A phase 1b study evaluating abemaciclib monotherapy in heavily pretreated patients with metastatic clear cell renal cell carcinoma (ccRCC) has shown no clinically meaningful activity. The trial's findings, presented at the 2024 Kidney Cancer Research Summit, temper enthusiasm for single-agent CDK4/6 inhibition in this setting but offer valuable insights for future combination strategies.
The study enrolled 11 patients with ccRCC who had received multiple prior lines of therapy. Patients were treated with single-agent abemaciclib until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS).
Key Findings
According to the data, none of the 11 patients experienced an objective response. One patient achieved stable disease, while eight experienced progressive disease. Two patients were unevaluable for response. The median progression-free survival was 1.8 months (95% CI, 1.5-1.9), and the median overall survival was 9.1 months (95% CI, 2.1-15.3). No new or unexpected toxicity signals were observed, with diarrhea and neutropenia being the most common adverse events.
Expert Commentary
Dr. Bradley McGregor, a senior physician at Dana-Farber Cancer Institute, noted the importance of these findings in the context of ongoing combination trials. "This is one small step [that] will give us insights into how we can interpret the data that’s going to be coming out from combination trials with CDK4/6 inhibitors," he said. He emphasized that the lack of single-agent activity provides a baseline for assessing the potential synergistic effects of CDK4/6 inhibitors when combined with other agents, such as HIF2a inhibitors.
Context and Future Directions
The treatment landscape for advanced RCC has evolved significantly with the advent of immuno-oncology (IO) and tyrosine kinase inhibitor (TKI) combinations. However, many patients eventually progress on these therapies, underscoring the need for novel treatment approaches. Preclinical data suggest that CDK4/6 inhibition may synergize with HIF2a inhibition, motivating clinical trials of these combinations. Several trials are underway evaluating CDK4/6 inhibitors, such as palbociclib, in combination with other agents like belzutifan or in combination with IO/TKI regimens.
Implications for Clinical Practice
While abemaciclib monotherapy did not demonstrate efficacy in this heavily pretreated population, the data inform the design and interpretation of ongoing and future combination trials. As Dr. McGregor explained, "As we await the results of [future] combination trials, if there is a marked improvement in ORR [with the combination of a CDK4/6 inhibitor and another agent], that would indicate a synergistic effect [of the combination], because we showed that abemaciclib alone would not offer clinical benefit."
