Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial
Mené en Chine sur 47 patients atteints d'un cancer du poumon non à petites cellules de stade métastatique (durée médiane de suivi : 8,6 mois), cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du sugémalimab (un inhibiteur de PD-L1) à une chimiothérapie de première ligne à base de sels de platine
Background : PD-1 inhibitor plus chemotherapy had been shown to be an effective first-line treatmentfor patients with metastatic non-small-cell lung cancer (NSCLC). However, there wasno robust evidence showing a PD-L1 inhibitor combined with chemotherapy benefited patients with squamous and non-squamous NSCLC. GEMSTONE-302 aimed to evaluate theefficacy and safety of a PD-L1 inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous or non-squamous NSCLC. Methods : This randomised, double-blind, phase 3 trial was done in 35 hospitals and academicresearch centres in China. Eligible patients were aged 18–75 years, had histologicallyor cytologically confirmed stage IV squamous or non-squamous NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no previous systemic treatment for metastatic disease, and an Eastern CooperativeOncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned(2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks) plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5 mg/mL per min, intravenously]and paclitaxel [175 mg/m2, intravenously] for squamous NSCLC, or carboplatin [AUC 5 mg/mL per min, intravenously]and pemetrexed [500 mg/m2, intravenously] for non-squamous NSCLC; sugemalimab group) or placebo plus the same platinum-based chemotherapy regimens for squamous or non-squamous NSCLC as in thesugemalimab group; placebo group) for up to four cycles, followed by maintenance therapywith sugemalimab or placebo for squamous NSCLC, and intravenous sugemalimab 500 mg/m2 or matching placebo plus pemetrexed for non-squamous NSCLC. Randomisation was doneby an interactive voice–web-response system via permuted blocks (block size was amixture of three and six with a random order within each stratum) and stratified byECOG performance status, PD-L1 expression, and tumour pathology. The investigators,patients, and the sponsor were masked to treatment assignment. The primary endpointwas investigator-assessed progression-free survival in the intention-to-treat population.Safety was analysed in all patients who received at least one treatment dose. Results reported are from a prespecified interim analysis (ie, when the study met the primaryendpoint) and an updated analysis (prespecified final analysis for progression-freesurvival) with a longer follow-up. This study is registered with ClinicalTrials.gov (NCT03789604), is closed to new participants, and follow-up is ongoing. Findings : Between Dec 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility;367 were ineligible, and the remaining 479 patients were randomly assigned to thesugemalimab group (n=320) or placebo group (n=159). At the preplanned interim analysis(data cutoff June 8, 2020; median follow-up 8·6 months [IQR 6·1–11·4]), GEMSTONE-302met its primary endpoint, with significantly longer progression-free survival in thesugemalimab group compared with the placebo group (median 7·8 months [95% CI 6·9–9·0] vs 4·9 months [4·7–5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39–0·64], p<0·0001]).At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR15·1–20·9), the improvement in progression-free survival was maintained (median 9·0months [95% CI 7·4–10·8] vs 4·9 months [4·8–5·1]; stratified HR 0·48 [95% CI 0·39–0·60], p<0·0001). The mostcommon grade 3 or 4 any treatment-related adverse events were neutrophil count decreased(104 [33%] of 320 with sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased (45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased (33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any treatment-related serious adverse events occurred in 73 (23%) patientsin the sugemalimab group and 31 (20%) patients in the placebo group. Any treatment-relateddeaths were reported in ten (3%) patients in the sugemalimab group (pneumonia withrespiratory failure in one patient; myelosuppression with septic shock in one patient;pneumonia in two patients; respiratory failure, abdominal pain, cardiac failure, andimmune-mediated pneumonitis in one patient each; the other two deaths had an unspecifiedcause) and in two (1%) patients in the placebo group (pneumonia and multiple organdysfunction syndrome). Interpretation : Sugemalimab plus chemotherapy showed a statistically significant and clinically meaningfulprogression-free survival improvement compared with placebo plus chemotherapy, inpatients with previously untreated squamous and non-squamous metastatic NSCLC, regardlessof PD-L1 expression, and could be a newfirst-line treatment option for both squamousand non-squamous metastatic NSCLC. Funding
The Lancet Oncology 2022