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

Abstract

e21010 Background: ICIs changed the way NSCLC is treated, but not all patients benefit from it. PD-L1 level is used to predict response to therapy, but its performance is sub-optimal. KRAS is important in NSCLC tumorigenesis, but the impact of its mutations in patients treated with ICIs is unclear. Similarly, studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs. Methods: We conducted a retrospective study including all consenting patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared in co-mutation subgroups using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. Overall response rate (ORR) and safety data was also compared in subgroups and will be detailed at the meeting. Results: We included 100 patients with known KRAS status. From these, 50 were wild-type ( KRASWT) and 50 were mutated ( KRASMut). The most frequent mutation was G12C (54%). Co-mutation status for TP53, STK11 and KEAP1 were known for, respectively, 40, 39 and 38 patients. Co-mutations for these genes were present in respectively 19 (47.5%), 8 (20.5%) and 4 (10.5%). Data comparing KRASMut and KRASWT showed non-significant differences in survival (median OS of respectively 21.1 vs. 17.7 months, p = 0.27). The presence of STK11 and/or KEAP1 mutations was associated with a negative impact on survival when compared with wild-type (median OS 7.4 vs 20.4 months, p = 0.001). When the presence of a KRAS mutation was compounded with STK11 and KEAP1, KRASMut (vs KRASWT) trended to a better prognosis in STK11+KEAP1WT tumors (median OS of 21.1 for KRASMut vs 15.8 for KRASWT, p = 0.15), but not in STK11+/-KEAP1Mut tumors (7.4 for KRASMut vs 7.0 for KRASWT). No influence on survival was seen in relationship to the TP53 co-mutation. Interestingly, the NLR was significantly higher with STK11 mutations (6.66Mut vs 3.59WT, p = 00012), slightly lower with TP53 mutations (3.23Mut vs 4.82WT, p = 0.047) but not impacted by KEAP1 (3.72Mut vs 4.20WT, p = 0.72) or KRAS mutations (4.32Mut vs 5.21WT, p = 0.34). Conclusions: The STK11 and KEAP1 mutations are significant adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11 mutations but not by KEAP1 mutations suggesting marked differences in the resistance mechanism for both mutations. In STK11-KEAP1WT tumors, KRAS mutations seems to be associated with improved survival in NSCLC patient treated with ICIs.

More to the RAS Story: KRASG12C Inhibition, Resistance Mechanisms, and Moving Beyond KRASG12C

“…There have been preliminary reports of comutations in STK11, KEAP, and TP53 modulating the responsiveness of patients with KRAS G12C alterations to either KRAS G12C inhibitors or to standard-of-care immunotherapy and chemotherapy. 22,[33][34][35][36][37][38][39][40][41][42][43][44] However, this is beyond the scope of this review and is not discussed further here.…”

Resistance to KRAS inhibition in advanced non-small cell lung cancer

“…Some studies have demonstrated that co-mutations in STK11 , KEAP1 , and TP53 could modulate the responsiveness of patients with KRAS alterations to either KRAS G12C inhibitors or to immunotherapy ( 14 – 16 , 18 , 95 ). Proulx-Rocray and colleagues (2021) showed that the presence of STK11 and/or KEAP1 mutations was associated with a negative impact on survival when compared with wild-type NSCLC patients treated with immune check point inhibitors ( 96 ). These authors also reported that in patients harboring KRAS mutation, improved prognosis was observed in STK11+KEAP1 wild-type tumors but not in STK11+/-KEAP1 mutant tumors.…”

Breaking the ‘Undruggable’ Barrier: Anti-PD-1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer Patients with KRAS Mutations—A Comprehensive Review and Description of Single Site Experience

“…There are indications that STK11 and KEAP1 mutations are significant adverse predictors for the efficacy of immune check point inhibitor (ICIs) therapy in NSCLC patients with KRAS mutations [49]. However, the neutrophil-lymphocyte ratio (NLR) is impacted by STK11 but not by KEAP1 mutations.…”

“…It suggests differences in the immunotherapy resistance mechanism connected with the presence of both mutations. The authors concluded that KRAS mutations could be associated with improved survival in NSCLC patients treated with immunotherapy in the absence of mutations in the STK11 and KEAP1 genes in tumor cells [49].…”