Fulvestrant ± Palbociclib in ER+/HER2- Breast Cancer: An Extended Follow-up of PALOMA-3 CCO Independent Conference Coverage*: The 2015 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, December 8-12, 2015 San Antonio, Texas *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. This program is supported by educational grants from Genentech and Novartis.

PALOMA-3: Background Standard-of-care therapy for pts with ER+ and/or PgR+ breast cancer includes selective ER modulators and aromatase inhibitors Overexpression of CDK-4/6 associated with proliferation of ER+ and/or PgR+ breast cancer Palbociclib: first-in-class, oral, selective CDK-4/6 inhibitor PALOMA-3: randomized, double-blind, placebo-controlled phase III trial of fulvestrant + palbociclib vs fulvestrant + placebo in ER+/HER2- metastatic breast cancer after progression on endocrine therapy Fulvestrant + palbociclib associated with significantly longer PFS than control arm; trial ended at interim analysis by DSMB[1] Current report: longer-term safety, efficacy, and subgroup analyses from PALOMA-3[2] DSMB, data and safety monitoring board; ER, estrogen receptor; PgR, progesterone receptor. 1. Turner NC, et al. N Engl J Med. 2015;373:209-2129. 2. Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01. Slide credit: clinicaloptions.com

PALOMA-3: Phase III Study Design Stratified by visceral metastases (yes/no), sensitivity to previous endocrine therapy, menopausal status Palbociclib 125 mg QD 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W (n = 347) Pts with HR+/HER2- MBC; PD after endocrine therapy; ≤ 1 chemotherapy regimen for advanced BC (N = 521) Tx to PD, toxicity, or study withdrawal Placebo 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W (n = 174) BC, breast cancer; CBR, clinical benefit rate; CR, complete response; HR, hormone receptor; MBC, metastatic breast cancer; PD, disease progression SD, stable disease; Tx, treatment. Primary endpoint: investigator-assessed PFS Secondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported outcomes, safety Slide credit: clinicaloptions.com Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.

PALOMA-3: Baseline Characteristics Baseline characteristics well balanced between arms; ~ 75% < 65 yrs of age Characteristic Palbociclib + Fulvestrant (n = 347) Placebo + Fulvestrant (n = 174) Median age, yrs (range) 57 (30-88) 56 (29-80) ER+ and PgR+, % 68.6 63.8 ER+ and PgR-, % 26.2 27.6 Sensitive to prior hormonal Tx, % 79.0 78.2 Metastatic disease at study entry, % 85.3 83.9 Prior AI ± GnRH agonist, % 67.8 Prior tamoxifen ± GnRH agonist, % 18.2 17.2 Prior neo/adjuvant chemotherapy, % 41.5 43.1 Prior lines of tx for metastatic disease, % 1 38.0 40.2 2 25.9 24.7 ≥ 3 11.8 9.2 AI, aromatase inhibitor; ER, estrogen receptor; GnRH, gonadotropin-releasing hormone; PgR, progesterone receptor; tx, treatment. Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01. Turner NC, et al. N Engl J Med. 2015;373:209-219. Slide credit: clinicaloptions.com

PALOMA-3: PFS in Overall Population and Specific Pt Subgroups Median follow-up: 8.9 mos Median PFS, Mos (95% CI) Palbociclib + Fulvestrant (n = 345) Placebo + Fulvestrant (n = 172) HR (95% CI) P Value ITT population 9.5 (9.2-11.0) 4.6 (3.5-5.6) 0.45 (0.36-0.59) < .0001 Pre-/perimenopausal pts 9.5 (7.4-NE) 5.6 (1.8-7.6) 0.50 (0.29-0.87) .0065 Postmenopausal women 9.9 (8.5-11.0) 3.9 (3.5-5.5) 0.45 (0.34-0.59) No earlier systemic therapy for metastatic disease 5.4 (2.1-10.9) 0.55 (0.32-0.92) .0214 Disease responsive to earlier endocrine therapy 10.2 (9.4-11.2) 4.2 (3.5-5.6) 0.42 (0.32-0.56) AIs as most recent therapy 3.7 (3.4-5.5) 0.42 (0.31-0.56) AI, aromatase inhibitor; ITT, intent to treat; NE, not evaluable. Slide credit: clinicaloptions.com Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.

PALOMA-3: Response and Clinical Benefit Rates Median follow-up: 8.9 mos Outcome, % (95% CI) Palbociclib + Fulvestrant (n = 345) Placebo + Fulvestrant (n = 172) Odds Ratio (95% CI) P Value ITT population ORR CBR 19.0 (15.0-23.6) 66.6 (61.3-71.5) 8.6 (4.9-13.8) 39.7 (32.3-47.3) 2.47 (1.36-4.91) 3.05 (2.07-4.61) .0019 < .0001 Pts with measurable disease at BL 24.6 (19.6-30.2) NR 10.9 (6.2-17.3) 2.69 (1.43-5.26) 3.10 (1.99-4.92) .0012 BL, baseline; CBR, clinical benefit rate; ITT, intent to treat; NR, not reported. Slide credit: clinicaloptions.com Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.

Palbociclib + Fulvestrant Palbociclib + Fulvestrant PALOMA-3: Grade 3/4 AEs Nonhematologic AE, n Palbociclib + Fulvestrant (n = 345) Placebo + Fulvestrant (n = 172) Infections 6 1 Fatigue 8 Headache 2 Vomiting Decreased appetite 3 Rash Back pain 4 Arthralgia Stomatitis Dizziness Dyspnea Pyrexia Insomnia Hematologic Event, n (%) Palbociclib + Fulvestrant (n = 345) Placebo + Fulvestrant (n = 172) Neutropenia 223 (65) 1 (< 1) Anemia 10 (3) 3 (2) Leukopenia 93 (27) 2 (1) Thrombocytopenia 6 (2) Febrile neutropenia incidence was similar with palbociclib + fulvestrant and placebo + fulvestrant (0.9% vs 0.6%, respectively) Discontinuations due to AEs were similar with palbociclib + fulvestrant and placebo + fulvestrant (4% vs 2%, respectively) AE, adverse event. Slide credit: clinicaloptions.com Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.

PALOMA-3: Conclusions In pts with ER+/HER2- breast cancer that has progressed after endocrine therapy The significant improvement in efficacy with the addition of palbociclib to fulvestrant was maintained through longer follow-up Benefit demonstrated across all subgroups No new safety concerns were identified; certain hematologic AEs were more common with palbociclib than fulvestrant alone The incidence of febrile neutropenia was similar for both treatment arms AE, adverse event; ER, estrogen receptor. Slide credit: clinicaloptions.com Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.

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