57P Retrospective comparative analysis of KRAS mutations in mNSCLC patients treated with first-line immunotherapy or chemoimmunotherapy

Activating mutations of KRAS are described in 25% of patients affected by metastatic non-small cell lung cancer (mNSCLC) and represent a biochemically heterogeneous group. The predictive role of KRAS subtypes is still unclear, since different amino acids substitutions lead to the activation of different downstream pathways that could influence response to immunotherapy (IO). We retrospectively evaluated 323 mNSCLC patients harbouring a missense mutation in 1 out of 3 hotspots in the guanosine triphosphatase domain of RAS (279 in codon G12, 26 in G13 and 18 in Q61); among G12 variants, the most frequent were: G12C (39.3%), G12V (21.4%) and G12D (13.3%). We analyzed overall survival (OS) in whole population, comparing different codons, different G12 variants or KRAS G12C mutation versus all the others. Then we analyzed progression-free survival (PFS) and OS in patients with a PD-L1≥50% treated with first-line (1L) IO and in PD-L1<50% cases receiving 1L chemoimmunotherapy (CT-IO), comparing the same populations above mentioned. Median follow up was 30 months. No differences in OS were evidenced in different codons (p = 0,37) or in different G12 variants (p = 0,26); only KRAS G12C mutations showed a slightly longer median OS when compared to all other mutations even if not statistically significant (17,99 vs 11,0 months; p=0,09). In patients with a PD-L1≥50% treated with 1L IO, no differences in PFS and OS were evidenced among different codons (p=0,95 and p=0,77, respectively), or G12 variants (p= 0,76 and p=0,70, respectively), or in KRAS G12C versus all other mutations (p=0,78 and p=0,89, respectively). By the contrary, in patients treated with CT-IO due to a PD-L1<50%, PFS was significantly longer in KRAS G12C mutated cases (14,6 vs 5,6 months; HR 0,53 95%CI: 0,31-0,89; p=0,02) as well as OS (not reached vs 15,8 months; HR 0,39; 95%CI: 0,21-0,74; p=0,01). No differences in PFS and OS among different codons (p=0,19 and p=0,13, respectively) or G12C variants (p=0,27 and p=0,11, respectively) were revealed. The KRAS G12C mutation seems a positive predictive indicator of response to 1L CT-IO in patients with a PD-L1<50%. Different KRAS mutations did not show a prognostic role in mNSCLC patients.