in counseling patients and helping to make more personalized decisions about who should receive a boost and who should not. It would be plausible, in my mind, to omit a boost in a patient with the variant allele and a biologically favorable tumor. Such a decision would have a negligible negative impact on tumor control and a significant positive impact on toxicity by lowering risk of fibrosis. The hypothesis that I am interested in studying, however, as an implication of our finding, is focused on a different clinical question. That clinical question centers around the best way to offer breast reconstruction for a patient who requires mastectomy and radiation therapy.

“It is well known that a radiation boost can yield a significant increase in the risk of fibrosis and an adverse cosmetic outcome.” fibrosis. It is well known that a radiation boost can yield a significant increase in the risk of fibrosis and an adverse cosmetic outcome. In our trial, every patient received a boost. I think it’s reasonable to conclude that if you do not have this variant allele and you do receive a boost, you’re not

Based on this finding, we would hypothesize that patients with the variant allele are at higher risk of fibrosis of the reconstructed breast and that these patients might require different approaches to breast reconstruction than patients without the variant allele. Continued on page 36

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FEATURE

Societies Weigh In on Medicare Advantage Step Therapy

BRYANT FURLOW

he American Medical Association (AMA), American Society of Clinical Oncology (ASCO), American Society for Radiation Oncology (ASTRO), the American Society of Hematology (ASH), and 90 other medical societies cosigned a letter on September 7, 2018, calling on the US Centers for Medicare & Medicaid Services (CMS) to reconsider its decision to allow Medicare Advantage plans to use “step therapy” or “fail first” cost-control programs for Part B drugs.1 Step therapy allows insurers to require physicians to prescribe less expensive medications as a first step; the patient is required to try certain medications before progressing to more expensive treatments.

More than 90 medical societies have called on the US government to reverse a policy allowing step therapy under Medicare Advantage. Participating plans will not be required to submit their step-therapy criteria for affected Part B drugs to CMS and can require off-label use of drugs before allowing access to on-label, FDA-approved treatments when off-label indications are “supported by widely used treatment guidelines or clinical literature that CMS considers to represent best practices,” according a CMS document.2 Describing the policy change as part of President Trump’s efforts to negotiate better prices and foster competition in the drug marketplace, CMS announced the change “empowers patients with more choices when picking a Medicare Advantage plan.”3 In their letter, the medical societies expressed concern about the use of step therapy to guide treatment decisions, stating that it could endanger patients

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undergoing treatment for cancer and other life-threatening diseases. “While step-therapy protocols are problematic for many patients on a variety of therapies, they are particularly concerning where physician-administered drugs are concerned,” the letter states. “In many cases, patients receiving drugs covered under Part B are especially vulnerable, many with serious or life-threatening conditions. Many cancer therapies, for example, are covered under Part B. For cancer patients, selecting the proper personalized treatment as quickly as possible can be critical to survival.” The new policy would take effect in January 2019. The medical societies asked CMS to abandon the change and stick with a 2012 policy that stops Medicare Advantage plans from using step therapy.

FEATURE Details are scarce, and it is not yet clear exactly how the policy will be implemented — or what the implications will be for oncology formularies. Just before the policy was announced, Department of Health and Human Services Secretary Alex Azar, who oversees CMS, met with ASCO officials and others. He acknowledged that there exists limited drug interchangeability in oncology and said he did not expect to see step therapy be a significant issue for patients with cancer, according to ASCO Vice President of Clinical Affairs Stephen Grubbs, MD, FASCO. “We’ve had that discussion and he said in no way does he want these policy changes to affect or delay treatment for patients with cancer,” Dr Grubbs said of his conversation with Azar. “He asked that if we find the policy delays therapy, we [should] report that immediately to him personally.” Particularly with increasingly rapid cancer drug approvals, it will be important to carefully monitor step-therapy restrictions, and to make sure appeals processes are quick, Dr Grubbs said. “The physician’s responsibility is to always pick the right drug for the right patient at the right time,” Dr Grubbs said. “In-class drug difference nuances can make one drug more appropriate for a given patient. […] Appeals have to be done in a timely fashion.” Even if those goals are achieved, the policy will add “one more layer of administrative burden,” Dr Grubbs asserted. “Our [ASCO] membership polling shows that the number 1 issue right now is the work [physicians] do for preauthorization.” “There’s no question that we have to reign in the costs of drugs. Nobody’s going to argue against that,” said Ramaswamy Govindan, MD, professor of oncology at the Washington University School of Medicine in St. Louis, Missouri. “But we have to do that

while making the best available treatments available to our patients, without physicians picking drugs based on cost. Efficacy and toxicity should always be the physicians’ primary criteria.” “Efficacy is foremost,” he said. “We don’t want to offer cheaper therapies that are cost-effective but not as effective for cancer patients.” In theory, Dr Govindan said, if efficacy and toxicity are truly equivalent for 2 anticancer drugs, there is no reason to object to a less costly therapy being tried first. “But in reality, I cannot think of many examples,” he added. Step therapy is “ill-advised” and would delay care by requiring additional steps of approval and restricted access to the newest drugs, noted oncologist Lucio Gordan, MD, of the Florida Cancer Specialists & Research Institute in Gainesville, Florida. Outcomes and disease control could be “gravely worsened” by step therapy, he said. It could even lead to avoidable toxicities, Dr Gordan speculated. Ironically,

treatment predictability, said Fred Schnell, MD, FACP, medical director of the Community Oncology Alliance in Washington, DC. “That’s the intent,” Dr Schnell said. “But the thing that really bothers me about step therapy in cancer is that if it’s a critical decision point at the front end of a patient’s care, and not fifth-line therapy for advanced colon cancer, the choices really can be life-or-death choices. A bad choice can lead to bad outcomes that are not reversible. This isn’t hypertension or diabetes — cancer’s not like that. Patients may never recover from a bad choice.” Oncology has dealt with step therapy for quite some time on the private insurance side, Dr Schnell noted. “It’s been a roller-coaster,” he said. “Some companies make it quite onerous and others focus on a few disease sites. None of the oncologists like it because the people making decisions on the payer side are, for the most part, not oncologists.” Because of their costs, tyrosine kinase inhibitors (TKIs) will “definitely be in the mix” as Medicare Advantage

