IFCT-2401 SPORADIC trial: Integrating cemiplimab to sequential hypofractionated chemoradiotherapy for unfit or elderly patients with unresectable stage III non–small cell lung cancer.

Abstract

TPS8128 Background: Patients with unresectable stage III non-small cell lung cancer (NSCLC) who are elderly or have significant comorbidities are frequently ineligible for concurrent chemoradiotherapy (CCRT). Sequential chemoradiotherapy (seq-CRT) remains the preferred approach in this population. While consolidation immunotherapy after CCRT improves survival, evidence supporting its optimal integration with seq-CRT is limited. Preclinical and clinical data suggest that combining chemotherapy and immunotherapy enhances tumor immunogenicity through increased antigen release, immune priming, and modulation of the tumor microenvironment. Hypofractionated radiotherapy may further potentiate immune-mediated effects while shortening overall treatment duration, which is particularly relevant for frail patients. The IFCT-2401 SPORADIC trial evaluates in unfit or elderly patients a sequential strategy integrating neoadjuvant chemo-immunotherapy prior to hypofractionated radiotherapy, followed by maintenance immunotherapy, in patients with unresectable stage III NSCLC not eligible for CCRT. Exploratory correlative studies include circulating biomarkers, immune profiling, lymphopenia, and metabolic response assessment. Methods: IFCT-2401 SPORADIC is a multicenter, randomized, open-label phase II trial (EU-CT 2024-517316-29-00). Patients are randomized in a 2:1 ratio to receive neoadjuvant chemotherapy alone (arm A) or neoadjuvant chemo-immunotherapy (arm B). Neoadjuvant treatment consists of three 28-day cycles of carboplatin (AUC 5, day 1) and paclitaxel (80 mg/m², days 1, 8 and 15). Cemiplimab (350 mg, every 3 weeks) is added in arm B. All patients subsequently receive curative hypofractionated thoracic radiotherapy (55 Gy in 20 fractions), followed by maintenance cemiplimab every 3 weeks for up to 12 months. Eligible patients have unresectable stage IIIA–C NSCLC. Three categories of patients are considered unfit for CCRT: age ≥70 years with ECOG performance status (PS) 0 to 1, age < 70 years with ECOG PS 0 to 1 and significant comorbidities or age < 70 years with ECOG PS 2. Key exclusion criteria include actionable oncogenic drivers, prior systemic therapy for NSCLC and active autoimmune disease. The primary endpoint is progression-free survival. A total of 152 patients are planned for enrollment across 25 centers. First patient was enrolled on November 17, 2025. Clinical trial information: EU-CT 2024-517316-29-00.