Treat HER Differently by OEM65

TREAT HER DIFFERENTLY WITH TYKERB Second Line: TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1 First Line: TYKERB is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.1 TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumabcontaining chemotherapy regimen for the treatment of metastatic breast cancer.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 re-treated with TYKERB. Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

TYKERB + CAPECITABINE MOA

IN HER2+ METASTATIC BREAST CANCER (MBC)—

TARGET HER2 FROM INSIDE THE CELL WITH AN INTRACELLULAR HER2 SUPPRESSOR1

TYKERB IS A TYROSINE KINASE INHIBITOR (TKI)1

NCCN The HERClinical Family Practice of Receptors Guidelines in Oncology™ treatment of HER2+ MBC patients11

1 Receptor activation

begins at the

A Small Molecule1

Crosses the cell membrane and intracellularly binds to the receptor’s TK domain2

extracellular domain

2 This stimulates the intracellular tyrosine

Directly inhibits TK

kinase, followed by

domain phosphorylation

phosphorylation4

of tyrosine2

3 This phosphorylation

activates downstream signaling cascade to the nucleus2

The HER (ErbB) family of 4 transmembrane receptors is essential for normal cell development; HER2 is the most well known of these receptors in breast cancer2 HER2-driven downstream signaling is unregulated in malignant cells,3 resulting in: —Uncontrolled cellular proliferation2 —Increased metastatic and invasive potential2 —Resistance to apoptosis2

Stops ensuing signal transduction that results in malignant behavior4

IMPORTANT SAFETY INFORMATION Important Safety Warnings for TYKERB: Patients with known severe hypersensitivity to TYKERB or any of its components should not take TYKERB. Also, patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women. If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea, nausea, vomiting, palmar-plantar erythrodysesthesia, rash, and fatigue The most common adverse reactions (≥20%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhea, rash, nausea, and fatigue

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

IN HER2+ METASTATIC BREAST CANCER (MBC)—

AFTER PROGRESSION ON ANTHRACYCLINE, TAXANE, AND 1L TRASTUZUMAB

TREAT HER DIFFERENTLY WITH TYKERB TYKERB + CAPECITABINE CASE STUDY

TYKERB + CAPECITABINE

HOW WOULD YOU TREAT THIS PATIENT DIFFERENTLY? A Case Study: 49-Year-Old Elementary Schoolteacher

Systemic Treatment of HER2+ Breast Cancer5 Evidence of metastasis EARLY BREAST CANCER

First sign of progression 1L METASTATIC DISEASE

DIAGNOSIS 2L METASTATIC DISEASE

Stage IIA, HER2+ (FISH+), ER–/PR+, 1.5-cm mixed

Anti-HER2 agent ie, trastuzumab

WITH OR WITHOUT

Cytotoxic chemotherapy/ies ie, taxanes, anthracyclines, platinum, etc

breast carcinoma

Anti-HER2 agent ie, trastuzumab

WITH OR WITHOUT

TYKERB + CAPECITABINE*†

Cytotoxic chemotherapy/ies ie, taxanes, anthracyclines, platinum, etc

*TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1

†

A 2010 NCCN preferred regimen in this setting.

PRESENTATION

TREATMENT

CURRENT STATUS

Presented nearly 3 years ago after a routine mammography—promptly underwent lumpectomy.

Began treatment with doxorubicin and cyclophosphamide followed by weekly paclitaxel for 3 months and trastuzumab for 12 months, with radiation in sequence.

Received vinorelbine plus trastuzumab for 6 weeks. Had a partial response (PR) and continued on maintenance trastuzumab monotherapy.

Surgical axillary staging showed 1 (2-mm diameter) positive node of 9 Chest and abdominal computerized tomography (CT) scans and bone scan were negative

Capecitabine initiated at month 8 4 months after completing maintenance trastuzumab, she presents with cough, chest pain, and low back pain.

While on trastuzumab monotherapy, her disease has progressed.

