Phase III SOLE: Continuous vs Intermittent Extended Letrozole After Adjuvant Endocrine Therapy in Early HR+ Breast Cancer 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. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Continuous vs Intermittent Letrozole After Endocrine Tx in Breast Cancer (SOLE): Background Extended adjuvant endocrine therapy with letrozole recommended after tamoxifen for postmenopausal women with HR-positive breast cancer[1] Magnitude of benefit limited in pts who received an AI during first 5 yrs[2] Extended therapy brings concerns about development of resistance to antihormonal therapy or spontaneous tumor growth in an estrogen-free environment[3] SOLE: randomized phase III trial evaluating use of intermittent letrozole as option to prolong sensitivity to endocrine treatment[4] Preclinical evidence for enhanced antitumor activity with a minimal concentration of estrogen achieved through intermittent AI therapy[5] AI, aromatase inhibitor; HR, hormone receptor; Tx, treatment. 1. Goss PE, et al. N Engl J Med. 2003;349:1793-1802. 2. Mamounas T, et al. SABCS 2016. Abstract S1-05. 3. Song RX, et al. J Natl Cancer Inst. 2001;93:1714-1723. 4. Colleoni M, et al. ASCO 2017. Abstract 503. 5. Sabnis GJ, et al. Cancer Res. 2008;68:4518-4524. Slide credit: clinicaloptions.com

SOLE: Study Design * * * * * 0 6 12 18 24 30 36 42 48 54 60 mos Stratified by prior adjuvant endocrine therapy (AI, SERM, or both) Continuous letrozole for 5 yrs (n = 2426) Postmenopausal women with clinically disease free HR+ lymph node-positive early BC who have completed 4-6 yrs of adjuvant endocrine therapy (N = 4851) Intermittent letrozole over 5 yrs (n = 2425) AI, aromatase inhibitor; BC, breast cancer; BCFI, breast cancer–free interval; DRFI, distant recurrence-free interval; HR, hormone receptor; QoL, quality of life; SERM, selective estrogen receptor modulator. 0 6 12 18 24 30 36 42 48 54 60 mos Endpoints Primary: DFS Secondary: BCFI, DRFI, OS * * * * * QoL substudy timepoints completed by 955 pts Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503.

SOLE: Pt Characteristics All Pts (N = 4851) Continuous Let (n = 2426) Intermittent Let (n = 2425) Median age at randomization, yrs 60 Tumor > 2 cm, % 52 Grade 3 disease, % 24 25 23 > 3 positive lymph nodes, % 33 HER2+, % 17 18 15 Prior AI only, % 43 Median duration of prior endocrine therapy, yrs 5 AI, aromatase inhibitor; Let, letrozole Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503.

SOLE: DFS (Primary Endpoint) Patients, n HR (95% CI) 5-Yr DFS, % Intermittent Continuous Intermittent Continuous 5-yr DFS 87.5% 100 All Pts 2425 2426 85.8 87.5 Prior Endocrine Therapy SERM(s) only Both SERM(s) and AI(s) AL(s) only 438 979 1008 435 977 1014 87.3 85.3 85.6 90.9 87.5 85.9 80 85.8% Continuous letrozole Intermittent letrozole 60 .25 .5 .75 1 1.5 2 Alive and Disease Free (%) Favors Intermittent Let Favors Continuous Let 40 DFS Event, % Continuous Let (n = 2426) Intermittent Let (n = 2425) DFS event 13.1 14.3 BC event as first site 8.9 8.7 Second malignancy (nonbreast) 3.1 3.9 Death without cancer event 0.9 1.4 Death, incomplete information 0.3 N 2426 2425 Events 319 346 HR (95% CI) 1.08 (0.93-1.26) P Value .31 20 AI, aromatase inhibitor; BC, breast cancer; DFS, disease-free survival; Let, letrozole; SERM, selective estrogen receptor modulator. Continuous Intermittent 1 2 3 4 5 6 Yrs Since Randomization Median follow-up: 60 mos Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503. Reproduced with permission.

