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Previously demonstrated survival benefits of crizotinib (Xalkori, Pfizer Inc.) as an adjuvant treatment for advanced ALK-positive non-small cell lung cancer (ALK+NSCLC) did not extend to the setting of surgically resected early-stage disease in the phase 3 E4512 trial.

At median follow-up of 58.3 months, median disease-free survival (DFS) was 72.8 months vs 75.1 months in 75 and 79 patients who were ALK+ on central lab testing and randomized to receive adjuvant crizotinib or to observation, respectively, and who were included in the efficacy analysis (hazard ratio [HR], 1.06).

No differences were observed in the DFS outcomes across subgroups based on sex, disease stage, and postoperative radiation, said David E. Gerber, MD, at World Conference on Lung Cancer (WCLC) 2025.

Overall survival (OS) data were immature; median OS was not reached in either group (HR, 0.49), said Gerber, a medical oncologist at the University of Texas Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas.

Crizotinib, an approved first-generation multitargeted tyrosine kinase inhibitor, has previously been shown to have efficacy in advanced ALK+NSCLC, but its role in the setting of surgically resected early-stage disease was unknown.

Method and Results

Gerber and his colleagues tested the hypothesis that the agent would improve DFS in surgically resected ALK+NSCLC. Study participants were 166 patients with resected stage IIA-IIIB ALK+NSCLC with negative margins who were identified through the adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST-Screen) and enrolled between August 2014 and May 2024. They had a mean age of 62 years and Eastern Cooperative Oncology Group performance status of 0-1.

Preoperative therapy and prior ALK inhibitor treatment were not allowed, however a djuvant chemotherapy and postoperative radiation therapy were permitted as these are common treatments following surgery in this setting, Gerber noted.

In the subgroup of patients who had received postoperative radiation therapy, which included 37% and 31% of those in the treatment and observation groups, respectively, no significant difference was observed in DFS (HRs, 1.86 and 0.68, respectively), he said.

Those randomized to the crizotinib group received 250 mg twice daily for up to 2 years or until recurrence or unacceptable toxicity. The median duration of therapy was 13.5 months. Those in the control group underwent observation for 2 years.

Of the 85 patients randomized to the crizotinib group and included in the safety analysis, 43% experienced grade 3 treatment-related adverse events. The most common of these were diarrhea in 6% of patients and edema in 4%. One patient experienced a grade 4 treatment-related stroke.

Other treatment-related adverse events included transient eye disorders, abdominal pain, increased alanine aminotransferase, and decreased neutrophil count.

“These toxicities…look an awful lot like the toxicities we’ve seen before from crizotinib in earlier trials, usually in metastatic lung cancer,” Gerber noted during a press briefing at the conference.

Dose reductions occurred in 22% of patients in the treatment group, and 27% discontinued treatment due to toxicities.

Enrollment stopped in 2024 when alectinib, a second-generation and more selective and effective ALK inhibitor, was approved, Gerber said, noting that at the time, 166 patients had been enrolled from 84 centers, which was close to the target enrollment of 168 patients. The trial was stopped in April 2025.

Alectinib showed superior efficacy over platinum-based chemotherapy in the ALINA trial. The drug also was found to have superior efficacy than crizotinib in the earlier head-to-head ALEX trial.

The ALK+ patients who were enrolled represented just 2% of the overall ALCHEMIST-Screen population.

How Will Findings Change Practice?

Invited discussant Jessica J. Lin, MD, director of precision medicine in thoracic oncology at Massachusetts General Hospital, Boston, said the findings will only change clinical practice in countries where alectinib is unavailable.

The data provide evidence against “reaching for adjuvant crizotinib” in those countries and underscore the need to broaden access to adjuvant alectinib, said Lin, who is also an assistant professor at Harvard Medical School, Boston.

Otherwise, where available, alectinib remains the standard of care for resected EGFR-mutated ALK+NSCLC, she added, noting that “biomarker testing in early-stage lung cancer, including for ALK+ disease, remains imperative.”

“Continued research is critical as we continue efforts to optimize adjuvant targeted therapy approaches,” she said.

Gerber reported receiving a commercial research grant from Genentech, the maker of alectinib. Lin reported having no disclosures.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.