LAUSR

Background:STK11 (also known as LKB1) and KEAP1 mutations have been associated with chemoresistance and poor outcomes and shown to be more frequent in PD-L1-negative tumors with high tumor mutational burden (TMB). We performed an exploratory analysis of KEYNOTE-042 (NCT02220894) to assess the prevalence of STK11 and KEAP1 mutations and their association with efficacy. Methods:STK11 and KEAP1 status and TMB were assessed by whole-exome sequencing (WES) in tumor tissue and matched-normal DNA. PD-L1 was assessed with the PD-L1 IHC 22C3 pharmDx assay. Descriptive analyses were performed to assess the correlation of STK11 and KEAP1 status with TMB and PD-L1 expression distributions and the association between STK11 and KEAP1 status and efficacy. Results: 429/1274 pts (34%) had evaluable WES data from tumor and normal DNA. STK11 and KEAP1 mutations were seen in 33 (8%) and 64 (15%) pts, respectively; 12 pts (3%) had both mutations. Pts with STK11 mutation tended to have a lower PD-L1 TPS than pts without (median [IQR] 15% [3-50] vs 40% [10-80]); TPS tended to be similar in pts with vs without KEAP1 mutation (40% [10-81] vs 40% [10-80]). TMB score tended to be higher in pts with vs without STK11 (median [IQR] 191 [104-272] vs 146 [72-253]) or KEAP1 (183 [114-283] vs 142 [68-252]) mutation. ORR, PFS, and OS with pembrolizumab were similar in pts with vs without STK11 or KEAP1 mutation; chemotherapy efficacy was lower in pts with vs without STK11 mutation (Table). Pembrolizumab was associated with better outcomes than chemotherapy regardless of STK11 or KEAP1 status (Table). 95% CIs were wide given the modest frequency of STK11 and KEAP1 mutations. Conclusions: The findings of this exploratory analysis suggest pembrolizumab monotherapy should be considered a standard first-line treatment option for advanced PD-L1-positive NSCLC regardless of STK11 or KEAP1 status. Citation Format: Byoung Chul Cho, Gilberto Lopes, Dariusz M. Kowalski, Kazuo Kasahara, Yi-Long Wu, Gilberto Castro, Hande Z. Turna, Razvan Cristescu, Deepti Aurora-Garg, Andrey Loboda, Jared Lunceford, Julie Kobie, Mark Ayers, M. Catherine Pietanza, Bilal Piperdi, Tony S. Mok. Relationship between STK11 and KEAP1 mutational status and efficacy in KEYNOTE-042: pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT084.