It is not yet clear exactly how the policy will be implemented — or what the implications will be for oncology formularies. that could increase costs if patients are treated in emergency departments or hospitals to manage those adverse effects. The new policy would require Medicare Advantage plans to offer a formulary-exception appeals process for patients but that would add a “convoluted review” by middlemen who are less familiar with cancer treatment than the patient’s team, Dr Gordan said. The utilization management approach is an attempt to cut costs and improve

plans adopt step-therapy restrictions, Dr Schnell predicted. “Myeloma will be a big target, too, because of the extreme cost of some therapeutics,” he said. Insurers who have adopted step-therapy restrictions for private health insurance plans have focused on myeloma and common, high-volume cancers like breast, colon, lung, and prostate cancer, he added. Biosimilars and supportive care drugs will also likely be affected, Dr Schnell

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FEATURE said. “Supportive antiemesis [drugs] and growth factors are expensive,” he noted. “Step therapy also ties up a lot of staff time to launch appeals and overcome objections,” Dr Schnell said. “That causes delays — it creates roadblocks for implementing care. Decisions can take forever, particularly if you appeal. It’s unclear who will field these appeals or what the timelines will be. Days trickle into weeks. That happens. Weeks trickle into months. And the patient is stuck in the middle.” For the moment, CMS is “offering suggestions rather than rules” about appeals, allowing Medicare Advantage

15 through December 7 — every year it could be difficult or impossible for patients to switch plans when the medication they need is subject to step-therapy restrictions, Donovan and others noted. The CMS policy proposal could add to already “very significant” pressures for community oncology practices, Dr Gordan cautioned, hastening a trend of shuttered practices and shifts to cancer care at more expensive health systems. The policy represents “cookbook medicine,” according to Ted Okon, executive director of the Community Oncology Alliance. “Step therapy isn’t new — it’s used on the commercial side and it’s

apply to Medicare Advantage programs, Donovan confirmed. “This is a new chapter in Medicare Advantage,” said Dr Grubbs. “It’s something we’ll have to watch very carefully.” ■ References

1. Centers for Medicare & Medicaid Services. Re: Memo of August 7th regarding prior authorization and step therapy for Part B drugs in Medicare Advantage. https://searchlf.ama-assn.org/undefined/documentDownload?uri=%2Funstructured%2Fbinary%2Fletter%2FLET TERS%2F2018-9-10-Signed-on-Letter-to-Verma-re-Step-Therapy.pdf. Updated September 7, 2018. Accessed September 11, 2018. 2. Centers for Medicare & Medicaid Services. CY 2019 Step Therapy Qs & As. https://dpap.

“A bad choice can lead to bad outcomes that are not reversible [...] Patients may never recover from a bad choice.”

lmi.org/DPAPMailbox/Documents/Part%20 B%20Step%20Therapy%20Questions%20 FAQs_8-29-18.pdf. Updated August 29, 2018. Accessed September 11, 2018. 3. Centers for Medicare & Medicaid Services. CMS empowers patients with more choices and takes action to lower drug prices. https://

plan insurers to self-regulate, said Caitlin Donovan of the National Patient Advocate Foundation, in Washington, DC. Without government oversight, plan transparency and the speed of appeals could become a problem, she warned. Because the Medicare Advantage enrollment period is yearly from October

caused horror stories. It’s not just branded drug vs generic and use the generic first. It puts the insurer in the position of middleman, telling physicians what they have to try first.” Several states have passed laws that limit step therapy for privately insured cancer patients.4 But no such protections

Expert Perspective

be safely treated with implant reconstruction — for example, those patients who do not have the variant alleles — and patients who may do better with autologous reconstruction, for example, those with the variant allele. We don’t know that for sure. It’s a hypothesis I’m very interested in evaluating, in light of our data. We’re working with our lab at MD Anderson to develop a CLIA [Clinical Laboratory Improvement

Continued from page 29

This really comes into play in making a decision about whether or not a patient should undergo implant reconstruction or autologous tissue-based reconstruction. Implant reconstruction with radiation typically caries a much higher risk of fibrosis than autologous reconstruction. I wonder if this allele could be used as a biomarker to select which patients may

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www.cms.gov/newsroom/press-releases/ cms-empowers-patients-more-choices-andtakes-action-lower-drug-prices. Updated August 7, 2018. Accessed September 11, 2018. 4. The National Psoriasis Foundation. Step therapy legislation by state. http://www.steptherapy.com/step-therapy-legislation-by-state/. Accessed September 11, 2018.

Amendments]-certified test for this polymorphism, which would allow us to request it for any of our patients, making it easier to do future research. ■ Reference

1. Grossberg AJ, Lei X, Xu T, et al. Association of transforming growth factorβpolymorphism C-509T with radiation-induced fibrosis among patients with early-stage breast cancer: a secondary analysis of a randomized clinical trial [published online July 19, 2018]. JAMA Oncol.

