A 14-gene molecular assay has demonstrated the ability to identify patients with early-stage nonsquamous non-small cell lung cancer (NSCLC) who derive significant benefit from adjuvant chemotherapy, according to interim results from the AIM-HIGH trial presented at the 2025 ASCO Annual Meeting. The study showed a 78% reduction in recurrence risk for patients assigned chemotherapy based on molecular risk stratification.
The international, multicenter, prospective, randomized trial enrolled patients with completely resected stage IA to IIA nonsquamous NSCLC who were classified as high or intermediate risk by the RiskReveal 14-gene prognostic assay. At 24 months, 96% of patients who received adjuvant chemotherapy remained alive without disease progression (95% CI, 92%-100%) compared with 79% of those under observation (95% CI, 70%-90%; HR, 0.22 [95% CI, 0.06-0.76; P =0.0087]).
Addressing Critical Unmet Need in Early-Stage Disease
"This is the first prospective randomized trial to show improvement in disease-free survival with a molecular risk discriminator in stage IA through IIA nonsquamous NSCLC," said David Spigel, MD, chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, during the press briefing.
The study addresses a significant clinical challenge, as the 5-year disease-free survival rate for even stage IA disease remains under 65%, contributing to over 100,000 deaths worldwide. Currently, adjuvant therapy is not typically recommended for patients with stage IA disease and is often deferred in patients with stages IB and IIA disease.
Molecular Risk Stratification Guides Treatment Decisions
The RiskReveal assay examines gene expression profiles in nonsquamous NSCLC to identify patients at high risk of early disease recurrence. The assay has been prospectively validated in over 1,400 patients with nonsquamous NSCLC. Patients identified as low risk by the assay were not included in the study, as validation data showed these patients had 5-year survival approaching 95% without adjuvant chemotherapy.
The trial randomly assigned high-risk patients to either observation (standard of care) or four cycles of platinum-based doublet chemotherapy per local standards. Immunotherapy and tyrosine kinase inhibitors were permitted at investigator discretion for appropriate patients.
Robust Efficacy Across Disease Stages
The interim analysis included 89 patients in the adjuvant chemotherapy arm and 111 patients in the control arm. Baseline characteristics were well balanced between groups, with median ages of 63 years (range, 52-74) in the chemotherapy arm versus 66 years (range, 56-76) in the observation arm. Approximately 47% of patients in both arms were female, and the majority had a smoking history.
Even when analysis was limited to patients with stage IA disease, a similar improvement in disease-free survival was observed. In the chemotherapy arm, 98% of stage IA patients were alive without disease progression (95% CI, 94%-100%) versus 78% of those in the observation arm (95% CI, 65%-93%; P = 0.0345).
The types of resection and choice of adjuvant chemotherapy regimens were balanced between arms. Most patients assigned chemotherapy received carboplatin/pemetrexed (35%), cisplatin/pemetrexed (29%), or cisplatin/vinorelbine (20%). Adverse events observed in the chemotherapy arm were consistent with known safety profiles of platinum-based doublet chemotherapy.
Early Trial Termination Due to Efficacy
The trial was stopped early by the independent data safety monitoring board due to the significant difference observed at interim analysis. Median follow-up was 19.5 months in the chemotherapy group and 19 months in the observation group, with median disease-free survival not yet reached in either group.
"Utilization of this 14-gene assay to precisely direct systemic adjuvant therapy in stage IA through IIA nonsquamous non-small cell lung cancer may substantially reduce the rates of early recurrence and death," Spigel noted.
Clinical Implementation and Decision-Making
The assay could particularly benefit patients and physicians facing uncertainty about adjuvant therapy decisions. "For those patients on the fence — when we understand the risks and benefits but we're still not sure what to do — this test is available with more information to help us make that decision," Spigel explained.
The molecular assay represents a shift from current protocols that rely primarily on disease stage and tumor size to determine potential benefit of adjuvant therapy. With an estimated 226,650 new lung cancer cases diagnosed annually, approximately 70,000 of which are stage I or II NSCLC, and about 70% being nonsquamous histology, this approach could impact treatment decisions for a substantial patient population.