Chest CT shows multiple pulmonary nodules and moderate effusion Bone scan shows solitary lesion at L5

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

IN HER2+ METASTATIC BREAST CANCER (MBC)—

AFTER PROGRESSION ON ANTHRACYCLINE, TAXANE, AND 1L TRASTUZUMAB

TREAT HER DIFFERENTLY WITH TYKERB PROVEN EFFECTIVE AFTER FIRST-LINE THERAPY FAILS IN MBC1 ™ * in the NCCN Practice Guidelines in Oncology treatment of HER2+ Time to Clinical Progression (Investigator Assessment) Intent-to-Treat Population1 Capecitabine (N=201)

121 (61%)

126 (63%)

23.9

Median TTP (weeks)

31.8%†

Response rate†

18.3

TYKERB + Capecitabine

17.4%

Lowered Risk of Progression by 28% to 43% vs

0.72 (0.56, 0.92) 0.00762

Hazard ratio (95% CI) P value

0.6

0.4

TYKERB + capecitabine Capecitabine

0.2

28% to 43%‡

Capecitabine Alone

1.0

Cumulative Progression-Free Survival

Number of TTP* events

0.8

TYKERB + capecitabine (N=198)

Number of TTP events

0.8 Median TTP (weeks)

TYKERB + capecitabine (N=198)

Capecitabine (N=201)

82 (41%)

102 (51%)

27.1

18.6 0.57 (0.43, 0.77) 0.00013

Hazard ratio (95% CI) P value

0.6

13.9%

23.7%

Response rate†

0.4

TYKERB + capecitabine Capecitabine

0.2

28% to 43% ‡ TYKERB + Capecitabine Lowered Risk of Progression by 28% to 43% vs Capecitabine Alone

0 0

100

Time (Weeks)

100

Time (Weeks)

*Time to progression (TTP) was considered to be time from randomization until objective tumor progression or death due to breast cancer. † Overall response rate was signiﬁcantly greater in the TYKERB plus capecitabine arm vs the capecitabine alone arm. ‡ These percentages are derived from the hazard ratios in both the investigator and independent assessments.

TYKERB was studied in a phase 3 clinical trial of 399 women with advanced or metastatic HER2+ breast cancer1 Approximately 95% of patients had prior treatment with an anthracycline, a taxane, and trastuzumab1

*The time from last tumor assessment to the data cutoff date was >100 days in approximately 30% of patients in the independent assessment. The prespeciﬁed assessment interval was 42 or 84 days. † Overall response rate was signiﬁcantly greater in the TYKERB plus capecitabine arm vs the capecitabine alone arm. ‡ These percentages are derived from the hazard ratios in both the investigator and independent assessments.

In light of early positive efficacy and tolerability results for women in the TYKERB plus capecitabine arm, a data safety monitoring board unanimously recommended halting trial enrollment1,6 Data were analyzed using both independent (blinded) and investigator radiologic reviews1,6

Patients were randomized into 2 treatment arms : —TYKERB 1250 mg orally daily throughout the trial + capecitabine 2000 mg/m2/day orally in 2 divided doses, Days 1-14 every 21 days (n=198) —Capecitabine 2500 mg/m2/day orally in 2 divided doses, Days 1-14 every 21 days (n=201) The primary end point was time to progression (TTP), considered to be time from randomization until objective tumor progression or death due to breast cancer1

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

TYKERB + CAPECITABINE TIME TO PROGRESSION

Cumulative Progression-Free Survival

1.0

™ * in the NCCN Practice Guidelines in Oncology treatment of HER2+ TIme toClinical Progression (Independent Assessment) Intent-to-Treat Population1

IN HER2+ METASTATIC BREAST CANCER (MBC)—

AFTER PROGRESSION ON ANTHRACYCLINE, TAXANE, AND 1L TRASTUZUMAB

TREAT HER DIFFERENTLY WITH TYKERB ADVERSE EVENTS WERE PREDOMINANTLY GRADES 1 AND 21

GRADE 3 AND 4 TOXICITIES Similar in the Combination and Capecitabine Arms1

TYKERB 1250 mg/day + capecitabine 2000 mg/m2/day (N=198)

Reactions

All grades* (%)

Grade 3 Grade 4 (%) (%)

Capecitabine 2500 mg/m2/day (N=191)

All grades* (%)

