Background: Sotorasib is a first-in-class oral, irreversible KRAS^G12C inhibitor approved for adults with pretreated KRAS G12C-mutated advanced NSCLC. In CodeBreaK 200, the first KRAS^G12C inhibitor randomized phase 3 trial, sotorasib demonstrated superior progression-free survival (PFS) and overall response rate (ORR) vs docetaxel and a more favorable safety profile. We report prespecified exploratory biomarker analyses comparing sotorasib vs docetaxel efficacy in molecularly-defined KRAS G12C-mutated advanced NSCLC subsets. Methods: In CodeBreaK 200, 345 pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib 960 mg daily or IV docetaxel 75 mg/m² Q3W. Primary endpoint was PFS by blinded independent central review (RECIST 1.1; key secondary endpoint: ORR). In prespecified exploratory analyses, baseline tissue and plasma samples were analyzed for key genomic alterations (eg, STK11, KEAP1, EGFR, MET, TP53), by central targeted next-generation sequencing (Skoulidis N Engl J Med 2021), and PD-L1 protein level by local standard of care testing in biomarker-evaluable cases; biomarker status was correlated with PFS and ORR. Inferred tumor mutation burden by plasma circulating tumor DNA (sum of mutant molecular variant reads) was assessed. Association of baseline genomic alterations with long-term benefit (PFS ≥ 6 m) vs early progression (PFS < 3 m; no complete/partial response) was evaluated. Results: Most prevalent KRAS G12C co-alterations in biomarker-evaluable cases with available tumor and/or plasma samples (n=317) were TP53 (181 [57.1%]), STK11 (119 [37.5%]), and KEAP1 (82 [25.9%]) in CodeBreaK 200, consistent with CodeBreaK 100; 55 (17.4%) pts had STK11 and KEAP1 co-alterations. Sotorasib showed superior clinical benefit vs docetaxel independently of PD-L1 expression and across all prespecified subgroups (eg, STK11,KEAP1, TP53). No clinical response occurred with either treatment in 26 (8.2%) pts with additional KRAS alterations, including amplifications. High baseline plasma tumor burden was associated with greater odds of early progression vs long-term benefit in both arms (odds ratio, 3.54 [95%CI 1.83-6.85] per tertile increase; p<0.0001). Correlation of KRAS G12C co-alterations with response detected a signal toward shorter median PFS (sotorasib, 2.8 m [95%CI 1.6-3.4]; docetaxel, 7.5 m [95%CI 3.0-NE]) with sotorasib vs docetaxel in pts with KRAS G12C and NOTCH1 co-altered tumors. Conclusions: Sotorasib demonstrated consistent clinical benefit vs docetaxel in all prespecified molecularly-defined subgroups (eg, STK11,KEAP1, TP53) in this exploratory analysis of CodeBreaK 200. No predictive biomarkers were confirmed, but novel hypothesis-generating signals were observed. Clinical trial information: NCT04303780.