Anna Mae Frey

Purpose: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative metastatic breast cancer is limited by resistance mechanisms, including mitogen-activated protein kinase (MAPK) pathway activation. We performed a phase I trial evaluating avutometinib, a dual rapidly accelerated fibrosarcoma/MAPK kinase (RAF/MEK) inhibitor, combined with abemaciclib and fulvestrant. Patients and Methods: Eligible patients had prior progression on CDK4/6i; prior fulvestrant was allowed. The primary endpoint was the maximum tolerated dose (MTD). Planned dose levels were abemaciclib 50, 100, or 150 mg orally twice daily, with avutometinib 2.4, 3.2, or 4 mg orally twice weekly (3 weeks on/1 week off) plus fulvestrant 500 mg intramuscularly every 28 days. Secondary endpoints included safety, pharmacokinetics (PK), overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS). Results: Sixteen patients were treated (median age 61; 88% visceral disease; 63% prior selective estrogen receptor degrader). The MTD and recommended phase II dose (RP2D) were abemaciclib 100 mg twice daily, avutometinib 3.2 mg twice weekly, and fulvestrant 500 mg intramuscularly every 28 days. Common treatment-related adverse events (TRAE) were creatine phosphokinase elevation (50%), neutropenia (50%), diarrhea (44%), and skin rash (44%). No grade 4 to 5 TRAEs occurred. ORR was 13% (2/15 patients with measurable disease), 24-week CBR 40% (6/15 patients with measurable disease), and median PFS 3.6 months (95% confidence interval, 2.1–not reached). PK was consistent with prior reports. Conclusions: The regimen was well tolerated at the RP2D, with no new safety signals, and showed preliminary clinical activity. A phase II trial is ongoing.

PURPOSE: The time required for in-clinic drug administration can substantially affect breast cancer patients' quality of life. Subcutaneous (SC) drug administration, as opposed to intravenous (IV), may reduce this time commitment. This study sought to estimate the difference in time burden between IV and SC administration of trastuzumab and pertuzumab (HP). METHODS: We prospectively enrolled a subcohort of patients participating in the ADEPT trial (ClinicalTrials.gov identifier: NCT04569747 , investigating adjuvant HP plus endocrine therapy for stage I human epidermal growth factor receptor 2–positive breast cancer) to this single-arm crossover time and motion substudy. Patients received two cycles of IV HP followed by two cycles of SC HP. During each cycle, time points in drug preparation and administration were captured. The primary end point was total patient time in the treatment chair. Additional end points included total patient treatment experience time and total pharmacy workflow time. A sample size of 22 patients was estimated to provide 90.7% power with two-sided alpha .05 to detect a difference of 70 minutes in the primary end point by treatment arm (IV v SC). RESULTS: Twenty-two patients were enrolled. The mean total patient time in the treatment chair was 61.8 minutes shorter with SC versus IV HP (22.5 v 84.3 minutes; P < .0001). The mean total patient treatment experience time (incorporating time spent waiting for treatment initiation and time spent in the treatment chair) was 81.8 minutes shorter for SC administration (96 v 177.8 minutes; P < .0001). The pharmacy workflow time was 78.2 minutes shorter for SC versus IV formulation (41 v 119.2 minutes; P < .0001). CONCLUSION: SC administration of HP shortened patient time burden by approximately 1 hour. SC drug administration can facilitate faster workflows for health care professionals and improve patients' breast cancer treatment experience.