Grade 3 Grade 4 (%) (%)

Gastrointestinal disorders Diarrhea

Nausea

TYKERB 1250 mg/day + capecitabine 2000 mg/m2/day (N=198) Capecitabine 2500 mg/m2/day (N=191)

Experienced by ≥2%

45 40

Patients (%)

Adverse Reactions Occurring in ≥10% of Patients1

35 30 25

Diarrhea

20 15 10

PPE*

Dyspnea

Nausea

Vomiting

Rash

Vomiting

Stomatitis

Dyspepsia

PPE†

Rash‡

Dry skin

The most common Grade 3 and 4 adverse reactions (NCI CTCAE v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%)1

—Most diarrhea resolved without treatment (Grade 1 and 2 cases) or could be managed with standard medication (eg, loperamide and diphenoxylate hydrochloride/atropine sulfate)7 —Generally, rash resolves, but when necessary, rash can be managed with oral steroids for a maximum 14 days8

Skin and subcutaneous tissue disorders

Pain in extremity

Back pain

Adverse Events

ADDITIONAL IMPORTANT SAFETY INFORMATION

Respiratory, thoracic, and mediastinal disorders 12

Psychiatric disorders Insomnia

TYKERB + CAPECITABINE SAFETY PROFILE

Musculoskeletal and connective tissue disorders

Dyspnea

with TYKERB

*PPE=palmar-plantar erythrodysesthesia.

General disorders and administrative site conditions Mucosal inﬂammation

of patients treated

*NCI CTCAE v3. † PPE=palmar-plantar erythrodysesthesia. ‡ Grade 3 dermatitis acneiform was reported in <1% of patients in the TYKERB plus capecitabine group.

Similar adverse events in single and combination treatment arms

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

IN HER2+ METASTATIC BREAST CANCER (MBC)—

TREAT HER DIFFERENTLY WITH TYKERB MONITORING HER CARDIAC RISK

CONVENIENT ORAL DOSING Adding TYKERB to Capecitabine Provides Efficacy and Convenience for Women With Advanced HER2+ MBC1

The Cardiac Safety of TYKERB Was Evaluated*9 LVEF

All patients (N=3689)

Total LVEF decrease

1.6% (60/3689)

Asymptomatic LVEF decrease

1.4% (53/3689)

Symptomatic LVEF decrease

0.2% (7/3689)

Pooled evaluation of left ventricular ejection

TYKERB 1250-mg daily dose Indicated with capecitabine dose of 2000 mg/ m2/day†

fraction (LVEF)9

*Tablets shown at actual size.

3689 patients in 44 phase 1 through 3 studies: 15% had received prior anthracyclines without trastuzumab therapy and 22.4% had received prior trastuzumab therapy alone or in combination with chemotherapy9

†

FIVE 250-mg TABLETS*

Administered orally once daily on Days 1-21 continuously in combination with capecitabine 2000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle.

TYKERB Should Be Taken as Directed

Among the 1.6% (60/3689) of patients with a decrease in LVEF, the mean decrease was 18.8% with a mean duration of 7.6 weeks9 †1

IN THE PIVOTAL TRIAL, LVEF WAS MONITORED AT APPROXIMATELY 8-WEEK INTERVALS Cardiac events were identiﬁed in 4 patients in the combination arm1 —3 patients experienced asymptomatic (Grade 2) LVEF adverse events

5 TABLETS O NC

E DA ILY

The indicated dosage of TYKERB is FIVE 250-mg tablets taken once daily continuously throughout treatment1

—1 patient experienced symptomatic (Grade 3) LVEF adverse events

DECREASED LVEF

TYKERB should be taken at least 1 hour before or 1 hour after a meal1 Capecitabine should be taken with food or within 30 minutes after food1

TYKERB/ capecitabine S

T 1

W Th F 9

13 14 15 16 17 18 19 20 21

The dosage of capecitabine is 2000 mg/m2/ day in 2 divided doses for the ﬁrst 14 days of each 21-day treatment cycle when taken in combination with TYKERB1

Do not crush, split, or dissolve TYKERB tablets10

Treatment should be continued until disease progression or unacceptable toxicity occurs1

The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea, nausea, vomiting, palmar-plantar erythrodysesthesia, rash, and fatigue

*Cardiac events deﬁned as NCI CTCAE Grade 3 or 4 toxicity or as a decrease in LVEF ≥20% relative to baseline and below the NCI CTCAE lower limit of normal. † LVEF decreases were deﬁned as signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE v3) or a ≥20% decrease in LVEF relative to baseline, which is below the institution’s lower limit of normal.

