Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial

Abstract

Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC.

Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC.

Design, setting, and participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021.

Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks.

Main outcomes and measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events.

Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group.

Conclusions and relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population.

Trial registration: ClinicalTrials.gov Identifier: NCT04063163.

Figure 1.. Recruitment, Randomization, and Flow of Patients With Extensive-Stage Small Cell Lung Cancer in the ASTRUM-005 Trial

The date of data cutoff was October 22, 2021. ^aScores range from 0 to 5 (higher scores indicate greater disability). ^bDetailed reasons appear in eTable 1 in Supplement 2. ^cPatients received at least 1 dose of study treatment.

Figure 2.. Kaplan-Meier Estimates of Overall and Progression-Free Survival

Data are from assessments by the independent radiology review committee using version 1.1 of the Response Evaluation Criteria in Solid Tumors. The tick marks indicate censored data. The median duration of follow-up for overall survival at the interim analysis was 12.5 months (IQR, 8.9-15.5 months) for the serplulimab group and 12.3 months (IQR, 8.6-14.9 months) for the placebo group. The median duration of follow-up for progression-free survival was 9.5 months (IQR, 5.6-13.2 months) for the serplulimab group and 8.4 months (IQR, 7.0-13.0 months) for the placebo group. HR indicates hazard ratio; NE, not evaluable.

Figure 3.. Subgroup Analysis for the Primary Outcome of Overall Survival

The date of data cutoff was October 22, 2021. The hazard ratios (HRs) and P values were not stratified for the patient subgroups and were stratified for the overall population. The median duration of follow-up for overall survival at the interim analysis was 12.5 months (IQR, 8.9-15.5 months) for the serplulimab group and 12.3 months (IQR, 8.6-14.9 months) for the placebo group in the overall population. NR indicates not reached; PD-L1, programmed cell death ligand 1. ^aFor the patient subgroups, the P values for interaction were calculated by adding treatment, subgroup factor, and a subgroup factor × treatment interaction term into a Cox proportional hazards model. ^bSelf-reported by the patients by selecting 1 or more racial designations (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Pacific Islander, White, or Other) or based on identity information provided by the patients. All non-Asian patients were White. ^cEastern Cooperative Oncology Group (ECOG) Performance Status Scale scores range from 0 to 5 (higher scores reflect greater disability). A score of 0 indicates fully active; 1, restricted in physically strenuous activity but ambulatory. ^dCalculated using a 2-sided stratified log-rank test.