Kidney cancer is the seventh most common type of cancer in men and the 10th most common type of cancer in women. Clear cell renal cell carcinoma (ccRCC) represents the most common histology of kidney cancer, accounting for nearly 80% of patients. All other histologies of kidney cancer have been collectively grouped as non-ccRCC (nccRCC), which includes papillary, chromophobe, unclassified RCC, and other subtypes.^1,2 As the most common histology, most novel regimens were specifically developed for ccRCC, where use of vascular endothelial growth factor (VEGF)–targeted therapies and immunotherapies have significantly improved patient outcomes. Currently, the standards of care for ccRCC are PD-1–based immune checkpoint inhibitor (ICI) combinations including combinations with anti–CTLA-4 immunotherapies or VEGF-targeted tyrosine kinase inhibitor (TKI) therapies based on multiple randomized phase 3 clinical trials demonstrating superiority as compared to TKI monotherapy.^3-6 Due to the rarity and heterogeneity of nccRCC, randomized trials for this disease group have been limited. Thus, despite the advances in ccRCC, the current standard of care for nccRCC is TKI monotherapy with cabozantinib receiving a National Comprehensive Cancer Network preferred designation.⁷ Furthermore, our clinical understanding of how to treat nccRCC has lagged our ability to histologically classify nccRCC. In most clinical studies, nccRCC is evaluated in the aggregate, with occasional studies excluding specific histologies.

Lenvatinib is a multitargeted TKI directed towards VEGFR1-3 and FGFR1-4, and pembrolizumab is an anti–PD-1 ICI. The combination of lenvatinib and pembrolizumab (LEN/PEM) was Food and Drug Administration–approved for ccRCC based on the results of the CLEAR study, where it demonstrated improved objective response rate, progression-free survival, and overall survival in comparison to sunitinib.⁴ Study KEYNOTE-B61 is a single-arm global phase 2 clinical trial evaluating the safety and efficacy of LEN/PEM in patients with metastatic nccRCC.⁸ A total of 158 patients were treated including 93 patients with papillary, 29 chromophobe, 21 unclassified, 6 translocation-associated, and 9 other histologies. Across the entire cohort, 78 (49%) had objective response, which included 9 patients (6%) with a complete response. The median progression-free survival was 17.9 months (95% CI 14, not reached). At the 12-month landmark analysis, 63% of patients remained progression-free and 82% of patients remained alive. Across all different histological subtypes, International Metastatic Renal Cell Carcinoma Database Consortium risk categories, and sarcomatoid feature status objective responses were seen. Notably, an objective response rate of 28% was seen in patient with chromophobe histology, which is an immune cell excluded histology. These data demonstrate promising antitumor activity and support the combination of LEN/PEM in patients with nccRCC.

Currently, only 1 TKI/ICI regimen has a National Comprehensive Cancer Network–designated recommendation, cabozantinib in combination with nivolumab (CABO/NIVO). In patients with papillary, unclassified, and translocation histologies (N=40), the combination of CABO/NIVO demonstrated an objective response rate of 48%, and a median progression-free survival of 13 months (95% CI 7,16), while in patients with chromophobe histology did not show any objective responses.^9,10 At landmark analyses, 51% of patients remained progression-free at 12 months and 23% of patients at 24 months. The overall survival was 70% at 18 months and 44% at 36 months.

The single-arm design of both the CABO/NIVO and LEN/PEM trials limit comparisons between the studied treatment combination and the previous standard of care. Though top-line objective response data appear similar between CABO/NIVO and LEN/PEM, comparisons between the 2 trials are not possible due to multiple significant differences. KEYNOTE-B61 included only treatment-naïve patients, while CABO/NIVO included treatment-naïve and patients with 1 prior systemic therapy; KEYNOTE-B61 is a global multicenter trial, while CABO/NIVO was a single-center study. Furthermore, due to the heterogeneity of nccRCC, it is also challenging to know whether the distributions of histologies in the trials were similar. Due to these differences in the studies, it is not possible to know the degree of overlap between patients who would respond to LEN/PEM vs CABO/NIVO. Taken as a whole, TKI/ICI combinations can demonstrate robust clinical activity in patients with nccRCC; however, randomized trials demonstrating superiority compared to prior standards of care are not yet available. Pending randomized trials to compare the regimens, robust translational studies may help identify specific populations and histologies which may preferentially benefit from regimens.