IN THE CLINIC

Bowel Preparation for Colorectal Cancer Screening: Improving Outcomes Stool burden can be challenging and make lesions that are potentially cancerous easier to miss.

olonoscopy is one of the primary screening modalities for colorectal cancer (CRC). During this procedure, the colonic mucosa can be directly visualized, and precancerous lesions such as tubular adenomas can be removed. Although colonoscopy is not considered a surgical procedure, it is still somewhat invasive and requires a bowel preparation in order to allow for complete visualization of the mucosa and identification of polyps. The bowel preparation is considered by patients as one of the most challenging components of the colonoscopy. Therefore, attention to detail with respect to the bowel preparation is crucial to improving adequate CRC screening. Close to 25% of bowel preparations are considered inadequate during colonoscopy.1,2,3 An “inadequate” prep had previously been documented using a more subjective, operator-dependent evaluation of the bowel, including terms such as “fair” and “poor”. This can lead to significant variability when interpreting colonoscopy results. In general terms, an inadequate prep may be defined by the presence of excess solid or semi-solid stool that could not be completely irrigated and suctioned, therefore, certain lesions such as polyps or cancers may have been missed. This

type of stool burden can be particularly challenging, potentially making lesions easier to miss. To remove some of the subjectivity associated with the nomenclature of bowel preparation, some standardized measures of evaluation utilize more objective scales. These scales include the Aronchick Bowel Preparation Scale, Ottawa Bowel Preparation Scale, and Boston Bowel Preparation Scale (BBPS).4 For example, the BBPS uses a scoring system of between 0 and 3 to evaluate the 3 parts of the colon: right, transverse, and left.5 Each part of the colon receives a numerical value and then these values are combined

C. ANDREW KISTLER, MD, PharmD

for a final score. A score of 6 or higher was considered adequate, while scores of less than 6 where deemed inadequate. The BBPS has been validated in clinical trials; a higher score generally leads to better polyp detection rates.5 Therefore, when reviewing a patient’s CRC screening and colonoscopy history, it is important to evaluate how the prep was described and if it was defined using an objective system. Inadequate bowel preparation can lead to an increased risk of adverse events in the patient, as well as decreased rates of detection for adenoma.6 A previously inadequate bowel preparation is the most important risk factor for an inadequate preparation in the future, so this is a key question to ask patients. Additional risk factors include patients of the male sex, a history of opioid use, a history of constipation, the presence of certain medical conditions (diabetes mellitus, cirrhosis, obesity, Parkinson disease), and poor health literacy.7 There are 2 primary protocols for the administration of a bowel preparation: single dose and split dose. In the single-dose prep, the patient takes the

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IN THE CLINIC entire volume (typically 2 to 4 liters) either the night before the procedure or the day of the procedure (for colonoscopies occurring in the afternoon). In the split-dose prep, half of the prep is given the evening before the procedure, followed by the second half given approximately 5 hours before the procedure. It is important to complete the second half of the prep no later than 2 hours before the procedure to avoid potential delays in receiving anesthesia.4

44.1% to 49.5% (P < .001), increased the adenoma detection rate from 26.7% to 31.8% (P < .001) and increased the observed percentage of patients with at least 1 adenoma that was 10 mm or greater from 6.7% to 8.2% (P = .04). There are several potential strategies to implement if a patient has had an inadequate prep previously or is at increased risk of inadequate prep. As mentioned previously, split-dosing regimens have better outcomes. At-risk

on detection of suspected colonic neoplasia.

Gastrointest Endosc. 2003;58(1):76-79. 2. Froehlich F, Wietlisbach V, Gonvers JJ, Burnand B, Vader JP. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European panel of appropriateness of gastrointestinal endoscopy European multicenter study. Gastrointest Endosc. 2005;61(3):378-384. 3. Ness RM, Manam R, Hoen H, Chalasani N. Predictors of inadequate bowel preparation for colonoscopy. Am J Gastroenterol. 2001;96(6):1797-1802. 4. The ASGE Standards of Practice Committee,

To remove subjectivity of the nomenclature, some standardized evaluation measures utilize more objective scales.

et al. Bowel preparation before colonoscopy.

Gastrointest Endosc. 2015;81(4):781-794. 5. Lai EJ, Calderwood AH, Doros G, Fix OK, Jacobson BC. The Boston bowel preparation scale: a valid and reliable instrument for colonoscopy-oriented research. Gastrointest

Endosc. 2009 Mar;69(3 Pt 2):620-625.

Split dosing has become the preferred modality for bowel prep based on multiple studies. In a meta-analysis conducted by Bucci and colleagues, a good or excellent preparation was found in 85% of patients (95% confidence interval [CI], 0.82-0.88) using split dosing compared with 63% of those who did not receive a split dose (95% CI 0.55-0.71).8 These findings were also seen in a subgroup analysis based on the different types of prep formulation (eg, high vs low volume), with split dosing having better rates of adequate prep by between 15% to 30%. In a separate study, split dosing was also shown to increase both the adenoma detection rate and polyp detection rate following the implementation of a split-dosing protocol.9 Split dosing increased the polyp detection rate from

patients should receive more extensive counseling and educational materials. A thorough medication reconciliation should be completed beforehand to see if there are medication options that could serve to limit certain medications known to promote constipation. The prep may be better tolerated by patients if it is chilled prior to ingestion, if flavor packets are used, and if it is sipped through a straw. Some patients may require a diet of 2 days of a clear liquid to prepare the bowel, especially if those patients have a history of constipation. Lower volume preps may also be easier to tolerate. â&#x2013;

6. Chokshi RV, Hovis CE, Hollander T, Early DS, Wang JS. Prevalence of missed adenomas in patients with inadequate bowel preparation on screening colonoscopy. Gastrointest Endosc. 2012;75(6):1197-1203. 7. Hassan C, Fuccio L, Bruno M, et al. A predictive model identifies patients most likely to have inadequate bowel preparation for colonoscopy. Clin Gastroenterol Hepatol. 2012;10(5):501-506. 8. Bucci C, Rotondano G, Hassan C, et al. Optimal bowel cleansing for colonoscopy: split the dose! A series of meta-analyses of controlled studies. Gastrointest Endosc. 2014;80(4):566-576. 9. Gurudu SR, Ramirez FC, Harrison ME, Leighton JA, Crowell MD. Increased adenoma

References

1. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality

detection rate with system-wide implementation of a split-dose preparation for colonoscopy. Gastrointest Endosc. 2012;76(3):603-608.

