APHINITY: Adjuvant Pertuzumab + Trastuzumab and Chemotherapy for HER2+ EBC CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals EBC, early breast cancer. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

APHINITY: Background Dual HER2 inhibition with addition of pertuzumab to trastuzumab + docetaxel as first-line therapy significantly extended PFS, OS in pts with HER2+ mBC[1] Combining pertuzumab with trastuzumab + docetaxel as neoadjuvant therapy also significantly increased pCR in pts with HER2+ EBC[2] Adjuvant trastuzumab + CT for a yr current SoC for HER2+ EBC However, some pts with HER2+ EBC will still have recurrent disease[3] APHINITY assessed efficacy, safety of adjuvant pertuzumab combined with trastuzumab + CT in pts with treatment/radiotherapy-naive HER2+ EBC[4] BC, breast cancer; CT, chemotherapy; EBC, early breast cancer; mBC, metastatic breast cancer; pCR, pathological CR; SoC, standard of care; tx, treatment. 1. Swain SM, et al. N Engl J Med. 2015;372:724-734. 2. Gianni L, et al. Lancet Oncol. 2012;13:25-32. 3. Cameron D, et al. Lancet. 2017;389:1195-1205. 4. von Minckwitz G, et al. ASCO 2017. Abstract LBA500. Slide credit: clinicaloptions.com

APHINITY: Study Design International, randomized, double-blind, placebo-controlled phase III trial[1,2] Primary endpoint: IDFS per modified STEEP definition[3] (excludes second primary non-BC as event) Secondary endpoints: IDFS per STEEP definition,[3] OS, distant recurrence-free survival, DFS, recurrence-free interval, safety, cardiac safety, health-related QoL Stratified by CT, nodal status, HR status, geographic region, protocol version (A vs B) Wk 52 Pts with HER2+ EBC, no prior invasive BC or anticancer tx or radiotherapy, node positive + any tumor size (no T0) or node negative + tumor size > 1 cm,* BL LVEF ≥ 55% (N = 4805) Pertuzumab + Trastuzumab + CT† (n = 2400) Surgery 10-yr follow-up Placebo + Trastuzumab + CT† (n = 2405) *Or node negative + 1 of following: for tumors > 0.5, ≤ 1 cm, at least 1 histologic/nuclear grade 3; ER negative and PgR negative; aged < 35 yrs. †Tx initiated ≤ 8 wks post surgery. Permitted CT: standard anthracycline or nonanthracycline regimens. Endocrine and/or radiotherapy could be started at end of adjuvant CT. BC, breast cancer; BL, baseline; CT, chemotherapy; DFS, disease-free survival; EBC, early breast cancer; HR, hormone receptor; IDFS, invasive disease-free survival; LVEF, left ventricular ejection fraction; QoL, quality of life; tx, treatment. 1. von Minckwitz G, et al. ASCO 2017. Abstract LBA500. 2. ClinicalTrials.gov. NCT01358877. 3. Hudis CA, et al. J Clin Oncol. 2007;25:2127-2132. Slide credit: clinicaloptions.com

APHINITY: Pt Characteristics in ITT Population Characteristic, n (%) Pertuzumab (n = 2400) Placebo (n = 2404) Nodal status 0 positive nodes + T ≤ 1 cm 0 positive nodes + T > 1 cm 1-3 positive nodes ≥ 4 positive nodes 90 (3.8) 807 (33.6) 907 (37.8) 596 (24.8) 84 (3.5) 818 (34.0) 900 (37.4) 602 (25.0) Adjuvant CT regimen (randomized) Anthracycline containing Nonanthracycline containing 1865 (77.7) 535 (22.3) 1877 (78.1) 527 (21.9) HR status (central determination) Negative (ER- and PgR-) Positive (ER+ and/or PgR+) 864 (36.0) 1536 (64.0) 858 (35.7) 1546 (64.3) Protocol version A Amendment B* 1828 (76.2) 572 (23.8) 1827 (76.0) 577 (24.0) CT, chemotherapy; HR, hormone receptor; ITT, intent to treat. *Capped node-negative enrollment in November 2012 (recruitment started November 2011); added 1000 node-positive pts and increased sample size to 4800 pts total. Slide credit: clinicaloptions.com von Minckwitz G, et al. ASCO 2017. Abstract LBA500.

