SWOG S2414 (INSIGHT): A randomized phase III trial incorporating pathologic complete response in participants with early-stage non-small cell lung cancer to optimize immunotherapy in the adjuvant setting.

Abstract

TPS8131 Background: Neoadjuvant chemo-immunotherapy (chemo-IO) followed by surgery is a standard of care for resectable clinical stage II-IIIB non-small cell lung cancer (NSCLC). Pathologic complete response (pCR), achieved in roughly 20% of patients, is associated with a favorable overall survival rate, but the benefit of additional adjuvant immunotherapy (IO) after pCR has not been independently studied and remains uncertain. The potential for overtreatment and unnecessary toxicity is a critical question in these patients. SWOG S2414 (INSIGHT) is designed to determine the optimal adjuvant therapy strategy for patients with pCR after neoadjuvant chemo-IO. Methods: INSIGHT (NCT06498635) is an open-label, randomized phase III trial, in which patients with clinical stage II-IIIB NSCLC who achieved pCR after standard of care neoadjuvant chemo-IO are randomized to adjuvant durvalumab IV every 28 days for up to 12 cycles (durvalumab, arm A) versus no further treatment (active surveillance, arm B). The primary objective is to compare disease free survival (DFS) between participants in the two arms. Key secondary endpoints include overall survival, event-free survival, and patient-reported quality of life (using the FACT-L and FACT-BRM) and symptoms (using PRO-CTCAE). The total enrollment goal is 306 participants. The design includes 2 interim analyses. Participants must have NSCLC with no known EGFR mutations or ALK fusions, and must have received at least two cycles of an FDA-approved neoadjuvant platinum-based chemo-IO regimen with an anti-PD-1/PD-L1 agent. Pathologic complete response will be confirmed by local pathology. Current Status: S2414 was activated on 3/14/2025, the first patient was registered on 4/1/2025. Enrollment is open and ongoing. Clinical Significance: INSIGHT is a pivotal trial addressing the therapeutic dilemma of adjuvant treatment for early-stage NSCLC patients with pCR after neoadjuvant chemo-IO. The results will help determine whether adjuvant IO provides a significant DFS benefit over surveillance in patients with a pCR, potentially leading to de-escalation of therapy and reduced toxicity. Funding: NIH/NCI grants U10CA180888, U10CA180819; additional support by AstraZeneca. Clinical trial information: NCI-2024-05588 .