INSIGHT Trial: De-Escalating Immunotherapy After Lung Cancer pCR

In an interview with Targeted Oncology, Bruna Pellini, MD, chief of thoracic medical oncology at Baptist Health Herbert Wertheim Cancer Institute, discusses the SWOG S2414 (INSIGHT) trial (NCT06498635).

INSIGHT is an open-label, randomized phase 3 trial designed to answer a key unresolved question in early-stage non–small cell lung cancer (NSCLC) treatment: whether patients who achieve a pathologic complete response (pCR) after neoadjuvant chemo-immunotherapy still benefit from additional adjuvant immunotherapy, or whether they can safely forgo it.

Neoadjuvant chemo-immunotherapy followed by surgery is now standard of care for resectable clinical stage II to IIIB NSCLC. About 20% of patients achieve pCR, which is linked to favorable long-term survival. However, it's unclear whether these "super-responders" need further immunotherapy afterward, raising concerns about overtreatment and unnecessary toxicity in patients who may already be cured.

The trial enrolls patients with stage II to IIIB NSCLC (without EGFR mutations or ALK fusions) who achieve a locally confirmed pCR after at least 2 cycles of an FDA-approved platinum-based chemo-immunotherapy regimen with an anti–PD-1/PD-L1 agent. Eligible patients are randomized to either adjuvant durvalumab (Imfinzi; administered intravenously every 28 days for up to 12 cycles) or active surveillance with no further treatment. The primary end point is disease-free survival (DFS), with key secondary end points including overall survival, event-free survival, and patient-reported quality of life and symptom measures (via FACT-L, FACT-BRM, and PRO-CTCAE). The trial targets enrollment of 306 participants and includes two planned interim analyses.

The study activated in March 2025, enrolled its first patient in April 2025, and is currently open and actively recruiting. It is funded by NIH/NCI grants, with additional support from AstraZeneca.

Clinically, INSIGHT addresses a pressing de-escalation question in early-stage NSCLC care: if positive, the results could establish active surveillance as a viable, lower-toxicity alternative to continued immunotherapy for patients who achieve pCR—potentially sparing many patients from a year of unnecessary treatment and its associated adverse effects.

REFERENCE

Cetnar JP et al. 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. J Clin Oncol. 44, TPS8131-TPS8131(2026). DOI:10.1200/JCO.2026.44.16_suppl.TPS8131