A Decade of Treating ALK-Rearranged Non-Small Cell Lung Cancer in a Lower Middle-Income Country: Changing Patterns and Improving Survival.

[INTRODUCTION] Data regarding the comparative efficacy of various generations of tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC) in lower middle-income countries (LMICs) is scarce.

[METHODS] A comprehensive assessment of anaplastic lymphoma kinase (ALK)-directed TKIs and treatment sequences was done for 249 patients (145 male, 104 female) with advanced NSCLC at a referral cancer hospital in New Delhi, India. The primary endpoints were overall survival (OS); progression-free survival on 1st-line (PFS1) therapy, 2nd-line (PFS2) therapy, and PFS1 + 2. Multivariable Cox proportional hazards and joint frailty modelling were used for progression events and OS, respectively.

[RESULTS] With a median follow-up of 48 months, median OS, PFS1, and PFS1 + 2 were 46.6 (95% CI 36.9-67.0), 18.2 (95% CI 14.5-26.8), and 33.1 months (95% CI 28.6-41.6), respectively. Third-generation TKIs significantly improved PFS and OS over 1st-generation TKIs, whether used 1st-line or later (HR PFS1 0.08, 95% CI 0.02-0.32, p < 0.001; HR OS 0.13, 95% CI 0.02-0.94, p = 0.043; HR PFS2 0.36, 95% CI 0.19-0.71, p = 0.003). Joint frailty modelling confirmed the correlation between repeated progression events and mortality (shared frailty parameter theta = 1.78, p < 0.001). Alectinib (HR 0.53, 95% CI 0.33-0.84, p = 0.007) and lorlatinib (HR 0.49, 95% CI 0.31-0.77, p = 0.002) reduced progression risk. Temporal trend analyses showed fewer treatment lines and significantly improved outcomes in patients with brain metastases with 3rd-generation TKIs.

[CONCLUSIONS] This relatively large LMIC real-world study shows similar outcomes to Western data, and improved survival and lower risk of intracranial progression with 2nd- and 3rd-generation ALK-directed TKIs.