To read more news and perspectives related to research about the detection and treatment of gastrointestinal cancers visit www.CancerTherapyAdvisor.com/gastrointestinalcancers.

38 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2018 | CancerTherapyAdvisor.com

VIEWPOINT

Expansion Cohort Trials Expected to Modernize Oncology Studies LEAH LAWRENCE

There is a push to create innovative adaptive trial designs that include more patients and, subsequently, more generalizable data.

he US Food and Drug Administration (FDA) released a draft guidance for industry that provided advice on designing and conducting adaptive clinical trials that would allow companies and researchers to assess different aspects of a drug in development in a single clinical trial — all while enrolling the minimum number of study participants necessary to obtain this information. The guidance, entitled “Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” is open for comment until October 12, 2018. “As part of our ongoing efforts to advance more efficient ways to develop medical products, the FDA is encouraging pioneering new ways that innovators can modernize the way they conduct clinical trials,” FDA Commissioner Scott Gottlieb, MD, said in a prepared statement.2 “The approach we’re describing in new guidance today is to help innovators to evaluate drugs in trials that are potentially lower cost, more efficient, and could enable us to learn more about the safety and efficacy when compared to traditional trial designs.” First-in-human expansion cohort trials have a “single protocol with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives,” according to the draft document.1 Among the possible objectives for the additional cohorts are assessment of antitumor activity, assessment of a reasonably safe

dose in specific populations, evaluation of alternative doses or schedules, establishment of dose and schedule for the investigational drug administered with other oncology drugs, or evaluation of the predictive value of a potential biomarker. The guidance provides recommendations in 4 areas. First, it lists characteristics of drug products best suited for consideration for development under a multiple expansion cohort trial. For example, a drug formulation with drug substances that have attributes that would allow for straightforward bridging between early drug product formulations and marketing formulations may be the type of investigational therapy that would be the most appropriate for multiple expansion cohort trials. The guidance also contains information about what to include in an investigational drug application submission to support the use of individual cohorts. Next, the guidance lists when to interact with the FDA on planning and conducting multiple expansion cohort studies. Finally, the guidance suggests how to construct safeguards for patients enrolled in first-in-human cohort studies and how to protect them from potentially synergistic drug toxicities. Meeting a Need The newly proposed guidance for expansion cohort trials was released with the hope of meeting several ongoing challenges within oncology clinical trials, according to Jennifer Miller, PhD, assistant professor at Yale University School of Medicine in New Haven, Conneticut.

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2018 | CANCER THERAPY ADVISOR 39

VIEWPOINT The first challenge is that a lot of patients with cancer do not qualify for treatment within clinical trials because inclusion and exclusion criteria are very narrow. “This puts pressure on the system to speed research and development and get approval for experimental therapies more quickly,” Dr Miller said. The next challenge in oncology trials is the drive to obtain real-world evidence on investigational therapies. “Because trials have narrow exclusion and inclusion criteria, the results often apply only to a narrow subset of patients,” Dr Miller said. “These patients tend to be healthier and younger than patients that end up taking the drug in the real world. There is a push to come up with innovative, adaptive trial designs that include more generalizable data.”

another effort intended to speed access to drugs, Dr Miller said. However, it is still unknown if the establishment of expansion trials will fulfill this need. A 2017 study from the Cleveland Clinic reviewed data from 252 phase 1 studies that were published in the Journal of Clinical Oncology from 2004 to 2014 to see if there was an association between the use of expansion cohorts and subsequent clinical development.3 The results showed that the addition of a phase 1 expansion cohort had no effect on phase 1 maximum-tolerated dose, recommended phase 2 dose, subsequent phase 2 trial, or FDA approval. Another 2017 study looked at 533 single-agent dose-finding adult oncology phase 1 trials published from 2006 to

According to Dr Gottlieb, “a lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials. Expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time.”2 But, according to Dr Miller, it is too early to know what effect this FDA guidance will have, or whether or not increased use of expansion cohorts will help speed access to drugs. ■ References

1. US Food and Drug Administration. Expansion cohorts: use in first-in-human clinical trials to expedite development of oncology drugs and biologics. Draft guidance for industry. https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/UCM616325.pdf. Accessed September 4, 2018.

A lot of patients with cancer don’t qualify for treatment within clinical trials because inclusion and exclusion criteria are very narrow.

2. US Food and Drug Administration. FDA in brief: FDA advances efforts to help modernize oncology drug trials. https://www.fda.gov/NewsEvents/ Newsroom/FDAInBrief/ucm616484. htm. Updated August 10, 2018. Accessed September 4, 2018.

Finally, the third challenge within oncology clinical trials is speeding up the entire process to allow for greater access to drugs for patients in need. There are 2 available avenues for this access outside of clinical trials: the FDA’s expanded access program and the recently approved right-to-try access. The use of expansion cohort trials is

2011 and subsequent phase 2 trials.4 Of the 381 drugs evaluated in these trials, 112 drugs had at least one phase 1 trial with an expansion cohort. This study showed that phase 1 trials with expansion cohorts of 2 to 20 patients had twice the rate of success in phase 2 trials compared with trials that did not include expansion cohorts.

