Abemaciclib Monotherapy Elicits No Response in Advanced RCC: Where the Field is Headed From Here

Bradley McGregor, MD

In a search for more treatment approaches that produce durable, meaningful responses in patients with metastatic clear cell renal cell carcinoma (ccRCC), a phase 1b study (NCT04627064) investigated single-agent abemaciclib (Verzenio) in heavily pretreated patients. However, according to data presented at the 2024 Kidney Cancer Research Summit, the monotherapy did not demonstrate clinically meaningful activity in this patient population.¹

Furthermore, although objective response rate (ORR) served as the study’s primary end point, none of the 11 patients enrolled in the abemaciclib monotherapy arm of the study experienced an objective response. When treated with abemaciclib, 1 patient had stable disease, 8 patients had progressive disease, and 2 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). Notably, no new toxicity signals were detected.

“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,” according to Bradley McGregor, MD, who is a senior physician, the director of Clinical Research at the Lank Center for Genitourinary Oncology, and a Marra Lochiatto Investigator at Dana-Farber Cancer Institute (DFCI), as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

In an interview with OncLive^®, McGregor discussed the findings from the phase 1b trial investigating abemaciclib monotherapy in patients with metastatic ccRCC and expanded on how, despite the dismal results of the trial, investigators can still derive practice-informing information from these findings. He also delved into how these results may offer additional insights into the use of CDK4/6 inhibitors in patients with RCC.

OncLive: How has the role of CDK4/6 inhibition affected the RCC treatment paradigm in recent years?

McGregor: There has been a lot of interest in developing new targets for RCC. Preclinical data indicates that CDK4/6 inhibition may be synergistic with HIF2a inhibition. However, as you look back at all the trials done with CDK4/6 inhibitors, there have not been studies investigating the role of [CDK4/6 inhibitor] monotherapy in ccRCC. Therefore, [in this phase 1b trial, we aimed to evaluate] the role of CDK4/6 inhibition plus HIF2a inhibitors in RCC. But we realized, as we looked to take that next step, that we needed to have data with a single-agent [CDK4/6 inhibitor first].

As we were developing this [trial], we planned to evaluate the role of abemaciclib plus belzutifan [Welireg], so the initial trial design had 2 different arms. Due to several reasons, that [investigation of the] combination of abemaciclib and belzutifan did not move forward. However, we enrolled 11 patients with ccRCC who were heavily pretreated and treated them with abemaciclib [alone] until unacceptable toxicity or progression.

What were the main findings from this phase 1b monotherapy approach?

People may wonder why we are talking about this study since, unfortunately, it [did not meet its primary end point]. In the 11 patients treated, there were no responses by RECIST criteria. All patients had rapid progression of the disease on their first scan. Additionally, although there was manageable toxicity, there were problems with diarrhea and neutropenia.

There are a lot of factors that come into play here. These were heavily pretreated patients. Some patients had received up to 9 lines of therapy prior to enrolling in the trial. This trial gives us important insight into the activity of abemaciclib monotherapy [in patients with ccRCC]. There are several trials ongoing that are investigating adding CDK4/6 inhibitors to existing [RCC treatment] paradigms.

There are trials in development evaluating palbociclib [Ibrance] and belzutifan [in patients with RCC]. [At DFCI], we have a trial that’s opening soon, SPARCC, investigating sasanlimab plus axitinib [Inlyta] and palbociclib. A lot of agents are out there and being thought about, and these [phase 1b abemaciclib monotherapy] data will be important as we look to identify contributive components [of individual agents that are under investigation in combination regimens]. The fact that we now have data [with this CDK4/6 inhibitor in ccRCC], albeit in just 11 patients, will help us frame the results of these combination trials in the future.

Despite patients not achieving a benefit with abemaciclib monotherapy in this study, why is it important to understand and discuss these results?

We are always looking for novel targets and better [therapies]. We’ve had amazing success with nivolumab [Opdivo] plus ipilimumab [Yervoy], as well as with immuno-oncology and TKI [combinations]. Unfortunately, for a lot of patients, those responses aren’t durable, and these patients ultimately need subsequent lines of therapy. We’re constantly looking for ways to enhance [the therapies] we have [with] new targets.

How may these results offer additional insights into the use of CDK4/6 inhibitors in combination with HIF2a inhibitors in patients with ccRCC?

When we evaluated the data with nivolumab plus ipilimumab, for instance, one of the issues was contribution components. Do patients need ipilimumab? [Were the outcomes] all driven by nivolumab? [We need to know the] single-agent activity [of each drug].

What we have shown [in this phase 1b trial with abemaciclib monotherapy] is that in this cohort of 11 patients, we did not achieve any responses. 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.

Reference

McGregor BA, Xie W, Xu W, et al. Phase IB trial of abemaciclib in advanced renal cell carcinoma. Presented at: 2024 Kidney Cancer Research Summit; July 11-12, 2024. Boston, MA.