IO/TKI Doublets Emerge as Standard of Care in Non-Clear Cell Renal Cell Carcinoma

Key Insights

• Phase 2 trials show that IO/TKI combinations, like lenvatinib plus pembrolizumab, demonstrate efficacy in non-clear cell renal cell carcinoma (non-ccRCC) with manageable safety profiles.
• KEYNOTE-B61 trial reported a 51% objective response rate (ORR) in non-ccRCC patients treated with lenvatinib and pembrolizumab, supporting NCCN guideline recommendations.
• Cabozantinib plus nivolumab also shows promise, with a 48% ORR in a phase 2 trial, establishing IO/TKI doublets as effective first-line options for non-ccRCC.

Immune-oncology (IO)/TKI doublet regimens are establishing themselves as the standard of care for patients with non-clear cell renal cell carcinoma (non-ccRCC), according to recent clinical trial data. These combinations have demonstrated efficacy and manageable safety profiles, offering new hope for a patient population with limited treatment options.

KEYNOTE-B61 Trial Highlights Lenvatinib Plus Pembrolizumab Efficacy

The phase 2 KEYNOTE-B61 trial (NCT04704219) evaluated the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) in patients with various non-ccRCC histologies, including papillary, chromophobe, translocation, and unclassified subtypes. The international trial included 158 patients who received the doublet at the standard dose. The objective response rate (ORR) was 51% (95% CI, 43%-59%). Notably, patients with chromophobe histology (n = 29) had an ORR of 35% (95% CI, 18%-54%). The median progression-free survival (PFS) was 17.9 months (95% CI, 15.1-22.1), and the median overall survival (OS) was not reached (95% CI, NR-NR). These findings support the National Comprehensive Cancer Network (NCCN) guideline recommendation for lenvatinib plus pembrolizumab as a frontline treatment for non-ccRCC.

Cabozantinib Plus Nivolumab Shows Promise

The NCCN also recommends cabozantinib (Cabometyx) plus nivolumab (Opdivo) for previously untreated non-ccRCC, based on a smaller phase 2 trial (NCT03635892). This trial included patients with papillary, translocation, and unclassified RCC. The ORR in the overall population (n = 40) was 48% (95% CI, 31.5%-63.9%). In the subgroup with papillary disease, the ORR was 47% (95% CI, 30%-64%). The median PFS with the doublet was 13 months (95% CI, 7-16), and the median OS was 28 months (95% CI, 23-43).

Expert Opinion

"Both doublets are effective treatment options for patients with non-ccRCC, and IO/TKI combination regimens should be the standard of care for this patient population," emphasizes Dr. Moshe Ornstein, MD, MA, medical oncologist at the Cleveland Clinic. He adds that treatment decisions in the upfront setting should rely on patient preference and individual data interpretation.