What is the evidence-based medicine (EBM) for serplulimab in cancer treatment?

Serplulimab: Evidence-Based Medicine Overview

Serplulimab is a novel anti-PD-1 monoclonal antibody with demonstrated survival benefits in extensive-stage small cell lung cancer (ES-SCLC) and emerging evidence in other malignancies, supported by high-quality phase III data showing superior overall survival compared to chemotherapy alone. 1, 2

Mechanism of Action

• Serplulimab blocks the PD-1 receptor on T cells, preventing interaction with PD-L1/PD-L2 ligands and thereby releasing the brake on T cell activation to enable enhanced anti-tumor immune responses 2
• The drug acts at the T cell-tumor cell interface, distinguishing it from anti-CTLA-4 agents that act at the T cell-dendritic cell interface 2
• Serplulimab demonstrates similar or better affinity and pre-clinical antitumor activity compared to pembrolizumab and nivolumab 3

Primary Clinical Indication: Extensive-Stage Small Cell Lung Cancer

Efficacy Data from ASTRUM-005 Trial

The ASTRUM-005 phase III trial represents the highest quality evidence for serplulimab, establishing it as a standard first-line option for ES-SCLC:

• Median overall survival: 15.4 months with serplulimab plus chemotherapy versus 10.9 months with chemotherapy alone (HR 0.63,95% CI 0.49-0.82, P < 0.001) 1, 4
• Median progression-free survival: 5.7 months versus 4.3 months (HR 0.48,95% CI 0.38-0.59) 1, 4
• Objective response rate: 80.2% versus 70.4% 1
• One-year survival rate: 61% versus 48% 2

Updated Long-Term Results

With extended median follow-up of 19.8 months, the survival benefit was sustained with median OS of 15.8 months in the serplulimab group versus 11.1 months in placebo (HR 0.62,95% CI 0.50-0.76, P < 0.001) 5

Treatment Protocol for ES-SCLC

• Serplulimab 4.5 mg/kg intravenously every 3 weeks combined with carboplatin and etoposide for 4 cycles, followed by maintenance serplulimab 1, 4
• Treatment continues until disease progression, unacceptable toxicity, or up to 2 years 4
• This regimen aligns with ASCO guideline recommendations for first-line platinum and etoposide plus immunotherapy in ES-SCLC 1

Emerging Indications

Colorectal Cancer (MSI-H/dMMR)

• Serplulimab 3 mg/kg intravenously every 2 weeks is recommended by the 2024 Chinese Society of Clinical Oncology (CSCO) guidelines for dMMR/MSI-H colorectal cancer 1
• This indication is supported by the broader evidence base for PD-1 inhibitors in MSI-H tumors, though specific phase III data for serplulimab in this setting are still emerging 1, 6

Metastatic Colorectal Cancer (pMMR/MSS)

• A phase 2 trial showed promising results with serplulimab plus HLX04 (bevacizumab biosimilar) and XELOX in treatment-naive mCRC 7
• Median PFS was 17.2 months versus 10.7 months (HR 0.60,95% CI 0.31-1.14), with 95.7% of patients having MSS tumors 7
• This represents an important potential breakthrough, as pMMR/MSS mCRC has historically been resistant to immunotherapy 7

Esophageal Squamous Cell Carcinoma

• Phase 2 data show serplulimab combined with chemotherapy achieved 60% ORR and median PFS of 7.8 months in first-line treatment of advanced ESCC 8
• As monotherapy in later-line settings, serplulimab showed 15% ORR with durable responses 8

Safety Profile and Toxicity Management

Overall Toxicity

• Grade 3-4 treatment-related adverse events occurred in 33.2% of patients in the ASTRUM-005 trial, compared to 27.6% with chemotherapy alone 4
• The safety profile is manageable with predominantly grade 1-2 adverse events 2, 3
• Treatment-related mortality ranges from 1.5-5% across immune checkpoint inhibitor trials, emphasizing the need for vigilant monitoring 2

Immune-Related Adverse Events (irAEs)

• 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 2
• Common immune-mediated side effects affect the skin, liver, kidneys, gastrointestinal tract, lungs, and endocrine systems 6
• Pneumonitis is one of the most serious side effects, occurring in approximately 3-7% of patients on checkpoint inhibitor therapy 6
• One treatment-related death from pneumonitis was reported in the ESCC combination study 8

Management Algorithm for irAEs

• Early recognition and prompt intervention with immunosuppression (typically corticosteroids) is critical for managing irAEs 2
• Multidisciplinary toxicity management is essential given the potential for treatment-related mortality 2
• Grade 3-4 irAEs require immediate corticosteroid therapy and temporary or permanent discontinuation of serplulimab depending on severity 2

Predictive and Prognostic Biomarkers

Molecular Predictors of Response

• A 15-protein signature constructed from differentially expressed proteins was associated with significantly longer OS and PFS in serplulimab-treated patients 5
• Patients harboring RB1 mutations or mutations in Notch pathway genes showed improved ORR, OS, or PFS compared to wild-type counterparts 5
• These biomarkers may help identify patients most likely to benefit from serplulimab therapy 5

Prognostic Factors

• Baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level were independent prognosticators in ES-SCLC patients 5
• These hematological parameters can help stratify patients and inform treatment decisions 5

Pharmacokinetics and Dosing

• Pharmacokinetic data demonstrate minimal accumulation of serplulimab after repeated administration 3
• Functional PD-1 blockade was observed across all dose levels tested (0.3,1.0,3.0, and 10.0 mg/kg) 3
• The maximum tolerated dose was not reached in phase I studies, supporting the safety of the approved dosing regimens 3

Clinical Positioning and Comparative Effectiveness

Comparison to Other Immunotherapies in ES-SCLC

While ASCO guidelines recommend durvalumab or atezolizumab as standard first-line options for ES-SCLC 1, serplulimab demonstrates:

• Numerically superior median OS (15.4 months) compared to durvalumab (12.9 months in CASPIAN) and atezolizumab (12.3 months in IMpower133) 1, 4
• More pronounced PFS benefit (HR 0.48) compared to durvalumab (HR 0.78) and atezolizumab (HR 0.77) 1, 4
• Meta-analyses show no significant difference between anti-PD-L1 and anti-PD-1 agents overall, but serplulimab's results are particularly robust 1

Important Caveats

• The ASTRUM-005 trial was conducted primarily in China, and generalizability to other populations requires confirmation 4
• Serplulimab is not yet widely approved outside of China, limiting its availability 4
• Direct head-to-head comparisons with other PD-1/PD-L1 inhibitors are lacking 1

Common Pitfalls and Clinical Pearls

• Do not use serplulimab in patients with severe autoimmune disease or organ transplantation, as these are contraindications to immunotherapy 1
• Monitor closely for pneumonitis, particularly in the first 3-6 months of treatment, as this is the most serious potentially fatal irAE 6, 8
• Consider baseline NLR and LDH levels to help prognosticate outcomes and counsel patients appropriately 5
• Test for RB1 and Notch pathway mutations if available, as these may predict enhanced benefit from serplulimab 5
• In MSI-H/dMMR colorectal cancer, serplulimab represents one of several effective PD-1 inhibitor options, with choice often determined by availability and institutional preference 1, 6