PALOMA-2: Addition of Palbociclib to Frontline Letrozole Significantly Improves PFS in Postmenopausal ER+/HER2- Advanced 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. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

PALOMA 2: Background CDKs: serine/threonine kinases that regulate cell cycle progression via interaction with cyclins[1] Palbociclib: selective oral CDK-4/6 inhibitor that blocks G1 to S cell cycle progression[2]; currently FDA approved to treat pts with HR+/HER2- MBC in combination with: Letrozole as initial hormonal-based tx for post-menopausal women PALOMA-1: open-label, randomized phase II study demonstrated 10-mo PFS improvement (P = .0004) with palbociclib + letrozole vs letrozole alone, leading to accelerated FDA approval for ER+/HER2- advanced breast cancer[3] Fulvestrant for women with disease progression following hormonal tx PALOMA-3: double-blind, randomized phase III study showed 5-mo PFS improvement (P < .0001) with palbociclib + fulvestrant vs fulvestrant + placebo in HR+/HER2- advanced breast cancer with PD after endocrine therapy[4] Current study, PALOMA-2, evaluated first-line palbociclib + letrozole vs placebo + letrozole in pts with ER+/HER2- advanced breast cancer[5] CDK, cyclin-dependent kinase; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MBC, metastatic breast cancer; PD, progressive disease; tx, treatment. 1. Musgrove EA, et al. Nat Rev Cancer. 2011;11:558-572. 2. Fry DW, et al. Mol Cancer Ther. 2004;3:1427-1438. 3. Finn RS, et al. Lancet Oncol. 2015;16:25-35. 4. Cristofanilli M, et al. Lancet Oncol. 2016;17:425-439. 5. Finn R, et al. ASCO 2016. Abstract 507. Slide credit: clinicaloptions.com References in slidenotes.

Palbociclib 125 mg QD (3/1 schedule) PALOMA 2: Study Design Multicenter, international, double-blind, randomized phase III trial Primary endpoint: PFS by investigator Secondary endpoints: response, OS, safety, biomarkers, pt-reported outcomes Stratified by disease site (visceral vs nonvisceral), disease-free interval (de novo metastatic; ≤ 12 mos vs > 12 mos), prior neoadjuvant or adjuvant hormonal therapy (yes vs no) Postmenopausal women with ER+/HER2- advanced breast cancer, no prior treatment for advanced disease, no AI resistance (N = 666) Palbociclib 125 mg QD (3/1 schedule) + Letrozole 2.5 mg QD (n = 444) Placebo (3/1 schedule) + Letrozole 2.5 mg QD (n = 222) AI, aromatase inhibitor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. Slide credit: clinicaloptions.com Finn R, et al. ASCO 2016. Abstract 507.

PALOMA 2: Baseline Characteristics (ITT) Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) Median age, yrs (range) 65 yrs or older, % 62 (30-89) 41 61 (28-88) 36 Race, % White/Black/Asian/other 77/2/15/6 77/1/14/8 ECOG PS, % 0/1/2 58/40/2 46/53/1 Disease site, % Visceral Nonvisceral Bone only 48 52 23 50 22 Disease-free interval, % > 12 mos ≤ 12 mos De novo advanced disease 40 38 42 Prior (neo)adjuvant hormonal therapy, % 56 57 ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status. Slide credit: clinicaloptions.com Finn R, et al. ASCO 2016. Abstract 507.

Palbociclib + Letrozole PALOMA 2: PFS Outcome Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) HR (95% CI); P Value Investigator-assessed Number of events, n (%) Median PFS, mos (95% CI) 194 (44) 24.8 (22.1-NR) 137 (62) 14.7 (12.9-17.1) 0.58 (0.46-0.72); < .000001 Blinded independent central review 152 (34) 30.5 (27.4-NR) 96 (43) 19.3 (16.4-30.6) 0.65 (0.51-0.84); .0005 Blinded independent central review confirmed investigator- assessed PFS advantage Benefit with palbociclib + letrozole evident across all subgroups NR, not reached. Slide credit: clinicaloptions.com Finn R, et al. ASCO 2016. Abstract 507.

PALOMA 2: Secondary Endpoints Outcome[1] Palbociclib + Letrozole Placebo + Letrozole OR (95% CI) P Value ITT population ORR,* % (95% CI) CBR,† % (95% CI) n = 444 42 (37.5-46.9) 85 (81.2-88.1) n = 222 35 (28.4-41.3) 70 (63.8-76.2) 1.40 (0.98-2.01) 2.39 (1.58-3.59) .0310 < .0001 Pts with measurable disease n = 338 55 (49.9-60.7) 84 (80.0-88.0) n = 171 44 (36.9-52.2) 71 (63.3-77.5) 1.55 (1.05-2.28) 2.23 (1.39-3.56) .0132 .0003 *Confirmed CR + PR. †Confirmed CR + PR + SD ≥ 24 wks. Clinical benefit consistent with phase II open-label PALOMA-1 study[2] CBR, clinical benefit rate; ITT, intent to treat; OR, odds ratio; SD, stable disease. 1. Finn R, et al. ASCO 2016. Abstract 507. 2. Finn RS, et al. Lancet Oncol. 2015;16:25-35. Slide credit: clinicaloptions.com

Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) PALOMA 2: Safety AEs (All Causality), % Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) Any Grade Grade 3 Grade 4 Any AE 99 62 14 95 22 2 Hematologic AE in ≥ 15% of pts in either arm Neutropenia* 80 56 10 6 1 < 1 Leukopenia* 39 24 Anemia* 5 9 Thrombocytopenia* 16 Nonhematologic AE in ≥ 25% of pts in either arm Fatigue 37 28 Nausea 35 26 Arthralgia 33 34 Alopecia Diarrhea 19 Cough 25 Headache 21 Hot flush 31 AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activity. *Includes clustered MedDRA-preferred terms. Slide credit: clinicaloptions.com Finn R, et al. ASCO 2016. Abstract 507.

Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) PALOMA 2: AE Summary Outcome, % Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) Serious AE 19.6 12.6 Serious AE occurring in ≥ 1% of pts Febrile neutropenia Pulmonary embolism 1.6 0.9 1.4 AE-related discontinuation 9.7 5.9 AE-related death 2.3 1.8 AE, adverse event; d/c, discontinuation. Most AEs resulting in d/c reported as single events, most commonly neutropenia with palbociclib (1.6%) or fatigue with placebo (0.9%) One on-study, treatment-related death because of pulmonary embolism/respiratory failure in placebo arm Slide credit: clinicaloptions.com Finn R, et al. ASCO 2016. Abstract 507.

PALOMA 2: Conclusions First-line palbociclib + letrozole significantly improved median PFS vs placebo + letrozole in women with ER+/HER2- advanced breast cancer Median PFS improved by > 10 mos compared to placebo 24.8 mos vs 14.5 mos, HR: 0.58 (95% CI: 0.46-0.72; P < .0001) Palbociclib clinical benefit observed in all prespecified subgroups Palbociclib well tolerated with neutropenia, leukopenia the most frequently reported AEs PALOMA-2[1] data confirm PALOMA-1[2] results and constitute the longest median PFS improvement to date in the front-line setting in advanced ER+ breast cancer AE, adverse event; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. 1. Finn R, et al. ASCO 2016. Abstract 507. 2. Finn RS, et al. Lancet Oncol. 2015;16:25-35. Slide credit: clinicaloptions.com

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