Researchers are making strides in identifying effective treatments for various subtypes of non-clear cell renal cell carcinoma (nccRCC), according to a presentation by Laurence Albiges, MD, PhD, at the 2024 Kidney Cancer Research Summit. The focus is on tailoring treatments to specific nccRCC subtypes, including papillary, chromophobe, translocation, fumarate hydratase (FH) deficient, renal medullary, collecting duct, and unclassified RCC.
Papillary RCC
In papillary RCC, the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) has shown promising results. A study reported an overall response rate (ORR) of 54% and a median progression-free survival (PFS) of 17.4 months with this combination. Furthermore, at the 18-month mark, the overall survival (OS) rate was above 70%, marking a significant improvement compared to historical OS rates of 1 to 1.5 years.
Another approach using durvalumab (Imfinzi) plus savolitinib (Orpathys) in 27 patients resulted in an ORR of 53%, a median PFS of 12 months, and a median OS of 27.4 months, highlighting progress in biomarker-based strategies.
Chromophobe RCC
For chromophobe RCC, combinations of lenvatinib/everolimus (Afinitor) (n = 9) and lenvatinib/pembrolizumab (n = 29) were evaluated. The lenvatinib/pembrolizumab combination reported an ORR of 34.5% and a median PFS of 26.2 months. A retrospective analysis of 99 patients with metastatic chromophobe RCC suggested that single-agent therapy may not be optimal, favoring combination approaches.
Translocation RCC
Immuno-oncology (IO) plus tyrosine kinase inhibitor (TKI) combinations appear to be the most effective for translocation RCC. A comparison of cabozantinib (n = 31) vs an IO-IO combination (n = 18) vs an IO-TKI combination (n = 11) showed ORRs of 17%, 6%, and 36%, respectively, and median OS of 17, 17.8, and 30.7 months, respectively. IO-TKIs, including lenvatinib/pembrolizumab, demonstrated the highest response rates, around 25%.
FH-Deficient RCC
In FH-deficient RCC, erlotinib (Tarceva) and bevacizumab (Avastin) resulted in an ORR of 64% and a median PFS of 21.1 months. Real-world data indicates a median OS of 44 months. A phase 2 study (NCT04981509) is exploring a triplet combination of atezolizumab (Tecentriq) with erlotinib and bevacizumab.
Renal Medullary RCC
For renal medullary RCC, platinum-based chemotherapy remains the standard, with an ORR of 29% and an OS of 13 months in a cohort of 45 patients.
Collecting Duct Carcinoma
A prospective trial evaluating the addition of bevacizumab to gemcitabine plus platinum-based chemotherapy for collecting duct carcinoma did not meet its predefined endpoints for PFS and OS, indicating no added benefit from bevacizumab in this context.
Unclassified RCC
In unclassified RCC, both cabozantinib/nivolumab and lenvatinib/pembrolizumab combinations reported 50% ORR rates.
Several ongoing trials, including the phase 3 PAPMET2 trial (NCT05411081), the phase 2 PAXIPEM trial (NCT05096390), and the phase 3 SAMETA trial (NCT05043090), aim to address remaining gaps in papillary RCC. Additionally, the phase 2 SUNNIFORECAST trial (NCT03075423) and the phase 3 STELLAR-304 trial (NCT05678673) are expected to report soon for all patients with nccRCC.
