The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and their influence on the NLR in NSCLC patients treated with immunotherapy

Abstract

Background

PD-L1 expression is used to predict NSCLC response to ICIs, but its performance is suboptimal. The impact of KRAS mutations in these patients is unclear. Studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs.

Patients & methods

This is a retrospective study of patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. ORR and safety were compared using Wald method.

Results

From 100 patients with known KRAS status, 50 were mutated (KRAS^Mut). Mutation in TP53, STK11 and KEAP1 were present, and their status known in, respectively, 19/40 (47.5 %), 8/39 (20.5 %) and 4/38 (10.5 %) patients. STK11^Mut and KEAP1^Mut were associated with shorter overall survival when compared with wild type tumors (respectively median OS of 3.3 vs 20.4, p = 0.0001 and 10.1 vs 17.7, p = 0.24). When KRAS status was compounded with STK11/KEAP1, KRAS^Mut trended to a better prognosis in STK11+KEAP1^WT tumors (median OS 21.1 vs 15.8 for KRAS^WT, p = 0.15), but not for STK11+/-KEAP1^Mut tumors. The NLR was strongly impacted by STK11 (6.0^Mut vs 3.6^WT, p = 0.014) and TP53 (3.2^Mut vs 4.8^WT, p = 0.048), but not by KEAP1 or KRAS mutations.

Conclusion

STK11^Mut and KEAP1^Mut are adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11^Mut but not by KEAP1^Mut, suggesting differences in their resistance mechanism. In STK11-KEAP1^WT tumors, KRAS^Mut seem associated with improved survival in NSCLC patients treated with ICIs.

MicroAbstract

Response of NSCLC to immunotherapy is not easily predictable. We conducted a retrospective study in 100 patients with NSCLC and a known KRAS status. By accounting for different co-mutations, KRAS mutation was found to be associated with a better median overall survival in STK11 and KEAP1 wild-type tumors (21.1 vs 15.8, p = 0.15). NLR was impacted by STK11, but not KEAP1 mutation, suggesting a difference in their resistance mechanism.