Belzutifan/cabozantinib combo promising in post-immunotherapy renal cell carcinoma

The combination of belzutifan (Welireg) and cabozantinib (Cabometyx) showed promising clinical activity for patients with advanced clear cell renal cell carcinoma (RCC) who had previously received immunotherapy and up to 2 systemic treatment regimens, according to results from cohort 2 of the phase 2 LITESPARK-003 study.^1,2

“While immunotherapy has changed the treatment landscape for advanced renal cell carcinoma, questions about what therapy to provide when patients experience disease progression on immunotherapy remain,” Dana-Farber Cancer Institute wrote in a statement.

The findings, which were published online in The Lancet Oncology, showed that at a median follow-up of 24.6 months (interquartile range (IQR), 22.1-32.2), the combo induced an objective response rate (ORR) of 30.8% (n =16; 95% CI, 18.7-45.1) in 52 evaluated patients. The ORR comprised 1 (2%) complete response (CR) and 15 (29%) partial responses.

“While immunotherapy has changed the treatment landscape for advanced renal cell carcinoma, questions about what therapy to provide when patients experience disease progression on immunotherapy remain. In this study, interim results of the combination of cabozantinib, a VEGF TKI, plus belzutifan, a HIF-2α inhibitor, show promising anti-tumor activity in this pre-treated patient group. The results suggest that the combination might fill and unmet need and provides a rationale for further study of combining a VEGF TKI and a HIF-2 inhibitor,” Dana-Farber Cancer Institute, the location of lead study author Toni Choueiri, MD, explained in a press release.²

Overall, LITESPARK-003 accrued patients with locally advanced or metastatic clear cell RCC who were either treatment-naïve (cohort 1) or had received treatment with no more than 2 prior lines of immunotherapy for advanced or metastatic RCC (cohort 2). Patients were required to have had an ECOG performance status of 0 or 1.1

Patients enrolled in the trial received belzutifan at 120 mg orally once daily and cabozantinib at 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal.

Baseline characteristics for cohort 2 showed that patients had a median age of 63 years (IQR, 57.5-68.5), 38 patients were male, and 14 patients were female. Regarding race, 48 patients were White, 2 patients were Black or African American, and 2 patients were Asian (4%).

Hypertension, which occurred in 14 (27%) patients, was the most frequently occurring grade 3/4 treatment-related adverse event (TRAE). There were 15 (29%) patients who experienced serious TRAEs. One patient death, due to respiratory failure, was considered by the investigators to be treatment related.

Belzutifan/cabozantinib in the first-line setting

Results from cohort 1 of LITESPARK-003, previously reported at the 2022 ESMO Congress, showed that the belzutifan/cabozantinib combination also had promising clinical activity as a first-line treatment for patients with locally advanced or metastatic clear cell RCC.³

Cohort 1 included 35 patients. At a median follow-up of 14.0 months, the ORR in these patients was 57% (n = 20), composed of a CR rate of 6% (n = 2) and a PR rate of 51% (n = 18). An additional 13 (37%) patients had stable disease, leading to an overall disease control rate of 94%.

Patients in cohort 1 had a median age of 64.0 years (range, 33-89) and 83% were male. The majority had an ECOG performance status of 0 (60%) and favorable-risk disease (60%). Twenty-six patients (74%) received prior nephrectomy.

Regarding safety, grade 3 or higher TRAEs occurred in 37% of patients, with no grade 4 or 5 TRAEs reported. One patient discontinued cabozantinib due to a TRAE and no patients discontinued belzutifan due to a TRAE. Serious TRAEs occurred in 2 patients.

The investigators are now eager to explore whether survival outcomes with longer follow-up will confirm the promising initial clinical activity of the combination in this setting.

References

1. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study [published online ahead of print March 31, 2023. Lancet Oncol. doi: 10.1016/S1470-2045(23)00097-9

2. Combination therapy a promising option for advanced kidney cancer patients already treated with immunotherapy. Dana-Farber Cancer Institute. Published Online March 31, 2023. Accessed April 6, 2023. https://bit.ly/41b42bF

3. Choueiri TK, Bauer T, Merchan J, et al. Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): cohort 1 of LITESPARK-003. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072