Eileen Wrabel

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.

Representativeness of Study Participants

Purpose:Cyclin-dependent kinase 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in patients with hormone receptor–positive metastatic breast cancer. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC).Patients and Methods:We conducted a single-arm phase II study of abemaciclib monotherapy in patients with Rb-positive mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate, disease control rate, and safety and tolerability.Results:A total of 27 patients were enrolled before the trial was closed early because of slow accrual. Patients had received a median of two lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the objective response rate was 0%, the clinical benefit rate was 14.8%, and the disease control rate was 22.2%. The median PFS was 1.94 months (95% confidence interval, 1.84–11.47), and the median OS was 8.44 months (95% confidence interval, 4.57–15.57). Median PFS and OS did not differ significantly based on androgen receptor and PD-L1 status. Pretreatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%).Conclusions:Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb-positive mTNBC.

Representativeness of Study Participants

Purpose: Cyclin-dependent kinase 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in patients with hormone receptor–positive metastatic breast cancer. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC). Patients and Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with Rb-positive mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate, disease control rate, and safety and tolerability. Results: A total of 27 patients were enrolled before the trial was closed early because of slow accrual. Patients had received a median of two lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the objective response rate was 0%, the clinical benefit rate was 14.8%, and the disease control rate was 22.2%. The median PFS was 1.94 months (95% confidence interval, 1.84–11.47), and the median OS was 8.44 months (95% confidence interval, 4.57–15.57). Median PFS and OS did not differ significantly based on androgen receptor and PD-L1 status. Pretreatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%). Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb-positive mTNBC.