3. Norris RE, Behtaj M, Fu P, Dowlati A. Evaluating the role of phase I expansion cohorts in oncologic drug development.

Invest New Drugs. 2017;35(1):108-114. 4. Bugano DDG, Hess K, Jardim DLF, et al. Use of expansion cohorts in phase I trials and probability of success in phase II for 381 anticancer drugs. Clin Cancer Res. 2017;23(15):4020-4026.

Read additional articles that highlight trending topics in oncology research visit www.CancerTherapyAdvisor.com/headlines. Recent articles include:

• Guideline Updates in Palliative Care • Who Determines What ‘Value’ Looks Like in Value-Based Cancer Care?

40 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2018 | CancerTherapyAdvisor.com

BREAST CANCER

TREATMENT REGIMENS Breast Cancer (Invasive) Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uNeoadjuvant/Adjuvant

Chemotherapya,b,c,d,e,f

Note: All recommendations are category 2A unless otherwise indicated.

REGIMEN

DOSING

Preferred Regimens for HER2-negative Disease1 Dose-dense AC followed by paclitaxel (Category 1)2,g

Dose-dense AC followed by weekly paclitaxel (Category 1)2,g TC (Category 1)3

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles (all cycles are with myeloid growth factor support; refer to NCCN Guidelines for Myeloid Growth Factors), followed by: Day 1: Paclitaxel 175mg/m2 via 3-hour IV infusion. Repeat cycle every 14 days for 4 cycles (all cycles are with myeloid growth factor support). Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles, followed by: Day 1: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks. Day 1: Docetaxel 75mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles (all cycles are with myeloid growth factor support).

Useful in Certain Circumstances Dose-dense AC (Category 1)2 AC followed by weekly paclitaxel (Category 1)8 CMF (Category 1)6

AC (Category 2B)4

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles (all cycles are with myeloid growth factor support). Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Paclitaxel 80mg/m2 by 1-hour IV infusion weekly for 12 weeks. Days 1–14: Cyclophosphamide 100mg/m2 orally Days 1 and 8: Methotrexate 40mg/m2 IV Days 1 and 8: 5-fluorouracil 600mg/m2 IV. Repeat cycle every 28 days for 6 cycles. Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles.

Other Recommended Regimens AC followed by docetaxel (Category 1)7

EC (Category 1)9 TAC (Category 1)5

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Docetaxel 100mg/m2 IV. Repeat cycle every 21 days for 4 cycles. Day 1: Epirubicin 100mg/m2 IV Day 1: Cyclophosphamide 830mg/m2 IV. Repeat cycle every 21 days for 8 cycles. Day 1: Docetaxel 75mg/m2 IV Day 1: Doxorubicin 50mg/m2 IV Day 1: Cyclophosphamide 500mg/m2 IV. Repeat cycle every 21 days for 6 cycles (all cycles are with myeloid growth factor support). continued

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2018 | CANCER THERAPY ADVISOR 41

BREAST CANCER

TREATMENT REGIMENS Breast Cancer (Invasive) Treatment Regimens uNeoadjuvant/Adjuvant REGIMEN

Chemotherapya,b,c,d,e,f (continued)

DOSING

Preferred Regimens for HER2-positive Disease AC followed by paclitaxel + trastuzumab10,h,i

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks, with: Trastuzumab 4mg/kg IV with first dose of paclitaxel, followed by: Trastuzumab 2mg/kg IV weekly to complete 1 year of treatment. As an alternative, trastuzumab 6mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.

AC followed by paclitaxel + trastuzumab + pertuzumab10,h,i

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 21 days for 4 cycles. Day 1: Trastuzumab 6mg/kg IV. Repeat cycle every 21 days to complete 1 year of trastuzumab therapy.

Dose-dense AC followed by paclitaxel + trastuzumab11,h,i

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles, followed by: Day 1: Paclitaxel 175mg/m2 via 3-hour IV infusion. Repeat cycle every 14 days for 4 cycles, plus: Trastuzumab 4mg/kg IV with first dose of paclitaxel, followed by: Trastuzumab 2mg/kg IV weekly to complete 1 year of treatment. As an alternative, trastuzumab 6mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.

Paclitaxel + trastuzumab12,j

Day 1: Paclitaxel 80mg/m2 IV weekly for 12 weeks with Trastuzumab 4mg/kg IV with first dose of paclitaxel followed by: Trastuzumab 2mg/kg IV weekly to complete 1 year of treatment OR Trastuzumab 6mg/kg IV every 21 days for 1 year following the completion of paclitaxel.

TCH13,i

Day 1: Docetaxel 75mg/m2 IV Day 1: Carboplatin AUC 6mg • min/mL IV. Repeat cycle every 21 days for 6 cycles, with: Trastuzumab 4mg/kg IV week 1, followed by 2mg/kg IV for 17 weeks, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. OR Trastuzumab 8mg/kg IV week 1, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy.

TCH chemotherapy + pertuzumab14,i

Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Docetaxel 75mg/m2 IV Day 1: Carboplatin AUC 6mg • min/mL IV. Repeat cycle every 21 days for 6 cycles, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy.

Useful in Certain Circumstances Docetaxel + cyclophosphamide + trastuzumab15,i

Day 1: Docetaxel 75mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, with: Trastuzumab 4mg/kg IV week 1, followed by: Trastuzumab 2mg/kg IV weekly for 11 weeks, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. OR Trastuzumab 8mg/kg IV week 1, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of treatment.

