Alectinib trumps crizotinib for ALK+ NSCLC

In the 7-year update of the phase III ALESIA trial, alectinib outdoes crizotinib for Asian patients with treatment-naïve, advanced or metastatic ALK+ non-small-cell lung cancer (NSCLC).

In the intention-to-treat cohort, median overall survival (OS) with alectinib was not evaluable (NE); with crizotinib, median OS was 80.8 months. OS rate at month 84 was higher with the former vs the latter (56 percent vs 49.6 percent). The stratified hazard ratio (HR) was 0.72 (95 percent confidence interval [CI], 0.46–1.14; p=0.16). [ESMO Asia 2024, abstract 629MO]

The OS benefit with alectinib vs crizotinib was consistent in patients with (median 72.8 vs 46.2 months; unstratified HR, 0.56, 95 percent CI, 0.28–1.14; 7-year OS rates 46 percent vs 39.3 percent) and without central nervous system (CNS) metastases (median NE for both; unstratified HR, 0.85, 95 percent CI, 0.47–1.56; 7-year OS rates 61.2 percent vs 54.8 percent) as assessed by an independent review committee.

Post-progression therapy, safety

There were fewer alectinib than crizotinib recipients who received ≥1 antineoplastic agent after disease progression (69 percent vs 78 percent). A similar trend was seen in terms of the proportion of participants who underwent radiotherapy (15 percent vs 22 percent) and those who received ≥1 ALK inhibitor following progression (49 percent vs 60 percent). The most common ALK inhibitors used in the alectinib arm were lorlatinib (17 percent) and crizotinib (15 percent), whereas in the crizotinib arm, the most common was alectinib (28 percent).

“Even with the longer treatment duration in the alectinib vs crizotinib arm (42.3 vs 12.6 months), the former had a safety profile that was similar to the latter. No new safety concerns were observed,” said Dr Thanyanan Reungwetwattana Baisamut from the Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, during her presentation at ESMO Asia 2024.

Overall, half of the participants had ≥1 grade 3–5 adverse events (AEs), 5 percent had ≥1 fatal AE, and about a third had ≥1 serious AE.

ALK positivity tied to CNS metastases risk

Approximately 5 percent of Asian patients with NSCLC have ALK rearrangements, which correlates with a high risk of developing CNS metastases. [Ann Oncol 2013;24:2371-2376; Lancet Oncol 2015;16:e510-21]

Baisamut and her team randomized 187 patients (median age 50 years, 53 percent men) 2:1 to receive either alectinib 600 mg BID or crizotinib 250 mg BID. Over 90 percent had stage IV disease at baseline, and about a third had CNS metastases at baseline. Less than 10 percent of participants received prior brain radiation and prior chemotherapy for localized disease.

Median follow-up was 75 months in the alectinib arm and 52 months in the crizotinib arm.

“This is the first randomized trial of an ALK inhibitor in patients with ALK+ NSCLC to report 7-year follow-up data,” said Baisamut. “After ≥7 years of follow-up, alectinib 600 m BID continued to yield a clinically meaningful OS benefit vs crizotinib in Asian patients with advanced ALK+ NSCLC.”

The updated results align with those reported in the global ALEX trial. [Ann Oncol 2020;31:1056-1064]

Alectinib has gained approval as first-line therapy for advanced ALK+ NSCLC and as adjuvant treatment for resected ALK+ NSCLC. [N Engl J Med 2024;390:1265-1276; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer; https://www.ema.europa.eu/en/medicines/human/EPAR/alecensa, accessed 7 January 2025]