Impact of KRAS mutations and subtypes on efficacy of immune-checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC)

KRAS mutations are detected in 25% of NSCLC. Data on ICI activity in these patients, particularly in each KRAS subtype are limited. The aim of this study was to collect further data in an international multi-center registry. We conducted a retrospective multicenter study of patients receiving ICI for advanced NSCLC harboring KRAS mutations (KRAS+) and compared them with data from KRAS wild-type patients (DRIVER-) and patients with other oncogenic addictions (DRIVER+). We pooled two large databases for this study (overall 26 centers). Anonymized data were evaluated for clinic-pathological characteristics and outcomes: best response (RECIST v1.1), progression-free survival (PFS) and overall survival (OS) from ICI initiation. We included 913 patients: 421 KRAS+ patients (G12C 168, other mutations 219, missing 34) and 492 controls (191 DRIVER- and 301 DRIVER+). KRAS+ patients were predominantly male (55.1%), former/current smokers (96.1%), and median-age was 62 yr. Patients were treated by ICI (PD-1/PD-L1 inhibitors) single agent mainly in second (53.4%) or third line (25.4%). Objective response rate was 22.6%, 13.4% and 12.8% (p=0.001), median PFS was 3.2months (m), 3.5m and 2.5m (p<0.001) and median OS was 13.9m, 14.1m, 13.4m (p=0.67) in KRAS+, DRIVER- and DRIVER+ cohorts, respectively. PFS was influenced by the number of lines of treatment, PD-L1 expression, performance status and type of mutation (p<0.05). Among KRAS+ patients, ORR was 26.9% and median PFS was 4.0m in KRAS G12C vs 18.8% and 2.9m in other KRAS types.Table:Molecular profileRR (%)PFS (m.) [CI95%]OS (from ICI initiation) (m.) [CI95%]KRAS mutationTotal22.63.2 [2.8-4.0]13.9 [10.4-16.0]KRAS G12C26.94.0 [2.8-6.4]15.0 [11.2-18.6]KRAS non G12C18.82.9 [2.5-3.9]11.9 [9.4-17.8]KRAS wild-type (DRIVER-)13.43.5 [2.7-4.4]14.1 [9.6-19.5]Other driver (DRIVER+)12.82.5 [2.1-2.8]13.4 [10.0-15.6] Open table in a new tab Based on a large collaborative registry, we suggest that patients with KRAS mutations and particularly G12C derive a greater benefit from ICI monotherapy than patients with other or no alterations. These results may help optimize the therapeutic strategy for KRAS mutated patients and provide rational for future combinations.