42 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2018 | CancerTherapyAdvisor.com

BREAST CANCER

TREATMENT REGIMENS Breast Cancer (Invasive) Treatment Regimens uNeoadjuvant/Adjuvant REGIMEN

Chemotherapya,b,c,d,e,f (continued)

DOSING

Other Recommended Regimens AC followed by docetaxel + trastuzumab12,h,i

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Docetaxel 100mg/m2 IV. Repeat cycle every 21 days for 4 cycles, with: Trastuzumab 4mg/kg IV week 1, followed by 2mg/kg IV weekly for 11 weeks, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy.

AC followed by docetaxel + trastuzumab + pertuzumab16,h,i

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy.

The selection, dosing, and administration of anticancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anticancer agents therefore requires a healthcare delivery team experienced in the use of anticancer agents and the management of associated toxicities in patients with cancer. b Retrospective evidence suggests that anthracycline-based chemotherapy regimens may be superior to nonanthracycline-based regimens in patients with HER2-positive tumors. c Randomized clinical trials demonstrate that the addition of a taxane to anthracycline-based chemotherapy provides an improved outcome. d CMF and radiation therapy may be given concurrently, or the CMF may be given first. All other chemotherapy regimens should be given prior to radiotherapy. e Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. f Nab-paclitaxel may be substituted for paclitaxel or docetaxel due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of nab-paclitaxel should not exceed 125mg/m2. g It would be acceptable to change the administration sequence to paclitaxel followed by dose-dense AC. h Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided. i Evaluate left ventricular ejection fraction (LVEF) before and during treatment. Although the optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known, the FDA recommends LVEF measurements every 3 months during treatment. j Paclitaxel + trastuzumab may be considered for patients with low-risk, T1, N0, M0, HER2-positive disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities. a

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2018. Available at: http://www.nccn. org/professionals/physician_gls/pdf/breast.pdf. Accessed July 12, 2018. 2. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431–1439. Erratum in: J Clin Oncol. 2003;21(11):2226. 3. Jones S, Holmes F, O’Shaughnessey J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research trial 9735. J Clin Oncol. 2009;27(8):1177–1183. 4. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from NSABP B-15. J Clin Oncol. 1990;8(9):1483–1496. 5. Goldhirsch A, Colleoni M, Coates AS, et al. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol. 1998;9(5):489–493. 6. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in adjuvant treatment of breast cancer. N Engl J Med. 2008; 358(16):1663–1671. 7. von Minckwitz G, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005;23(12):2676–2685.

8. Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001;19(12):3103–3110. 9. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005;352(22): 2302–2313. 10. Romond EH, Perez EZ, Bryant J, et al. Trastuzumab plus a djuvant chemotherapy for operable HER2 positive breast cancer. N Engl J Med. 2005;353(16):1673–1684. 11. Dang C, Fornier M, Sugarman S, et al. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008;26(8):1216–1222. 12. Tolaney S, Barry W, Dang C, et al. Adjuvant paclitaxel and trastuzumab for node-negative HER2-positive breast cancer. N Engl J Med. 2015;372:134-141. 13. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14): 1273–1283. 14. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline–containing and anthracycline-free chemo therapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278–2284. 15. Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013;14(11):1121–1128. 16. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32.

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2018 | CANCER THERAPY ADVISOR 43

LYMPHOMA

TREATMENT REGIMENS Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uSystemic

Therapy for Diffuse Large B-cell Lymphoma1

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

First-line Therapy R-CHOP (Category 1)2–7

Days 1, 22, and 43: Rituximab 375mg/m2 IV 7 days prior to beginning CHOP regimen Day 1: Cyclophosphamide 750mg/m2 IV + doxorubicin 50mg/m2 IV bolus + vincristine 1.4mg/m2 IV bolus (max dose 2mg) Days 3, 24, and 45: Prednisone 100mg orally 5 days. Repeat each cycle every 3 weeks for 3 cycles. Radiotherapy begins 3 weeks after last cycle of R-CHOP.

Dose-dense R-CHOP 14 (Category 3)8–10

Day 1: Cyclophosphamide 750mg/m2 IV + doxorubicin 50mg/m2 IV + vincristine 2mg IV Days 1-5: Prednisone 100mg orally. Repeat every 2 weeks for 6 cycles. Granulocyte colony-stimulating factor (G-CSF) was given on day 4 or 6.

Dose-adjusted EPOCH + rituximab11–13

Day 1: Rituximab 375mg/m2 IV Days 1–4: Etoposide 50mg/m2 IV + doxorubicin 10mg/m2 IV + vincristine 0.4mg/m2 IV Day 5: Cyclophosphamide 750mg/m2 IV Days 1–5: Prednisone 60mg/m2 orally twice daily. Administer G-CSF 5 mcg/kg SQ daily until an ANC >5 × 109/L above nadir level starting day 6. Repeat cycle every 3 weeks for 6 cycles.

First-line Therapy for Patients With Poor Left Ventricular Functiona,b RCEPP14

Days 1 and 8: Cyclophosphamide 600mg/m2 IV Day 1 OR 8: Rituximab 375mg/m2 IV Day 1: Etoposide IV 70mg/m2 IV (or days 1–3 if not giving oral etoposide) Days 2 and 3: Etoposide 140 mg/m2 orally (rounded to the nearest 50mg capsule) Days 1–10: Procarbazine 60mg/m2 orally + prednisone 60mg/m2 orally. Repeat every 4 weeks until disease progression, or unacceptable toxicity.

RCDOP15,16

Day 1: Cyclophosphamide 750mg/m2 IV + liposomal doxorubicin 30mg/m2 IV + vincristine 2mg IV Days 1–5: Prednisone 60mg/m2 IV Day 8: Rituximab 375mg/m2 IV for cycle 1; administer on day 0 in subsequent cycles. Repeat cycle every 3 weeks for 6–8 cycles.

