Impact of STK11 and KRAS co-mutations on outcomes with immunotherapy in non-small cell lung cancer.

Abstract

e15135 Background: While the use of monoclonal antibodies targeting the PD-1 axis in metastatic non-small cell lung cancer (NSCLC) continues to expand since initial FDA approval in 2015, factors predictive of response still remain to be determined. Mutation status may provide insight as to which subgroups exhibit resistance to checkpoint inhibitor therapy. Methods: We conducted a single center retrospective analysis of patients with metastatic NSCLC treated at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) and identified patients that harbor either STK11 mutation alone (S) or co-mutations with STK11 and KRAS (S/K). Genomic results were obtained from Guardant360 and Foundation One testing in blood and tissue, respectively. Results: We identified 37 S patients and 36 S/K patients and determined no significant differences in progression-free survival (PFS). However, overall survival (OS) was significantly increased in patients with S/K co-mutation (20.3 ± 4.1 months) vs. patients with S alone (11.9 ± 1.9 months, p = 0.028). Furthermore, S/K patients who received immunotherapy had longer OS (20.7 ± 5.6 months) vs. S patients (13.6 ± 3.4 months, p = 0.049). We further investigated any population-specific factors that may contribute to the enhanced survival in the S/K cohort that had received immunotherapy, as previous studies have reported that STK11/KRAS co-mutations may confer a resistance to PD-1 axis-directed therapy. We found that S/K patients were older at diagnosis and were more likely to have received nivolumab (as compared to newer therapies pembrolizumab and atezolizumab). In addition, S/K patients were more likely to have longer smoking histories (81% smoked more than 30 pack-years at diagnosis) vs. S patients (53%, p = 0.01) and also had a higher number of additional targetable mutations found on NGS (4.7 ± 0.4 vs. 2.9 ± 0.3, p = 0.001). The most commonly identified mutations were TP53 (30%), KEAP1 (19%), CDKN2A/B (18%), SMARCA4/BRG1 (16%), and ARID1A (11%). Conclusions: Our study reveals an interesting analysis of potential predictors of resistance to immunotherapy with the utilization of precision medicine in combination with patient characteristics to identify the most appropriate treatment regimens for patients with NSCLC. Further studies will explore whether patients receiving immunotherapy as first line could overcome any inherent resistance to PD-1 axis-directed therapy from non-modifiable factors at diagnosis.

Impact of the STK11/KRAS co-mutation on the response to immunotherapy in a real-world pan-cancer cohort

“…Several studies associated STK11/KRAS co-mutation with worse progression-free survival and overall survival after ICI treatment of NSCLC. [13][14][15][16] In this study we aimed to test whether STK11/KRAS co-mutation plays a predictive role in response to ICI or not, in an observational real-world pan-cancer cohort.…”

The Landscape of Immunotherapy Resistance in NSCLC

“…STK11 mutations in NSCLC may be associated with worse outcomes with ICIs since the inactivation of this serine threonine kinase involved in various cellular functions is associated with a low T lymphocytes tumor infiltration and a “cold” tumor microenvironment ( 21 , 22 ). However, it is not clear whether the impact of STK11 mutations is predictive of poor response to ICIs specifically, or simply prognostic of aggressive tumor evolution ( 23 – 25 ). Furthermore, in an exploratory analysis of the KEYNOTE-042 trial comparing single-agent pembrolizumab to chemotherapy, STK11 mutations did not appear to impact the efficacy of ICIs, while they were associated with a worse prognosis in the chemotherapy cohort ( 26 ).…”

Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy

“…In contrast, transversion mutations (substitution of a purine by a pyrimidine or vice versa) in the Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) gene and tumor suppressor gene TP53 alone predicted better outcomes [ 69 ]. Another study reported that NSCLC patients on anti-PD-1 IO who harbored co-mutations of STK11 and KRAS ( n = 36) detected in ctDNA had longer OS in comparison to patients who harbored STK11 mutations alone (13.6 ± 3.4 months, p = 0.049, n = 37) [ 70 ]. The OAK and POPLAR clinical trials showed that mutations in the kelch-like ECH-associated protein 1 ( KEAP1 ) and nuclear factor erythroid-2-related factor-2 ( NFE2L2 ) genes detected in ctDNA were associated with poorer OS and PFS (OS: HR = 1.7, p < 0.001; PFS: HR = 1.4, p < 0.001) in NSCLC patients receiving IO [ 71 ].…”