Adjuvant Chemotherapy Improves DFS in Molecularly Higher-Risk NSCLC

Adjuvant Chemotherapy in Higher-Risk NSCLC

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Adjuvant chemotherapy yielded a disease-free survival (DFS) benefit vs observation in patients with stage IA to IIA nonsquamous non–small cell lung cancer (NSCLC) who were identified as high or intermediate risk by the 14-gene RiskReveal prognostic assay, according to data from an interim analysis of the AIM-HIGH trial (NCT01817192) presented in a press briefing ahead of the 2025 ASCO Annual Meeting.1

In the overall population of the international, multicenter, prospective, randomized trial, at 24 months, 96% of patients with stage IA to IIA disease and received chemotherapy were alive without disease progression(95% CI, 92%-100%) compared with 79% of those who underwent observation (95% CI, 70%-90%; HR, 0.22 [95% CI, 0.06-0.76; P =.0087]).

A similar improvement in DFS was observed in patients with only stage IA disease. In the chemotherapy arm, 98% of these patients were alive without disease progression (95% CI, 94%-100%) vs 78% of those in the observation arm (95% CI, 65%-93%; P = .0345).

“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,” David Spigel, MD, said during the press briefing. “Interim analysis was designed to detect a large discrepancy in outcomes between treated and untreated patients.”

Spigel, the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, highlighted the need for improved outcomes in early-stage NSCLC, noting that the 5-year DFS rate for even stage IA disease remains under 65%, contributing to over 100,000 deaths worldwide. Although adjuvant therapy is a common treatment in later stages of disease, it is not typically recommended for patients with stage IA disease and is often deferred in patients with stages IB and IIA disease.

“RiskReveal is a 14-gene lung cancer assay that examines the gene expression profile for nonsquamous NSCLC and is used to identify patients at high risk of early disease. This assay has been prospectively validated in over 1400 patients with nonsquamous NSCLC. Identifying patients who are at highest risk of recurrence is a priority in the [management] of NSCLC,” Spigel explained.

The AIM-HIGH trial enrolled patients aged 18 years and older with completely resected stage IA, IB, or IIA nonsquamous NSCLC. Following surgery, tumor tissue was analyzed using a commercially available 14-gene prognostic assay to identify patients at high or intermediate risk of early recurrence. Patients identified as low risk were not included in the study.2

The trial randomly assigned high-risk patients to either undergo observation (the standard of care) or receive 4 cycles of platinum-based doublet chemotherapy per local standards. Immunotherapy and TKIs were permitted at the investigator’s discretion for appropriate patients.

The primary end point of the study was DFS, with routine CT scans and surveillance conducted for 5 years or until recurrence or death.

The interim analysis, which led to early stopping of the trial by the independent data safety monitoring board due to the significant difference observed, included 89 patients in the adjuvant chemotherapy arm and 111 patients in the control arm.1 Baseline characteristics, including gender, smoking history (predominantly former or current smokers), ECOG performance status (0 or 1), and stage of cancer (IA, IB, or IIA), were well balanced between the 2 arms.

The median age of patients in the adjuvant chemotherapy arm was 63 years (range, 52-74) vs 66 years (range, 56-76) in the observation arm. In total, 47% of patients in both arms were female; 90% and 86% of patients, respectively, had a history of smoking; 67% and 65% of patients, respectively, had an ECOG performance status of 0; 31% and 34% of patients, respectively, had an ECOG performance status of 1; and 1% of patients in each arm had an unknown ECOG performance status. A total of 97% of patients in the adjuvant chemotherapy arm had a histology of adenocarcinoma vs 93% of those in the control arm, and stage IB disease was the most common disease stage in each arm (39% vs 41%).

The types of resection (primarily lobectomy) between the arms and the choice of adjuvant chemotherapy regimens among patients who received chemotherapy were also balanced. The adverse events observed in the chemotherapy arm were consistent with the known safety profiles of platinum-based doublet chemotherapy.

“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 said.

References

1. Spigel D, Westeel V, Anderson IC, et al. An international, multicenter, prospective randomized trial of adjuvant chemotherapy for stage IA-IIA non-small cell lung cancer identified as high-risk by a 14-gene molecular assay. J Clin Oncol. 2025;43(suppl 17):LBA8027. doi:10.1200/JCO.2025.43.17_suppl.LBA8027
2. Adjuvant chemotherapy in patients with intermediate or high risk stage I or stage IIA non-squamous non-small cell lung cancer: AIM-HIGH (adjuvant intervention in molecular high risk patients). ClinicalTrials.gov. Updated April 13, 2025. Accessed May 28, 2025. https://clinicaltrials.gov/study/NCT01817192