USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRAS(G12C)) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFR(L858R) and EGFR(Delta 19)) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01-1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49-2.63; P<0.0001), while classical activating mutations with EGFR(T790M) showed no difference compared to classical activating mutations without EGFR(T790M) in OS (adjusted HR, 0.96; 95% CI, 0.48-1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39-1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A (USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32-0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38-0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75-8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88-6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRAS(G12C) mutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFR(T790M) showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Automated summary

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs). The results showed that lung cancer patients with KRAS(G12C) mutation combined with TP53 mutation exhibited promising efficacy with ICI therapy. However, classical activating mutations of EGFR had negative effects on the survival outcomes, while USH2A missense mutation was associated with better outcomes.