Abstract 691P
Background
Immune checkpoint inhibitors (ICIs) have achieved impressive success in advanced renal clear cell carcinoma (ccRCC), yet responses vary and predictive biomarkers are urgently needed. Growing evidence has suggested that specific genetic mutations may serve as immune biomarkers for immune checkpoint blockade therapy of many solid cancer.
Methods
Clinical ICIs-treated cohorts of advanced ccRCC with annotated response and survival data and matched mutational data were collected and consolidated. The predictive function of all mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated.
Results
In the discovery cohort, among 12379 genes in 245 advanced ccRCC treated with ICIs, NANOGNB-mutant (NANOGNB-MUT) was enriched in patients responding to ICI treatment (P<0.001). Compared with other responsive related gene mutations, NANOGNB was mutated in largest proportion (5% advanced ccRCC). Significant differences were observed between NANOGNB-MUT and NANOGNB-wildtype (NANOGNB-WT) regarding objective response rate (ORR, 54.55% versus 21.37%, P<0.001), durable clinical benefit (DCB, 63.64% versus 30.34%, P<0.001), progression-free survival (PFS, hazard ratio=0.45 [95% confidence interval, 0.22 to 0.92], P=0.022), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of NANOGNB-MUT (P>0.05 in non-ICI-treated cohorts, 280 advanced ccRCCs). NANOGNB-MUT was associated with known predictors of ICB therapy efficacy, such as higher tumor mutational burden (TMB), neoantigen load and the number of mutations in the DNA damage-repair pathway. In addition, NANOGNB-MUT tumors had damaged DNA damage response, highly infiltrating TILs, and relatively activated antitumor immunity, suggesting that NANOGNB mutations may serve as a potential biomarker to guide ICB therapy in advanced ccRCCs.
Conclusions
NANOGNB-MUT was strongly associated with higher ORR, better DCB, longer PFS in advanced ccRCCs in ICIs, suggesting that NANOGNB-MUT is a novel predictive biomarker for ICIs for ccRCCs.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Zhiwen Luo, Xinyu Bi and Xingang Bi.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.