Abemaciclib Monotherapy Does Not Elicit Responses in Advanced Renal Cell Carcinoma

Treatment with single-agent abemaciclib (Verzenio) did not demonstrate clinically meaningful activity in heavily treated patients with metastatic clear cell renal cell carcinoma (ccRCC), according to findings from a phase 1b study (NCT04627064) presented at the 2024 Kidney Cancer Research Summit.¹

Responses were not observed in any of the 11 patients, according to Bradley McGregor, MD, the director of Clinical Research for the Lank Center of Genitourinary Oncology and medical oncologist specializing in genitourinary malignancies at Dana-Farber Cancer Institute, in Boston, Massachusetts, said in oral presentation of the data. One patient had stable disease, 8 experienced disease progression, and 2 were not evaluable for response.

The median progression-free survival (PFS) was only 1.8 months (95% CI, 1.5-1.9) and the median overall survival (OS) was 9.1 months (95% CI, 2.1-15.3).

“All in all, where does this leave us? Why am I even up here talking about a trial with such negative results? I think it’s really important because there are ongoing combination trials, right? [For example,] LITESPARK-024 [NCT05468697] is looking to combine belzutifan [Welireg] with palbociclib [Ibrance] vs belzutifan alone, and we need to have an idea of contribution of components,” McGregor said. “…Now, at least we have this limited dataset of 11 patients to show that abemaciclib did not have any single-agent activity. If we see a marked improvement in outcomes with a combination of abemaciclib plus palbociclib, it would really imply that the synthetic lethality we saw in the preclinical models is there.”

It is well known that progression from G1 to S phase represents an important checkpoint mediated through RB, which is expressed in 95% of RCCs, and that this is regulated through sequential phosphorylations by CDK. Preclinical data have supported the rationale for utilizing CDK4/6 inhibitors in this disease, McGregor said. For example, the CDK4/6 inhibitor PD-0332991 was found to hinder RCC proliferation at nanomolar doses.

“There was [also] some great work [where] palbociclib seemed to have a synthetic lethality with HIF2 inhibition. But regardless of HIF2, there seemed to be some monotherapy activity, as well,” McGregor said. Moreover, in preclinical mouse models, abemaciclib in combination with sunitinib (Sutent) resulted in a “dramatic reduction” in tumor sizes without overt toxicity.

“There are a lot of trials that are ongoing that are looking at CDK4/6 inhibitors in RCC, often in combination with other agents,” he added. “But as we look through the literature, despite all these trials that are ongoing, there are actually no dedicated trials to date that tested CDK4/6 inhibitors [as] monotherapy. We actually went back, went to phase 1 trials when they first developed these drugs, and we really couldn’t find any data of activity of CDK4/6 inhibitors.”

When designing the trial, McGregor and colleagues originally planned to have 2 arms, one in which they would test abemaciclib monotherapy to understand the role of single-agent CDK4/6 inhibition and the other to test abemaciclib in combination with belzutifan. However, the combination arm was aborted due to an inability to obtain belzutifan from the sponsor and the fact that other combination trials of HIF2 inhibitors and CDK4/6 inhibitors were initiated.

The nonrandomized study enrolled patients with advanced ccRCC who were refractory to at least 1 VEGFR TKI and 1 immune checkpoint inhibitor. Patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, measurable disease by RECIST 1.1 criteria, and normal organ and marrow function.²

Patients received abemaciclib at the standard recommended starting dose twice daily as part of 28-day study cycles. Treatment continued until radiographic progression, intolerable toxicity, or withdrawal.

The primary objective was to examine objective response rate with the agent.1 The planned sample size was 11 patients, which allowed for a 0.80 probability to observe at least 2 responses if the true ORR is 25% or higher, McGregor said.

All 11 patients received treatment with the CDK4/6 inhibitor and discontinued. Reasons for discontinuation included disease progression (n = 8), patient decision (n = 2), or physician decision (n = 1).

The median patient age was 62 years (range, 54-68). All patients were White, 64% were male, 18% had sarcomatoid differentiation, and 18% had rhabdoid differentiation. Regarding risk group by International mRCC Database Consortium criteria, 18% had favorable risk, 73% had intermediate risk, and 9.1% had poor risk. Metastatic sites at most recent recurrence included adrenal glands (27%), bone (36%), brain (9.1%), liver (27%), lung (73%), lymph nodes not otherwise specified (73%), peritoneum (46%), pleura (18%), soft tissue (9.1%), and other (46%).

“I really want to point out that the number of prior lines of therapy was 4, but ranged anywhere from 1 to 9, so these were heavily pretreated patients,” McGregor underscored.

Regarding safety, most patients (91%) experienced treatment-related adverse effects (AEs), but no AEs were grade 4 or 5 in severity. Twenty-seven percent of patients experienced a grade 3 event that led to dose reductions.

AEs included increased creatinine (82%), diarrhea (82%), anemia (45%), nausea (36%), decreased neutrophil count (27%), fatigue (18%), anorexia (18%), weight loss (18%), and increased alanine aminotransferase (9.1%).

“No new toxicity signals, although I would argue patients didn’t enjoy it,” McGregor said. “I’m sure if we did a [patient-reported outcomes analysis,] it would not have been the greatest results, but maybe partly because of the disease progression.”

He concluded by underscoring that the data from the phase 1b study may be utilized to inform interpretation of ongoing trials exploring novel combinations including CDK4/6 inhibitors such as LITESPARK-024 and another initiative, referred to as SPARCC, which will examine the combination of sasanlimab plus axitinib (Inlyta) and palbociclib. The primary end point will be ORR and secondary end points include PFS, OS, and safety.

References

1. 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.
2. ABEMA alone or in COMBO with MK-6482. ClinicalTrials.gov. Updated January 11, 2024. Accessed July 12, 2024. https://clinicaltrials.gov/study/NCT04627064