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

TYKERB + CAPECITABINE CARDIAC SAFETY/DOSING

TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Conﬁrm normal LVEF before starting TYKERB, and continue evaluations during treatment

Avoid strong CYP3A4 inhibitors or inducers. If unavoidable, consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 CYP3A4 inhibitor or consider gradual dose increase in patients coadministered a strong CYP3A4 inducer1

TREAT HER DIFFERENTLY WITH TYKERB INDICATION (in combination with capecitabine) TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

Diarrhea—Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB. Proactive management of diarrhea with anti-diarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and ﬂuids, and interruption or discontinuation of therapy with TYKERB.

INDICATION (in combination with letrozole)

Interstitial Lung Disease/Pneumonitis—TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥Grade 3 (NCI CTCAE), TYKERB should be discontinued.

TYKERB is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumabcontaining chemotherapy regimen for the treatment of metastatic breast cancer.

DOSE MODIFICATION GUIDELINES For dose modiﬁcation guidelines, please see accompanying Prescribing Information.

ADDITIONAL IMPORTANT SAFETY INFORMATION Contraindication—TYKERB is contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Decreased Left Ventricular Ejection Fraction—TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with conditions that could impair LVEF. Conﬁrm normal LVEF before starting TYKERB, and continue evaluations during treatment.

QT Prolongation—TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered. Pregnancy—Pregnancy Category D: TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions—The most common (>20%) adverse reactions during treatment with TYKERB plus capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue. The most common (≥20%) adverse reactions during treatment with TYKERB plus letrozole were diarrhea, rash, nausea, and fatigue.

References: 1. TYKERB Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2010. 2. Rowinsky EK. Signal events: cell signal transduction and its inhibition in cancer. Oncologist. 2003;8(suppl 3):5-17. 3. Baselga J, Arteaga CL. Clinical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005;23(11):2445-2459. 4. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk 1/2 and AKT pathways. Oncogene. 2002;21:6255-6263. 5. National Comprehensive Cancer Network Web site. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. v.1.2010. www.nccn.org. Accessed January 21, 2010. 6. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743. 7. Crown JP, Burris HA III, Boyle F, et al. Pooled analysis of diarrhea events in patients with cancer treated with lapatinib. Breast Cancer Res Treat. 2008;112:317-325. 8. Lacouture ME, Laabs SM, Koehler M, et al. Analysis of dermatologic events in patients with cancer treated with lapatinib. Breast Cancer Res Treat. 2009;114(3):485-493. 9. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008;83(6):679-686. 10. Taking medicines. National Institutes of Health Senior Health Web site. http://nihseniorhealth.gov/taking medicines/takingmedicines safely/01.html. Accessed November 16, 2009. 11. Barrios CH, Sampaio C, Vinholes J, Caponero R. What is the role of chemotherapy in estrogen receptor-positive, advanced breast cancer? Ann Oncol. 2009;20(7):1157-1162. 12. Johnston SRD. Integration of endocrine therapy with targeted agents. Breast Cancer Res. 2008;10(suppl 4):S20. 13. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as ﬁrst-line therapy for postmenopausal hormone receptor–positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538-5547. 14. Femara Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2009.

Please see accompanying Prescribing Information.

IMPORTANT SAFETY INFORMATION

Patients With Severe Hepatic Impairment—If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued.

