Lenvatinib (lenva) + pembrolizumab (pembro) demonstrated encouraging antitumor activity and controllable safety characteristics in treatment-naive (n=23) or earlier cured metastatic RCC (n=105, initially medicated with immune checkpoint inhibitor [ICI]; n=19, previously treated ICI naive) patients; there were 145 cases of clear cell RCC and 2 instances of non-clear cell RCC, in the research of 111/KEYNOTE-146 trial (NCT02501096; N=147). For a study, the researchers examined the relationship between clinical outcomes and gene expression signatures and DNA variations for particular RCC-specific driver genes of interest in the exploratory investigation. Lenva 20 mg orally once daily + pembro 200 mg intravenously once every 3 weeks were given to patients with metastatic RCC. Pts who were treatment-naive (n=10) and ICI pretreated (n=70) were included in the study; the disease had evaluable RNA-sequencing data for the 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) and 11 other signatures (angiogenesis; glycolysis; gMDSC; hypoxia; mMDSC; MVD; MYC; proliferation; RAS; stroma/EMT/TGF; WNT ) and information from whole-exome sequencing (WES) for individual genes’ DNA variations (VHL, PBRM1, BAP1, and SETD2). Before the beginning of medication, specimens were obtained. Using logistic regression and Cox proportional hazards, the correlations between each signature score and ORR and PFS per immune-related RECIST were explored. The Hochberg step-up approach was used to correct one-sided P values for TcellinfGEP (hypothesized positive relationship) and two-sided P values for all other signatures (no hypothesized link) for multiplicity; significance was determined at α equals 0.05. The relationship between each gene’s DNA variations and ORR was analyzed descriptively. The cutoff for clinical data was August 18, 2020.RNA sequencing and WES data were available for 80 (54%) and 60 (41%) of the 147 medicated pts, respectively.TcellinfGEP was not linked to ORR (P=0.827) or PFS (P=0.741), and the other 11 signatures were not before or after TcellinfGEP modification. The table illustrated the ORR for DNA variations. Responses were seen independent of biomarker status in an exploratory survey of pts with metastatic RCC included in Study 111/KEYNOTE-146 treated with lenva + pembro. The relationships between gene signatures and clinical outcomes were not statistically substantial. Clinical benefit was found regardless of VHL, PBRM1, BAP1, or SETD2 mutations status. Biomarker analysis in more extensive randomized datasets offered further evidence on their function in RCC.