Post-Surgery Nivolumab Shows No DFS Improvement in EGFR/ALK-Negative NSCLC

Administering nivolumab (Opdivo) after standard-of-care adjuvant therapy did not improve disease-free survival (DFS) compared with best supportive care among patients with resected lung adenocarcinoma without sensitizing EGFR and ALK alterations, according to data from the phase 3 ECOG-ACRIN EA5142 or ALCHEMIST trial (NCT02595944) presented at the 2026 American Society of Clinical Oncology Annual Meeting (ASCO) and simultaneously published in JAMA.^1,2

Data showed a median DFS of 71.3 months among patients who received nivolumab (n = 466) and 68.8 months among those who received observation (n = 469) across the intent-to-treat (ITT) population (HR, 0.97; 95% CI, 0.81-1.17; P = .39). Additionally, the median DFS was 89.9 months vs 78.5 months in each respective arm among patients with a tumor PD-L1 proportion of at least 50% (HR, 0.86; 95% CI, 0.59-1.25; P = .43).

Of note, there was a trend towards improved DFS with nivolumab among patients who had squamous disease (HR, 0.70; 95% CI, 0.49-1.00; P = .051) or no prior adjuvant therapy (HR, 0.70; 95% CI, 0.43-1.15; P = .16). Although the study was not powered for overall survival (OS), an exploratory analysis revealed an HR of 1.02 (95% CI, 0.82-1.26) across the ITT population and 0.82 (95% CI, 0.53-1.28) among those with PD-L1 expression at least 50%.

“In patients with resectable EGFR/ALK-negative NSCLC, after upfront surgery and planned and adjuvant therapy, nivolumab [did] not improve DFS. I would say there is no change in the standard of care, which is preoperative chemotherapy and immunotherapy,” Jamie E. Chaft, MD, an attending physician and Ning Zhao Chair in Honor of Gregory J. Riely, MD, PhD, at Memorial Sloan Kettering Cancer Center, stated in the presentation. “I would argue that the role of postoperative immunotherapy, whether or not preoperative therapy was given, remains unclear.”

Investigators conceived the EA5142 protocol to fill a therapeutic need in completely resected EGFR- or ALK-negative nonsquamous NSCLC and open an opportunity for squamous disease. The trial aimed to test a therapy with signals of benefit; at the time, nivolumab was being assessed in the second-line care of advanced NSCLC, and PD-L1 was being considered as a predictive biomarker. The study’s goal was to improve both DFS and OS across this patient population.

Patients with resected stage IB (of 4 cm or larger), II, or IIIA disease, no prior immunotherapy, no contraindication to nivolumab, and completion of planned adjuvant therapy were randomly assigned 1:1 to receive nivolumab at 480 mg intravenously every 4 weeks or observation for up to a year. Long-term follow-up occurred for 10 years.

DFS across the ITT population and among patients with PD-L1 expression of at least 50% was a primary end point, with a target of 35% improvement in median DFS from 40 to 54 months with nivolumab. OS was a coprimary end point; if the ITT or PD-L1–high groups showed significant improvement in DFS, investigators would formally assess OS.

The median age was 66 years (range, 33-85) in the nivolumab group and 67 years (range, 39-92). Most patients in each respective arm were male (52% vs 52%) and had formerly smoked (59% vs 58%). Additionally, the majority of patients in each arm had adenocarcinoma (65% vs 63%), stage IIA (39% vs 37%) or IIIA disease (33% vs 31%), prior adjuvant chemotherapy (88% vs 87%), and a PD-L1 expression of 1% to 49% (40% vs 42%).

Regarding safety, the most common grade 3 treatment-related adverse effects (TRAEs) with durvalumab included pneumonitis (n = 15), diarrhea (n = 11), and maculopapular rash (n = 9). Grade 4 toxicities included hyponatremia (n = 2), adrenal insufficiency (n = 1), colitis or pruritus (n = 1), and pneumonitis (n = 1). There were 2 grade 4 TRAEs, which included hypoxia (n = 1) and pneumonitis (n = 1).

Chaft noted that the trial’s strengths included the fact that it was a large, randomized study assessing a real-world population with standard-of-care follow-up. Limitations included a liberal time to postoperative enrollment period of 28 to 300 days, which potentially led to the selection of a lower-risk population, and the study not being blinded.

A potentially fatal flaw of the study design, according to Chaft, was that the assumption of DFS was wrong for the population. The target improvement in DFS from 40 to 54 months was not clearly explained by the median time to enrollment for the nivolumab (6.4 months; IQR, 5-8) and observation groups (6.5 months; IQR, 5-8).

Chaft stated that the trial will be re-assessed in a population that is positive for circulating tumor DNA or minimal residual disease. Other future directions include a pooled analysis of all adjuvant immunotherapy studies, the publication of results from other adjuvant concurrent chemoimmunotherapy studies, and the evaluation of the contribution of the adjuvant phase of the perioperative treatment paradigm.

Disclosures: Chaft noted consulting or advisory roles with AstraZeneca/MedImmune, Boehringer Ingelheim, Exact Sciences, Foundation Medicine, Genentech/Roche, Lilly, Merck, Natera, Nuvation Bio, and Revolution Medicines; research funding from AstraZeneca/MedImmune (Inst), BeiGene (Inst), Bristol-Myers Squibb (Inst), Genentech/Roche (Inst), Lilly (Inst), and Merck (Inst); and uncompensated relationships with AstraZeneca, Boehringer Ingelheim, Lilly, and Merck.

References

1. Chaft J, Sun Z, Rudin CM, et al. Randomized phase III study of nivolumab after surgery and adjuvant chemotherapy in NSCLC (ECOG-ACRIN EA5142, ALCHEMIST). J Clin Oncol. 2026;44(suppl 16):8000. doi:10.1200/JCO.2026.44.16_suppl.8000
2. X Chaft JE, Sun Z, Rudin CM, et al. Adjuvant nivolumab vs observation in resected non–small cell lung cancer: a randomized clinical trial. JAMA. Published online June 1, 2026. doi:10.1001/jama.2026.8992