Adjuvant chemotherapy for stage IA–IIA non-squamous, non-small-cell lung cancer identified as molecular high-risk by a 14-gene expression profile (AIM-HIGH): an international, randomised, phase 3 trial

Abstract

Background

Survival for non-small-cell lung cancer (NSCLC) remains unacceptably low, even in stage IA–IIA. Current guidelines recommend adjuvant treatment for patients considered to be at high risk in stages IB and IIA, but suggest criteria that have not been validated to predict benefit. A previously validated, CLIA-certified 14-gene expression profile has identified patients with high-risk non-squamous NSCLC tumours in stages IA–IIA who benefitted from adjuvant chemotherapy in a non-randomised prospective study. In this prespecified interim analysis, we aimed to assess the efficacy and safety of platinum-based adjuvant chemotherapy in patients with stage IA–IIA molecular high-risk non-squamous NSCLC in a randomised trial.

Methods

AIM-HIGH, a randomised, phase 3 trial, was done at 45 centres in France, Germany, and the USA. Patients aged 18 years or older with stage IA–IIA non-squamous NSCLC, an adequate tumour sample, and an Eastern Cooperative Oncology Group performance status of 0–1 underwent risk stratification with the 14-gene assay. Patients with a molecular high risk, defined as those receiving a high-risk or an intermediate-risk score, were randomly assigned (1:1) to four cycles of platinum-based adjuvant chemotherapy (using local institutional standard of care regimens) or observation. Randomisation was stratified according to age, sex, and tumour size of 4 cm or more. The primary outcomes for the study and for this prespecified interim analysis were 48-month and 24-month disease-free survival, respectively, in the modified intention-to-treat (mITT) population, which was defined as randomly assigned patients who continued to meet eligibility criteria either at chemotherapy initiation or at random assignment to observation; an early interim analysis was prespecified to detect a large difference between groups. This trial is registered at ClinicalTrials.gov, NCT01817192, and is closed to enrolment.

Findings

Between Sept 11, 2020, and Feb 7, 2025, 449 patients were enrolled and underwent risk stratification. 236 patients with molecular high risk were randomly assigned to chemotherapy (n=124) or observation (n=112). At the time of the prespecified interim analysis, 87 patients were evaluable in the mITT population (47 [54%] males and 40 [46%] females; median age 63 years [IQR 52–74]) in the chemotherapy group and 107 (58 [54%] males and 49 [46%] females; 66 years [56–76]) in the observation group. 48 (55%) patients in the chemotherapy group and 58 (54%) patients in the observation group had stage IA disease; 34 (39%) and 44 (41%), respectively, had stage IB disease, and five (6%) and five (5%), respectively, had stage IIA disease. Six (3%) of 200 patients in the mITT population had died at the time of the interim analysis. 24-month disease-free survival was 96% (95% CI 92–100) with adjuvant chemotherapy versus 79% (70–90) with observation (hazard ratio 0·22 [0·06–0·76]; p=0·0087).

Interpretation

The 14-gene assay identified patients with molecular high risk who benefitted from adjuvant chemotherapy. Use of the assay to determine eligibility for adjuvant therapy in stage IA–IIA non-squamous NSCLC has the potential to substantially improve otherwise persistently poor outcomes.

Funding

Razor Genomics.