IN HR+/HER2+ METASTATIC BREAST CANCER—

TYKERB + LETROZOLE PATIENT ID/MOA

WHEN CYTOTOXIC CHEMOTHERAPY IS NOT IMMEDIATELY NEEDED

TREAT HER DIFFERENTLY FIRST LINE IN THE ABSENCE OF SYMPTOMATIC VISCERAL CRISIS Cytotoxic-free chemotherapy should be considered for initial treatment of postmenopausal women with HR+/HER2+ MBC for whom hormonal therapy is indicated1,5,11

Proposed Mechanism of Action1

HR+/HER2+ MBC ABSENCE OF VISCERAL CRISIS5

SYMPTOMATIC VISCERAL CRISIS5

Patients with the absence of visceral crisis (including bone, soft tissue, asymptomatic visceral disease)

Patients with symptomatic visceral crisis (including shortness of breath, fatigue, etc)

Cytotoxic chemotherapy-free treatment option could be considered appropriate

TREATMENT OPTIONS

Anti-HER2 therapy plus cytotoxic chemotherapy

TARGET 2 DIFFERENT PATHWAYS WITH TYKERB + LETROZOLE1,12

Hormonal therapy

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

estrogen precursor

HR+

LETROZOLE

HER2 receptor

HER2+

estrogen

STANDARD OF CARE

TYKERB estrogen receptor

Anti-HER2 therapy + cytotoxic chemotherapy

FDA APPROVED—TYKERB + letrozole is the ﬁrst and only indicated targeted therapy in a cytotoxic-free combination regimen

INDICATIONS TYKERB is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumabcontaining chemotherapy regimen for the treatment of metastatic breast cancer

CELL PROLIFERATION AND GROWTH

Hormone receptor positive breast cancer cells (with ER [estrogen receptor] and/or PgR [progesterone receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies1 Similarly, hormone receptor positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy1

The most common adverse reactions (≥20%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhea, rash, nausea, and fatigue The most common Grade 3 and 4 adverse reactions (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 [NCI CTCAE v3]) with TYKERB plus letrozole compared to letrozole were diarrhea and fatigue

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

IN HR+/HER2+ METASTATIC BREAST CANCER—

WHEN CYTOTOXIC CHEMOTHERAPY IS NOT IMMEDIATELY NEEDED

TREAT HER DIFFERENTLY FIRST LINE EGF 30008: A LARGE PHASE 3, RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL1,13

BOTH GROUPS OF PATIENTS WERE WELL BALANCED

Study Design: N=1286 (including n=219 HER2+)1,13

HR+/HER2+ Patient Baseline Characteristics1,13

ER+ and/or PgR+ Postmenopausal HER2+, HER2-ve/ unknown

Stage IIIB/IIIC/IV

No prior treatment for MBC

A N

Median age (years) Letrozole 2.5 mg daily + placebo

D O

STRATIFICATION Disease sites — Bone only/ visceral or soft tissue

Interval since adjuvant tamoxifen therapy — <6 months, ≥6 months or none

PRIMARY ENDPOINT Investigator assessment of progression-free survival (PFS)* in HER2+ patients

I Z E

Letrozole (n=108)

Interval since prior adjuvant tamoxifen ≥6 months/none

73 (66%)

67 (62%)

≤6 months

38 (34%)

41 (38%)

0 or 1

Bone only

16 (14%)

18 (17%)

Visceral or soft tissue

95 (86%)

90 (83%)

Liver

33 (30%)

37 (34%)

Lung

43 (39%)

40 (37%)

ECOG performance status

TYKERB + letrozole (n=111)

TYKERB + LETROZOLE STUDY DESIGN

PATIENT POPULATION

Sites of disease Letrozole 2.5 mg daily + lapatinib 1500 mg daily

KEY SECONDARY ENDPOINTS Overall survival (OS)

Lymph node

57 (51%)

43 (40%)

Soft tissue

35 (32%)

31 (29%)

Other

19 (17%)

18 (17%)

Overall reponse rate (ORR) Safety

There were no signiﬁcant differences in patient baseline characteristics between the 2 groups1,13

Approximately 50% of the HER2 positive population had prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy1,13 Only 2 patients had prior trastuzumab. However, trastuzumab was not approved for adjuvant use at the time of the study initiation1,13

IMPORTANT SAFETY INFORMATION *PFS was deﬁned as the interval of time between date of randomization and the earlier date of ﬁrst documented sign of disease progression or death due to any cause.

