Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- Breast Cancer 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.

Neoadjuvant Palbociclib + Anastrozole: 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 Active in metastatic breast cancer in combination with aromatase inhibitor or fulvestrant[1-3] Current study evaluates the combination of palbociclib + anastrozole as neoadjuvant therapy in pts with stage II/III ER+/HER2- breast cancer[4] ER, estrogen receptor; PgR, progesterone receptor. 1. Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01. 2. Turner NC, et al. N Engl J Med. 2015;373:209-219. 3. Finn RS, et al. Lancet Oncol. 2015;16:25-35. 4. Ma CX, et al. SABCS 2015. Abstract S6-05. Slide credit: clinicaloptions.com

Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: Trial Design Pts with ER+/HER2-, stage II or III BC, ECOG PS 0-2 (N = 50) Anastrozole 1 mg QD x 28 days x 6 cycles* Palbociclib 125 mg QD Days 1-21 of 28 Concurrent with anastrozole cycles 1-4 Surgery *Cycle 0 with no palbociclib, cycles 1-4 with palbociclib, cycle 5 with palbociclib added for 10-12 days prior to surgery only in the last 20 pts enrolled; to assess molecular changes with anastrozole ± palbociclib Primary endpoint: complete cell cycle arrest, defined as Ki67 ≤ 2.7% on Day 15 after first 2 wks of the combination treatment. Protocol calls for removal from study if Ki67 > 10% at biopsy Secondary endpoints: clinical, radiologic, pathologic response, toxicity, rate of complete cell cycle arrest and rate of change in Ki67 by subtype and PIK3CA mutations; explore effect of palbociclib on molecular resistance mutations using next-generation sequencing on prespecified gene panel BC, breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Palbociclib + Anastrozole Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: Baseline Characteristics Characteristic Palbociclib + Anastrozole (N = 50) Median age, yrs (range) 57 (34-79) Premenopausal, % 36 Postmenopausal, % 64 Clinical stage, % II/IIA IIB IIIA IIIB/C 40 32 24 4 BC, breast cancer; ER, estrogen receptor. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Palbociclib + Anastrozole Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: Complete Cell Cycle Arrest Primary endpoint of CCCA, defined as Ki67 ≤ 2.7% on Day 15 after first 2 wks of the combination treatment Study objective: demonstrate a CCCA rate of 66% Response, % (90% CI) Palbociclib + Anastrozole (n = 45) Overall group (n = 45) 87 (75-94) PIK3CA wild-type genotype (n = 28) 79 (62-90) PIK3CA mutant genotype (n = 15) 100 (82-100) PIK3CA genotype undetermined (n = 2) 100 (NE) BC, breast cancer; CCCA, complete cell cycle arrest; ER, estrogen receptor; NE, not estimable. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Palbociclib + Anastrozole Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: CCCA by Tx Component Response, n Palbociclib + Anastrozole (N = 43) Ki67 < 2.7% with anastrozole alone 11 Ki67 < 2.7% with addition of palbociclib 26 Ki67 > 2.7% throughout treatment 6 BC, breast cancer; CCCA, complete cell cycle arrest; ER, estrogen receptor; Tx, treatment. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: CCCA Subgroup Analyses ΔKi67 Geometric Mean, P Value Cycle 0 Day 1 vs Cycle 1 Day 1 Cycle 1 Day 1 vs Cycle 1 Day 15 Ki67 < 2.7% by PIK3CA genotype Wild type, n = 28 Mutant, n = 15 < .001↓* .002↓ < .001↓ Ki67 < 2.7% by intrinsic subtype Luminal A, n = 18 Luminal B, n = 11 ΔKi67 Geometric Mean, P Value Cycle 1 Day 1 vs Surgery Cycle 1 Day 15 vs Palbociclib administration before surgery 4 wks washout, n = 26 Additional palbociclib 10-12 days before surgery, n = 8 .0187↑ .0111↓ < .0001↑ .2885↑ BC, breast cancer; CCCA, complete cell cycle arrest; ER, estrogen receptor. *Arrows indicate direction of change. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Palbociclib + Anastrozole Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: Clinical Response Response assessed for all pts who completed at least 3 cycles (n = 41) 5 pts off study per protocol: > 10% Ki67, n = 4; goserelin failure, n = 1 Response, n (%) Palbociclib + Anastrozole (N = 46) Overall response 31 (67; 95% CI: 54-79) CR 11 (24) PR 20 (43) Stable disease 6 (13) BC, breast cancer; ER, estrogen receptor. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Palbociclib + Anastrozole Palbociclib + Anastrozole Palbociclib + Anastrozole in ER+/HER2- BC: Grade 3/4 AEs and Dose Reductions AE, % Palbociclib + Anastrozole (N = 50) Neutropenia 26 ALT elevation 4* AST elevation 2* Hypertension Cholecystitis *All grade 3. No deaths or febrile neutropenia reported 1-Level Dose Reduction by Related AE, n Palbociclib + Anastrozole (N = 50) Grade 3 increase in ALT or AST 2 Grade 3 neutropenia 3 Grade 4 neutropenia 1 Grade 2 rash AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BC, breast cancer; ER, estrogen receptor. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

Neoadjuvant Palbociclib + Anastrozole in ER+/HER2- BC: Conclusions In pts with ER+/HER2- BC treated with palbociclib and anastrozole in the neoadjuvant setting: The combination improved cell cycle arrest over that seen with anastrozole alone Benefit seen regardless of PIK3CA genotype or luminal A or B status The combination was well tolerated with a low rate of grade 3/4 AEs, no deaths, and no febrile neutropenia Rebound Ki67 level after washout indicates that palbociclib efficacy requires ongoing administration The authors conclude that this study supports further evaluation of this combination in the adjuvant setting AE, adverse event; BC, breast cancer; ER, estrogen receptor. Slide credit: clinicaloptions.com Ma CX, et al. SABCS 2015. Abstract S6-05.

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