Highlights
The final overall survival (OS) analysis of the landmark ALEX trial has established a new milestone in the management of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). Key highlights include:
- Alectinib demonstrated a median OS of 81.1 months, compared to 54.2 months for crizotinib, representing one of the longest survival outcomes reported in metastatic NSCLC.
- The hazard ratio (HR) for death was 0.78, with a more pronounced benefit observed in patients with baseline central nervous system (CNS) metastases (HR 0.68).
- Duration of response (DOR) was nearly four times longer with alectinib (42.3 months) than with crizotinib (11.1 months).
- Long-term safety remains consistent with previous reports, with no new cumulative toxicity concerns identified after years of follow-up.
Background: The Evolution of ALK Inhibition
The identification of ALK rearrangements in 2007 revolutionized the treatment landscape for a specific subset of NSCLC patients, typically younger non-smokers. While crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), initially set the standard by outperforming chemotherapy, its efficacy was often limited by the rapid development of resistance and poor penetration of the blood-brain barrier. This left a significant unmet medical need, as the brain remains a frequent site of progression for ALK-positive disease.
Alectinib, a potent and highly selective second-generation ALK TKI, was designed to overcome these limitations. It possesses superior CNS penetration and activity against several crizotinib-resistant ALK mutations. The Phase III ALEX trial was initiated to compare the head-to-head efficacy and safety of alectinib versus crizotinib in treatment-naïve patients, with initial results previously establishing alectinib’s superiority in progression-free survival (PFS). This final analysis provides the much-anticipated mature overall survival data.
Study Design: The ALEX Methodology
The ALEX study was a global, randomized, open-label Phase III trial. A total of 303 treatment-naïve patients with stage III or IV ALK-positive NSCLC were enrolled. The participants were randomly assigned in a 1:1 ratio to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily).
The primary endpoint was investigator-assessed PFS. Secondary endpoints, which are the focus of this final report, included overall survival (OS), duration of response (DOR) in confirmed responders, and long-term safety. Randomization was stratified by ECOG performance status, race, and the presence or absence of CNS metastases at baseline. Importantly, crossover between treatment arms was not mandated by the protocol, reflecting a more contemporary real-world treatment sequence where patients may receive various subsequent therapies upon progression.
Key Findings: A Deep Dive into Overall Survival
At the data cut-off on April 28, 2025, the median duration of follow-up was 53.5 months for the alectinib arm and 23.3 months for the crizotinib arm. The disparity in follow-up time itself highlights the extended duration of benefit experienced by patients in the alectinib group.
Unprecedented Survival Durability
The final analysis revealed a median OS of 81.1 months (95% CI: 62.3–not estimable) for patients treated with alectinib, compared to 54.2 months (95% CI: 34.6–75.6) for those receiving crizotinib. This results in a hazard ratio of 0.78 (95% CI: 0.56–1.08). While the confidence interval for the HR crosses the unit, the clinical significance of an 81-month median survival in the metastatic setting is profound. It suggests that many patients with ALK-positive NSCLC can now expect to live for nearly seven years or more when treated with modern first-line TKIs.
Intracranial Efficacy
Alectinib’s ability to cross the blood-brain barrier was a critical differentiator in this trial. Among patients with CNS metastases at baseline, the median OS was 63.4 months with alectinib versus 30.9 months with crizotinib (HR 0.68; 95% CI: 0.40–1.15). For patients without CNS metastases at baseline, the median OS reached an astonishing 94.0 months with alectinib compared to 69.8 months with crizotinib (HR 0.87; 95% CI: 0.58–1.32).
Duration of Response (DOR)
The robustness of the response to alectinib was further evidenced by the DOR data. In patients who achieved a confirmed response, the median DOR was 42.3 months for alectinib, compared to only 11.1 months for crizotinib (HR 0.41). This nearly four-fold increase in the duration of response underscores why alectinib has become the preferred first-line agent.
Safety and Tolerability in Long-term Use
Safety is a paramount concern for therapies intended for long-term use. In the ALEX trial, the median duration of treatment for alectinib was 28.1 months. Despite this significantly longer exposure compared to crizotinib, alectinib continued to demonstrate a favorable safety profile. The most common adverse events included constipation, edema, and myalgia, which were generally manageable and rarely led to treatment discontinuation.
No new or unexpected safety signals emerged during the extended follow-up period. The incidence of Grade 3-5 adverse events remained lower in the alectinib arm relative to the total duration of exposure, confirming that alectinib is not only more effective but also better tolerated than first-generation inhibitors.
Expert Commentary: Clinical Implications
The final OS data from the ALEX trial solidify alectinib’s position as a standard of care for first-line ALK-positive NSCLC. For clinicians, these results provide the highest level of evidence to support the use of second-generation TKIs early in the disease course. The survival benefit, particularly in patients with brain metastases, addresses one of the most challenging aspects of lung cancer treatment.
However, the oncology community continues to look forward. While alectinib has set a high bar, questions remain regarding the optimal sequencing of third-generation inhibitors like lorlatinib and the management of emergent resistance mutations (such as G1202R). Furthermore, the 81.1-month median OS suggests that we are moving toward a paradigm where metastatic ALK-positive NSCLC can be managed as a chronic disease for many patients.
Conclusion
The final overall survival analysis of the Phase III ALEX study confirms that alectinib provides sustained, long-term systemic and intracranial efficacy. With a median OS of 81.1 months and a superior safety profile, alectinib remains a foundational therapy in the first-line treatment of ALK-positive advanced NSCLC. These findings offer immense hope to patients and provide a clear evidence-based pathway for clinicians worldwide.
Funding and ClinicalTrials.gov
The ALEX study was funded by F. Hoffmann-La Roche Ltd. The trial is registered with ClinicalTrials.gov, number NCT02075840.
References
Peters S, Camidge R, Dziadziuszko R, et al. 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. 2026 Jan;37(1):92-103. doi: 10.1016/j.annonc.2025.09.018. Epub 2025 Oct 17. PMID: 41110693.