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

IN HR+/HER2+ METASTATIC BREAST CANCER—

WHEN CYTOTOXIC CHEMOTHERAPY IS NOT IMMEDIATELY NEEDED

TREAT HER DIFFERENTLY FIRST LINE SIGNIFICANT IMPROVEMENT IN PROGRESSION-FREE SURVIVAL (PFS)1 Progression-Free Survival for the HER2+ Population Letrozole (2.5 mg) PFS 13 weeks (3.0 months)*

n=219 HR=0.71 (0.53, 0.96) P=0.019

0.8

TYKERB + letrozole

0.6

Letrozole

29% TYKERB + Letrozole Improvement in ProgressionFree Survival vs

DIAGNOSIS Stage I inﬁltrating lobular breast cancer ER+/PR–, HER2+ conﬁrmed by FISH

Letrozole 0.4

PRESENTATION Presented 4 years ago

0.2

Lumpectomy performed at initial diagnosis

0 0

100

120

140

160

180

200

Time (Weeks) *4.3 weeks=1 month.

At the time of updated analysis, the data for survival analysis were not mature1 Median PFS for patients taking TYKERB + letrozole was 35.4 weeks (8.2 months) compared to 13 weeks (3.0 months) for patients taking letrozole (P=0.019)1

Subsequent treatment plan called for 6 cycles of TCH followed by tamoxifen therapy for 5 years

TREATMENT Local radiation therapy was administered following completion of chemotherapy treatment. Trastuzumab continued for 12 months Completed 3 years of adjuvant tamoxifen and upon a scheduled routine follow-up, PET revealed intrathoracic and intraabdominal nodal metastasis

CURRENT STATUS Postmenopausal

TYKERB + LETROZOLE EFFICACY/CASE STUDY

Cumulative Progression-Free Survival

A Case Study: 52-Year-Old Retired Biologist

TYKERB (1500 mg) + letrozole (2.5 mg) PFS 35.4 weeks (8.2 months)*

1.0

WHAT TREATMENT OPTIONS WOULD YOU CONSIDER FOR THIS PATIENT?

ECOG PS=0 Asymptomatic supraclavicular adenopathy with 2 small liver lesions Normal liver function tests and serum creatinine levels

An independent assessment showed a signiﬁcant increase in response rate (27.9% for TYKERB + letrozole compared to 14.8% for letrozole)1

IMPORTANT SAFETY INFORMATION The most common adverse reactions (≥20%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhea, rash, nausea, and fatigue The most common Grade 3 and 4 adverse reactions (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 [NCI CTCAE v3]) with TYKERB plus letrozole compared to letrozole were diarrhea and fatigue

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

IN HR+/HER2+ METASTATIC BREAST CANCER—

WHEN CYTOTOXIC CHEMOTHERAPY IS NOT IMMEDIATELY NEEDED

TREAT HER DIFFERENTLY FIRST LINE HEPATIC PARAMETERS OF MAXIMUM TOXICITY NCI CTCAE V3 GRADE 3 OR 4 AT ANY POSTSCREENING VISIT (SAFETY POPULATION)

TYKERB + LETROZOLE ADVERSE EVENTS PROFILE Adverse Reactions Occurring in ≥10% of Patients1

Number (%) of Subjects1

TYKERB 1500 mg/day + letrozole 2.5 mg/day (N=654)

Reactions

All grades* (%)

Grade 3 (%)

Grade 4 (%)

Letrozole 2.5 mg/day (N=624)

All grades* (%)

TYKERB 1500 mg/day + letrozole 2.5 mg/day

Grade 3 Grade 4 (%) (%)

Gastrointestinal disorders Diarrhea

Nausea

Vomiting

Anorexia

Rash†

Dry skin

Alopecia

Pruritus

Nail disorder

Letrozole 2.5 mg/day

All grades (%)

Grade 3 (%)

Grade 4 (%)

All grades (%)

Grade 3 (%)

Grade 4 (%)

AST

ALT

Total bilirubin

Skin and subcutaneous tissue disorders

General disorders and administrative site conditions

Asthenia

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

The most common Grade 3 and 4 adverse reactions (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 [NCI CTCAE v3]) with TYKERB plus letrozole compared to letrozole were diarrhea and fatigue

Nervous system disorders Headache Respiratory, thoracic, and mediastinal disorders Epistaxis

The safety proﬁle of TYKERB was consistent with previously reported results from trials of TYKERB in the advanced or metastatic breast cancer population1 *NCI CTCAE v3. † In addition to the rash reported under “Skin and subcutaneous tissue disorders,” 3 additional subjects in each treatment arm had rash under “Infections and infestations”; none were Grade 3 or 4.

