The impact of eligibility criteria on Kirsten rat sarcoma G12C inhibitor trials in patients with non-small cell lung cancer.

[BACKGROUND] 20% of patients with cancer are estimated to be ineligible for phase III trials because of restrictive eligibility criteria. Ineligibility rates for earlier phase trials are even greater. In response, several groups, including the US Food and Drug Administration, have advocated for more inclusive study designs. We examined Kirsten rat sarcoma virus (KRAS) G12C inhibitor trials to determine if inclusivity has shifted in the development of molecularly targeted therapies.

[METHODS] We evaluated phase I-III studies of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC) by applying criteria from 15 US trials to a multi-institutional real-world cohort of patients with metastatic NSCLC and universal KRAS testing (n = 2383). Eligibility analysis, multivariate logistic regression for ineligibility, and a Cox proportional hazards model were used on patients with KRAS G12C-mutated NSCLC (n = 185) to compare trial enrollment and overall survival under various eligibility modifications.

[RESULTS] Of patients with metastatic KRAS G12C-mutated NSCLC, 60%-70% were ineligible for any KRAS inhibitor clinical trial, including studies aiming to establish first-line standard of care. Eligibility criteria remained unchanged from phase I to phase III. Performance status, renal function, and active brain metastases were the main causes of trial ineligibility. Liberalizing criteria for renal function and brain metastases increased enrollment by 25% without affecting overall survival (P = .49), whereas allowing worse performance status reduced study effect sizes (P = .001 in second-line and P = .04 in first-line).

[CONCLUSIONS] Most patients with metastatic KRAS G12C-mutated NSCLC are excluded from trials. There is substantial potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.