Efficacy of olaparib in advanced cancers occurring in patients with germline or somatic tumor mutations in homologous recombination (HR) genes, a Belgian Precision phase II basket study

Abstract

associations of EPHA3 mutations with tumor mutation burden (TMB), PD-L1 expression, microsatellite instability-high (MSI-H), tumor-infiltrating lymphocytes (TILs), and clinical response to ICIs. This will be very helpful for identifying patients who may benefit from immunotherapy. Methods: The ICIs cohort from the MSKCC was used for exploring the associations between EPHA3 mutations and ICIs efficacy. The relationships between EPHA3 mutations and TMB, PD-L1 expression, and MSI-H were investigated in our Chinese cohort. The TCGA cohort was used for analyzing the link between EPHA3 mutations and TILs. Results: First, we analyzed the associations between EPHA3 mutations and overall survival (OS) after ICIs therapy. For all enrolled patients, those who harbored EPHA3 mutations had a relatively longer OS compared to those without mutations (40 vs 18 months, P ¼ 0.0102). However, EPHA3 mutations displayed divergent predictive roles in different cancer types. The median OS was significantly longer in the Mut group compared to the WT group for NSCLC (36 vs 11 months, P ¼ 0.0167). There were no associations between EPHA3 mutations and ICIs efficacy for patients with melanoma, glioma, bladder, colorectal, esophagogastric, breast, and head and neck cancers. Second, the results from our cohort showed that the median TMB was higher in the Mut group for NSCLC (14.6 vs 6.6 muts/Mb, P < 0.0001). And we did not find the associations of EPHA3 mutations with PD-L1 expression and MSI-H. Third, the analysis in the TCGA cohort revealed that NSCLC patients with EPHA3 mutations were infiltrated with increased activated natural killer cells (P ¼ 0.0131). Conclusions: Our data indicated that EPHA3 mutations were associated with prolonged OS in NSCLC, rather than other cancer types, suggesting that it might act as a predictive biomarker for ICIs therapy in NSCLC. EPHA3 mutations were also correlated with higher TMB and increased activated natural killer cells in NSCLC. Background: Dovitinib is a tyrosine kinase inhibitor that inhibits VEGFR1-3, PDGFR, FGFR1-3, c-KIT, FLT3 and topoisomerase 1 and 2. Dovitinib is in development with a tumor agnostic biomarker based on 58 genes associated with sensitivity and resistance to dovitinib. The most advanced development is in renal cell carcinoma (RCC), which is presented here.