Frontline Cabozantinib Yields Early Responses After CPI Combos in RCC

First-line cabozantinib (Cabometyx) given after checkpoint inhibitor-based combination therapy for patients with locally advanced or metastatic renal cell carcinoma (RCC) with a clear-cell component had early responses, according to data from the phase 2 CaboPoint trial (NCT03945773) presented at the 2023 Genitourinary Cancer Symposium.

Data from the 3-month analysis showed that cabozantinib elicited an objective response rate (ORR) of 29.5% (95% CI, 20.3%-40.2%) in the total population (n = 88), which comprised a complete response (CR) rate of 1.2% and a partial response (PR) rate of 30.5%; the stable disease (SD) rate was 51.2%. Fourteen patients (17.1%) experienced disease progression.

The patients who received cabozantinib after having progressed following treatment with 2 checkpoint inhibitors (cohort A; n = 60), namely ipilimumab (Yervoy) and nivolumab (Opdivo), experienced an ORR of 31.7% (95% CI, 20.3%-45.0%). Among those who responded, 33.3% had a PR, 50.9% had SD, and 15.8% experienced disease progression.

In those who were treated with cabozantinib after having progressed following treatment with a checkpoint inhibitor plus a VEGFR TKI (cohort B; n = 28), the ORR was 25.0% (95% CI, 10.7%-44.9%); this was comprised of a 4.0% CR rate and a 24.0% PR rate. Moreover, 52.0% achieved SD, and 20.0% had progressive disease.

“CaboPoint is the first prospective study to assess the efficacy of cabozantinib in a pure second-line setting in what is our routine practice, meaning after a doublet regimen [has failed],” lead study author Laurence Albiges, MD, PhD, of Gustave Roussy, Université Paris-Saclay, France, said in a presentation on the data. “The interim analysis demonstrated a high response rate, and of course, we are waiting for further results that will hopefully be presented later this year.”

It is standard practice to offer patients with an advanced RCC a CPI-based combination as frontline treatment, Albiges said. The multitargeted TKI, cabozantinib, is FDA approved for use as a single agent in patients with advanced RCC who previously received a VEGF-targeted therapy. Cabozantinib in combination with nivolumab is also approved as a frontline agent for patients with advanced RCC.

CaboPoint enrolled patients with histologically confirmed, advanced or metastatic RCC with a clear-cell component who had radiographic disease progression after CPI/CPI (cohort A) or CPI/VEGF therapy (cohort B). Those who received prior cabozantinib or who had untreated brain or leptomeningeal metastases were excluded.

Participants were administered cabozantinib at the standard dose of 60 mg daily.

The primary end point of the trial was ORR by RECIST v1.1 criteria in cohort A by independent central review (IRC). Secondary end points comprised ORR in cohort B by IRC, ORR for both cohorts by local investigator review, time to response, DOR, disease control rate, progression-free survival, overall survival, and change in disease-related symptoms, as well as safety and tolerability.

“The interim analysis was predefined to be realized and assess response rates when 80% of patients within cohort A had reached at least 3 months of follow-up,” Albiges said.

The data cutoff date for the interim analysis was July 12, 2022. At this time, 88 patients had at least 3 months of follow-up.

In the total population, the median age was 64.0 years (range, 41-83), and 75.0% were male. The ECOG performance status was 0 in 56.8% of patients, and 1 in 43.2% of patients. Regarding International Metastatic Renal Cell Carcinoma Database Consortium risk group, 7.4% had favorable risk, 44.4% had intermediate risk, 12.3% had poor risk, and this information was unknown or missing in 35.8% of patients.

“We had a large number of patients who were up-front metastatic, and therefore, did not have prior cytoreductive nephrectomy,” Albiges noted.

The metastatic localization at the start of cabozantinib treatment in the overall population was the lungs (69.0%), lymph nodes (49.4%), bones (31.0%), liver (21.8%), and the brain (3.4%). Moreover, 31.0% of patients had 1 metastatic site, 25.3% had 2 sites, and 43.7% had at least 3 sites. Most patients (67.0%) previously received nivolumab plus ipilimumab; 22.7% previously received pembrolizumab (Keytruda) plus axitinib (Inlyta), and 9.1% had prior avelumab (Bavencio) plus axitinib.

Subgroup analyses were also conducted and demonstrated that efficacy with cabozantinib was observed spanning several subgroups.

In those who were younger than 65 years, second-line cabozantinib elicited an ORR of 37.0% (95% CI, 23.2%-52.5%); in those older than 65 years, the ORR was 21.4% (95% CI, 10.3%-36.8%). Cabozantinib elicited an ORR of 31.8% (95% CI, 20.9%-44.4%) in men and 22.7% (95% CI, 7.8%-45.4%) in women. According to ECOG performance status, the ORR was 38.0% (95% CI, 24.7%-52.8%) in those with a status of 0, and 18.4% (95% CI, 7.7%-34.3%) in those with a status of 1. The ORRs in those who had 1, 2, or at least 3 metastatic sites were 51.9% (95% CI, 32.0%-71.3%), 27.3% (95% CI, 10.7%-50.2%), and 15.8% (95% CI, 6.0%-31.3%), respectively.

In all patients who had IMDC intermediate risk (n = 36), the ORR achieved with second-line cabozantinib was 33.3% (95% CI, 18.6%-51.0%); in cohort A (n = 25) and B (n = 11) patients with IMDC intermediate risk, the ORRs were 40.0% (95% CI, 21.1%-61.3%) and 18.2% (95% CI, 2.3%-51.8%), respectively.

“I’d like to draw your attention to the fact that patients with IMDC intermediate [risk] who [were in] cohort A had a response rate of 40%; this is what we can expect from a potent VeGF TKI after a doublet IO [has failed],” Albiges underscored.

Those who received treatment for less than 6 months in the first line experienced a higher ORR than those who received treatment for 6 months or longer, at 34.1% (95% CI, 20.1%-50.6%) and 25.5% (95% CI, 13.9%-40.4%), respectively. “In a patient [who had] a first-line regimen [fail] within 6 months, so almost a primary-refractory patient to combination therapy, the response rate was 34% with the VEGF TKI cabozantinib,” Albiges said. “This depicts the fact that we need to offer second-line treatment, including to our patients who promptly [had] their first-line combination regimen [fail.]”

The phase 2 trial is ongoing, with data from the final analysis anticipated in September 2023.

Reference

1. 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