ALTERNATIVE: Dual HER2 Blockade + Aromatase Inhibitor in Postmenopausal Women With HER2+, HR+ MBC 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 HR, hormone receptor; mBC, metastatic breast cancer. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

ALTERNATIVE: Background HER2+ MBC generally treated with CT and HER2 blockade, irrespective of HR status[1] Decreased risk of progression with addition of single HER2 blockade to endocrine therapy without CT in HER2+, HR+ MBC[2,3] Dual HER2 blockade associated with greater clinical benefit in neoadjuvant[4] and MBC[5] settings vs single HER2 blockade ALTERNATIVE compared CT-sparing regimen of dual HER2 blockade with LAP + TRAS vs single HER2 blockade with LAP or TRAS in combination with AI treatment in pts with progressive HER2+, HR+ MBC following TRAS + CT[6] AI, aromatase inhibitor; CT, chemotherapy; ET, endocrine therapy; HR, hormone receptor; LAP, lapatinib; mBC, metastatic breast cancer; TRAS, trastuzumab. 1. Montemurro F, et al. Ann Oncol. 2013;24:2715-2724. 2. Kaufman B, et al. J Clin Oncol. 2009;27:5529-5537. 3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546. 4. Baselga J, et al. Lancet. 2012;379:633-640. 5. Swain SM, et al. N Engl J Med. 2015;372:724-734. 6. Gradishar WJ, et al. ASCO 2017. Abstract 1004. Slide credit: clinicaloptions.com

ALTERNATIVE: Study Design International, randomized phase III trial (data cutoff: March 11, 2016) Stratified by prior TRAS in (neo)adjuvant or metastatic setting, choice of AI (steroidal vs nonsteroidal) Postmenopausal women with HER2+, ER+, and/or PgR+ MBC whose disease progressed during/after TRAS + CT in (neo)adjuvant or metastatic setting; prior ET in (neo)adjuvant and/or first-line metastatic settings allowed; ECOG PS 0/1, not appropriate for CT (N = 355) LAP 1000 mg/day + TRAS* + AI† (n = 120) Until PD, unacceptable AE, death, withdrawal, or investigator discretion TRAS* + AI† (n = 117) LAP 1500 mg/day + AI† (n = 118) *TRAS loading dose 8 mg/kg IV, then 6 mg/kg IV Q3W. †Investigator’s choice: LET 2.5 mg/day, ANA 1 mg/day, or EXE 25 mg/day. AE, adverse event; AI, aromatase inhibitor; ANA, anastrozole; CBR, clinical benefit rate; CNS, central nervous system; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; EXE, exemestane; LAP, lapatinib; LET, letrozole; MBC, metastatic breast cancer; PD, progressive disease; PS, performance status; QoL, quality of life; TRAS, trastuzumab. Primary endpoint: PFS with LAP + TRAS + AI vs TRAS + AI (investigator assessed by radiographic imaging) Changed from original primary endpoint of OS per non–data-driven protocol amendment in agreement with regulatory authorities (March 18, 2016) Secondary endpoints: other PFS comparisons, ORR, CBR, OS, safety, QoL Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

ALTERNATIVE: Baseline Characteristics Histology confirmed by central testing HR+: 241/285 pts (84.5%) HER2+: 190/270 pts (70.4%) HER2+ and HR+: 154/190 (81% of HER2+) Pt or Disease Characteristic, % LAP + TRAS + AI (n = 120) TRAS + AI (n = 117) LAP + AI (n = 118) Median age, yrs (range) 57 (32-80) 54 (30-84) 57 (33-82) Metastases Visceral Nonvisceral Both 24 35 41 22 42 15 Disease per organ Bone Breast Liver Lung Lymph nodes Other 51 12 28 48 39 11 32 44 47 27 43 26 Measurable disease at screening 74 71 68 Tx History, % LAP + TRAS + AI (n = 120) TRAS + AI (n = 117) LAP + AI (n = 118) Earlier anticancer tx CT Hormonal 100 96 97 98 Trastuzumab use (Neo)adjuvant Metastatic setting* 74 26 65 35 71 29 ≥ 3 prior CT regimens 4 2 6 AI, aromatase inhibitor; CT, chemotherapy; HR, hormone receptor; LAP, lapatinib; TRAS, trastuzumab; tx, treatment. *With or without (neo)adjuvant. Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

