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: HRmut = 0.35/HRwildtype = 0.64; atezolizumab plus bevacizumab vs. sunitinib: HRmut = 0.55/HRwildtype = 0.82; nivolumab vs. everolimus: HRmut = 0.17/HRwildtype = 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.
Sun et al. (Sat,) studied this question.