Treat HER Differently 1st line Annotated

TYKERB + Letrozole First-Line Sales Aid

Annotated Guide TKB894R0

for Oncology Account Managers

For sales training purposes only. Not to be shown to or left with healthcare professionals.

TKB978R0

TYKERB + Letrozole First-Line Sales Aid ANNOTATED GUIDE FOR ONCOLOGY ACCOUNT MANAGERS

EACH ANNOTATED PAGE INCLUDES 

Insights into TYKERB. Background information, including market research results or insights from the brand team.

The information in this section is FYI ONLY and cannot be shared with your customers

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Explanations of key selling points.

How-to-use and other selling tips

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Engaging questions for physicians.

Sample questions to initiate productive, 2-way dialogue with customers / HCPs

TKB894R0

p.2

For sales training purposes only. Not to be shown to or left with healthcare professionals.

FRONT COVER INSIGHT INTO TYKERB  A comprehensive sales aid (supporting both 1L and 2L indications) using the Treat Her Differently promotional campaign is under review

by FDA / DDMAC (TKB953R0).  The comprehensive sales aid will be rolled out later in summer 2010, once FDA / DDMAC comments are received and changes incorporated.  Early market research indicates that TYKERB + letrozole is being used in the 3L+ setting. Utilize this piece to drive appropriate firs-line use of TYKERB + letrozole

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The 1L indication for TYKERB identifies the appropriate patient type.

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When discussing the TYKERB 1L indication, it is important to note that the complete indication includes this statement that TYKERB + an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for treatment of MBC. You are required to review this statement when you introduce the new 1L indication with your customer

BOXED WARNING for hepatoxicity appears on the front and back cover of the sales aid. Always review the TYKERB BOXED WARNING and Important Safety Information on every sales call.

ENGAGING QUESTIONS Doctor, TYKERB + letrozole has recently been approved in the 1L setting for the treatment of HER2+ postmenopausal women with HR+ MBC for whom hormonal therapy is indicated. In addition, TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of MBC. What are your thoughts on this? p.3

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Patient Identification − PAGE 2 INSIGHT INTO TYKERB In market research, the information on “Patient Identification” was well received because it clearly identifies the type of patient you should be directing physicians to treat with TYKERB + letrozole in the 1L setting: “HR+ / HER2+ POSTMENOPAUSAL MBC IN THE ABSENCE OF SYMPTOMATIC VISCERAL CRISIS.” •

“IN THE ABSENCE OF SYMPTOMATIC VISCERAL CRISIS” refers to the absence of symptoms related to metastases in the viscera (lungs, liver, abdomen). Other disease sites without symptoms: bone, soft tissue, and lymph nodes.

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Here you will see the phrase "Treat HER Differently First Line.” This graphic also appeared in a convention panel at ASCO 2010 (TKB900R0).

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You can use the term “Treat HER Differently First Line” with physicians in the following context: “Treat your patients differently first-line with TYKERB − the first HER2+ directed agent indicated in combination with letrozole for the 1L treatment of HR+ / HER2+ MBC.”

Both approved indications for TYKERB are listed – if you need to refer to the 2L indication.

Always close each sales call with a review of Important Safety Information for TYKERB.

ENGAGING QUESTIONS Doctor, TYKERB is the first HER2+ directed agent indicated in combination with letrozole for first-line HR+ / HER2+ MBC. In the absence of symptomatic visceral crisis, TYKERB + letrozole may be considered for initial treatment of postmenopausal women with HR+ / HER2+ MBC for whom hormonal therapy is indicated. What are your thoughts on this? p.4

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Mechanism of Action − PAGE 3 INSIGHT INTO TYKERB •

In market research, many physicians reported that the MOA information presented here provided a reason-to-believe in the potential effects of TYKERB + letrozole

The proposed MOA visual for TYKERB + letrozole illustrates how both agents target 2 different pathways in HR+ and HER2+ breast cancer cells: • • •

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TYKERB crosses the cell membrane, blocking EGFR and HER2 inside the cell Letrozole works outside the cell, blocking the conversion of “estrogen precursors” (androgens) to estrogens Together, both agents could potentially block or inhibit cell proliferation and growth

Activation of growth factor receptors (EGFR / HER2) is associated with endocrine resistance

Review BOXED WARNING for hepatotoxicity and Important Safety Information (included on every spread).

ENGAGING QUESTIONS Doctor, what potential benefits do you see in targeting 2 different pathways with TYKERB + letrozole? p.5

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Study Design − PAGE 4

INSIGHT INTO TYKERB •

As you know, TYKERB + letrozole is indicated ONLY in HR+ / HER2+ MBC and NOT in women with HER2– MBC. Information and results for the HER2– population were added to provide complete context of the study population.

