Adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC): a phase II trial

Abstract

Background: This phase II prospective trial aimed to investigate the efficacy and safety of adebrelimab (PD-L1 antibody) plus first-line chemotherapy followed by sequential thoracic radiotherapy (TRT) combined with adebrelimab in extensive-stage small-cell lung cancer (ES-SCLC). Biomarkers associated with potential therapeutic effects were also explored.

Methods: Patients with previously untreated ES-SCLC were enrolled at Shandong Cancer Hospital and Institute (Jinan, China). Patients received 4-6 cycles of adebrelimab (20 mg/kg, D1, Q3W) combined with EP/EC (etoposide, 100 mg/m², D1-3, Q3W and cisplatin, 75 mg/m², D1, Q3W or carboplatin, AUC = 5, D1, Q3W). Then patients with response sequentially underwent consolidative TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation), and maintenance adebrelimab until disease progression or intolerable adverse events (AEs). The primary endpoint was overall survival (OS). Genomic and circulating tumour DNA (ctDNA) profiling were also analyzed with tumour tissues and peripheral blood. This trial was registered with ClinicalTrials.gov, NCT04562337.

Findings: From October 2020 to April 2023, 67 patients diagnosed with ES-SCLC were enrolled and received at least one dose of study treatment. All patients were included in the efficacy and safety analyses. 45 patients received sequential TRT as planned. The median OS and progression-free survival (PFS) was 21.4 months (95% CI: 17.2-not reached months) and 10.1 months (95% CI: 6.9-15.5 months), respectively. The confirmed objective response rate was 71.6% (48/67, 95% CI: 59.3-82.0%) and disease control rate was 89.6% (60/67, 95% CI: 79.7-95.7%). There were no treatment-related deaths. The most common grade 3 or higher treatment-related adverse events (TRAEs) were hematological toxicities. The incidence of any grade and G3+ pneumonitis was 25% (17/67) and 6% (4/67), respectively. No unexpected adverse events were observed. Patients without co-mutations of TP53/RB1 in both tissue and peripheral blood displayed longer PFS (tissue, P = 0.071; ctDNA, P = 0.060) and OS (tissue, P = 0.032; ctDNA, P = 0.031).

Interpretation: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety.

Funding: This study was funded by the National Natural Science Foundation of China (82172865), Jiangsu Hengrui Pharmaceuticals Co., Ltd. and Amoy Diagnostics Co., Ltd.

Keywords: Adebrelimab; ES-SCLC; Immunotherapy; Predictive biomarker; Radiotherapy.

Fig. 1

Flow diagram of the trial. FFPE, formalin-fixed paraffin-embedded; C, cycle; D, day; ctDNA, circulating tumour DNA.

Fig. 2

Kaplan–Meier curves for PFS and OS. (A) OS in all patients. (B) OS in patients received TRT or no TRT. (C) PFS in all patients. (D) PFS in patients received TRT or no TRT. PFS, progression-free survival; OS, overall survival; CI, confidence interval; NR, not reached; TRT, thoracic radiotherapy.

Fig. 3

DNA sequencing results from SCLC patients' FFPE samples. (A) Patients with immunotherapy were divided into DCB and NDB groups according to whether they progressed within 6 months, somatic mutational features, including TMB between the two group were compared. (B) A forest plot showed the association of different variables with OS or PFS in the patients receiving immunotherapy with or without radiotherapy (IO, N = 28), and in the patients receiving both immunotherapy and sequential radiotherapy (IO + RT, N = 20). “TMB_group” indicates the calculation of the HR and p-value for the TMB_high group (IO, N = 12; IO + RT, N = 8) compared to the TMB_low group (IO, N = 16; IO + RT, N = 12). “TP53&RB1_mut” indicates the calculation of the HR and p-value for patients with concurrent mutations in TP53 and RB1 genes (IO, N = 8; IO + RT, N = 3) compared to other patients (IO, N = 20; IO + RT, N = 17). (C) OS of SCLC patients harboring TP53/RB1 double mutations, compared with patients with other somatic mutations. (D) OS of SCLC patients with high TMB level (≥10 Mut/Mb), compared with patients with low TMB level (<10 Mut/Mb). FFPE, formalin-fixed paraffin-embedded; DCB, durable clinical benefit; NDB, no durable clinical benefit; TMB, tumour mutation burden; OS, overall survival; ctDNA, circulating tumour DNA.

Fig. 4

Dynamic monitoring of ctDNA in SCLC patients. (A) A forest plot showed the association of different markers with survival (PFS or OS) in the patients receiving immunotherapy with or without radiotherapy (IO), and in the patients receiving both immunotherapy and sequential radiotherapy (IO + RT). “TP53&RB1” indicates the calculation of the HR and p-value for patients with concurrent mutations in TP53 and RB1 genes (IO, N = 11; IO + RT, N = 6) compared to other patients (IO, N = 24; IO + RT, N = 18) in ctDNA of C1D1. “TMB” indicates the calculation of the HR and p-value for the TMB_high group (IO, N = 14; IO + RT, N = 10) compared to the TMB_low group (IO, N = 21; IO + RT, N = 14) in ctDNA of C1D1. “C7D1_MUT” indicates the calculation of the HR and p-value for the C7D1_mut group (IO + RT, N = 5) compared to the C7D1_wt group (IO + RT, N = 9). PFS (B) and OS (C) of patients with ctDNA TP53/RB1 double mutations in C1D1, compared with patients with other ctDNA mutations. (D) ctDNA mutation landscape and clinical features of each patient at C7D1. (E) PFS of patients with ctDNA mutation in C7D1, compared with patients without ctDNA mutations in C7D1. ctDNA, circulating tumour DNA; PFS, progression-free survival; OS, overall survival; C, cycle; D, day.