Treat HER Differently First Line

Prescribe first-line TYKERB + letrozole

Treat Her Differently First Line TYKERB IS THE FIRST HER2+ DIRECTED AGENT INDICATED IN COMBINATION WITH HORMONAL THERAPY FOR 1ST-LINE HER2+/HR+ MBC Indication TYKERB is indicated in combination with an aromatase inhibitor for the treatment of patients with hormone-receptor–positive advanced or metastatic breast cancer that overexpresses the HER2 receptor.1 BOXED WARNING: HEPATOTOXICITY TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB.

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NEW FIRST-LINE DATA: EGF30008 TRIAL

In HER2+/HR+ advanced or metastatic breast cancer—

HER2+ Population In HER2+/HR+ advanced or metastatic breast cancerâ&#x20AC;&#x201D;

Prescribe first-line TYKERB + letrozole

Treat Her Differently First Line In the absence of visceral crisis, noncytotoxic chemotherapy should be considered for initial treatment of HeR2+ MBC because of proven efficacy and favorable toxicity profile2

HER2+/HR+ MBC Nonvisceral Crisis3

Visceral Crisis3

Defined by NCCN. Patients with asymptomatic visceral disease (including bone, soft tissue, asymptomatic visceral disease)

Defined by NCCN. Patients with symptomatic visceral disease (including shortness of breath, fatigue, etc)

Aggressive therapy, such as cytotoxic chemotherapy plus anti-HER2 therapy, is appropriate

Cytotoxic chemotherapy-free treatment option could be considered appropriate

Treatment Options

Only indicated HER2 + AI combination: TYKERB + letrozole

Anti-HER2 therapy + cytotoxic chemotherapy

Standard of Care

Anti-HER2 therapy

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Anti-HER2 therapy + cytotoxic chemotherapy

In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

eGF30008: A Large Phase III, Randomized, Double-Blind, Controlled Trial 1

1286 HR+ advanced OR metastatic patients PREPLANNED ANALYSIS OF 219 HER2-POSITIVE patients • HR+ and/or PgR+ • Postmenopausal • Stage IIIB/IIIC/IV • No prior treatment for metastatic disease

1069 HER2-NEGATIVE patients • HER2 negative • Postmenopausal • Stage IIIB/IIIC/IV • No prior treatment for metastatic disease

Stratification • Disease sites: bone only/visceral or soft tissue • Interval since adjuvant tamoxifen therapy: <6 months, ≥6 months, or none Primary end point • Investigator assessment of progression-free survival (PFS) • The first group of HER2+ patients received letrozole 2.5 mg daily plus placebo • The second group of HER2+ patients received letrozole 2.5 mg daily plus TYKERB 1500 mg daily Secondary end points • Overall survival (OS) • Overall response rate (ORR) • Clinical benefit rate (CBR) • Safety

Treat HER differently first line The most common adverse reactions (>20%) during therapy with TYKERB plus letrozole compared to letrozole alone were diarrhea, rash, and nausea.

The most common grade 3 and 4 adverse reactions (NCI CTC AEv3) with TYKERB plus letrozole compared to letrozole alone were diarrhea and fatigue.

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HER2+ Population In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

HER2+ Patient Baseline Characteristics Letrozole (n=108)

Letrozole + TYKERB (n=111)

59

60

27.8

29.2

≥6 months/none

67 (62%)

73 (66%)

≤6 months

41 (38%)

38 (34%)

0 or 1

0 or 1

Bone only

18 (17%)

16 (14%)

Visceral or soft tissue

90 (83%)

95 (86%)

Liver

37 (34%)

33 (30%)

Lung

40 (37%)

43 (39%)

Lymph node

43 (40%)

57 (51%)

Soft tissue

31 (29%)

35 (32%)

Other

18 (17%)

19 (17%)

Median age (years) Median time from initial diagnosis (months) Interval since prior adjuvant tamoxifen

ECOG performance status Sites of disease

• Both groups of patients were well balanced and there were no significant differences Treat HER differently first line

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HER2+ Population In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

Treat Her Differently First Line TREAT HER2+/HR+ METASTATIC BREAST CANCER BY TARGETING 2 DIFFERENT PATHWAYS with TYKERB + letrozole

Potential therapeutic implications of cross-talk between Hr and growth factor signaling pathways • Hormone receptor–positive breast cancer cells [estrogen receptor (HR) and/or progesterone receptor (PgR)] that also overexpress the HER2 receptor may be dependent on signaling through both receptors to continuously activate the molecular pathways that sustain proliferation and survival • In these HR+/HER2+ cells, blockade of hormone receptor-mediated signaling, for example with letrozole, may not completely abolish activation of these pathways as signaling through the HER2 receptors will continue to activate downstream signaling • Blockade of both the HR and the HER2 signaling by combining letrozole with an HER2receptor tyrosine kinase inhibitor may provide more complete inhibition of tumor growth

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HER2+ Population In HER2+/HER+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

significant improvement in pfs For TYKERB + letrozole vs letrozole alone1 100

n=219 TYKERB (1500 mg) + letrozole (2.5 mg) PFS 8.2 months

Cumulative Progression-free

80

Letrozole (2.5 mg) PFS 3 months P=0.019

60

40

20

0 0

20

40

60

80

100

120

140

160

180

200

Time (Weeks) Note: At the time of updated analysis, the data for survival analysis were not mature.

