Abemaciclib + Endocrine or HER2-Targeted Therapies in Metastatic 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. This program is supported by educational grants from Genentech and Novartis.

Abemaciclib Combinations in MBC: Background Abemaciclib: investigational oral small molecule inhibitor of CDK 4/6[1] Induces cell cycle arrest in Rb-proficient cancers Exhibits clinical activity as single agent[2] and acceptable safety profiles in combination with either fulvestrant[3] or aromatase inhibitors[4] in previously treated HR+ MBC Current study evaluated safety and antitumor activity of abemaciclib when given with endocrine or HER2-targeted therapies for the treatment of MBC[5] HR, hormone receptor; MBC, metastatic breast cancer. 1. Gelbert LM, et al. Invest New Drugs. 2014;32:825-837. 2. Tolaney SM, et al. SABCS 2014. Abstract P5-19-13. 3. Patnaik A, et al. ASCO 2014. Abstract 534. 4. Tolaney SM, et al. ASCO 2015. Abstract 522. 5. Goetz MP, et al. SABCS 2015. Abstract P4-13-25. Slide credit: clinicaloptions.com

Abemaciclib Combinations in MBC: Study Design Phase Ib study Primary objective: safety Secondary objective: antitumor activity, PK Abemaciclib 200 mg Q12H + Cohort A: Letrozole 2.5 mg QD (n= 20) Cohort B: Anastrozole 1 mg QD (n = 16) Cohort C: Tamoxifen 20 mg QD (n = 15) Cohort D: Exemestane 25 mg QD (n = 15) Cohort E*: Abemaciclib 150/200 mg Q12H + Exemestane 25 mg QD + Everolimus 5 mg QD (n = 17) Pts with HR+, HER2- MBC; premenopausal + ovarian suppression or postmenopausal; ECOG PS 0 or 1; no prior CT for MBC (N = 83) Pts with HER2+ MBC; pre- or postmenopausal; ECOG PS 0 or 1; ≥ 1 prior CT for MBC (N = 10) Cohort F:* Abemaciclib 150/200 mg Q12H + + Trastuzumab 6-8 mg/kg IV on Day 1 of 21-day cycle (n = 10) CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; HR, hormone receptor; MBC, metastatic breast cancer; PK, pharmacokinetics; PS, performance status. *Abemaciclib 3 + 3 dose escalation with fixed doses of the combination drug(s). Sequential enrollment. Sequential dose adjustments of 50 mg allowed for toxicity. Abemaciclib given until progression, unacceptable toxicity, or pt elected to stop. Goetz MP, et al. SABCS 2015. Abstract P4-13-25. ClinicalTrials.gov. NCT02057133. Slide credit: clinicaloptions.com

Abemaciclib Combinations in MBC: Baseline Characteristics Abe + Let (n = 20) Abe + Ana (n = 16) Abe + Tam Abe + Exe (n = 15) Abe + Exe/Eve Abe + Tras 150 mg (n = 13) 200 mg (n = 4) (n = 6) Age, median yrs (range) 59.0 (33-73) 55.5 (26-72) 59.5 (46-77) 52.0 (40-73) 57.0 (41-73) 64.5 (50-68) 53.5 (45-64) (48-76) White race, % 100 88 93 92 75 ECOG PS, % 1 2 80 15 5 81 19 25 20 31 61 8 67 33 Prior systemic therapies, median n (range) (1-4) 3 (1-8) (1-6) 4 2.5 (2-5) 10.5 (1-15) 6.5 (4-8) Measurable disease, % 45 56 50 62 83 HR/HER status, % HR+/HER- HR+/HER+ HR-/HER2+ 17 Abe, abemaciclib; Ana, anastrozole; ECOG, Eastern Cooperative Oncology Group; Eve, everolimus; Exe, exemestane; HR, hormone receptor; Let, letrozole; MBC, metastatic breast cancer; PS, performance status; Tam, tamoxifen; Tras, trastuzumab. Slide credit: clinicaloptions.com Goetz MP, et al. SABCS 2015. Abstract P4-13-25.