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A note about the sample size and statistical considerations from study EGF 30008: 218 patients with HER2+ MBC were needed to have 80% power to detect a 55% increase in median PFS (α=0.05). 1280 patients were needed to recruit the 218 HER2+ patients to have >90% power to detect a 30% increase in median PFS

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While these results are in the 1L metastatic setting, the opportunity for TYKERB is not just 1L, as many physicians still routinely use trastuzumab + AI as 1L treatment of HR+ / HER2+ MBC. TYKERB + letrozole can still be used 2L and even 3L in these HR+ / HER2+ postmenopausal patients for whom hormonal therapy is indicated after trastuzumab fails Study “EGF 30008” was a phase 3, randomized, double-blind, active control, multicenter, multicountry clinical trial conducted at 212 centers. The study enrolled 1286 postmenopausal women with HR+ MBC. No prior therapy for advanced or metastatic disease was allowed.  219 (17%) were HER2+

 952 (74%) were HER2–

 HER2 status not confirmed in 115 (9%)

Patients were randomized to: •

TYKERB 1500 mg/day + letrozole 2.5 mg/day; OR letrozole 2.5 mg/day + placebo

Patients were stratified by: •

Sites of disease (soft tissue / visceral or bone-only) and interval since adjuvant endocrine therapy (<6 mo since discontinuation; or 6 mo since discontinuation; or no prior endocrine therapy)

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Primary study endpoint was time to progression in HER2+ patients; overall survival, response rate, and safety were secondary endpoints

Approximately half of the HER2+ study population received prior adjuvant/neo-adjuvant chemotherapy; 56% had prior hormonal therapy − mostly tamoxifen. Prior AI use was very low, and only 2 patients had prior trastuzumab; both of these agents are currently part of SOC for adjuvant therapy in HER2+ patients. However, trastuzumab was not approved for adjuvant use during the time of study initiation.

Always close each sales call with a review of Important Safety Information for TYKERB.

ENGAGING QUESTIONS Doctor, can you share with me the clinical characteristics you consider when choosing to treat postmenopausal HR+ / HER2+ MBC patients with hormonal therapy? p.6

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Patient Characteristics − PAGE 5

INSIGHT INTO TYKERB Information on patient characteristics is essential, because it clearly defines the typical TYKERB patient (HR+ / HER2+) in the 1L MBC setting with regard to age, prior adjuvant endocrine therapy, performance status, and site of disease. Information in PATIENT CHARACTERISTICS is paralleled on p.7 in the CASE STUDY.

Both the TYKERB + letrozole group and the letrozole + placebo group were well balanced.

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In HER2+ population, median age in the TYKERB + letrozole group was 60 years (range, 44-85) and in the letrozole + placebo group was 59 years (range, 45-87)

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Approximately 2 of 3 patients had either no prior endocrine therapy or it had been at least 6 months or more since they stopped prior adjuvant endocrine therapy

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All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, normal organ function, and a left ventricular ejection fraction (LVEF) within the institutional range of normal

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Patients with extensive symptomatic visceral disease were excluded. The majority of patients (>90%) had stage IV disease and a median of 2 metastatic sites (range, 1-7)

Review Important Safety Information, including most common AEs (20%) and the most common Grade 3 AEs (NCI Common Terminology Criteria for AEs, version 3).

ENGAGING QUESTIONS Doctor, do the patient characteristics described here reflect the typical patient type with HR+ / HER2+ MBC you treat in your practice? p.7

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Clinical Efficacy − PAGE 6

INSIGHT INTO TYKERB In market research, according to all physicians, progression-free survival (primary endpoint) represents the most influential starting point in any discussion of efficacy.

The magnitude of the benefit in PFS achieved with TYKERB + letrozole was widely described as being “quite compelling” (although not surprising); the 5-month difference strongly supported use of TYKERB + letrozole in this patient population.

KEY SELLING MESSAGES TO BE DELIVERED ON EVERY CALL • In the HER2+ subgroup (n = 219), the addition of TYKERB to letrozole resulted in a statistically significant 29% improvement in PFS vs letrozole + placebo − Median PFS with TYKERB + letrozole was 35.4 weeks (8.2 months) vs 13.0 weeks (3.0 months) for letrozole + placebo (P = 0.019; HR = 0.71) − Response rate for TYKERB + letrozole was 27.9% vs 14.8% for letrozole alone − Overall survival data are not yet mature In the HER2– subgroup (n = 952), there was no improvement in PFS or response rates with TYKERB + letrozole as compared to letrozole + placebo.

Always close each sales call with a review of Important Safety Information for TYKERB.

