Abstract CT028: A single-arm phase 1 trial of avutometinib (RAF/MEK inhibitor), abemaciclib (abema), and fulvestrant in CDK4/6 inhibitor (CDK4/6i)-pretreated patients (pts) with HR+ metastatic breast cancer (MBC)

Abstract Introduction: CDK4/6i improve survival in HR+ MBC but efficacy is limited by mechanisms of resistance including MAPK pathway activation. Avutometinib (VS-6766), a RAF/MEK inhibitor, may reverse CDK4/6i resistance, and enhances abema’s anti-proliferative effect in preclinical studies. The safety and tolerability of avutometinib combined with abema and fulvestrant is unknown. Methods: Eligible pts had HR+/HER2- MBC, prior progression on CDK4/6i, and measurable/evaluable disease. Prior fulvestrant was allowed but not required. Primary endpoint was maximum tolerated dose (MTD) of the regimen, determined using Bayesian Optimal Interval design with target toxicity rate 0.25. Planned dose levels were: avutometinib (2.4, 3.2, 4.0 mg PO BIW, 3 weeks on/1 week off), abema (50, 100, 150 mg PO BID, continuous), and fulvestrant (500 mg IM q28d). Dose escalation prioritized avutometinib to address MAPK-driven resistance. Secondary endpoints were safety, pharmacokinetics (PK), overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) by RECIST 1.1. Results: 16 pts began protocol therapy from 2/2023-8/2024. Median follow-up was 9.8 mos. Pts had median age 61 yrs, 31% had visceral disease, all had received prior endocrine therapy for MBC (median 2 lines, range 1-5), all had received prior CDK4/6i (69% palbociclib, 19% ribociclib, 19% abema), 69% had spent >12 mos on a prior CDK4/6i for MBC, 44% received prior fulvestrant, 63% received any prior selective estrogen receptor degrader, and 25% received prior chemo for MBC. 15 pts were evaluable for dose-limiting toxicities (DLTs). At dose level (0,0) (abema 150 mg + avutometinib 3.2 mg), there were 2/2 DLTs (grade 3 diarrhea and liver enzyme elevation). At dose level (-1,0) (abema 100 mg + avutometinib 3.2 mg) there were no DLTs (0/9). At dose level (-1,1) (abema 100 mg + avutometinib 4 mg) there were 3/4 DLTs (grade 3 mucositis and rash, grade 2 visual disturbance). The MTD and recommended phase 2 dose was abema 100 mg PO BID, avutometinib 3.2 mg PO BIW, and fulvestrant 500 mg IM q28d. All pts experienced treatment-related adverse events (TRAEs), with the most frequent being creatine phosphokinase elevation (50%; grade 3: 19%), neutropenia (50%; grade 3: 6%), diarrhea (44%; grade 3: 6%), rash (44%; grade 3: 19%), and fatigue (44%; grade 3: 0%). There were no grade 4-5 TRAEs. ORR was 13% (1 CR, 1 PR; including a pt previously treated with fulvestrant and abema), 24-week CBR was 25%, and median PFS was 3.6 months (95% CI: 2.1-not reached). PK data will be presented. Conclusions: The combination of avutometinib, abema, and fulvestrant showed a manageable safety profile and preliminary efficacy in HR+/HER2- MBC resistant to CDK4/6i. A single-arm phase 2 trial is ongoing to further evaluate the clinical efficacy in this population. Citation Format: Adrienne G. Waks, Elia Segui, Tianyu Li, Marla Lipsyc-Sharf, Eliza Kallfelz, Molly DiLullo, Ashka Patel, Tasnim Rahman, Katherine E. Junkins, Anna M. Frey, Hajer A. Rahee, Emma Kelly, Michael Stalteri, Eileen Wrabel, Heather A. Parsons, Philip D. Poorvu, Ann H. Partridge, Daniel L. Abravanel, Nancy Poorvu, Barbara LeStage, Peter Sicinski, Sara M. Tolaney, Nikhil Wagle, Nabihah Tayob, Geoffrey I. Shapiro. A single-arm phase 1 trial of avutometinib (RAF/MEK inhibitor), abemaciclib (abema), and fulvestrant in CDK4/6 inhibitor (CDK4/6i)-pretreated patients (pts) with HR+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT028.