Abemaciclib in Combination with Therapies for Patients with Metastatic Breast Cancer: A Phase 1b Study

Sara M Tolaney ^1* Komal Jhaveri ² Teresa Helsten ³ Shannon Puhalla ⁴ Alison Conlin ⁵ E Claire Dees ⁶ Muralidhar Beeram ⁷ Sonya C Chapman ⁸ Andrew Lithio ⁸ Lacey M Litchfield ⁸ Matthew Goetz ⁹

• ¹ Dana–Farber Cancer Institute, Boston, United States
• ² Memorial Sloan Kettering Cancer Center, New York, New York, United States
• ³ University of California, San Diego, La Jolla, California, United States
• ⁴ University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ⁵ Providence Cancer Center, Providence Portland Medical Center, Portland, United States
• ⁶ University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
• ⁷ South Texas Accelerated Research Therapeutics,, San Antonio, TX, United States
• ⁸ Eli Lilly (United States), Indianapolis, Indiana, United States
• ⁹ Mayo Clinic, Rochester, Minnesota, United States

Background: The oral, selective, and potent small molecule cyclin-dependent kinases (CDK) 4/6 inhibitor (CDK4/6i) abemaciclib has demonstrated efficacy in advanced breast cancer and high-risk early breast cancer. This Phase 1b study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapies (Parts A–D), exemestane+everolimus (Part E), or fulvestrant+LY3023414 (a PI3K/mTOR inhibitor; Part G) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), or trastuzumab (Part F), or trastuzumab+pertuzumab (Part H) in patients with HER2-positive (HER2+) MBC. Patients and Methods: This study enrolled women aged ≥18 years old with either HR+, HER2- (Parts E and G), or HER2+ (Parts F and H) MBC. Additional requirements included measurable disease or non-measurable but evaluable bone disease (Parts E and F), or measurable disease (Parts G and H), an Eastern Cooperative Oncology Group performance status of 0–1, and no prior treatment with CDK4/6i (Parts E, F, and H). Adverse events were graded, and tumor response was assessed. Results: Nineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane+everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant+LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab+pertuzumab (with prophylactic loperamide). The most common treatment-emergent adverse events (TEAEs) were diarrhea, fatigue, neutropenia, and nausea. Grade ≥3 TEAEs were reported in 16, 18, 10, and 4 patients in Parts E–H, respectively. Abemaciclib had no effect on the pharmacokinetics of the combination study drugs. The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E–H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F. Conclusions: Overall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC.