MA.17R: Reduced Risk of Recurrence With Extending Adjuvant Letrozole Beyond 5 Yrs in Postmenopausal Women With Early-Stage Breast Cancer CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *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.

MA.17R Extended Letrozole: Study Background 5 yrs of AI therapy, either initially or after 2-5 yrs of tamoxifen, standard of care for postmenopausal women with HR-positive early breast cancer Based largely on results of Canadian Cancer Trials Group MA.17 trial, which compared 5 yrs of letrozole vs placebo following 5 yrs of tamoxifen[1,2] DFS and OS outcomes superior with letrozole Extending AI treatment with letrozole to 10 yrs may further reduce risk of breast cancer recurrence Randomized, double-blind, placebo-controlled MA.17R trial designed to test efficacy of extending AI treatment with letrozole out to 10 yrs[3] AI, aromatase inhibitor; DFS, disease-free survival; HR, hormone receptor. 1. Goss PE, et al. N Engl J Med. 2003;349:1793-1802. 2. Jin H, et al. J Clin Oncol. 2012;30:718-721. 3. Goss PE, et al. ASCO 2016. Abstract LBA1. Slide credit: clinicaloptions.com

MA.17R: Study Design Primary endpoint: DFS (from randomization) Secondary endpoints: OS, CBC, safety, QoL Stratification by lymph node status at diagnosis, prior adjuvant chemotherapy, interval between last AI dose and randomization, duration of prior tamoxifen Postmenopausal pts with ER+ and/or PgR+ breast cancer who completed 4.5-6 yrs of letrozole 2.5 mg PO QD ± prior tamoxifen (N = 1918) Letrozole 2.5 mg PO QD for 5 yrs (n = 959) Follow-up Median follow-up: 6.3 yrs Placebo for 5 yrs (n = 959) AI, aromatase inhibitor; CBC, contralateral breast cancer; DFS, disease-free survival; ER, estrogen receptor; PgR, progesterone receptor; QoL, quality of life. Follow-up Slide credit: clinicaloptions.com Goss PE, et al. ASCO 2016. Abstract LBA1.

MA.17R Extended Letrozole: Baseline Characteristics Letrozole (n = 959) Placebo (n = 959) Median age, yrs (range) 65.6 (60.3-72.0) 64.8 (59.6-71.1) White (non-Hispanic), % 92.2 91.6 ECOG PS 0, % 88.8 89.3 Median time from diagnosis, yrs (range) 10.6 (7.5-11.5) 10.6 (7.8-11.6) Tumor size T1, % 57.6 55.8 Nodal status N0, % 46.5 46.7 Hormone receptor positive, % 98.5 99.1 > 4.5 yrs on prior tamoxifen, % 70.5 72.2 Adjuvant chemotherapy, % 58.5 58.1 Mastectomy, % 47.9 49.2 ECOG, Eastern Cooperative Oncology Group; PS, performance status Slide credit: clinicaloptions.com Goss PE, et al. ASCO 2016. Abstract LBA1.

MA.17R: DFS and OS After Median Follow-up of 6.3 Yrs DFS benefit of extended letrozole in all prespecified subgroups 5-yr OS: 93% vs 94% (HR: 0.97; P = NS) DFS Outcomes Letrozole Placebo HR (95% CI) P Value Overall 5-yr DFS, % 95 91 0.66 (0.48-0.91) .01 Events, n (%) 67 (7.0) 98 (10.2) New contralateral breast cancers, n (%) 13 (1.4) 31 (3.2) .007 Locoregional recurrences, n 19 30 Distant recurrences, n 42 53 Bone recurrences, n 28 37 AI, aromatase inhibitor; DFS, disease-free survival; NS, not significant. Slide credit: clinicaloptions.com Goss PE, et al. ASCO 2016. Abstract LBA1.

MA.17R: Safety Compliance similar between letrozole and placebo arms: 62.5% vs 62.3% No clinically significant differences in QoL between arms Adverse Event, % Letrozole (n = 959) Placebo (n = 959) P Value Hot flashes/flushes 38 37 NS Arthralgia 53 50 Myalgia 28 25 Bone pain 18 14 .01 Vaginal dryness 11 10 Elevated alkaline phosphatase 12 9 Elevated ALT .02 Cardiovascular event ALT, alanine aminotransferase; NS, not significant; QoL, quality of life. Slide credit: clinicaloptions.com Goss PE, et al. ASCO 2016. Abstract LBA1.

MA.17R: Fractures During Treatment Bone health and bone protection similar between arms at baseline Bone Events, % Letrozole (n = 959) Placebo (n = 959) P Value Bone fracture 14 9 .001 Location of bone fracture Spine Wrist Pelvis Hip Femur Tibia Ankle Other 1.8 2.8 0.1 0.7 0.9 0.5 2.0 7.1 1.7 0.6 0.4 1.2 5.0 .12 .09 .08 .79 .17 .74 .14 .06 New-onset osteoporosis 11 6 < .0001 Slide credit: clinicaloptions.com Goss PE, et al. ASCO 2016. Abstract LBA1.

MA.17R: Conclusions MA.17R first study to demonstrate benefit of extending AI treatment beyond 5 yrs Letrozole treatment for 10 yrs decreased risk of disease recurrence by 34% Majority of benefit in reduction of contralateral breast cancer No new toxicities observed Bone health remains important in weighing risks/benefits Treatment extension did not adversely impact QoL OS not improved by extending letrozole beyond 5 yrs Investigators note that AIs readily available worldwide, and introducing 10 yrs of AI therapy as standard of care should improve global burden of breast cancer AI, aromatase inhibitor; QoL, quality of life Slide credit: clinicaloptions.com Goss PE, et al. ASCO 2016. Abstract LBA1.

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