RGCVP17

Day 1: Rituximab 375mg/m2 IV + cyclophosphamide 750mg/m2 IV + vincristine 1.4mg/m2 (maximum dose 2mg) IV Days 1 and 8: Gemcitabine 750-1000mg/m2 IV Days 1–5: Prednisolone 100mg orally per day. Day 9: Pegfilgrastim 6mg SC. Repeat every 3 weeks for 6 cycles (Patients considered high risk for CNS relapse can receive methotrexate 12.5mg IT for 3 cycles).

DA-EPOCH + rituximab18

Day 1: Rituximab 275mg/m2 Days 1–4: Doxorubicin 10mg/m2 IV + etoposide 50mg/m2 IV + vincristine 0.4mg/m2 IV Day 5: Cyclophosphamide 750mg/m2 IV Days 1–5: Prednisone 60mg/m2 orally. Administer G-SCF on day 6 until ANC exceeds nadir. Repeat cycle every 3 weeks.

44 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2018 | CancerTherapyAdvisor.com

LYMPHOMA

TREATMENT REGIMENS Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma uSystemic

Therapy for Diffuse Large B-cell Lymphoma1 (continued)

REGIMEN

DOSING

First-line Therapy for Patients With Poor Left Ventricular Functiona,b (continued) RCEOP19

Day 1: Rituximab 375mg/m2 IV Day 1: Cyclophosphamide 750mg/m2 IV + etoposide 50mg/m2 IV + vincristine 1.4mg/m2 IV (max dose 2mg) Days 1–5: Prednisone 100mg orally Days 2–3: Etoposide 100mg/m2 orally. For limited-stage disease, repeat cycle every 3 weeks for 3–4 cycles; for advanced-stage disease, repeat cycle every 3 weeks for 6 cycles.

First-Line Therapy for Very Frail Patients and Patients >80 Years of Age With Comorbidities R-mini-CHOP20

Day 1: Rituximab 375mg/m2 IV Day 1: Cyclophosphamide 400mg/m2 IV + doxorubicin 25mg/m2 IV + vincristine 1mg IV Days 1–5: Prednisone 40mg/m2 orally. Repeat every 3 weeks for 6 cycles.

RGCVP17

Day 1: Rituximab 375mg/m2 IV + cyclophosphamide 750mg/m2 IV + vincristine 1.4mg/m2 (maximum dose 2mg) IV Days 1 and 8: Gemcitabine 750-1000mg/m2 IV Days 1-5: Prednisolone 100mg orally per day. Day 9: Pegfilgrastim 6mg SC. Repeat every 3 weeks for 6 cycles (Patients considered high risk for CNS relapse can receive methotrexate 12.5mg IT for 3 cycles).

RCEPP14

Days 1 and 8: Cyclophosphamide 600mg/m2 IV Day 1: Etoposide IV 70mg/m2 IV (or days 1–3 if not giving oral etoposide) Days 2 and 3: Etoposide 140 mg/m2 orally (rounded to the nearest 50mg capsule) Days 1–10: Procarbazine 60mg/m2 orally + prednisone 60mg/m2 orally. Repeat every 4 weeks until disease progression, or unacceptable toxicity.

RCDOP15,16

First-line Consolidation (optional) High-dose therapy with autologous stem cell rescue in patients with age-adjusted IPI high-risk disease (Category 2B)21

Induced with 5 cycles of CHOP or R-CHOP followed by autotransplantation at the first response to induction therapy with CHOP with or without rituximab for 3 cycles.

Lenalidomide maintenance for patients 60 - 80 years of age (Category 2B)22

Days 1 to 21: Lenalidomide 25mg daily. Repeat every 4 weeks for 24 months.

Concurrent Presentation With CNS Disease Parenchymal1

Systemic methotrexate 3g/m2 or more on day 15 of a 21-day R-CHOP cycle that has been supported by growth factors.

Leptomeningeal1

Methotrexate/cytarabine IT. Consider Ommaya reservoir placement and/or systemic methotrexate 3–3.5g/m2.

Second-line and Subsequent Therapy (for patients with intention to proceed to high-dose therapy)1,c,d DHAP ± rituximab23–25 ESHAP ± rituximab26,27

Days 1–4: Cisplatin 100mg/m2 IV via 24-hour infusion + cytosine 2g/m2 in 2 pulses each given 12 hours apart IV + dexamethasone 40mg orally or IV ± rituximab 375mg/m2 IV prior to DHAP. Repeat in 3–4 weeks for 6-10 cycles. Days 1–4: Etoposide 40–60mg/m2 Days 1–5: Methylprednisolone 250–500mg IV Day 5: Cytarabine 2g/m2 IV over 2–3 hours Days 1–4: Cisplatin 25mg/m2 IV via 24-hour infusion, ± Day 1 or 5: Rituximab 375mg/m2 IV. Repeat every 3–4 weeks for 3 cycles. continued

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LYMPHOMA

TREATMENT REGIMENS Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma uSystemic

Therapy for Diffuse Large B-cell Lymphoma1 (continued)

REGIMEN

DOSING

Second-line and Subsequent Therapy (for patients with intention to proceed to high-dose therapy)1,c,d (continued) GDP ± rituximab28,29

Days 1 and 8: Gemcitabine 1000mg/m2 IV over 30 minutes Days 1–4: Dexamethasone 40mg orally Day 1: Cisplatin 75mg/m2 IV OR carboplatin at AUC 5mg·min/mL IV over 30 minutes, ± Day 8: Rituximab 375mg/m2 slow IV infusion for CD20-positive disease. Repeat every 3 weeks for up to 6 cycles.

