Benefit Of Immunotherapy In Advanced Nsclc Patients Selected By Kras Mutations: A Single Institute Retrospective Analysis

Background: Kirsten Rat Sarcoma (KRAS) viral oncogene is the most common oncogenic driver in non-small cell lung cancer (NSCLC), altered in around 25–30% adenocarcinomas and present in both localized and advanced disease. Within KRAS, G12C, G12 V and G12A mutations are generally related with the smoking habit. Despite being highly prevalent aberrations, the predictive and prognostic roles of these molecular alterations still are investigational in NSCLC patients treated with immunotherapy (IT). Methods: We retrospectively assessed the efficacy outcomes (response rates [RR], progression-free survival [PFS]) in KRASm advanced NSCLC patients who received IT in our institution between 2016 and 2020, considering correlation with G12C, G12D and G12 V mutations. Histological features and co-occurring mutations (detected by ctDNA next-generation sequencing [NGS], tissue NGS or both) were also collected. Stata 15.1 was used for the analysis. Results: Sixty-nine patients were included. Mean age was 62 (39–80), men represented 63.7%, heavy smokers were 73.8%, and adenocarcinoma histology was 82.6%. KRAS G12C was the most common KRAS subtype (41.9%), followed by G12D (19.4%), and G12 V (16.1%). PDL1 status was known in 91% (24.6% <1%, 26% 1–49%, 40.5% >50%). Main pathogenic co-mutation identified by NGS were: TP53, CDKN2A, BRCA2, PIK3CA, CDK4/CDK6, and ALK. Variants of Unknown Significance (VUS) were: GNAS, MET, MYC, and SMAD4. At 1st line, chemo-IT was used in 14 patients (38.8%) and IT alone in 22 (61.2%). At 1st line, RR was the same for G12C, G12D, and G12 V (50%). There were no differences between PFS for KRAS G12C and non-G12C (8.2 vs 9.3 m, p = 0.66), not for G12D and non-G12D (9.6 vs 8.7 m, p = 0.75), and not for G12 V and non-G12 V (7.1 vs 9.2 m, p = 0.58). At 2nd line, IT alone was used in 30 patients (90.1%). In this setting, RR were slightly higher for KRAS G12D (50%) than for G12C (25%) and for G12 V (0%), but without significant differences. Median PFS was not statistically superior for any KRAS subtype. Conclusions: Our results suggest that KRAS G12C, G12D or G12 V mutations could not be a good predictive factor for response to immunotherapy. This study was limited by its retrospective design and limited selection of patients. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.