Clinical Overview — Overview of Efficacy

2.5.4.1 Pivotal Trial Summary

The pivotal Phase III trial, STUDY-401, was a randomized, double-blind, placebo-controlled, multicenter study evaluating Olverastinib in patients with advanced NSCLC who had progressed on first-line platinum-based chemotherapy. A total of 542 patients were randomized 1:1 to receive either Olverastinib 50 mg once daily (n=271) or placebo (n=271). The primary endpoint was achieved with a hazard ratio of 0.65 (95% CI: 0.52–0.81, p<0.001) in the intent-to-treat populationi , representing a clinically meaningful and statistically significant improvement in overall survival.

Median overall survival was 14.8 months in the Olverastinib arm compared to 9.2 months for placeboi . The treatment effect was consistent across pre-specified subgroups including age, sex, ECOG performance status, and PD-L1 expression level.

2.5.4.2 Supporting Evidence

Findings from STUDY-401 are supported by data from a prior Phase II study (STUDY-203) and are consistent with the cross-trial efficacy observed in the recent ESMO 2025 published meta-analysis of EGFR-mutant NSCLC therapiesi . Together, these sources establish a coherent benefit profile for the proposed indication.

2.5.4.3 Benefit-Risk Assessment

The proposed dosing regimen of 50 mg once daily was selected based on the population pharmacokinetic exposure-response analysis described in Module 2.7.2, which demonstrated that exposures at this dose maximize the probability of achieving the target inhibitory concentration without exceeding the safety threshold established in the Phase I studyi .

Per ICH E2A, the most frequently reported treatment-emergent adverse reactions (occurring in >10% of patients) were rash (32%), diarrhoea (28%), fatigue (24%), and pruritus (14%), all of which are coded to MedDRA v27.1 preferred termsi . The overall safety profile is consistent with the established class effect for EGFR tyrosine kinase inhibitors.