1. CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 PHEREXA: No PFS Benefit of Adding Pertuzumab to Trastuzumab + Capecitabine in HER2+ MBC Progressing on or After Trastuzumab-Based Therapy *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 activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. Capecitabine + Tmab ± Pmab in HER2+ MBC (PHEREXA): Background  HER2-positive MBC eventually progresses on first-line HER2-targeted therapy, necessitating subsequent treatment –Second-line trastuzumab + capecitabine well tolerated with improved ORR and TTP vs capecitabine alone [1] –Second-line trastuzumab + pertuzumab also active and safe in this population [2]  PHEREXA: phase III trial assessing benefit of adding pertuzumab to trastuzumab + capecitabine in pts with HER2-positive MBC who progressed during/after 1 line of trastuzumab-based therapy [3] 1. von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2006. 2. Baselga J, et al. J Clin Oncol. 2010;28:1138-1144. 3. Urruticoechea A, et al. ASCO 2016. Abstract 504. Slide credit: clinicaloptions.comclinicaloptions.com

3. PHEREXA: Study Design  Multicenter, randomized, open-label phase III trial  Primary endpoint: PFS by independent review  Secondary endpoints: OS, PFS by investigator, TTP, TTF, ORR, CBR, DoR, biomarkers, safety Pts with HER2+ MBC who have received Tmab and a taxane and progressed during/after Tmab- based therapy (N = 452) Pertuzumab* 420 mg IV Q3W + Trastuzumab † 6 mg/kg IV Q3W + Capecitabine 1000 mg/m 2 PO BID for 14d Q3W (n = 228) Trastuzumab † 6 mg/kg IV Q3W + Capecitabine 1250 mg/m 2 PO BID for 14d Q3W (n = 224) Slide credit: clinicaloptions.comclinicaloptions.com Urruticoechea A, et al. ASCO 2016. Abstract 504. Stratified by prior CNS disease, measurable/nonmeasurable disease, response to first-line trastuzumab Treated until PD or unacceptable toxicity *Loading dose: 840 mg IV. † Loading dose: 8 mg/kg IV.

4. PHEREXA: Baseline Characteristics CharacteristicPmab + Tmab + Capecitabine (n = 228) Tmab + Capecitabine (n = 224) Median age, yrs (range)5455 European, %7282 Race, %  White/Asian/black/other76/20/0/485/9/< 1/6 ER/PgR status, %  Positive/negative/unknown55/43/155/44/1 Visceral disease, %65 Prior trastuzumab setting, %  Neo/adjuvant and first-line MBC  First-line MBC only 27 73 24 76 Trastuzumab duration in first-line MBC, %  < 6 mos  6-12 mos  > 12 mos 27 28 45 21 37 42 Median time since last trastuzumab, mos1.441.41 Slide credit: clinicaloptions.comclinicaloptions.com Urruticoechea A, et al. ASCO 2016. Abstract 504.

5. PHEREXA: Survival Slide credit: clinicaloptions.comclinicaloptions.com Urruticoechea A, et al. ASCO 2016. Abstract 504. Reproduced with permission. PFS (IRF)OS Cape + Tmab + Pmab Cape + Tmab Median PFS, Mos 11.1 9.0 100 80 60 40 20 0 PFS (%) Mos 06551015202530354045505560 Arm A Arm B 224 228 142 165 74 99 38 58 26 39 21 23 11 95 3434 2323 1212 010100 Cape + Tmab + Pmab Cape + Tmab Median OS, Mos 36.1 28.1 100 80 60 40 20 0 OS (%) Mos 08010203040506070 Arm A Arm B 224 228 190 205 130 162 51 66 19 31 6 12 010100 *Statistical significance cannot be claimed because of hierarchical testing of OS after PFS by IRF assessment. HR: 0.82 (95% CI: 0.65-1.02) P =.07 HR: 0.68 (95%CI: 0.51-0.90)*

