Alectinib versus crizotinib in previously untreated ALK-positive advanced non-small cell lung cancer: final overall survival analysis of the phase III ALEX study

S Peters; R Camidge; R Dziadziuszko; S Gadgeel; A T Shaw; D-W Kim; M Pérol; D R Rosell; P Cheema; D Wan-Teck Lim; J J Lin; N Pavlakis; J S Ahn; L Zhang; V Henschel; A A Higgerson; V McNally; I Rooney; A Scalori; V Smoljanovic; T Mok

doi:10.1016/j.annonc.2025.09.018

Alectinib versus crizotinib in previously untreated ALK-positive advanced non-small cell lung cancer: final overall survival analysis of the phase III ALEX study

Ann Oncol. 2025 Oct 17:S0923-7534(25)04788-X. doi: 10.1016/j.annonc.2025.09.018. Online ahead of print.

Authors

S Peters¹, R Camidge², R Dziadziuszko³, S Gadgeel⁴, A T Shaw⁵, D-W Kim⁶, M Pérol⁷, D R Rosell⁸, P Cheema⁹, D Wan-Teck Lim¹⁰, J J Lin¹¹, N Pavlakis¹², J S Ahn¹³, L Zhang¹⁴, V Henschel¹⁵, A A Higgerson¹⁵, V McNally¹⁶, I Rooney¹⁷, A Scalori¹⁶, V Smoljanovic¹⁵, T Mok¹⁸

Affiliations

¹ Centre Hospitalier Universitaire Vaudois (CHUV) Oncology Department, Lausanne, Switzerland. Electronic address: solange.peters@chuv.ch.
² University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
³ Department of Oncology & Radiotherapy and Early Phase Clinical Trials Centre, Medical University of Gdańsk, Gdańsk, Poland.
⁴ Karmanos Cancer Institute, Detroit, MI, USA.
⁵ Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of South Korea.
⁷ Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France.
⁸ IOR, Dr Rosell Oncology Institute, Dexeus University Hospital, Barcelona, Spain.
⁹ University of Toronto, William Osler Health System, Brampton, Ontario, Canada.
¹⁰ Division of Medical Oncology, National Cancer Center Singapore, Singapore.
¹¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹² Royal North Shore Hospital, Sydney University, Sydney, Australia.
¹³ Department of Hematology & Oncology, Samsung Medical Center, Seoul, South Korea.
¹⁴ Sun Yet-sen University Cancer Center, Guangdong, China.
¹⁵ F. Hoffmann-La Roche Ltd, Basel, Switzerland.
¹⁶ Roche Products Ltd, Welwyn Garden City, United Kingdom.
¹⁷ Genentech Inc., South San Francisco, CA, USA.
¹⁸ State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong.

PMID: 41110693
DOI: 10.1016/j.annonc.2025.09.018

Abstract

Background: ALEX, a global, randomized, phase III trial evaluated alectinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). This final analysis provides mature overall survival (OS), duration of response (DOR) and long-term safety data.

Patients and methods: Treatment-naïve patients with stage III/IV ALK-positive NSCLC were randomly assigned to receive alectinib (600 mg twice daily [BID]) or crizotinib (250 mg BID) until disease progression, unacceptable toxicity, withdrawal, or death. Primary endpoint was investigator-assessed progression-free survival (previously reported). Key secondary endpoints included OS, DOR and safety.

Results: A total of 303 patients (alectinib, n=152; crizotinib, n=151) were enrolled. At the updated data cutoff (28 April 2025), after a median follow-up of 53.5 (alectinib) and 23.3 (crizotinib) months, median OS was 81.1 (95% CI 62.3-not estimable) versus 54.2 (95% CI 34.6-75.6) months, respectively (hazard ratio [HR] 0.78; 95% CI 0.56-1.08). Improvement in median OS was observed with alectinib in patients with and without CNS metastases at baseline (with CNS metastases: 63.4 [n=59] versus 30.9 [n=53] months with alectinib versus crizotinib, respectively [HR 0.68; 95% CI 0.40-1.15]; without CNS metastases: 94.0 [n=93] versus 69.8 [n=98] months [HR 0.87; 95% CI 0.58-1.32]). Median DOR in confirmed responders was longer with alectinib (42.3 months, 95% CI 31.3-51.3) versus crizotinib (11.1 months, 95% CI 7.9-13.0 [HR 0.41; 95% CI 0.30-0.56]). Long-term safety (median duration of alectinib treatment, 28.1 months) remained consistent with earlier reports, with no new or unexpected safety concerns identified.

Conclusions: These final OS data show the sustained long-term systemic and intracranial efficacy of alectinib in the first-line treatment of ALK-positive NSCLC and confirm alectinib as a standard of care in this setting.

Keywords: ALEX; alectinib; anaplastic lymphoma kinase; non-small cell lung cancer; overall survival.