First-line serplulimab plus chemotherapy with or without HLX04 versus chemotherapy in locally advanced or metastatic non-squamous non-small-cell lung cancer (ASTRUM-002): a randomised, double-blind, multicentre phase 3 trial
Mené en Chine sur 642 patients atteints d'un cancer du poumon non à petites cellules non épidermoïde de stade localement avancé ou métastatique (âge : 18-75 ans ; durée médiane de suivi : 23,4 mois), cet essai multicentrique de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout de serplulimab (un anti-PD-1) avec ou sans HLX04 (un biosimilaire du bévacizumab) à une chimiothérapie de première ligne
Background: Whether the addition of bevacizumab to a programmed cell death protein-1 (PD-1) inhibitor plus chemotherapy can provide further survival benefits as first-line treatment in non-squamous non-small-cell lung cancer (NSCLC) without EGFR sensitising mutations, or ALK/ROS1 rearrangements, is unknown. We evaluated serplulimab (an anti-PD-1 antibody) plus HLX04 (a bevacizumab biosimilar) and chemotherapy in non-squamous NSCLC.
Methods: ASTRUM-002 is a randomised, double-blind, multicentre, phase 3 trial with a three-arm design. Patients (aged ≥18 years and ≤75 years) with locally advanced or metastatic non-squamous NSCLC without EGFR sensitising mutations or ALK/ROS1 rearrangements and previous systemic therapy were randomly assigned (1:1:1; stratified by PD-L1 expression, smoking history, and brain metastasis) to receive serplulimab (4·5 mg/kg intravenously) plus HLX04 (15 mg/kg intravenously) and chemotherapy (pemetrexed and carboplatin; group A), serplulimab plus chemotherapy plus HLX04 placebo (group B), or chemotherapy plus serplulimab placebo plus HLX04 placebo (group C). The primary endpoint was the blinded independent central review assessed progression-free survival per the Response Evaluation Criteria in Solid Tumors version 1.1, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03952403, and is complete.
Findings: Between Nov 25, 2019, and June 15, 2022, 642 patients were enrolled across 72 hospitals in China; six in the safety run-in phase and the remaining 636 patients were randomised to group A (212 patients), B (214), or C (210). 465 (73%) were male, 171 (27%) were female, and 599 (94%) were of Han ethnicity. By the data cutoff date of June 15, 2023, the median follow-up duration was 23·4 months (95% CI 21·6–24·9) in group A, 23·1 (21·4–25·6) in group B, and 23·0 (20·7–25·6) in group C. Median progression-free survival was 12·6 months (95% CI 8·7–14·0; 123 events) in group A, 11·0 months (95% CI 8·4–12·7; 130 events) in group B, and 5·6 months (95% CI 4·8–6·8; 156 events) in group C. A significant reduction was seen in risk of progressive disease or death for patients in group B compared with group C (hazard ratio [HR] 0·55, 95% CI 0·43–0·69; p<0·0001). No significant improvement in progression-free survival was seen for group A compared with group B (HR 0·86, 0·67–1·11; p=0·25). Treatment-related serious adverse events occurred in 82 (39%) patients in group A, 79 (37%) in group B, and 51 (24%) in group C. Grade 3 or worse treatment-related adverse events occurred in 149 (71%) patients in group A, 142 (66%) in group B, and 119 (57%) in group C. Treatment-related adverse events leading to death occurred in ten (5%) patients in group A, five (2%) in group B, and seven (3%) in group C.
Interpretation: The addition of serplulimab to chemotherapy led to significantly longer progression-free survival in patients with locally advanced or metastatic non-squamous NSCLC compared with chemotherapy alone and represents an alternative first-line treatment option for this patient population. HLX04 plus serplulimab and chemotherapy did not confer further statistical benefit compared with serplulimab plus chemotherapy.
The Lancet Respiratory Medicine , résumé, 2025