First-line serplulimab plus chemotherapy in extensive-stage small-cell lung cancer: Updated results and biomarker analysis from the ASTRUM-005 randomized clinical trial

Abstract

Background: The ASTRUM-005 study previously demonstrated a significant overall survival (OS) benefit with serplulimab (a programmed death 1 inhibitor) plus chemotherapy versus chemotherapy alone in previously untreated extensive-stage small-cell lung cancer (ES-SCLC). Here, we report updated efficacy and safety results after an extended median follow-up of 19.8 months, along with the first report on findings from exploratory biomarker analyses.

Methods: A total of 585 patients were randomized in a 2:1 ratio to receive 4.5 mg/kg serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks, together with carboplatin and etoposide. The primary endpoint was OS. In addition, genomic profiling was performed to identify mutated genes, and quantitative serum proteome profiling was conducted to identify differentially expressed proteins (DEPs) between responders and non-responders of serplulimab plus chemotherapy. Regression analysis was subsequently used to construct a protein signature based on the DEPs. The associations between efficacy outcomes (objective response rate [ORR], OS, and progression-free survival [PFS]) and gene mutation status or DEP expression were also examined with regression analysis. Furthermore, the prognostic value of hematological parameters was evaluated.

Results: In the intent-to-treat population, the median OS was 15.8 months in the serplulimab group versus 11.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval, 0.50-0.76; P < 0.001). We identified 181 DEPs between responders and non-responders in the serplulimab group, from which a 15-protein signature was constructed. In the serplulimab group, patients with a higher 15-protein signature score were associated with significantly longer OS and PFS. Also, patients harboring tumor-suppressor retinoblastoma-1 (RB1) mutations or mutations in Notch pathway members showed improved ORR, OS, or PFS compared with their wild-type counterparts. Baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level were independent prognosticators of patients with ES-SCLC.

Conclusions: First-line serplulimab provided a sustained clinical benefit over placebo in patients with ES-SCLC. A 15-protein signature and mutations in RB1 or Notch pathway genes may serve as predictive biomarkers for benefits from serplulimab plus chemotherapy, while baseline NLR and LDH were independent prognosticators for ES-SCLC.

Keywords: ASTRUM‐005; ES‐SCLC; Serplulimab; phase 3.

FIGURE 1

Consolidated Standards of Reporting Trials diagram of this study. ^a Full reasons for exclusion have been reported previously [8]. ^b The month of death was missing for 1 patient, who was excluded from overall survival analysis according to the statistical analysis plan. Abbreviations: ECOG, Eastern Cooperative Oncology Group; PD‐L1, programmed death‐ligand 1.

FIGURE 2

Survival outcomes of all 585 enrolled ES‐SCLC patients treated with serplulimab or placebo plus chemotherapy. (A) Overall survival. (B) Progression‐free survival according to IRRC assessments per RECIST v1.1. The tick marks indicate censored data. P values were for descriptive analysis and were not adjusted for multiplicity. Abbreviations: CI, confidence interval; ES‐SCLC, ES‐SCLC, extensive‐stage small‐cell lung cancer; HR, hazard ratio; IRRC, independent radiology review committee; RECIST, Response Evaluation Criteria in Solid Tumors.

FIGURE 3

Subgroup analysis of OS in ES‐SCLC patients treated with serplulimab or placebo plus chemotherapy. (A) Forest plot of OS in subgroups stratified by age, sex, race, baseline ECOG performance status, baseline smoking status, brain metastasis, liver metastasis, PD‐L1 expression (TPS or CPS), and MSI status. (B‐E) Kaplan‐Meier curves of OS in Asian patients (B), in non‐Asian patients (C), in patients with liver metastasis (D), and in patients without liver metastasis (E). P values were for descriptive analysis and were not adjusted for multiplicity. ^aHazard ratios were stratified for the overall population. ^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. ^cECOG performance status scores for patients in this study ranged from 0 to 1. A score of 0 indicates fully active; a score of 1 is restricted in physically strenuous activity but ambulatory. Abbreviations: CI, confidence interval; CPS, combined positive score. ECOG, Eastern Cooperative Oncology Group; ES‐SCLC, extensive‐stage small‐cell lung cancer; HR, hazard ratio; MSI, microsatellite instability; MSI‐H, MSI‐high; MSI‐L, MSI‐low; MSS, microsatellite stable; No., number; OS, overall survival; PD‐L1, programmed death‐ligand 1; TPS, tumor proportion score.

FIGURE 4

Survival outcomes of ES‐SCLC patients treated with serplulimab or placebo plus chemotherapy, stratified by the 15‐protein signature score. (A) Progression‐free survival assessed by IRRC according to RECIST v1.1. (B) Overall survival assessed by IRRC assessments according to RECIST v1.1. The tick marks indicate censored data. P values were for descriptive analysis and were not adjusted for multiplicity. Abbreviations: CI, confidence interval; ES‐SCLC, extensive‐stage small‐cell lung cancer; HR, hazard ratio; IRRC, independent radiology review committee; NE, not evaluable; RECIST, Response Evaluation Criteria in Solid Tumors.