• Median PFS for patients taking TYKERB + letrozole was 8.2 months compared with 3 months for patients taking letrozole alone1 • Adding TYKERB to letrozole therapy more than doubled PFS compared with patients taking letrozole alone (P=0.019)1 • 29% reduction in the risk of disease progression • Some patients can significantly delay the need for cytotoxic chemotherapy intervention Treat HER differently first line Important safety warnings for TYKERB: patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women.

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HER2+ Population In HER2+/HER+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

Treat Her Differently First Line TYKERB + LETROZOLE IMPROVED PFS ACROSS PATIENT SUBGROUPS Forrest Plot of Odds Ratio (95% CI) for Investigator-Evaluated ProgressionFree Survival by Subgroups of Baseline Covariates—HER2+ Population All HER2+ (n=219) Truly naive (n=42) No prior AC but prior radiology and surgery (n=59) Had prior cytotoxic chemotherapy (n=112) Had prior hormone therapy (n=122) Had measurable disease (n=168) Natural menopause (n=210) Age <65 yr (n=141) Age ≥65 yr (n=78) With liver metastases (n=71) Without liver metastases (n=148) Metastases number <3 (n=130) Metastases number ≥3 (n=89) 0.0

0.2

0.4

0.6

0.8

1.0

1.2

Favors Lapatinib + Letrozole

1.4

1.6

1.8

2.0

Favors Letrozole

Hazard Ratio (95% CI)

• As a group, all HER2+ patients treated with Tykerb + letrozole showed a statistical improvement in PFS vs letrozole alone • Patient subgroups showed a significant improvement or trend favoring Tykerb + letrozole • Of note, in those with natural menopause, measurable disease, liver metastases, and ≥3 metastases, there was a statistically significant difference in favor of TYKERB + letrozole

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HER2+ Population In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

Significant Increase in Response AND CLINICAL BENeFIT 1

With TYKERB + letrozole—IndependEnt Assessment P=0.003 TYKERB + letrozole

47.7%

Letrozole P=0.02

28.7%

27.9% 14.8%

Response rate n=108

Clinical benefit rate n=111

• Clinical benefit was defined as complete response, partial response, or stable disease for ≥6 months Treat HER differently first line BOXED WARNING: HEPATOTOXICITY TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB.

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Overall Population In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

TYKERB + LETRoZOLE IS GENeRALLY WELL TOLERATED Adverse reactions occurring in 10% of patients1 TYKERB 1500 mg/day + letrozole 2.5 mg/day (n=654) Grade 3 (%)

Grade 4 (%)

All grades* (%)

Grade 3 (%)

Grade 4 (%)

11

<1

0

9

<1

0

14

<1

0

13

<1

0

Diarrhea

64

9

<1

20

<1

0

Nausea

31

<1

0

21

<1

0

Vomiting

17

1

<1

11

<1

<1

Reactions

All grades* (%)

Letrozole 2.5 mg/day (n=624)

Metabolism and nutrition disorders Anorexia Nervous system disorders Headache Gastrointestinal disorders

Skin and subcutaneous tissue disorders Rash†

44

1

0

13

0

0

Dry skin

13

<1

0

4

0

0

Alopecia

13

<1

0

7

0

0

Pruritus

12

<1

0

9

<1

0

Nail disorder

11

<1

0

<1

0

0

General disorders and administrative site conditions Fatigue

20

2

0

17

<1

0

Asthenia

12

<1

0

11

<1

0

<1

0

2

<1

0

Respiratory, thoracic, and mediastinal disorders Epistaxis

11

*NCI CTC v3. † In addition to the rash reported under “Skin and subcutaneous tissue disorders,” 3 additional subjects in each treatment arm had rash.

• Grade 3 and 4 adverse events for combination TYKERB + letrozole therapy were similar to those occurring with letrozole alone Treat HER differently first line

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Overall Population In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

HEPATIC PARAMETERS OF MAXIMUM TOXICITY CTCAE GRADE 3 OR 4 AT ANY POSTSCREENING VISIT (SAFETY POPULATION) Number (%) of subjects Letrozole (2.5 mg) + placebo (n=624)

Letrozole (2.5 mg) + lapatinib (1500 mg) (n=654)

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Total bilirubin

65 (11%)

8 (1)

2 (<1)

140 (22%)

6 (<1)

1 (<1)

AST

237 (36%)

13 (2)

2 (<1)

336 (53%)

36 (6)

0

ALT

213 (35%)

9 (1)

0

298 (46%)

33 (5)

1 (<1)

Source data: Study EGF30008, Table 8.337.

Note: table displays maximum toxicity grade at any scheduled/unscheduled postbaseline visit.

Grade 3=severe AE; Grade 4=life-threatening or disabling AE.

