Impact of STK11 copy loss on clinical outcomes to PD-(L)1 blockade in non–small cell lung cancer.

Abstract

9059 Background: STK11 is among the most commonly altered genes in non-squamous lung cancers. While STK11 mutation is associated with diminished efficacy of immune checkpoint inhibition (ICI), particularly in KRAS mutated tumors, it is not known whether STK11 copy deletion influences outcomes to ICI. Methods: Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with ICI whose tumors underwent genomic profiling were included. Clinical outcomes to ICI were analyzed according to KRAS mutation and STK11 deletions. STK11 copy number variations (CNVs) were determined using an internal informatic pipeline. Kaplan-Meier methodology was used to estimate event-time distributions. Results: Of 559 patients with non-squamous NSCLCs (Nsq-NSCLC), 40.4% (N = 226) had a KRAS mutation ( KRASmut), 18.4% (N = 103) had an oncogenic STK11 mutation ( STK11mut), and 22.5% had either single (N = 123), or bi-allelic (N = 3) deletion ( STK11del). Given that 32.5% of STK11del cases had a concurrent oncogenic STK11 mutation in our cohort, to isolate the impact of STK11del on ICI outcomes we excluded samples with STK11mut from this analysis. In all comers with NSCLC, STK11del had no impact on objective response rate (22.2% versus 23.8%, P = 0.8), progression-free (PFS, HR 0.90, P = 0.30), and overall survival (OS, HR 0.96, P = 0.79) to ICI. When we examined the impact of STK11del on clinical outcomes to PD-(L)1 blockade among KRASmut cases we found that STK11del was associated with a numerically lower ORR (13.3% versus 30.0%, P = 0.12), and a significantly shorter PFS (HR 0.57, P = 0.018) compared to cases without STK11del. No difference in OS were observed between these groups (HR 0.77, P = 0.39). Among KRASwt NSCLCs, STK11del cases had a similar ORR (22.6% versus 22.9%, P = 0.99), PFS (HR 0.92, P = 0.63), and OS (HR 1.18, P = 0.32) to PD-(L)1 inhibition compared to cases without STK11del. Among KRASmut but not KRASwt NSCLCs, cases with STK11del had significantly lower PD-L1 expression compared to those without STK11 deletions (27.5% versus 70%, P = 0.01). Conclusions: STK11 deletion is associated with low response rate and short progression-free survival among KRAS mutant NSCLCs. Future analyses will incorporate additional cases to increase sample size and immunopathologic findings to assess impact of mono and bi-allelic deletion on protein expression.