Alterations in STK11 to limit response to immune checkpoint inhibitors in lung cancer.

Abstract

e21503 Background: The use of immune checkpoint inhibitors (ICIs) drastically transformed the treatment of lung cancer. However, a variety of response rates have been observed in patients due to intrinsic or acquired resistances. STK11 mutated patients represent a subgroup of lung cancer patients with diminished outcomes when given ICIs, with some of these patients developing hyperprogressive disease (HPD). Methods: In this study, a retrospective cohort of 384 lung cancer patients previously treated with ICIs was identified from the City of Hope Thoracic Registry (THOR) with a cutoff date of November 11, 2018. Next-generational sequencing (NGS) was performed on 246 patients. 24 of these patients were harboring an alteration in STK11. Data was collected on these patients until December 31, 2019. HPD was exclusively defined by time-to-treatment failure (TTF) < 2 months (TTF is defined as the time from the start of treatment with ICI to ICI discontinuation for any reason, including progression, patient preference, toxicity, or death). Overall survival (OS) and progression free survival (PFS) was started from the initiation of ICI therapy. OS and PFS was calculated between 2 groups (HPD vs non-HPD) using the Mantel-Cox Log-rank test. Results: Almost half (11/13; 45.8%) of the patients with STK11 developed HPD. There was a significant difference between HPD and non-HPD patients in median OS (2 vs 23 months; p = 0.0013) and median PFS (1 v 9 months; p < 0.0001). The median age was 66 (range, 41-90) years old with the majority of patients female (14/24; 58.3%). Most of the patients are deceased (16/24; 66.7%). 91.7% of STK11 patients histologically were adenocarcinoma and 91.7% were smokers with a median pack year history of 40 (range, 4-90). All of the patients had metastatic disease presenting with stage IV disease (21/24; 87.5%). ICI therapies used were pembrolizumab (11/24; 45.8%), Atezolizumab (8/24; 33.3%), nivolumab (4/24; 16.7%), and durvalumab (1/24; 4.2%). PD-L1 expression varied: negative (8/24; 33.3%), 1%- < 50% (7/24; 29.2%), ≥50% (4/24; 16.7%), and not reported (5/24; 20.8%). The most commonly occurring co-mutations were found in TP53 (14/24; 58.3%), KRAS (12/24; 50.0%), SMARCA4 (9/24; 37.5%), PRKDC (8/24; 33.3%) and LRP1B (8/24; 33.3%). Three patients had a pathological co-mutation that is targetable (1 ALK rearrangement, 1 EGFR exon 19 deletion, and 1 RET fusion). Conclusions: STK11 patients who developed HPD had worse OS and PFS compared to STK11 patients without HPD. These results are preliminary and additional analysis is needed to compare differences between various cohorts.