P33.14 STK11/LKB1, KRAS Mutations and Immune-Related Adverse Events as Predictors of Response to Immunotherapy in Lung Cancer

Abstract

Programmed death-ligand 1 (PD-L1) and tumor mutational burden (TMB) might help us predict responses to check point inhibitors (CPI), but we don’t have biomarkers that can predict resistance. Preliminary reports of mutations (mut) in STK11/LKB1 have suggested that they can confer CPI resistance. We investigated the role of STK1/LKB11, KRAS mut as markers of poor response to CPI in patients (pts) with non-small cell lung cancer (NSCLC). Additionally, we previously reported evidence that immune-related adverse events (irAEs) and its utility in identifying potential responders to CPIs. We investigated the role of STK11/LKB1 mut, KRAS mut and irAEs as predictors of response to CPIs in patients (pts) with non-small cell lung cancer (NSCLC). Pts with stage IIIB-IV NSCLC who were treated with CPI were prospectively tested (NGS) for KRAS and STK11/LKB1 mut were evaluated for progression free survival (PFS) and overall survival (OS). Log-rank tests were used to compare OS and PFS, chi-squared tests were used to compare 1-year survivals and proportions among different variables, and Kaplan-Meier survival curves were used to report OS and PFS. Furthermore, since Hispanics (H) are often not stratified in clinical trials, we sought to evaluate if incidence of irAEs and STK11 mut were similar between H and non-Hispanic (NH) pts. Of the 127 pts: 31 pts had an STK11 mut and 14 had an STK11+KRAS mut. Median age was 65y (27-88y). Males comprised 54% of the total pts and 24% of pts were H. STK11 mut pts had an inferior median PFS (5.6 vs 6.28 months; p-value 0.35) and significant difference in median OS (8.6 vs 12.1months; p-value 0.035) compared with STK11 wt pts. OS at 12 months was significantly higher in the STK11 wt group versus the STK11 mut group (73% vs 55%; p-value 0.03). Pts with STK11+KRAS mut had shorter OS and PFS than patients with wt (5m vs 11m and 3m vs 5m) but the differences were not significant, however the 1-year survival was better for wt pts compare with pts with both mutations (70% vs 40%) p-0.03. 48 pts experienced an irAE and 77 did not. The irAEs positive group had increased median PFS (9.5 vs 4.4 months; p-value 0.0047) and OS (14.2 vs 7.3 months; p-value < 0.001) compared to the irAEs negative group. OS at 12 months was 85% in the irAEs positive group compared to 60% in the irAEs negative group (p-value 0.001). There were no significant differences in incidence of irAEs and STK11/LKB1 mut status for H vs. NH pts. STK11/LKB1 mut pts and pts carrying KRAS mut concomitantly had shorter OS, PFS and 1-year survival compared with similarly treated pts with wt, however some numbers are not significant. CPIs treated NSCLC pts that experienced irAE had improved survival outcomes compared to those without irAEs. These findings are consistent with other studies that have reported STK11/LKB1 muts as a major genomic driver of primary resistance to CPI, and validate our previous report that described the utility of irAEs in predicting response to CPIs.