STK11/LKB1 revisited: A prognostic rather than predictive biomarker for immune checkpoint inhibitor in EGFR/ALKWT nonsquamous non-small cell lung cancer (NSCLC).

Abstract

e21548 Background: Previous retrospective studies identified the mutation of serine/threonine-protein kinase (STK11, also known as Liver Kinase B1 [LKB1]) as predictor to the benefit from immune checkpoint inhibitor (ICI) in KRAS-mutant lung adenocarcinoma. This conclusion was drawn from merely the patients receiving ICI, lacking the indispensable control group undergoing chemotherapy. Therefore, we hereby revisit the impact of STK11 mutation in both immunotherapeutic and chemotherapeutic cohorts, in addition to TCGA database as a control cohort representing prognosis. Methods: 6 immunotherapeutic cohorts involving 807 patient-level data (Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK-atezolizumab), 1 chemotherapeutic cohort (POPLAR/OAK-docetaxel, n = 244), and TCGA database (n = 485) were included to comprehensively re-examine the questionably predictive effect of STK11 mutation on the benefit from immunotherapy in patients with EGFR/ALKWT non-squamous NSCLC. Results: In the 6 immunotherapeutic cohorts, STK11 mutation was associated with shorter progression-free survival (PFS, HR = 1.54, 95%CI 1.17-2.03, P = 0.002) and overall survival (OS, HR = 1.57, 95%CI 1.16-2.11, P = 0.003), but no statistically lower overall response rate (ORR, RR = 0.71, 95%CI 0.39-1.28, P = 0.251). Similarly, in the patients receiving docetaxel, worse ORR and PFS at borderline level and significantly reduced OS (HR = 1.82, 95%CI 1.18-2.80, P = 0.006) were observed. Specifically, in the POPLAR/OAK cohort retrieved from two randomized controlled trials comparing atezolizumab and docetaxel, STK11 mutation and treatment choice separately impacted on OS, but the interaction between these two variables was barely profound (HR 1.10, 95%CI 0.60-2.01, P = 0.766), indicating the prognostic, but not predictive utility of STK11 mutation. Furthermore, in TCGA database, STK11 mutation was linked with poorer prognosis, with the similar hazard ratio in immunotherapeutic cohorts. Conclusions: Genomic abberation of STK11 remarkably worsens prognosis among 6 immunotherapeutic cohorts, 1 chemotherapeutic cohort, and TCGA database, demonstrating the prognostic, but not predictive utility of STK11 mutation in patients with EGFR/ALKWT non-squamous NSCLC.