• There was no significant difference in hepatic function between treatment groups

Cardiac parameters Incidence/characteristics of cardiac events in patients from EGF30008 Characteristics

TYKERB (1500 mg) + letrozole (2.5 mg) (n=654)

Letrozole (2.5 mg) + placebo (n=624)

All grades (%)

Grades 3 or 4 (%)

All grades (%)

Grades 3 or 4 (%)

Symptomatic

<1

<1

<1

<1

Asymptomatic

4

<1

<1

0

32/654 (4.9%)

6/654 (0.9%)

15/624 (2.4%)

2/624 (0.3%)

Any cardiac event*

Total patients (%)

*Cardiac event defined as ejection fraction decreased, left ventricular dysfunction, ventricular dysfunction, and cardiac failure.

• LVEF was monitored at 8-week intervals Treat HER differently first line Important safety warnings for TYKERB: patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women.

The most common grade 3 and 4 adverse reactions (NCI CTC v3) with TYKERB plus letrozole compared to letrozole alone were diarrhea and fatigue.

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In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

TYKERB + letrozole provides A noncytotoxic, all-oral regimen TYKERB 1500-mg Daily Dose

6

250-mg Tablets Indicated with letrozole 2.5 mg/day

TYKERB should be taken as directed • The indicated dosage of TYKERB is six 250-mg tablets taken once daily by mouth continuously, in combination with an aromatase inhibitor1 • When TYKERB is coadministered with the aromatase inhibitor letrozole, the recommended dosage of letrozole is 2.5 mg once daily1 • Avoid strong CYP3A4 inhibitors or inducers. If unavoidable, consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 inhibitor or consider gradual dose increase in patients coadministered a strong CYP3A4 inducer*1 • T YKERB should be taken on an empty stomach with letrozole at least 1 hour before or 1 hour after a meal1 • Letrozole should be taken with or without food4 • The dosage of letrozole is 2.5 mg daily when taken in combination with TYKERB1,5 • Do not crush, split, or dissolve TYKERB tablets5 • Treatment should be continued until disease progression or unacceptable toxicity occurs1 * These drugs include, but are not limited to: protease inhibitors such as ritonavir, macrolide antibiotics such as erythromycin, azole antifungals such as fluconazole, and nefazodone, quercetin, aprepitant, and verapamil.

Treat HER differently first line

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HER2+ Population

Dose Modification Guidelines Cardiac Events TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is grade 2 or greater by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institutionâ&#x20AC;&#x2122;s lower limit of normal. TYKERB in combination with an aromatase inhibitor may be restarted at a reduced dose of 1250 mg/day after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic.

Hepatic Impairment Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of TYKERB reduced. A dose reduction from 1500 mg/day to 1000 mg/day of TYKERB in combination with an aromatase inhibitor in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment.

Other Toxicities Discontinuation or interruption of dosing with TYKERB may be considered when patients develop >grade 2 NCI toxicity and can be restarted when toxicity improves to grade 1 or less. If the toxicity recurs, then TYKERB in combination with an aromatase inhibitor should be restarted at a lower dose of 1250 mg/day.

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In HER2+/HR+ advanced or metastatic breast cancer—

Prescribe first-line TYKERB + letrozole

Treat Her Differently First Line TYKERB IS THE FIRST HER2+ DIRECTED AGENT INDICATED IN COMBINATION with hormonal therapy for first-line her2+/hr+ mbc Increased progression-free survival • TYKERB + letrozole more than doubled PFS for HER2+/HR+ advanced or metastatic breast cancer patients (P=0.019)

Increased response rate • Response rate for TYKERB + letrozole was 27.9% compared with 14.8% for letrozole alone (P=0.003) and clinical benefit rate was 47.7% for TYKERB + letrozole compared to 28.7% for letrozole alone (P=0.02)

WELL TOLERATED AND Manageable safety profile • The combination of TYKERB + letrozole was manageable and predictable, with no unexpected toxicity • The most common grade 3 and 4 adverse reactions with TYKERB + letrozole compared to letrozole alone were diarrhea and fatigue

noncytotoxic, All-oral regimen • The indicated dosage of TYKERB is six 250-mg tablets taken once daily by mouth; when TYKERB is coadministered with the aromatase inhibitor letrozole, the recommended dosage of letrozole is 2.5 mg once daily1 Important safety warnings for TYKERB: patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women.

The most common adverse reactions (>20%) during therapy with TYKERB plus letrozole compared to letrozole alone were diarrhea, rash, and nausea.

References: 1. TYKERB Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2009. 2. Barrios CH, Sampaio C, Vinholes J, et al.

What is the role of chemotherapy in estrogen receptor-positive, advanced breast cancer? Ann Oncol. 2009;20:1157-1162. 3. Prat A, Baselga J. The role of hormonal therapy in the management of hormonal receptor-positive breast cancer with co-expression of HER-2. Nature. 2008;5(9):531. 4. Femara Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2009. 5. National Institutes of Health Senior Health Web site. Taking medicines. http://nihseniorhealth.gov/takingmedicines/howtotakemedicines/11.html. Accessed July 13, 2009.

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