GemOX ± rituximab30

Day 1: Gemcitabine 1000mg/m2 and oxaliplatin 100mg/m2 ± rituximab 375mg/m2 IV.. Repeat every 15 days if ANC >1 × 109/L and platelet count >100 × 109/L; if not, then every 3 weeks. Days 1–3: Etoposide 100mg/m2 IV bolus Day 2: Carboplatin AUC 5mg·min/mL (max dose 800mg) IV bolus and ifosfamide admixed with mesna both at a dose of 5g/m2 via 24-hour continuous IV beginning day 2 Days 5–12 (or days 7–14): Filgrastim 5mcg/kg/day for cycles 1–2, increased to 10mcg/kg/day following cycle 3 until completion of peripheral blood stem cell collection, ± Days 1 and 3: Rituximab 375mg/m2 IV and on cycle 1, give additional dose rituximab 375mg/m2 on Day 2. Repeat every 14 days or when ANC >1000 cells/mcL and platelet count >50000/mcL. Day 1: Mitoxantrone 8mg/m2 IV Days 1-3: Ifosfamide 2g/m2 IV + mesna IV + etoposide 100mg/m2 IV, ± Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 4 weeks for 2 cycles, followed by high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT). Patients in remission after HDC-ASCT may receive rituximab 375mg/m2 IV weekly for 4 weeks.

ICE ± rituximab31–33

MINE ± rituximab34,35

Second-line and Subsequent Therapy (non-candidates for high-dose therapy)c.d Bendamustine ± rituximab36–38

Days 1–2: Bendamustine 120mg/m2 IV, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 4 weeks for up to 6 cycles.

Brentuximab vedotin for CD30+ disease (Category 2B)39

Brentuximab vedotin 1.8mg/kg IV over 30 minutes every 3 weeks. Repeat cycle until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

CEPP ± rituximab (PO and IV)40

Days 1 and 8: Cyclophosphamide 600mg/m2 IV Day 1: Etoposide IV 70mg/m2 IV (or on days 1–3 if not giving oral etoposide) Days 2 and 3: Etoposide 140mg/m2 orally (rounded to the nearest 50 mg capsule) Days 1–10: Procarbazine 60mg/m2 orally + prednisone 60mg/m2 orally, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 4 weeks until disease progression or unacceptable toxicity.

CEOP ± rituximab41

Day 1: Cyclophosphamide 750mg/m2 IV, vincristine 1.4mg/m2 IV, and epirubicin 60mg/m2 IV Days 1–5: Prednisone 100mg/day orally, ± Day 0: Rituximab 375mg/m2 IV. Repeat every 3 weeks for at least 6 cycles.

DA-EPOCH ± rituximab42,43

Days 2–4: Doxorubicin 15mg/m2 via continuous IV infusion + etoposide 65mg/m2 via continuous IV infusion + vincristine 0.5mg via continuous IV infusion Day 5: Cyclophosphamide 750mg/m2 IV Days 1–14: Prednisone 60mg/m2 orally, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 3 weeks for 4-6 cycles.

GDP ± rituximab28,29

Days 1 and 8: Gemcitabine 1000mg/m2 IV Days 1–4: Dexamethasone 40mg IV Days 1–3: Cisplatin 25mg/m2 IV Or carboplatin AUC 5mg·min/mL on day 1, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 3 weeks for 2–6 cycles (max of 4 cycles if using carboplatin).

GemOx ± rituximab44,45

Days 1 and 8: Gemcitabine 1200mg/m2 30-minute IV infusion Day 2: Oxaliplatin 120mg/m2 2-hour IV infusion, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 3 weeks for 6 cycles.

46 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2018 | CancerTherapyAdvisor.com

LYMPHOMA

TREATMENT REGIMENS Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma uSystemic

Therapy for Diffuse Large B-cell Lymphoma1 (continued)

REGIMEN

DOSING

Second-line and Subsequent Therapy (non-candidates for high-dose therapy)c.d (continued) Lenalidomide ± rituximab (non-GCB DLBCL)46-48

Days 1–21: Lenalidomide 20mg orally ± rituximab 375mg/m2 IV weekly during cycle 1. Repeat every 4 weeks until complete response.

Rituximab49

Day 1: Rituximab 375mg/m2 IV during each cycle of chemotherapy for up to 8 infusions.

Gemcitabine + vinorelbine ± rituximab (Category 3)50,51

Days 1 and 8: Gemcitabine 1000mg/m2 + vinorelbine 30mg/m2 OR Days 1 and 8: Gemcitabine 880mg/m2 + vinorelbine 25mg/m2 + rituximab 375mg/m2. Repeat every 3 weeks for up to 6 cycles.

Ibrutinib (non-GCB DLBCL)52

Ibrutinib 560mg orally daily. Repeat every 4 weeks until disease progression or unacceptable toxicity.

Inclusion of any anthracycline or anthracenedione in patients with impaired cardiac functioning should have more frequent cardiac monitoring. There are limited published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the first-line treatment of DLBCL for patients with poor left ventricular function. c If additional anthracycline is administered after a full course of therapy, careful cardiac monitoring is essential. Dexrazoxane may be added as a cardioprotectant. d Rituximab should be included in second-line therapy if there is a relapse after a reasonable remission (>6 mo); however, rituximab should often be omitted in patients with primary refractory disease. a

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continued

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for Lymphoma

RECENTLY FEATURED TOPICS INCLUDE: Bortezomib-Based Frontline Therapy Boosts Survival in Mantle Cell Lymphoma Replacement of vincristine with bortezomib in R-CHOP regimen significantly improved median OS in previously untreated patients with mantle cell lymphoma.

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