Abemaciclib Combinations in MBC: Treatment-Emergent AEs, Cohorts A-D TEAEs in > 33% of Pts in Any Cohort, % Abe + Let (n = 20) Abe + Ana (n = 16) Abe + Tam (n = 16) Abe + Exe (n = 15) Grade 1/2 Grade 3 Diarrhea 55 45 60 31 63 67 27 Fatigue 65 20 19 44 53 13 Nausea 15 75 6 Vomiting 30 10 40 Anemia 25 Decreased appetite 5 50 Abdominal pain Dehydration 7 Rash WBC decreased 70 56 Neutrophils decreased Lymphocytes decreased Platelet count decreased Creatinine increased 100 88 Hypercalcemia Abe, abemaciclib; AE, adverse event; Ana, anastrozole; Exe, exemestane; Let, letrozole; MBC, metastatic breast cancer; TEAE, treatment-emergent adverse event; Tam, tamoxifen; WBC, white blood cell. Slide credit: clinicaloptions.com Goetz MP, et al. SABCS 2015. Abstract P4-13-25.

Abemaciclib Combinations in MBC: Treatment-Emergent AEs, Cohorts E and F TEAEs in > 33% of Pts in Any Cohort, % Abe + Exe/Eve Abe + Tras 150 mg (n = 13) 200 mg (n = 4) 150 mg (n = 4) 200 mg (n = 6) Grade 1/2 Grade 3 Diarrhea 62 15 75 25 50 17 83 Fatigue 54 8 100 33 Nausea 31 Vomiting Anemia 23 Decreased appetite 38 Abdominal pain 46 Dehydration Rash WBC decreased Neutrophils decreased Lymphocytes decreased Platelet count decreased Creatinine increased 92 Abe, abemaciclib; AE, adverse event; Eve, everolimus; Exe, exemestane; G, grade; MBC, metastatic breast cancer; TEAE, treatment-emergent adverse event; Tras, trastuzumab; WBC, white blood cell. Slide credit: clinicaloptions.com Goetz MP, et al. SABCS 2015. Abstract P4-13-25.

Abemaciclib Combinations in MBC: PFS and Tumor Response, Cohorts A-E Abe + Let (n = 20) Abe + Ana (n = 16) Abe + Tam Abe + Exe (n = 15) Abe + Exe/Eve 150 mg (n = 13) 200 mg (n = 4) Best overall response CR PR SD PD Unknown 10 50 30 19 69 6 56 7 27 40 20 15 39 46 75 25 ORR (CR + PR) All pts Pts with measurable disease 22 33 38 Disease control rate (CR + PR + SD) 60 88 73 54 Clinical benefit rate (CR + PR + SD > 24 wks) 81 Not mature 6-mo PFS, % (95% CI) 76.2 (42.7-91.7) 66.7 (56.4-96.5) 73.3 (43.6-89.1) 75.2 (40.7-91.4) 12-mo PFS, % (95% CI) 79.4 (48.8-92.9) 64.2 (33.3-83.6) Abe, abemaciclib; Ana, anastrozole; Eve, everolimus; Exe, exemestane; Let, letrozole; MBC, metastatic breast cancer; PD, progressive disease; SD, stable disease; Tam, tamoxifen; Tras, trastuzumab. Slide credit: clinicaloptions.com Goetz MP, et al. SABCS 2015. Abstract P4-13-25.

Abemaciclib Combinations in MBC: Conclusions Abemaciclib + endocrine and HER2-targeted therapies achieved tumor responses in pts with MBC No observed drug–drug interactions between abemaciclib and tamoxifen, exemestane, or trastuzumab Most frequent grade 3 toxicities included diarrhea, neutropenia, and leukopenia Ongoing randomized phase III trials are evaluating abemaciclib + AIs and the antiestrogen fulvestrant in MBC Recommended abemaciclib dose 150 mg Q12H in combination with AI, tamoxifen, or exemestane AI, aromatase inhibitor; MBC, metastatic breast cancer. Goetz MP, et al. SABCS 2015. Abstract P4-13-25.ClincalTrials.gov. NCT0224662. ClincalTrials.gov. NCT02107703. Slide credit: clinicaloptions.com

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