What is the mechanism, toxicity, and indication of Serplulimab (monoclonal antibody)?

Serplulimab: Mechanism, Toxicity, and Indications

Serplulimab is an anti-PD-1 monoclonal antibody approved for extensive-stage small cell lung cancer (ES-SCLC) in combination with platinum-etoposide chemotherapy, demonstrating superior survival outcomes compared to chemotherapy alone with manageable immune-related toxicities. 1

Mechanism of Action

Serplulimab blocks the PD-1 receptor on T cells, preventing its interaction with PD-L1/PD-L2 ligands, thereby releasing the brake on T cell activation and enabling enhanced anti-tumor immune responses. 1

• Serplulimab is a recombinant, humanized IgG4 monoclonal antibody that binds to PD-1 with similar or better affinity than pembrolizumab and nivolumab 2
• The antibody robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions, which may mitigate CD28 dephosphorylation by SHP2 and facilitate sustained T cell activation 3
• This mechanism differs from CTLA-4 inhibitors (like ipilimumab), which primarily interfere at the T cell-dendritic cell interface, whereas anti-PD-1 agents like serplulimab act at the T cell-tumor cell interface 1
• Serplulimab effectively reduces regulatory T cell populations in the tumor microenvironment while augmenting effector and memory T cell populations 3

Clinical Indications

The primary FDA-recognized indication is first-line treatment of extensive-stage small cell lung cancer in combination with carboplatin and etoposide, followed by maintenance serplulimab. 1

ES-SCLC (Primary Indication)

• The ASTRUM-005 phase III trial demonstrated significant improvements: median OS 15.4 vs 10.9 months (HR 0.48), median PFS 5.7 vs 4.3 months, and ORR 80.2% vs 70.4% compared to chemotherapy alone 1
• Treatment regimen: carboplatin and etoposide for 4 cycles plus serplulimab, followed by maintenance serplulimab 1
• One-year survival rate was 61% with serplulimab versus 48% with placebo 1

Advanced Squamous NSCLC

• The ASTRUM-004 phase III trial showed serplulimab plus nab-paclitaxel and carboplatin improved median OS (HR 0.73, p=0.010) and PFS (HR 0.53) in treatment-naïve patients 4
• This represents an emerging indication for first-line squamous non-small cell lung cancer 4

Other Solid Tumors (Investigational)

• Phase I data demonstrated 8.0% objective response rate and 60.0% disease control rate across various metastatic solid tumors, supporting further investigation 2
• Combination with HLX07 (anti-EGFR) showed 60% ORR in advanced esophageal squamous cell carcinoma 5

Toxicity Profile

Serplulimab exhibits a manageable safety profile with predominantly grade 1-2 adverse events, though immune-related adverse events require vigilant monitoring and early intervention. 1

Common Adverse Events

• Any-grade treatment-related adverse events occur in approximately 35-45% of patients 1, 4, 6
• Most frequent toxicities include nausea (24.1%), fatigue, and immune-related adverse events 2
• Grade ≥3 adverse events occur in 13.8-35.2% of patients, comparable to other PD-1 inhibitors 1, 2, 4

Immune-Related Adverse Events (irAEs)

• Immune-related adverse events are caused by non-specific immune system activation and can affect any organ system 1
• Common irAEs include skin, gastrointestinal, endocrine, pulmonary, and musculoskeletal toxicities 1
• Less frequent but serious irAEs include pneumonitis (treatment-related death reported in 3.3% in one study), myocarditis, neurologic disorders, and severe colitis 1, 5
• The incidence of irAEs with anti-PD-1 agents like serplulimab is ≤30% for any grade and ≤20% for grade ≥3 severity, lower than anti-CTLA-4 agents 1

Management Principles

• Early recognition and prompt intervention with immunosuppression (typically corticosteroids) is critical for managing irAEs 1
• Treatment-related mortality ranges from 1.5-5% across immune checkpoint inhibitor trials, emphasizing the need for multidisciplinary toxicity management 1
• irAEs typically have delayed onset (within first 8-12 weeks) and prolonged duration compared to chemotherapy toxicities 1

Elderly Population

• In patients ≥70 years with ES-SCLC, serplulimab showed 44.19% any-grade AEs, with only 11.63% grade ≥3 events, demonstrating favorable tolerability in elderly patients 6

Comparative Safety

• Serplulimab demonstrates similar or lower toxicity rates compared to other anti-PD-1 agents, with no notable dose-dependent toxicity differences across evaluated dose levels (0.3-10 mg/kg) 2
• Treatment-related deaths (1.5-6%) are comparable to other immune checkpoint inhibitors 1