ENGAGING QUESTIONS Doctor, what impact on progression-free survival would you expect from 1L hormonal therapy in postmenopausal women with HR+ / HER2+ MBC ? What treatment do you currently use 1L, 2L, and 3L in these patients? p.8

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Case Study − PAGE 7

INSIGHT INTO TYKERB. •

Many questions received from the field focus on “Patient Type / Characteristics” − − −

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What does the typical HR+ / HER2+ patient look like?

How do they present? How are they managed in the adjuvant setting?

What is their status when they are being considered for TYKERB + letrozole?

Information in the CASE STUDY parallels PATIENT CHARACTERISTICS on p.5. −

The case study clearly defines the typical TYKERB patient (HR+ / HER2+) in the 1L MBC setting with regard to age, prior adjuvant therapy, performance status, symptom status, and sites of disease.

WHAT 1L TREATMENT OPTIONS WOULD YOU CONSIDER FOR THIS PATIENT?

HR+ / HER2+ postmenopausal MBC in the absence of symptomatic visceral crisis • Patient was initially diagnosed at age 52. Following lumpectomy, patient was treated with: - Dose-dense AC→T (high-dose Adriamycin and Cytoxan, followed by Taxol) - Local radiation therapy - Adjuvant tamoxifen for 5 years • Patient had completed 3 years of tamoxifen when intra-abdominal and thoracic metastases were discovered during routine follow-up • Patient is currently 56 years old and postmenopausal; this is similar to the median age in EGF 30008 for the TYKERB + letrozole group (60 years, range, 44-85) - ECOG (Eastern Cooperative Oncology Group) Performance Status was 0: fully active, able to carry on all pre-disease performance without restriction - Patient has an asymptomatic supraclavicular adenopathy (enlargement of glandular tissues). Supraclavicular means above the clavicle (ie, collarbone) - Patient also had 2 small lesions on her liver and normal liver and kidney function tests

Review Important Safety Information and Safety Warnings for TYKERB.

ENGAGING QUESTIONS Doctor, what treatment has the most potential in this clinical setting (postmenopausal HR+ / HER2+ MBC)?

Would you feel comfortable using TYKERB + letrozole 1L in this patient? p.9

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Safety Profile (Common AEs) − PAGE 8

INSIGHT INTO TYKERB In market research, most physicians were able to visually separate the grade 3 / 4 toxicities from all grades. Moreover, the vast majority of oncologists described the TYKERB safety profile as “not surprising,” and suggested that the AE info does not significantly discourage use of the TYKERB + letrozole. Physicians also reported that they expect diarrhea and rash to be the primary differential AE when adding TYKERB to letrozole

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The most common AEs (all grades, ≥20%) occurring with TYKERB + letrozole vs letrozole alone were diarrhea (64%, 20%), rash (44%, 13%), nausea (31%, 21%), and fatigue (20%, 17%). The most common Grade 3/4 AEs with TYKERB + letrozole vs letrozole alone were diarrhea (9%, <1%) and fatigue (2%, <1%)

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The incidence of diarrhea with TYKERB + letrozole was 64% all grades, and 9% and <1% for grades 3/4, respectively. For letrozole + placebo, incidence of diarrhea for all grades was 20%, and <1% and 0% for grades 3/4, respectively. Patients with grade 3/4 diarrhea in TYKERB + letrozole were managed as follows: -15% discontinued drug -36% dose interruption

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- 19% dose reduction - 31% supportive measures

The TYKERB Diarrhea Management Card (TKB822R0) contains a quick reassessment of PI data and ASCO guidelines for managing diarrhea. The card will be updated for 1L TYKERB + letrozole when DDMAC changes are received. The card is level III (FYI only) and not approved for use with HCPs.

The safety profile of TYKERB in the 1L setting was consistent with previously reported results from trials of TYKERB in the 2L setting in advanced or MBC.

ENGAGING QUESTIONS Doctor, informing patients of potential GI side effects with TYKERB is very important so that patients know what to expect.

When prescribing TYKERB, what suggestions do you provide for proactive management of side effects, such as diarrhea? p.10

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Safety Profile (Hepatic) − PAGE 9 INSIGHT INTO TYKERB •

EGF 30008 was the first trial to evaluate the long-term hematologic and non-hematologic adverse events occurring with TYKERB in a trastuzumab-naïve population.

Hepatic effects associated with TYKERB (and associated BOXED WARNING) are well established: •

Hepatic abnormalities (all grades) with TYKERB + letrozole vs letrozole alone: - Increased AST (53%, 36%) - Increased ALT (46%, 35%) - Increased total bilirubin (22%, 11%)

Definitions •

ALT (alanine transferase) and AST (aspartate transaminase) are enzymes present in liver and other tissues. ALT and AST levels are elevated with liver damage or toxicity

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Bilirubin is a substance formed when red blood cells are broken down. Bilirubin is part of the bile, which is made in the liver and stored in the gallbladder. The abnormal buildup of bilirubin causes jaundice and is a sign of liver damage or toxicity

Review Important Safety Information and Safety Warnings for TYKERB.

