Dr Braun on Biopsy Site Selection in Biomarker Testing in ccRCC

David Braun, MD, PhD, assistant professor of medicine (Medical Oncology), member, Center of Molecular and Cellular Oncology (CMCO), Yale Cancer Center discusses findings from a molecular analysis of cohort A of the phase 2 HCRN GU16-260 study (NCT03117309) assessing first-line nivolumab (Opdivo) and salvage nivolumab plus ipilimumab (Yervoy) in patients with advanced clear cell renal cell carcinoma (ccRCC).

In this analysis, investigators aimed to elucidate the association between molecular subtypes and treatment outcomes in this patient population.

Braun notes that the study identified all molecular subtypes, and there was a surprising deviation from expected patterns in those patients with International Metastatic RCC Database Consortium (IMDC) favorable-risk disease. Typically, favorable-risk disease is characterized by angiogenic subtypes—clusters 1 and 2—that dominate this risk category, Braun says. However, this study found a lower prevalence of these clusters within patients with favorable-risk disease.

Findings from the analysis showed favorable outcomes were observed in patients classified as cluster 4, Braun says. These patients experienced an overall response rate (ORR) or 63.6%, a median progression-free survival (PFS) of 16.7 months, and a 1-year PFS rate of 63.6%. This observation supports the hypothesis that a favorable immune subtype enhances the effectiveness of immunotherapy, Braun explains.

Surprisingly, the ORR was also high in patients classified as clusters 1 (66.7%) and 3 (46.2%), Braun continues. He adds that transcriptomic signatures, although enriched, did not fully predict ORR in this small dataset.

Notably, a secondary analysis revealed significant heterogeneity in biopsy samples obtained from primary and metastatic sites in regard to molecular subtypes. In 22 patients with paired samples from primary and metastatic sites, 12 patients exhibited different subtypes between these locations, Braun explains. This finding underscores the importance of biopsy site selection in biomarker-driven studies and suggests that heterogeneity between tumor sites may influence treatment classification and subsequent outcomes, Braun concludes.