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.

Abstract

LBA8027 Background: Despite advances in late-stage treatments, survival of early-stage non-small cell lung cancer (NSCLC) remains dismal, with 5-year disease free survival (DFS) of only 65% even in stage Ia. Preliminary, non-randomized clinical data suggest the predictive efficacy of RiskReveal, a 14-gene expression profile, in identifying stage Ia-IIa patients with non-squamous NSCLC who benefit from adjuvant therapy. We undertook an international, multicenter, randomized clinical trial to confirm these findings. Here, we report the results of an early interim analysis that was planned to detect a large discrepancy in outcomes between arms. Methods: 421 patients who underwent resection of stage pIa-IIa NSCLC were categorized as low-, intermediate-, or high-risk by the RiskReveal assay. Intermediate- and high-risk patients were randomized to observation or to 4 cycles of platinum-based adjuvant chemotherapy. The modified intent-to-treat (mITT) population was defined as randomized patients who continued to meet eligibility criteria either at the time of chemotherapy initiation or at randomization to observation. The primary endpoint was DFS in the mITT population, defined as the time from randomization to disease recurrence, exclusive of new primary lung cancer, or death from any cause. DFS was compared between arms using a log-rank test and Kaplan-Meier analysis. An early interim analysis was planned with a type I error rate of 0.02. Results: Of 194 evaluable patients at the time of the interim analysis, 87 had been randomized to adjuvant chemotherapy (55% stage Ia), and 107 to observation (55% stage Ia). There were no significant differences between the groups with respect to age, sex, or tumor size >4 cm; median follow-up was 19.5 months in the chemotherapy arm and 19.0 months in the observation arm. At 24 months, adjuvant chemotherapy significantly improved DFS compared to observation, with a HR of 0.22 (95% CI 0.06, 0.76; p=0.0087). DFS at 24 months was 96% with adjuvant chemotherapy (95% CI 0.92, 1.00) vs. 79% with observation (95% CI 0.70, 0.90). Median DFS was not reached in either group. Conclusion: A 14-gene molecular assay identified a high-risk population of stage Ia-IIa non-squamous NSCLC patients who benefited substantially from adjuvant chemotherapy. Improved survival in lung cancer is best achieved by optimizing outcomes in the earliest stages of disease. Identification of patients who benefit from adjuvant chemotherapy using this predictive test could result in a dramatic improvement in survival for the growing percentage of patients diagnosed in stages I-IIa. Although the study DSMB recommended a halt to enrollment, follow up continues and may provide further confirmation of this benefit. Clinical trial information: NCT01817192 .