Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial
Anaplastic lymphoma kinase (ALK) rearrangements occur in approximately 5-6% of non-small cell lung cancer (NSCLC) cases and are linked to a higher risk of central nervous system (CNS) involvement. Envonalkib, a new ALK inhibitor, has shown promising anti-tumor activity and safety in advanced ALK-positive NSCLC, as demonstrated in an initial phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) aimed to assess the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC. A total of 264 participants were randomized in a 1:1 ratio to receive either envonalkib (n = 131) or crizotinib (n = 133).
The median progression-free survival (PFS) assessed by an independent review committee (IRC) was significantly longer for envonalkib at 24.87 months (95% confidence interval [CI]: 15.64-30.36) compared to 11.60 months (95% CI: 8.28-13.73) for crizotinib (hazard ratio [HR] = 0.47, 95% CI: 0.34-0.64, p < 0.0001). The confirmed objective response rate (ORR) was also higher in the envonalkib group (81.68% vs. 70.68%, p = 0.056), with a longer duration of response (median, 25.79 months [95% CI: 16.53-29.47] vs. 11.14 months [95% CI: 9.23-16.59], p = 0.0003). In participants with baseline brain lesions, the IRC-assessed CNS-ORR was significantly better with envonalkib compared to crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were still immature, with median OS not reached in either group (HR = 0.84, 95% CI: 0.48-1.47, p = 0.5741). The 12-month OS rates were 90.6% (95% CI: 84.0%-94.5%) for envonalkib and 89.4% (95% CI: 82.8%-93.6%) for crizotinib. Grade ≥3 treatment-related adverse events occurred in 55.73% of the envonalkib group and 42.86% of the crizotinib group. Overall, envonalkib significantly improved PFS and delayed the progression of brain metastases in advanced ALK-positive NSCLC.