ENGAGING QUESTIONS Doctor, how do you manage patients when hepatic toxicities occur during treatment? p.11

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Dosing − PAGE 10

INSIGHT INTO TYKERB In market research, many physicians suggested that having an “ALL-ORAL REGIMEN” represents an advantage for TYKERB + letrozole, particularly for certain patient types, (eg, elderly, patients not wanting to come to the office, patients with poor venous access).

Recommended dosing for TYKERB + letrozole 1L is as follows: •

TYKERB 1500 mg daily -

+

Letrozole 2.5 mg daily (one 2.5-mg tablet)

TYKERB is taken as 6 tablets (250-mg each) administered all at once Tablets shown in the figure are actual size Dividing the daily dose is not recommended 1500 mg/day is the maximum tolerated dose for TYKERB when administered concurrently with letrozole (based on Phase 1 study results)

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Timing of the TYKERB dose with food is important in order to minimize diarrhea

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TYKERB should be on an EMPTY stomach – at least 1 hour before or 1 hour after food.

This includes snacks

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Letrozole can be taken either with or without food

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Avoid strong CYP3A4 inhibitors or inducers during treatment with TYKERB, which may require dose modification. Be aware of the different CYP3A4 inhibitors or inducers listed below the table. In market research, some physicians praised inclusion of the commonly used CYP3A4 inhibitors and inducers, as these are generally not well known by oncologists

ENGAGING QUESTIONS Doctor, what are the benefits and challenges of administering an all-oral regimen in patients with MBC? p.12

For sales training purposes only. Not to be shown to or left with healthcare professionals.

Dose Modification Guidelines − PAGE 11 INSIGHT INTO TYKERB In market research, the majority of physicians perceived the cardiac and hepatic DOSE MODIFICATION GUIDELINES to be clear and in sufficient detail to be useful in clinical practice. Most physicians were satisfied with the “other toxicities” section of the page to serve as a miscellaneous category for other common AEs, such as diarrhea and rash.

The new TYKERB Dosing Card (TKB874R0) is a useful tool for detailing recommended dosing and administration. The card includes comprehensive dosing guidelines for 1L (side 1) and 2L (side 2), as well as Important Safety Information and BOXED WARNING.

Review Important Safety Information and Safety Warnings for TYKERB.

ENGAGING QUESTIONS Doctor, are you familiar with the dose modification guidelines for TYKERB + letrozole in the event of toxicities? p.13

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Important Safety Information â&#x2C6;&#x2019; PAGES 12-13

Use this spread to review the Indication (in combination with letrozole) and Important Safety Information and BOXED WARNING for TYKERB. The reference list is also included at the bottom of this spread.

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BACK COVER The back cover provides a quick, detailed summary, including Indications, Efficacy, Dosing, Safety, and BOXED WARNING. KEY SELLING POINTS: •

In the HER2+ subgroup (n = 219), the addition of TYKERB to letrozole resulted in a statistically significant 29% improvement in PFS vs letrozole + placebo -

Median PFS with TYKERB + letrozole was 35.4 weeks (8.2 months) vs 13.0 weeks (3.0 months) for letrozole + placebo (P = 0.019; HR = 0.71)

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Response rate for TYKERB + letrozole was 27.9% vs 14.8% for letrozole + placebo

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In the HER2– subgroup (n = 952), there was no improvement in PFS or response rates with TYKERB + letrozole as compared to letrozole + placebo

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An all-oral regimen (1500 mg/day); 6 tablets administered all at once

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Patients with known severe hypersensitivity to TYKERB or any of its components should not take TYKERB. Also, patients may experience decreased LVEF, hepatotoxicity, diarrhea, interstitial lung disease, 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 (≥20%) adverse reactions were diarrhea, rash, nausea, and fatigue TYKERB + letrozole offers a 1L oral treatment approach for postmenopausal women with HR+ / HER2+ MBC deemed suitable for endocrine therapy.

Review BOXED WARNING and Important Safety Information for TYKERB on every call.

ENGAGING QUESTIONS TYKERB is the first HER2+ directed agent indicated in combination with letrozole for 1L treatment of HR+ / HER2+ MBC. Doctor, do you have any patients in your practice who might be suitable candidates for TYKERB + letrozole? p.15

For sales training purposes only. Not to be shown to or left with healthcare professionals.