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

TYKERB + LETROZOLE SAFETY PROFILE

Fatigue

IN HR+/HER2+ METASTATIC BREAST CANCER—

WHEN CYTOTOXIC CHEMOTHERAPY IS NOT IMMEDIATELY NEEDED

TREAT HER DIFFERENTLY FIRST LINE TYKERB + LETROZOLE PROVIDES A CYTOTOXIC-FREE, ALL-ORAL REGIMEN

Cardiac Events—TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal. TYKERB in combination with letrozole 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.

TYKERB 1500-mg Daily Dose Indicated with letrozole 2.5 mg/day

*Tablets shown at actual size.

SIX 250-mg TABLETS*

5 TABLETS ONC

E D A I LY

+ LETROZOLE 2.5 mg O

E DAI

Avoid strong CYP3A4 inhibitors or inducers. If unavoidable, consider dose reduction of TYKERB in patients CYP3A4 coadministered a strong CYP3A4 inhibitor or consider gradual dose increase in patients coadministered a strong CYP3A4 inducer1

Do not crush, split, or dissolve TYKERB tablets10

The dosage of letrozole is 2.5 mg daily when taken in combination with TYKERB1

IMPORTANT SAFETY INFORMATION TYKERB should be taken with letrozole on an empty stomach, at least 1 hour before or 1 hour after food1 Letrozole can be taken with or without food14

Treatment should be continued until disease progression or unacceptable toxicity occurs1

Important Safety Warnings for TYKERB: Patients with known severe hypersensitivity to TYKERB or any of its components should not take TYKERB. Also, patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women. If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered The most common adverse reactions (≥20%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhea, rash, nausea, and fatigue The most common Grade 3 and 4 adverse reactions (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 [NCI CTCAE v3]) with TYKERB plus letrozole compared to letrozole were diarrhea and fatigue

Please see complete Important Safety Information on pages 12 and 13, including BOXED WARNING, and accompanying Prescribing Information.

TYKERB + LETROZOLE DOSING

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 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 CTCAE toxicity and can be restarted when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB in combination with letrozole should be restarted at a lower dose of 1250 mg/day.

TYKERB Should Be Taken as Directed The recommended dose of TYKERB is SIX 250-mg tablets taken orally once daily continuously in combination with letrozole1

DOSE MODIFICATION GUIDELINES

TREAT HER DIFFERENTLY WITH TYKERB SECOND-LINE INDICATION (in combination with capecitabine) TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1

FIRST-LINE INDICATION (in combination with letrozole) TYKERB is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.1 TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumabcontaining chemotherapy regimen for the treatment of metastatic breast cancer.1

28% to 43%* TYKERB + Capecitabine Lowered Risk of Progression by 28% to 43% vs Capecitabine Alone

SECOND LINE (HER2+ MBC)1 Investigator Assessment: TYKERB + capecitabine signiﬁcantly improved median TTP vs capecitabine; 23.9 weeks vs 18.3 weeks, respectively (P=0.00762) Independent Assessment: TYKERB + capecitabine signiﬁcantly improved median TTP vs capecitabine; 27.1 weeks vs 18.6 weeks, respectively (P=0.00013)

29% TYKERB + Letrozole Improvement in Progression-Free Survival vs Letrozole

FIRST LINE (HR+/HER2+ MBC)1 TYKERB + letrozole signiﬁcantly improved PFS vs letrozole; 35.4 weeks (8.2 months) vs 13 weeks (3.0 months), respectively (P=0.019)

*These percentages are derived from the hazard ratios in both the investigator and independent assessments.