1. CCO Independent Conference Coverage*: The 2015 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, December 8-12, 2015 San Antonio, Texas ExteNET: DFS With Neratinib in HER2+ BC After Adjuvant Trastuzumab *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Genentech and Novartis.

2. ExteNET: Background  In pts with HER2+ breast cancer, relapse has occurred in up to 26.3% of pts within 8.4 yrs of follow-up after adjuvant trastuzumab [1-4] –Highest risk of relapse within first year after trastuzumab [4] –Relapse risk lower among those without nodal metastases [5]  Neratinib, oral TKI of HER1, HER2, and HER4 –Data suggest efficacy in pts with HER2+ metastatic breast cancer treated with trastuzumab [6] –Diarrhea most common AE, within first mo of treatment  Current report is 3-yr exploratory analysis of neratinib after adjuvant chemotherapy with trastuzumab in pts with local HER2+ breast cancer enrolled in phase III ExteNET study [7] References in slidenotes. Slide credit: clinicaloptions.comclinicaloptions.com

3. ExteNET: Phase III Study Design  Primary endpoint: iDFS in ITT population at 2 yrs  Results of primary analysis: 2-yr iDFS improved with neratinib vs placebo (93.9% vs 91.6%, HR: 0.67; P =.009) –Hormone receptor+ (n = 1631): HR: 0.51; P =.001 –HER2+ 60% (n = 1463): HR: 0.51; P =.002 Slide credit: clinicaloptions.comclinicaloptions.com Chan A, et al. SABCS 2015. Abstract S5-02. Pts with HER2+ local BC; adj. trastuzumab completed ≤ 1 yr before study entry plus chemo; lymph node+ disease or no pCR; known ER and PgR status (N = 2840) iDFS: 2- and 5-yr F/U OS: 5-yr F/U Neratinib 240 mg/day Placebo 1 yr

4. ExteNET: Baseline Characteristics (3-Yr Analysis) Slide credit: clinicaloptions.comclinicaloptions.com Chan A, et al. SABCS 2015. Abstract S5-02. Characteristic, % Neratinib (n = 1420) Placebo (n = 1420) Median age, yrs (range)52 (25-83)53 (24-81) Negative nodal status23.623.7 Positive hormone receptor status57.7 57.3 Earlier trastuzumab regimen concurrent with chemo 60.363.3 Neoadjuvant anthracycline or anthracycline + taxane 80.679.7 Median time from trastuzumab, mos (range) 4.2 (0.4-30.9)4.3 (0.3-40.6)

5. 100 90 80 70 60 50 0 Neratinib (n = 1420) Placebo (n = 1420) 48 ExteNET Current Analysis: 3-Yr iDFS* Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. Slide credit: clinicaloptions.comclinicaloptions.com 2-sided P =.023 HR: 0.74 (95% CI: 0.56-0.96) 97.8% 95.6% 94.1% 91.6% 94.1% 89.9% 90.5% 88.6% 06121824303642 Disease-Free Survival (%) Mos After Randomization

6. Pts with hormone receptor–positive BC and trastuzumab completed ≤ 1 yr prior to study, neratinib vs placebo: 92.0% vs 86.9% (HR: 0.57; P =.004). ExteNET: 3-Yr iDFS in Pts With Trastuzumab Completed ≤ 1 Yr Prior to Study Entry Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. Slide credit: clinicaloptions.comclinicaloptions.com 100 90 80 70 60 50 0 Neratinib (n = 1152) Placebo (n = 1145) 48 2-sided P =.020 HR: 0.72 (95% CI: 0.54-0.95) 97.7% 95.2% 93.7% 90.6% 91.5% 88.9% 89.9% 87.5% 06121824303642 Mos After Randomization Disease-Free Survival (%)

7. ExteNET: 3-Yr iDFS in Pts With Centrally Confirmed HER2 Positivity Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. Slide credit: clinicaloptions.comclinicaloptions.com (n = 863) (n = 846) 100 90 80 70 60 50 0 Neratinib (n = 863) Placebo (n = 846) 48 2-sided P =.037 HR: 0.70 (95% CI: 0.50-098) 06121824303642 Mos After Randomization Disease-Free Survival (%) Pts with hormone receptor–positive BC and confirmed HER2+, neratinib vs placebo: 92.8% vs 86.3% (HR: 0.43; P <.001). 97.7% 94.8% 94.1% 91.0% 91.8% 89.6% 90.4% 87.9%

8. Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. ExteNET: 3-Yr iDFS by Hormone Receptor Status Slide credit: clinicaloptions.comclinicaloptions.com 100 90 80 70 60 50 0 100 90 80 70 60 50 0 0612182430364248 Mos After Randomization 0612182430364248 Mos After Randomization Neratinib (n = 816) Placebo (n = 815) 2-sided P =.003 HR: 0.57 (95% CI: 0.39-0.82) Disease-Free Survival (%) 98.0% 96.1% 95.4% 91.5% 93.6% 89.3% 92.3% 87.9% Neratinib (n = 604) Placebo (n = 605) 2-sided P =.938 HR: 0.57 (95% CI: 0.67-1.45) 97.5% 94.9% 92.5% 91.8% 90.6% 89.9% 89.5% 88.1% Hormone Receptor PositiveHormone Receptor Negative

9. ExteNET: Adverse Events and QoL  Diarrhea, main adverse event –Grade 3 diarrhea occurred in 39.9% of pts on neratinib –Median duration: 5 days (range: 1-139) –Most resolved in < 30 days; 1.4% pts hospitalized  Difference in QoL observed between arms in first mo but no differences seen afterward Slide credit: clinicaloptions.comclinicaloptions.com Chan A, et al. SABCS 2015. Abstract S5-02.

10. ExteNET: Conclusions  Neratinib significantly improved iDFS in pts with HER2+ breast cancer with PD after adjuvant trastuzumab –3-yr exploratory analysis consistent with and supports 2-yr primary endpoint analysis  Greatest benefit seen in those with –Centrally confirmed HER2+ disease –Completion of trastuzumab within 1 yr of study entry –Hormone receptor–positive disease  Data collection ongoing for prespecified 5-yr iDFS and OS endpoints Chan A, et al. SABCS 2015. Abstract S5-02. Slide credit: clinicaloptions.comclinicaloptions.com

11. Go Online for More CCO Coverage of SABCS 2015! Short slideset summaries of all the key data Additional CME-certified slideset on with expert faculty commentary on all the key studies clinicaloptions.com/oncology