ALTERNATIVE: PFS and OS Primary endpoint: 38% reduction in risk of progression with LAP + TRAS + AI vs TRAS + AI in ITT population Trend across all subgroups favors therapy with LAP + TRAS + AI for PFS analysis Endpoint LAP + TRAS + AI (n = 120) TRAS + AI (n = 117) LAP + AI (n = 118) PFS PFS events, n (%) 62 (52) 75 (64) 74 (63) mPFS, mos (95% CI) 11.0 (8.3-13.8) 5.7 (5.5-8.4) 8.3 (5.8-11.2) HR (95% CI) vs TRAS + AI 0.62 (0.45-0.88) P = .0064 - 0.71 (0.51-0.98) P = .0361 OS OS events, n (%) 21 (18) 30 (26) 31 (26) mOS, mos (95% CI) 46.0 (46.0-NR) 40.0 (23.0-NR) 45.1 (22.3-NR) 0.60 (0.35-1.04) P = .070 0.82 (0.49-1.36) P = .440 AI, aromatase inhibitor; ITT, intent to treat; LAP, lapatinib; mOS, median OS; mPFS, median PFS; NR, not reached; TRAS, trastuzumab. Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

ALTERNATIVE: Response Endpoint, % LAP + TRAS + AI (n = 120) TRAS + AI (n = 117) LAP + AI (n = 118) Best response CR PR SD PD 5 27 43 15 < 1 13 45 31 7 12 53 24 CBR 41 33 ORR: CR + PR,* % (95% CI) 31.7 (23.5-40.8) 13.7 (8.0-21.3) 18.6 (12.1-26.9) *Pts with unknown/missing responses categorized as nonresponders. AI, aromatase inhibitor; CBR, clinical benefit rate; LAP, lapatinib; mOS, median OS; NR, not reached; PD, progressive disease; SD, stable disease; TRAS, trastuzumab. Odds ratio for ORR vs TRAS + AI LAP + TRAS + AI: 2.83 (95% CI: 1.43-5.89; P = .0017) LAP + AI: 1.492 (95% CI: 0.69-3.3; P = .2829) Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

ALTERNATIVE: Pt Disposition and Safety Disposition, n LAP + TRAS + AI (n = 118) TRAS + AI (n = 116) LAP + AI (n = 119) Protocol therapy ongoing 29 21 19 Treatment discontinued 89 95 100 Reason for discontinuation PD 75 84 83 AE 5 7 11 Other 9 4 6 AE, % LAP + TRAS + AI (n = 118) TRAS + AI (n = 116) LAP + AI (n = 119) Drug-related AEs 83 42 74 Any-cause SAE 14 10 17 Drug-related SAE 5 2 4 On-treatment deaths* 3 AE, adverse event; AI, aromatase inhibitor; LAP, lapatinib; PD, progressive disease; SAE, serious adverse event; TRAS, trastuzumab. *All deaths due to PD except 2 in LAP + AI group (cardiogenic shock and organ failure) and 1 in TRAS + AI group (cardiopulmonary arrest). Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

ALTERNATIVE: Adverse Events AEs in ≥ 15% of Pts In Any Arm,* % LAP + TRAS + AI (n = 118) TRAS + AI (n = 116) LAP + AI (n = 119) All Grade 3/4 Grade 3-4 Any Any event 92 34 74 22 32 Diarrhea 69 13 9 51 6 Rash 36 2 28 3 Paronychia 30 15 Nausea Decreased appetite 18 Stomatitis 17 < 1 Cough 8 ALT increase 7 4 AST increase 5 Headache 10 16 AE, adverse event; AI, aromatase inhibitor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LAP, lapatinib; TRAS, trastuzumab. Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

ALTERNATIVE: Conclusions PFS significantly prolonged with addition of dual HER2 blockade (LAP + TRAS) + AI vs TRAS + AI in pts with HER2+/hormone receptor+ MBC previously treated with ET and TRAS (mPFS: 11.0 vs 5.7 mos; HR: 0.62; P = .0064) PFS benefit observed in all subgroups ORR, CBR, OS also improved with LAP + TRAS + AI Trend for PFS benefit with dual HER2 blockade + AI vs LAP + AI also observed (mPFS: 11.0 vs 8.3 mos) mPFS prolonged with LAP + AI vs TRAS + AI (HR: 0.71; P = .0361) LAP + TRAS + AI associated with more frequent AEs Similar serious AE rates in all arms, with lower rate of AE-related d/c in LAP + TRAS + AI arm Investigators concluded that dual HER2 blockade with LAP + TRAS + AI provides effective, well-tolerated non-CT option for pts in which CT is not appropriate AE, adverse event; AI, aromatase inhibitor; CBR, clinical benefit rate; CT, chemotherapy; d/c, discontinuation; ET, endocrine therapy; LAP, lapatinib; mBC, metastatic breast cancer; mPFS, median PFS; TRAS, trastuzumab. Slide credit: clinicaloptions.com Gradishar WJ, et al. ASCO 2017. Abstract 1004.

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