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

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.