CaboPoint Data Underscore Potential for Cabozantinib Following Frontline Combination Therapy in Advanced RCC

Preliminary prospective data from the phase 2 CaboPoint study (NCT03945773) indicate that the TKI cabozantinib (Cabometyx) could serve as a potential second-line option for patients with locally advanced or metastatic clear-cell renal cell carcinoma (RCC) who progressed on standard first-line combinations. The VEGF TKI showed activity, regardless of whether the first-line regimen was comprised of an immune checkpoint inhibitor (ICI) doublet or an ICI plus a VEGF TKI, according to Laurence Albigès, MD, PhD.

In April 2016, the FDA approved cabozantinib as a second-line treatment for patients with advanced RCC who previously received antiangiogenic therapy based on data from the phase 3 METEOR trial (NCT01865747), in which the agent improved median progression-free survival (PFS) and overall survival (OS) vs everolimus (Afinitor).1 Although cabozantinib is already approved for second-line use in select patients, there is a lack of prospective data establishing its efficacy after a first-line ICI-based combination regimen.²

Data from the 3-month analysis of CaboPoint were presented at the 2023 Genitourinary Cancers Symposium showed that cabozantinib induced an overall response rate (ORR) of 29.5% (95% CI, 20.3%-40.2%) in the total population (n = 88); this included a complete response (CR) rate of 1.2% and a partial response (PR) rate of 30.5%. The stable disease rate was 51.2%, and disease progression occurred in 17.1% of patients.PRs were observed in cohorts A and B, at 33.3% and 24%, respectively. No new safety signals with the agent were observed.²

“Irrespective of [prior] IO/IO or IO/TKI [treatment], it is important that our patients gain access to second line therapy after first line failure,” Albigès, the lead study author, said in an interview with OncLive^®. “We obviously have a signal of activity with a potent VEGF TKI [in the form of cabozantinib] in this setting.”

In the interivew, Albigès, who is also a medical oncologist and head of the Genitourinary Unit in the Department of Medical Oncology at Gustave Roussy Institute, France, discussed what inspired the launch of the CaboPoint study examining second-line cabozantinib in patients with advanced RCC, the efficacy of this approach, and the next steps for this research.

OncLive^®: What was the rationale for conducting the CaboPoint study?

Albigès: The standard of care for clear cell RCC is combination therapy, [with] either an ICI doublet or an ICI plus a VEGF TKI. However, we don’t know what treatment to administer [after] a combination regimen [has failed]. We will usually [administer] a VEGF TKI that we haven’t used in the first line. The CaboPoint study was developed to [evaluate] the activity and safety of cabozantinib as a second-line [treatment] after [progression on] a first-line combination.

Please expand on the design of the study. What was examined? What does this research bring to the paradigm?

[CaboPoint is] a phase 2 nonrandomized study with 2 cohorts. Cohort A was for patients who [had an] immuno-oncology [IO]/IO regimen [of] nivolumab [Opdivo] plus ipilimumab [Yervoy] fail, and cohort B [included] patients who had an IO plus VEGF TKI [combination fail]. Overall, over 120 patients have been enrolled [in the study]. However, at this meeting, we are reporting [results from] an interim analysis of the first 88 patients for whom we had more than 3 months of follow-up [data]. The primary objective of the study is ORR.

What is important to note about the baseline characteristics of this population?

In the CaboPoint study, 88 patients were included in this interim analysis. As anticipated, the first 60 patients of cohort A were all previously treated with a combination of IO/IO. For cohort B, it is important [to note] the first-line regimen received. The vast majority [of these patients] received axitinib [Inlyta] plus pembrolizumab. The rest of the patients were exposed to axitinib plus avelumab [Bavencio].

It’s interesting to see that even patients [with] primary refractory disease [to their] first-line [regimen], meaning progressive disease within the first 6 months, we see a response rate of over 32% with cabozantinib. This highlights the fact that our patients should gain access to second-line therapy, because we can rescue resistance in the first line.

Could you expand on the efficacy data reported from the interim analysis at the 2023 Genitourinary Cancers Symposium?

In this interim analysis, the overall ORR was [29.5%], with a split of [33.3%] in cohort A and [24.0%] in cohort B. We can also emphasize the fact that the vast majority of those patients had International Metastatic RCC Database Consortium [IMDC] intermediate [risk]. In patients who had IMDC intermediate risk at the start of second-line therapy with cabozantinib who [had previously been treated with] nivolumab plus ipilimumab, we saw [partial] responses. I think [these are] very interesting data.

What was observed with regard to safety?

The safety profile we observed on the study was in-line with prior reports of cabozantinib used in sequence after single-agent TKI or IO [therapy]. No further safety signals [were observed]. Cabozantinib is a potent VEGF TKI that we’ve learned to manage. In this study, patients were treated at the full dose of 60 mg per day. In the case of toxicity, we could dose reduce.

Were there any limitations to this research that should be noted?

There is no main limitation on the study. We want to know how we can do better in the second line. These are preliminary data, so we need to see more—[especially] the PFS and OS data.That [information] will be [shared] in the full analysis, [which] is anticipated by the end of this year. This is the main information that is still pending. Ultimately, [we want to know] what we can add to cabozantinib, or [whether] there is any other agent that we should compare it with in the second line?

What does this research mean for the paradigm?

Until now, [we only had] data [on] agents that had been used in sequence after single-agent TKI followed by single-agent IO. [We had no] second-line data after a combination regimen. Having data on the activity of cabozantinib as a pure second-line [therapy] is very important. The next move will be [to ask whether] we need to add cabozantinib [to another therapy]. We are all eagerly waiting [for results] from the [phase 3] CONTACT-03 study [NCT04338269] looking at cabozantinib [monotherapy] vs cabozantinib plus PD-L1 inhibition [with] namely, atezolizumab [Tecentriq]. It is important to know whether we’ll have to sustain PD-1 or PD-L1 inhibition after first-line failure.

What is the significance of this year’s meeting for the RCC paradigm?

The 2023 Genitourinary Cancers Symposium is a very important meeting. It [gives us] the opportunity to bring up [new] science and have up-to-date data. The field of RCC is evolving extremely fast—not only in the metastatic setting, but in the adjuvant setting. We’re all eagerly waiting for new mechanisms of action and new drugs.

Editor’s Note: Dr Albiges reports serving as a consultant or in an advisory role for Astellas Pharma (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Ipsen (Inst), Janssen (Inst), MSD (Inst), Pfizer (Inst), Roche (Inst).

References

1. Exelixis announces FDA approval of Cabometyx (cabozantinib) tablets for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. News release. Exelixis, Inc. April 25, 2016. Accessed March 16, 2023. https://ir.exelixis.com/news-releases/news-release-details/
2. Albiges L, Powles T, Sharma A, et al. CaboPoint: interim results from a phase 2 study of cabozantinib after checkpoint inhibitor therapy in patients with advanced renal cell carcinoma. J Clin Oncol. 2023;41(suppl 6):606. doi:10.1200/JCO.2023.41.6_suppl.606