PBRM1 loss-of-function mutations and response to immune checkpoint blockade in clear cell renal cell carcinoma

The biological role of PBRM1 loss-of-function (LOF) mutations mediating response to immune checkpoint blockade (ICB) in clear cell renal cell carcinoma (ccRCC) remains an area of active investigation. A recent study (hereafter, the MSK study) evaluated this hypothesis in a clinically heterogeneous single institution retrospective ccRCC cohort using targeted sequencing and did not find a univariable statistically significant association for PBRM1 LOF and time-to-treatment failure (TTF), but did report a significant association between continuous tumor mutational burden (TMB) and ICB TTF. We re-analyzed this cohort to (i) match the methodology from previous studies and (ii) account for differences in cohort development, statistical approaches, mutation classifications, and outcome measurements. Univariable analysis of the PBRM1 LOF mutation hypothesis, when performed analogously to prior studies, demonstrated a modest statistically significant association with TTF on ICB (p = 0.047; HR = 0.7, 95% CI = 0.49 - 0.99). By contrast, when using the different methodology presented in the MSK study, statistical modeling demonstrated that there was insufficient power to detect this association given the altered classification scheme and modest effect size. In addition, after appropriately normalizing TMB to account for anomalous outliers, TMB was not significantly associated with ICB response in ccRCC. Thus, this study provides further support for the biological association between PBRM1 LOF and favorable clinical outcomes on ICB in specific ccRCC clinical contexts. However, we again strongly caution against interpreting that this PBRM1 biological association, likely one of many modest mediators of tumor-immune-stromal interactions, achieves broadly generalizable predictive biomarker status for ICB in diverse clinical contexts. The PBRM1 LOF biological association has only been shown to be modestly predictive in the post-VEGF TKI ICB-monotherapy ccRCC patient population. Given emerging data about the biological role of PBRM1 in contributing to interwoven immune and angiogenesis programs (among many others), and the rapidly shifting therapeutic combination strategies invoking these processes in ccRCC, focused biological and predictive biomarker analyses in specific clinical settings using appropriately annotated clinical trial cohorts are necessary.