APHINITY: Interim Analysis of IDFS Data cutoff in December 2016 after 379 IDFS events (median f/u: 45.4 mos) Most first events were visceral, distant 98.6% 96.4% 94.1% 92.3% 100 98.8% 95.7% 93.2% 90.6% 80 (Expected: 89.2%) IDFS Event, n (%) Pertuzumab (n = 2400) Placebo (n = 2404) All pts with IDFS event 171 (7.1) 210 (8.7) First event type Distant recurrence Locoregional recurrence Contralateral BC Death 112 (4.7) 26 (1.1) 5 (0.2) 28 (1.2) 139 (5.8) 34 (1.4) 11 (0.5) All pts with distant recurrence 119 (5.0) 145 (6.0) First distant recurrence site Lung/liver/pleural effusion CNS Other Bone 43 (1.8) 46 (1.9) 9 (0.4) 21 (0.9) 61 (2.5) 45 (1.9) 30 (1.2) 60 IDFS (%) 40 Pertuzumab Placebo Stratified HR: 0.81 (95% CI: 0.66-1.00; P = .045) 20 BC, breast cancer; CNS, central nervous system; f/u, follow-up; IDFS, invasive disease-free survival; ITT, intent to treat. 6 12 18 24 30 36 42 48 Mos Pts at Risk, n Pertuzumab Placebo 2400 2404 2309 2335 2275 2312 2236 2274 2199 2215 2153 2168 2101 2108 1687 1674 879 866 ITT population. Slide credit: clinicaloptions.com von Minckwitz G, et al. ASCO 2017. Abstract LBA500. Reproduced with permission.

APHINITY: Secondary Endpoints 3-Yr Endpoint, % Pertuzumab (n = 2400) Placebo (n = 2404) HR (95% CI)* P Value IDFS (modified STEEP) Node positive Node negative HR positive HR negative 94.1 92.0 98.4 94.8 92.8 93.2 90.2 97.5 94.4 91.2 0.81 (0.66-1.00) 0.77 (0.62-0.96) 1.13 (0.68-1.86) 0.86 (0.66-1.13) 0.76 (0.56-1.04) .045 .019 .644 .277 .085 IDFS (STEEP) 93.5 92.5 0.82 (0.68-0.99) .043 OS† 97.7 0.89 (0.66-1.21) .467 DRFI 95.7 95.1 0.82 (0.64-1.04) .101 DRFI, distant recurrence-free interval; HR, hormone receptor; IDFS, invasive disease-free survival; ITT, intent to treat. ITT population. *Stratified HR for overall IDFS, unstratified HR for IDFS subgroups. †OS for first interim analysis at 26% of target events. Slide credit: clinicaloptions.com von Minckwitz G, et al. ASCO 2017. Abstract LBA500.

Treatment Difference (95% CI) APHINITY: Safety Outcome, n (%) Pertuzumab (n = 2364) Placebo (n = 2405) Treatment Difference (95% CI) Primary cardiac endpoint Heart failure NYHA III/IV + LVEF drop* Cardiac death† Recovered according to LVEF 17 (0.7) 15 (0.6) 2 (0.08) 7 (0.3) 8 (0.3) 6 (0.2) 4 (0.2) 0.4% (0% to 0.8%) Asymptomatic or mildly symptomatic LVEF drop‡ 64 (2.7) 67 (2.8) -0.1% (-1.0% to 0.9%) Grade ≥ 3 AEs Neutropenia Febrile neutropenia Decreased neutrophil count Diarrhea Anthracycline CT, n/N (%) Nonanthracycline CT, n/N (%) Anemia 385 (16.3) 287 (12.1) 228 (9.6) 232 (9.8) 137/1834 (7.5) 95/528 (18.0) 163 (6.9) 377 (15.7) 266 (11.1) 230 (9.6) 90 (3.7) 59/1894 (3.1) 31/510 (6.1) 113 (4.7) Fatal AE 18 (0.8) 20 (0.8) AE, adverse event; BL, baseline; CT, chemotherapy; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. *LVEF drop defined as ejection fraction decrease ≥ 10% from BL to below 50%. †Determined by Cardiac Advisory Board per prospective definition. ‡Secondary cardiac endpoint. Slide credit: clinicaloptions.com von Minckwitz G, et al. ASCO 2017. Abstract LBA500.

APHINITY: Conclusions Adjuvant pertuzumab + trastuzumab + CT significantly reduced risk of recurrence events vs placebo + trastuzumab + CT in pts with HER2+ EBC HR: 0.81 (95% CI: 0.66-1.00; P = .045) Pts with node-positive or HR-negative disease had greatest IDFS benefit Most recurrences to distant sites (pertuzumab: 4.7%; placebo: 5.8%) Investigators concluded: No new safety signals identified with addition of pertuzumab to trastuzumab + CT Low incidence of cardiac events No difference in fatal AE rates between arms (0.8% for both) Increased diarrhea incidence with pertuzumab (any-grade: 71.2% vs 45.2% with placebo) Ongoing follow-up important to determine long-term IDFS, safety, and OS AE, adverse event; CT, chemotherapy; EBC, early breast cancer; HR, hormone receptor; IDFS, invasive disease-free survival. Slide credit: clinicaloptions.com von Minckwitz G, et al. ASCO 2017. Abstract LBA500.

Go Online for More CCO Coverage of ASCO 2017! Short slideset summaries and additional CME-certified analyses with expert faculty commentary on key studies in: Breast, gastrointestinal, genitourinary, lung, and skin cancers Gynecologic and hematologic malignancies clinicaloptions.com/oncology