Correlation of KRAS G12C Mutation and High PD-L1 Expression with Clinical Outcome in NSCLC Patients Treated with Anti-PD1 Immunotherapy

Abstract

Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 improved the survival of non-small cell lung cancer (NSCLC) patients with PD-L1 expression ≥50% and without alterations in EGFR, ALK, ROS1, RET. However, markers able to predict the efficacy of ICIs, in combination with PD-L1 expression are still lacking. Our aim in this hypothesis-generating pilot study was to evaluate whether the KRAS G12C variant may predict the efficacy of ICIs in advanced NSCLC patients with PD-L1 ≥ 50%. Methods: Genomic DNA or tissue sections of 44 advanced ICI-treated NSCLC cases with PD-L1 ≥ 50% without EGFR, ALK, ROS1, RET alterations were tested using Next Generation Sequencing, Fluorescence in Situ Hybridization and immunohistochemistry. Statistical analyses were carried out fitting univariate and multivariate time to event models. Results: KRAS G12C mutant patients (N = 11/44) showed a significantly longer progression-free survival (PFS) at univariate and multivariate analyses (p = 0.03). The Kaplan–Meier plot of the PFS time-to-event supports that G12C positive patients have a longer time to progress. PFS improvement was not observed when any KRAS mutations were compared to wild-type cases. Conclusions: Given the limitations due to the small sample size and exploratory nature of this study, we tentatively conclude the KRAS G12C mutation should be considered in future trials as a predictive marker of prolonged response to first-line ICIs in NSCLC patients overexpressing PD-L1. This finding could be relevant as anti-KRAS G12C therapies enter the therapeutic landscape of NSCLC.

Characteristics and Treatment Outcomes in Advanced-Stage Non-Small Cell Lung Cancer Patients with a KRAS G12C Mutation: A Real-World Study

“…On the contrary, PD-L1 positivity (TPS > 1%) was identified as a positive prognostic marker for OS. Interestingly, a recent exploratory study suggested that the KRAS G12C -mutation could be associated with a prolonged response to 1 L immunotherapy in PD-L1-overexpressing NSCLC [ 32 ]. PD-L1 is a relevant biomarker in NSCLC, but its role in KRAS G12C -mutated cancers is not yet clear.…”

Current treatments for non-small cell lung cancer

“…Moreover, the immune checkpoint development also benefits NSCLC patients. If the mutation in patients does not concern the mutations above, then the programmed death ligand 1 (PD-L1) mutation maybe a better choice, but there are still some limits, for example, the mutation of PD-L1 at least appears 50% mutation in the lung cancer patients (38). The combination of programmed death 1 (PD-1) and PD-L1 would decrease immune response; therefore, the tumor cells will escape the The main causes and symptoms of lung cancer, as well as methods of diagnosis and therapies.…”

Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers

“…A poorer prognosis is found in patients with co-occurring mutations of KRAS and STK11 or KEAP1 [ 106 , 107 ] or KRAS c.34G > T (p.G12C) and PD-L1 expression [ 105 , 108 ]. Regarding the correlation between KRAS mutations and PD-L1 expression, a recent contribution of our group reported the potential role played by the KRAS c.34G > T (p.G12C) variant in the prolonged survival found in NSCLC patients showing a PD-L1 overexpression [ 109 ].…”

“…PD-L1 expression has been shown to be in close relationship with KRAS status, and KRAS mutations were described as possible biomarkers for immune checkpoint inhibitor efficacy [ 114 ], in particular the c.34G > T (p.G12C) mutant variant [ 109 , 135 , 136 , 137 , 138 , 139 ]. Monotherapy of immune checkpoint inhibitors in advanced lines demonstrated a higher objective response rate (26%) in KRAS -mutant patients when compared with other oncogene-driven NSCLC patients (BRAF, ROS1, MET, EGFR, HER2, RET, ALK) as reported in immunotarget study [ 140 ].…”