KRAS G12 isoforms exert influence over up-front treatments: A retrospective, multicenter, Italian analysis of the impact of first-line immune checkpoint inhibitors in an NSCLC real-life population

Abstract

BackgroundKRAS is commonly mutated in non-small cell lung cancer (NSCLC); however, the prognostic and predictive impact of each G12 substitution has not been fully elucidated. The approval of specific G12C inhibitors has modified the idea of KRAS “undruggability”, and although the first-line standard consists of immune checkpoint inhibitors (ICIs) with or without chemotherapy, as suggested at ASCO 2022, the outcome in KRAS-mutated population is still controversial.MethodsWe retrospectively described the clinical and pathological characteristics of a homogeneous G12 mutated cohort of 219 patients treated in four Italian oncologic units. We evaluated the outcome (PFS at 18 months and OS at 30 months) of those who underwent standard first-line treatment according to PD-L1 status, focusing on differences across single mutations.ResultsIn the study population, 47.9% of patients harbor the KRAS G12C mutation; 20.5%, G12V; 17.4%, G12D; and 8.2%, G12A. Smoking was a common behavior of patients harboring transversions and transition mutations. PD-L1 expression does not show particular distribution in the case series, although we recorded a prevalence of PD-L1 <1% in G12V (51.4%) compared to G12A (26.7%). ICIs alone was the clinician’s choice in 32.7% of patients, and the chemo-immune combination in 17.3% of patients. We described the independent prognostic role of young age (p = 0.007), female gender (p = 0.016), and an ICI-based regimen (p = 0.034) regardless of mutations. Overall, our data confirm the worst prognostic value of G12V mutation apart from treatment choice unlike the other major mutations (C, D, and A) that showed a favorable trend in PFS.ConclusionsKRAS G12 mutations are confirmed to have different characteristics, and the outcome is influenced by ICI first-line regimen. This study provides valuable information for further analysis in the future.

Understanding the feasibility of chemotherapeutic and immunotherapeutic targets against non-small cell lung cancers: an update of resistant responses and recent combinatorial therapies

“…Therefore, despite inadequate clinical data, there is a high probability of KRAS G12C inhibitors being ineffective in many sufferers. Intriguing curiosity prevails for screening KRAS G12C inhibitors in combination with ICIs [ 56 , 57 ]. In several preclinical studies, these combinations are being pursued as KRAS G12C positive tumor cell lines exhibit an immunosuppressive environment attenuated by KRAS inhibition [ 58 , 59 ].…”

“…Experimental evidence for reduced ERK activity via KRAS G12C TKIs does establish a suppressed ERK-driven RTKs/Src homology phosphotyrosine phosphatase 2 (SHP2) inhibition, further regulating NRAS, HRAS, and KRAS G12C to activate the MAPK/ERK signaling [52,54]. It could be a further certainty that tumor cells may no longer depend on RAS pathway for survival and proliferation [55]. Therefore, despite inadequate clinical data, there is a high probability of KRAS G12C inhibitors being ineffective in many sufferers.…”

Unconventional strategy could be the future: From target to KRAS broad range treatment

“…The complexity of the mechanisms in which KRAS is involved, and particularly the modulation of the peri-tumor inflammatory response, is evident and not completely well understood. Several retrospective analyses described in KRAS mutated patients a different performance of ICIs, with or without CT [ 37 , 38 ]. A glimmer of hope in understanding such intricate tangles as the treatment of patients mutated for KRAS comes from the recent presentation of post-hoc analysis of data from the POSEIDON trial.…”