Adjuvant crizotinib did not improve survival in resected ALK-positive lung cancer

Adding two years of the targeted drug crizotinib after surgery did not lengthen the time patients with resected, ALK-positive non-small-cell lung cancer (NSCLC) lived free of their cancer, according to the phase 3 E4512 trial run by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) and funded by the US National Cancer Institute [s1][s2]. After a median 65·7 months of follow-up, the hazard ratio for disease-free survival was 1·08 — no benefit, and if anything a point estimate on the wrong side of 1 [s1].

The result is worth reporting precisely because nothing commercial rode on it. This was an independent, government-funded cooperative-group trial, not a company registration study, and it asked a question that industry had largely moved past: does a first-generation ALK inhibitor earn a place after the tumour is already cut out [s1][s2]?

What the trial tested

Crizotinib is an established first-generation ALK inhibitor, long approved for advanced ALK-positive NSCLC [s1]. E4512 tested whether giving it earlier — as adjuvant therapy after complete resection — could keep early-stage disease from returning [s1]. Patients with resected tumours 4 cm or larger, or with positive lymph nodes, negative surgical margins, no prior neoadjuvant treatment, ALK positivity, and good performance status were randomly assigned 1:1 to crizotinib 250 mg orally twice daily or to observation (the comparator was changed from an initial double-blind placebo) for up to two years [s1]. Adjuvant chemotherapy was allowed but not required. The primary endpoint was disease-free survival in the centrally confirmed ALK-positive intention-to-treat population [s1].

What it found

Between Aug 18, 2014, and May 10, 2024, 166 of 168 planned patients were enrolled — 85 to crizotinib and 81 to observation [s1]. Accrual was stopped when the US Food and Drug Administration approved a different, later-generation ALK inhibitor, adjuvant alectinib, for resected ALK-positive NSCLC, which changed the standard of care mid-trial [s1]. Of the enrolled patients, 153 (92%) had centrally confirmed ALK-positive tumours; among them, 99 (65%) were female and 121 (79%) were White [s1].

Median disease-free survival was 74·6 months (95% CI 71·2 to not assessable) in the crizotinib group and 106·2 months (67·8 to not assessable) in the observation group, for a hazard ratio of 1·08 (90% CI 0·67–1·73; 95% CI 0·61–1·90; p=0·80) [s1]. A hazard ratio of 1 means no difference, and the confidence interval here sits squarely across it, so the trial found no signal that crizotinib delayed recurrence [s1].

The drug was not free of cost to patients either. Grade 3 or higher adverse events of any attribution occurred in 46 (58%) of those who took crizotinib, most commonly diarrhoea (8 patients, 10%), oedema (4, 5%), and hypertension (4, 5%); serious adverse events occurred in 21 (27%) [s1]. One death in the crizotinib group was judged not to be treatment-related [s1].

How to read it

Three things bound the result. First, it is small — 166 patients, well short of the numbers that adjuvant lung-cancer trials usually need — and it was stopped before completion, so a modest true benefit cannot be entirely ruled out by this trial alone [s1]. Second, the point estimate did not merely fail to reach significance; it pointed slightly away from benefit, which is not what a partially effective drug tends to do [s1]. Third, and most important for patients today, crizotinib is a first-generation agent, and the very event that halted the trial — the approval of adjuvant alectinib — means the practical question has already been answered by a better drug [s1].

The authors' own conclusion is blunt: adjuvant crizotinib does not prolong disease-free survival, and it should not be recommended as adjuvant therapy for resected ALK-positive NSCLC [s1]. A cancer stage determines how aggressively disease is treated after surgery, and this trial removes one candidate from the menu rather than adding one.

Why it matters

Negative trials rarely make headlines, but they do real work: they stop patients being given a drug, with its diarrhoea, oedema, and hypertension, for no measured gain. Because E4512 was publicly funded and run through a cooperative group, it could pursue a question whose commercial answer had already shifted, and report a null result without a sponsor's interest in the outcome [s1][s2]. That is a different kind of evidence from the industry-sponsored registration trials that dominate oncology, and it is contrasted here with the positive signal seen when immunotherapy was added to radiotherapy in early-stage lung cancer, itself a null trial on its primary measure.

What to watch

The live questions now concern the newer ALK inhibitors in the adjuvant setting and how long their benefit lasts once treatment stops, since crizotinib's failure here does not speak to drugs that bind ALK more tightly or cross into the brain more readily [s1]. Whether adjuvant decisions should be guided by molecular residual-disease testing rather than tumour size and nodes is a separate, unsettled matter this trial did not address [s1].

This article describes research and regulatory context and is not medical advice. Decisions about lung-cancer treatment are for patients and their treating clinicians.

Sources

• Crizotinib versus observation or placebo for surgically resected early-stage ALK-positive non-small-cell lung cancer (ECOG-ACRIN E4512): a phase 3 trial — The Lancet Respiratory Medicine, 25 August 2026
• Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Removed by Surgery (NCT02201992) — ClinicalTrials.gov, U.S. National Library of Medicine, last updated 19 December 2025