6. PHEREXA: Next Anticancer Therapies Subsequent Treatment in ≥ 10% of Pts,* %Pmab + Tmab + Capecitabine (n = 228) Tmab + Capecitabine (n = 218) ≥ 1 systemic treatment72 TKIs (eg, lapatinib)3235 Monoclonal antibodies  Tmab  Pmab  Other 29 1 35 34 4 < 3 Antimetabolites3330 Vinca alkaloids2334 Antineoplastic agents22 T-DM11918 Cytotoxic antibiotics1920 Taxanes1518 Alkylating agents1412 Aromatase inhibitors11 Platinum compounds1210 Slide credit: clinicaloptions.comclinicaloptions.com *Additional agents included antiestrogens, angiogenesis inhibitors, topoisomerase inhibitors, gonadotropin and analogues, and sex hormones. Urruticoechea A, et al. ASCO 2016. Abstract 504.

7. PHEREXA: Safety Overview Safety Event, %Pmab + Tmab + Capecitabine (n = 228) Tmab + Capecitabine (n = 218) Any AE9798 Grade ≥ 3 AE5260 Serious AE2524 AE leading to discontinuation of any tx 2119 AE leading to capecitabine dose modification 7279 AE resulting in death< 1*1†1† Slide credit: clinicaloptions.comclinicaloptions.com Urruticoechea A, et al. ASCO 2016. Abstract 504. *Due to general deterioration in physical health (n = 1). † Due to cardiac arrest (n = 1), subarachnoid hemorrhage (n = 1).

8. PHEREXA: Adverse Events AE,* %Pmab + Tmab + Capecitabine (n = 228) Tmab + Capecitabine (n = 218) All GradesGrade ≥ 3All GradesGrade ≥ 3 Diarrhea70165910 Nausea393453 Hand–foot syndrome56107322 Rash1505< 1 Nasopharyngitis11060 Neutropenia134186 Insomnia10< 160 Slide credit: clinicaloptions.comclinicaloptions.com Urruticoechea A, et al. ASCO 2016. Abstract 504. *Occurring in ≥ 10% of pts in either arm, with a ≥ 5% difference between arms.

9. PHEREXA: Cardiac Safety  All symptomatic LVSD considered possibly related to study treatment –5/5 pts received anthracyclines; 4/5 pts had cardiac medical history; 3/5 pts received chest radiotherapy –3/5 pts had BL LVEF < 50% –At clinical cutoff, 4 cases had resolved, 1 resolving but lost to follow-up Cardiac Event, n (%) Pmab + Tmab + Capecitabine (n = 228) Tmab + Capecitabine (n = 218) LVSD17 (7)7 (3) Symptomatic LVSD*  NYHA Class II  NYHA Class III  NYHA Class IV 5 (2) 3 (1) 1 (< 1) 00000000 Asymptomatic LVSD † 15 (7)7 (3) Slide credit: clinicaloptions.comclinicaloptions.com Urruticoechea A, et al. ASCO 2016. Abstract 504. *Symptomatic congestive heart failure and LVEF drop. † Asymptomatic LVEF drop ≥ 10% below BL and value < 50%, or asymptomatic LVEF drop requiring tx or leading to d/c.

10. PHEREXA: Conclusions  Addition of pertuzumab to trastuzumab + capecitabine in HER2+ MBC pts progressing during/after trastuzumab: –Does not significantly improve PFS, as assessed by independent review facility –Increases median OS by 8 mos; statistical significance could not be claimed due to hierarchical test of OS after primary endpoint (PFS by IRF)  No new safety signals observed Urruticoechea A, et al. ASCO 2016. Abstract 504. Slide credit: clinicaloptions.comclinicaloptions.com

11. Go Online for More CCO Coverage of ASCO 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in:  Breast, Genitourinary, and Lung cancers  Hematologic malignancies  Immunotherapy clinicaloptions.com/oncology