Abstract CT084: Relationship between <i>STK11</i> and <i>KEAP1</i> mutational status and efficacy in KEYNOTE-042: pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC
Authors: 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
Journal: Cancer Research (2020)

Abstract 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. STK11KEAP1With MutationWithout MutationWith MutationWith MutationPembroChemoPembroChemoPembroChemoPembroChemo(n = 16)(n = 17)(n = 214)(n = 182)(n = 31)(n = 33)(n = 199)(n = 166)ORR, % (95% CI)31 (11-59)6 (&amp;lt;1-29)29 (23-36)24 (18-30)35 (19-55)18 (7-35)29 (22-35)23 (17-30)PFS, median, mo (95% CI)5 (2-NR)5 (4-11)6 (4-7)6 (6-7)6 (4-24)6 (4-7)6 (4-6)6 (6-8)PFS, HR (95% CI)0.75 (0.36-1.57)0.91 (0.74-1.13)0.67 (0.38-1.17)0.96 (0.77-1.20)OS, median, mo (95% CI)18 (10-NR)8 (6-13)17 (13-23)12 (11-15)17 (7-NR)9 (7-26)17 (13-23)12 (11-15)OS, HR (95% CI)0.37 (0.16-0.86)0.83 (0.65-1.05)0.75 (0.42-1.35)0.78 (0.61-0.99) 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.