S1900E: A Phase II Study Examining Impact of Co-Mutations on Sotorasib for Previously Treated Stage IV/recurrent KRAS G12C Mutated (MUT) Non-Squamous (Non-Sq) Non-Small Cell Lung Cancer (NSCLC) (ECOG-ACRIN Led Lung-MAP Sub-study).

8518 Background: In previously treated KRAS G12C MUT NSCLC, the allosteric KRAS G12C inhibitor sotorasib had superior outcomes compared to docetaxel (ORR 28% vs 13%). S1900E was the first to prospectively test sotorasib in KRAS G12C MUT NSCLC according to co-mutations (CO-MUT) in tumor suppressor genes such as TP53, STK11, and KEAP1 . We report on the results of TP53 and STK11 CO-MUT cohorts of S1900E and hypothesized that CO-MUT would not impact the efficacy of sotorasib. Methods: Pts with KRAS G12C MUT identified by FoundationOne CDx tissue assay in the LUNGMAP screening master protocol were assigned to S1900E. Pts with stage IV/recurrent non-sq NSCLC who had progressed after ≥1 line of systemic therapy, and were ECOG PS 0-1 were eligible. There were 3 biomarker cohorts: 1 ( TP53 CO-MUT & wild type [WT] STK11 , KEAP1 / NFE2L2 / CUL3) ; 2 ( STK11 CO-MUT & WT TP53 , KEAP1/NFE2L2 / CUL3) ; 3 (all others). The primary objective was to evaluate the confirmed objective response rate (ORR) per RECIST 1.1 in each cohort. Accrual goals for Cohorts 1 and 2 were 40 and 25 evaluable pts, respectively, based on a 1-stage binomial design with 90% power to rule out a 14% ORR (historical second-line docetaxel ORR) at the 1-sided 5% level. Results: S1900E completed accrual with 118 total pts and 103 evaluable from Apr 2021-Dec 2024; 59 (57%) were female and 86 (84%) were non-Hispanic white. In the TP53 CO-MUT (N=48; 40 evaluable) and STK11 CO-MUT (N=28; 25 evaluable) cohorts, respectively, 48% and 68% received only one prior line of therapy, 70% and 76% received both platinum chemotherapy and PD-(L)1 immunotherapy, 68% and 24% were female, known PD-L1 expression (≥1% / ≥50%) was 95%/45% and 43%/0%, and almost all had smoked. In the TP53 CO-MUT cohort, confirmed ORR was 35% (CI 23-47). In the STK11 CO-MUT cohort, confirmed ORR was 16% (CI 4-28). Disease control rate (DCR), duration of response (DOR), investigator progression-free survival (PFS), and overall survival (OS) (Table 1) had numerically higher values in the TP53 CO-MUT cohort. Adverse event rates ≥ Grade 3 were similar to prior reports of single agent sotorasib. Conclusions: TP53 CO-MUT cohort met its primary endpoint, while the STK11 CO-MUT cohort did not, suggesting that STK11 CO-MUT have detrimental effect on sotorasib in KRAS G12C NSCLC. S1900E Cohort 3, which may include KEAP1/NFE2L2 and other CO-MUT, will be reported later, as will resistance patterns identified through ctDNA analysis. Clinical trial information: NCT04625647 . TP53 CO-MUT (N=40) STK11 CO-MUT (N=25) ORR (90% CI) 35% (23-47) 16% (4-28) DCR (90% CI) 78% (67-88) 60% (44-76) Follow-Up Median mo 19.5 16.8 DOR [Median mo (95% CI)] 7.1 (2.7-11.5) 6.2 (1.6-NA) PFS [Median mo (95% CI)] 5.7 (3.0-8.4) 4.1 (2.6-7.1) OS [Median mo (95% CI)] 18.2 (12.2-33.7) 8.0 (5.1-14.2)