NF1/2 mutations predict favorable benefit from immune checkpoint inhibitor-based therapies over VEGFR/mTOR inhibitors in clear cell renal cell carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced clear cell renal cell carcinoma (ccRCC), but the biomarkers predicting benefits from ICI-based therapies over conventional VEGFR/mTOR inhibitors remain incompletely elucidated. In this study, we analyzed clinical, mutational, and/or transcriptomic data of multiple cohorts, including five clinical trials (JAVELIN Renal 101 [n = 885], IMmotion151 [n = 715], and CheckMate-009/010/025 [n = 1006]), two prognostic cohorts (TCGA-KIRC, n = 537; ICGC, n = 475). Pharmacogenomic analysis was conducted using the cancer cell line encyclopedia (CCLE) database. Our results revealed that only NF1/2 mutations exhibited a consistent relationship with benefits from ICI-based therapies over VEGFR/mTOR inhibitors among all the common mutations in the JAVELIN Renal 101, IMmotion151, and CheckMate-009/010/025 trials (pooled estimate of interaction effect, P = 0.028). In the multivariable models, ICI benefits were higher in the NF1/2-mutant group compared with the NF1/2-wildtype group (avelumab plus axitinib vs. sunitinib: HR = 0.35/HR = 0.64; atezolizumab plus bevacizumab vs. sunitinib: HR = 0.55/HR = 0.82; nivolumab vs. everolimus: HR = 0.17/HR = 0.73). NF1/2 mutations were associated with greater expression of the genes related to FGFR rather than VEGFR or PI3K-AKT-mTOR in advanced ccRCCs and higher sensitivity to FGFR inhibitors instead of VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines. Compared with the NF1/2-wildtype advanced ccRCCs, those with mutated NF1/2 had an inferior prognosis (HR = 2.53). This tendency was not changed by everolimus (HR = 2.66), but was abrogated slightly by sunitinib (HR = 1.59) and considerably by ICI-based therapies, including nivolumab monotherapy (HR = 1.12), atezolizumab plus bevacizumab (HR = 1.10), and avelumab plus axitinib (HR = 0.69). Overall, our findings suggest that NF1/2 mutations can serve as predictive biomarkers for favorable benefits from ICI-based treatments over VEGFR/mTOR inhibitors in advanced ccRCCs.