Retifanlimab Versus Placebo in Combination With Platinum-Based Chemotherapy in Patients With First-Line Non-Squamous or Squamous Metastatic Non-Small Lung Cancer (POD1UM-304): A Phase 3, Multiregional, Placebo-Controlled, Double-Blind, Randomised Study

Abstract

Background: Checkpoint inhibitors, including combinations with standard-of-care chemotherapy, have shown survival benefit in patients with metastatic non-small-cell lung cancer (NSCLC); however, access to these drugs varies. We aimed to evaluate the efficacy of the PD-1 inhibitor retifanlimab plus platinum-based chemotherapy as first-line treatment for non-squamous or squamous metastatic NSCLC. Methods: POD1UM-304 was a phase 3, multiregional, placebo-controlled, double-blind, randomised study conducted in approximately 124 hospitals and private clinical centres in 16 countries. Male and female adults aged 18 years or older with squamous or non-squamous stage IV NSCLC (staging by American Joint Committee on Cancer version 8) with Eastern Cooperative Oncology Group performance status 0 or 1 and no previous systemic therapy for metastatic NSCLC were eligible. Patients were randomly assigned (2:1) using interactive response technology to receive intravenous retifanlimab 375 mg or matching placebo on day 1 of each 21-day cycle plus standard platinum-based chemotherapy according to tumour histology for up to 2 years. Patients with non-squamous NSCLC received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 for four cycles, or carboplatin area under the curve (AUC) 5 on day 1 for four cycles, followed by pemetrexed 500 mg/m2 on day 1 of each subsequent 21-day cycle, all administered intravenously, until disease progression or unacceptable toxicity. Patients with squamous NSCLC received intravenous carboplatin AUC 6 plus intravenous paclitaxel 200 mg/m2 on day 1 for four cycles or intravenous nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 for four cycles. Treatment with retifanlimab or placebo was given for up to 35 cycles, unless there was disease progression, unacceptable toxicity, or withdrawal of consent. Randomisation was stratified by PD-L1 expression tumour proportion score, geographical region, and predominant tumour histology. The primary endpoint was overall survival, defined as time from randomisation until death due to any cause, analysed in the full analysis set. Safety was evaluated in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04205812) and is active but no longer enrolling. Findings: Between Sept 11, 2020, and March 14, 2023, 1388 patients were assessed for eligibility, 583 of whom were randomly assigned to retifanlimab plus chemotherapy (n=391) or placebo plus chemotherapy (n=192). 381 (65%) patients had non-squamous NSCLC and 202 (35%) had squamous NSCLC; 467 (80%) patients were male and 116 (20%) were female. Median age was 64 years (IQR 58–68). Median overall survival was longer in the retifanlimab plus chemotherapy group than in the placebo plus chemotherapy group (18·1 months [95% CI 16·2–21·0] vs 13·4 months [11·0–16·7]; hazard ratio 0·75 [95% CI 0·60–0·93]; p=0·0042). Overall, higher incidences of treatment-emergent adverse events that were serious (158 [41%] of 389 vs 57 [30%] of 190), grade 3 or worse (238 [61%] vs 103 [54%]), or led to retifanlimab or placebo dose delay (169 [43%] vs 67 [35%]) or discontinuation (33 [8%] vs nine [5%]) were observed in the retifanlimab plus chemotherapy group than in the placebo plus chemotherapy group. The proportions of fatal COVID-19-related treatment-emergent adverse events were similar in the retifanlimab plus chemotherapy group and the placebo plus chemotherapy group (four [1%] vs five [3%]). Interpretation: Retifanlimab improved overall survival compared with placebo when added to platinum-based chemotherapy, with a safety profile that is representative of previous PD-1 and PD-L1 inhibitor–chemotherapy combinations. Adding retifanlimab to first-line chemotherapy could be a potential treatment option for patients with squamous or non-squamous metastatic NSCLC. Funding: Incyte. © 2025 Elsevier B.V., All rights reserved.