Background: KRAS mutant NSCLC is further defined molecularly by specific mutation subtypes and co-mutations in tumor suppressor genes. Two targeted therapeutics, sotorasib and adagrasib, are currently approved for the treatment of previously treated advanced KRAS G12C mutant NSCLC. Sotorasib has also demonstrated superiority to docetaxel in the randomized phase III CodeBreaK 200 study (de Langen et al Lancet. 2023 Feb 7 Epub). The impact of co-mutations in tumor suppressors, including TP53 and STK11, on the efficacy of first generation KRAS G12C inhibitors has been inconclusive. The S1900E substudy aims to prospectively understand, using rigorous biomarker testing/definitions, the impact of co-mutations on the clinical activity of sotorasib in pts with KRAS G12C mutant NSCLC. Methods: S1900E is a phase 2 open-label study of sotorasib in biomarker-defined cohorts for pts who have KRAS G12C stage IV/recurrent non-sq NSCLC, received at least one line of systemic treatment, and are naïve to KRAS G12C inhibitors. Pts are assigned to S1900E under the Lung-MAP screening protocol (NCT03851445) using FoundationOne F1CDx next generation sequencing assay on tissue (Foundation Medicine, Cambridge, MA). S1900E cohorts include: #1) Presence of TP53 co-mutation AND Wild Type STK11, KEAP1, NFE2L2, CUL3; #2) Presence of STK11 co-mutation AND Wild Type TP53, KEAP1, NFE2L2, CUL3; 3) All pts not eligible for Cohorts 1 and 2 (e.g. dual co-mutations in STK11 and TP53; co-mutations in KEAP1, NFE2L2, CUL3, or others; or lack of any co-mutations). Pts with treated, clinically controlled, and asymptomatic brain metastases are eligible and with amendment 3 (Mar 20 2022), eligibility expanded to pts with asymptomatic untreated brain metastases. Sotorasib is dosed 960 mg oral daily. The primary objective is to evaluate the RECIST 1.1 response rate (ORR) per cohort. For cohorts 1 and 3, the target sample size is 40 eligible pts based on a design with 92% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 34%; ≥10 responses would rule out a 14% ORR. Cohort 2 has a target sample size of 25 eligible pts with 93% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 40%; ≥7 responses would rule out a 14% ORR. Secondary endpoints include PFS, OS, duration of response, and toxicity. Circulating tumor DNA is being collected at day 1 of cycle 1, 2, and 3 and at progression. Enrollment started April 2 2021 with conservative accrual targets met, currently with 72% enrolled (84/116) as of Feb 14 2023, including 37, 16, and 31 pts, in cohorts 1, 2, and 3, respectively. Clinical trial information: NCT04625647.