The impact of eligibility criteria on KRASG12C inhibitor trials in patients with NSCLC.

Background: 20% of cancer patients are estimated to be ineligible for phase III trials due to restrictive eligibility criteria. In response, several groups, including the FDA, have advocated for more inclusive study designs. We examined 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 patient with KRAS G12C-mutated NSCLC (N = 185) to compare trial enrollment and overall survival under various eligibility modifications.

Results: 60-70% of patients with metastatic KRAS G12C-mutated NSCLC 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 significant potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.