SOLE: Breast Cancer–Free Interval and Distant Recurrence-Free Interval 5-yr BCFI 91.2% 5-yr DCFI 93.2% 100 100 90.9% 92.5% 80 80 Continuous letrozole Intermittent letrozole Continuous letrozole Intermittent letrozole 60 60 Percent Without Breast Cancer Percent Without Distant Recurrence 40 40 N 2426 2425 Events 217 214 HR (95% CI) .98 (.81 - 1.18) P Value .84 N 2426 2425 Events 179 159 HR (95% CI) .88 (.71 - 1.09) P Value .25 20 BCFI, breast cancer–free interval; DRFI, distant recurrence-free interval. 20 Continuous Intermittent Continuous Intermittent 1 2 3 4 5 6 1 2 3 4 5 6 Yrs Since Randomization Yrs Since Randomization Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503. Reproduced with permission.

Yrs Since Randomization SOLE: OS 5-yr OS 94.3% Patients, n HR (95% CI) 5-Yr OS, % 100 Intermittent Continuous Intermittent Continuous 93.7% 80 All Pts 2425 2426 94.3 93.7 Continuous letrozole Intermittent letrozole Prior Endocrine Therapy SERM(s) only Both SERM(s) and AI(s) 60 438 979 435 93.8 94.2 94.7 96.4 94.1 92.2 Percent Alive 977 40 AL(s) only 1014 1008 N 2426 2425 Events 170 146 HR (95% CI) 0.85 (0.68-1.06) P Value .16 20 AI, aromatase inhibitor; SERM, selective estrogen receptor modulator. .25 .5 .75 1 1.5 2 Continuous Intermittent Favors Intermittent Favors Continuous 1 2 3 4 5 6 Yrs Since Randomization Median follow-up: 60 mos Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503. Reproduced with permission.

SOLE: Treatment Adherence Time to Permanent Discontinuation of Letrozole 2 98%, 97%, 97%, 91% resumed after planned interruption Intermittent Letrozole: % of Days on Letrozole (3-Mo Intervals) 1.0 0.8 0.6 0.4 0.2 Mean Percentage of Days on Treatment 20 1 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Quarter Since Randomization 100 80 60 Continuous letrozole Intermittent letrozole Percent on Treatment 40 8% stopped for DFS event 24% stopped early, other reasons 39% completed 5 years 29% continue on treatment DFS, disease-free survival. 20 1 2 3 4 5 6 Yrs Since Randomization Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503. Reproduced with permission.

SOLE: Safety Select AEs, % Continuous Let (n = 2411) Intermittent Let (n = 2417) Any Grade Grade 3-5 Any grade 3-5 AE 34.5 36.2 Arthralgia 68.7 6.3 65.8 5.6 Hot flushes/flashes 54.3 2.9 52.9 2.4 Osteoporosis 46.9 0.7 47.5 1.1 Fatigue 44.9 41.5 2.0 Hypertension 43.8 21.4 44.6 24.2 Insomnia 43.2 42.0 2.2 Myalgia 37.1 36.1 Depression 34.1 2.5 Bone pain 28.7 27.3 1.9 Fractures 8.9 2.7 8.3 2.6 CNS cerebrovascular ischemia 1.7 1.2 1.4 1.0 Cardiac ischemia 1.5 0.9 1.8 0.8 CNS hemorrhage 0.5 0.3 0.6 0.4 AE, adverse event; CNS, central nervous system; Let, letrozole. Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503.

SOLE: Conclusions Extended intermittent letrozole did not improve DFS vs continuous dosing in postmenopausal women with HR+ breast cancer Trend toward differential effect seen depending on prior endocrine therapy (AI vs SERM) No change in safety profile with intermittent vs continuous dosing Study investigators suggest that this data could provide clinically relevant information for pts who could benefit from temporary treatment breaks during extended letrozole therapy Translational studies ongoing with prospectively collected tissue samples AI, aromatase inhibitor; DFS, disease-free survival; HR, hormone receptor; SERM, selective estrogen receptor modulator. Slide credit: clinicaloptions.com Colleoni M, et al. ASCO 2017. Abstract 503.

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