Efficacy of alectinib for ALK-positive NSCLC according to tumor burden and body mass index: A pooled analysis of the randomized phase III trials ALEX and J-ALEX

Background: Although first-line alectinib is highly effective, outcomes in ALK-positive NSCLC remain variable. Methods: We conducted an individual patient-level pooled analysis of the phase III ALEX (NCT02075840) and JALEX (JapicCTI-132316) trials to explore new prognostic and predictive factors. The primary endpoint was PFS. Multivariate Cox and random effects models accounted for trials independence. Baseline characteristics analyzed included high vs. low tumor burden (sum of target lesions by RECIST v1.1 above/below the median) and body mass index (BMI). Results: 500 patients were included (alectinib n = 249, crizotinib n = 251). Baseline characteristics were balanced between the two arms. Median follow-up was 17.1months. Alectinib compared to crizotinib improved PFS (HR 0.41, 95%CI 0.31-0.55, p < 0.001) but not OS (HR 0.80, 95%CI 0.50-1.28, p = 0.353). In the whole population, high tumor burden correlated with shorter PFS (HR 1.88, 95%CI 1.44-2.45, log-rank p <0.001) and OS (HR 2.24, 95%CI 1.40-3.58, log-rank p < 0.001), confirmed in multivariate analysis (PFS HR 1.66, 95%CI 1.26-2.20, p < 0.001). Significant interaction was found between treatment and tumor burden in PFS cox model (p for interaction=0.002). The PFS benefit of alectinib vs. crizotinib was greater in low tumor burden (HR 0.25, 95%CI 0.16-0.41, p < 0.001) than in high tumor burden (HR 0.52, 95%CI 0.36-0.76, p = 0.001). In multivariate analysis, BMI> 25 kg/m2 (n = 144) did not correlate with PFS (HR 0.92, 95%CI 0.68-1.25, p = 0.375) but was associated with longer OS (HR 0.50, 95%CI 0.29-0.88, p = 0.025). No significant BMI-treatment interaction was observed. Conclusions: Tumor burden was prognostic and predictive in ALK-positive NSCLC. Treatment intensification may benefit patients with high tumor burden.