Serplulimab Plus Chemotherapy Redefines First-Line Standards in Non-Squamous NSCLC: Results from the ASTRUM-002 Trial

Highlights

Survival Benefit

First-line serplulimab plus chemotherapy nearly doubled median progression-free survival (PFS) compared to chemotherapy alone (11.0 months vs. 5.6 months; HR 0.55).

The Quadruplet Question

Adding the bevacizumab biosimilar HLX04 to the serplulimab-chemotherapy regimen (Group A) resulted in a median PFS of 12.6 months, but this was not statistically superior to the triplet regimen (Group B) (HR 0.86; p=0.25).

Safety and Tolerability

Treatment-related adverse events of grade 3 or higher occurred in 71% of the quadruplet group and 66% of the triplet group, highlighting a manageable but significant toxicity profile.

Background and Clinical Rationale

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. For patients with non-squamous histology lacking targetable mutations such as EGFR or ALK, the standard of care has shifted toward immune checkpoint inhibitors combined with platinum-based chemotherapy. However, clinicians continue to explore whether inhibiting the vascular endothelial growth factor (VEGF) pathway can synergize with programmed cell death protein-1 (PD-1) blockade to further improve outcomes.

The ASTRUM-002 trial was designed to address this clinical uncertainty by evaluating serplulimab, a novel anti-PD-1 antibody, in combination with chemotherapy, with or without the bevacizumab biosimilar HLX04. The trial sought to determine if a quadruplet approach could surpass the efficacy of a triplet immunotherapy-chemotherapy regimen.

Study Design and Methodology

ASTRUM-002 was a randomized, double-blind, multicenter, phase 3 trial conducted across 72 hospitals in China. The study enrolled 636 patients with locally advanced or metastatic non-squamous NSCLC who had not received prior systemic therapy and lacked EGFR/ALK/ROS1 rearrangements.

Patients were randomized in a 1:1:1 ratio into three distinct treatment arms:

Group A (Quadruplet)

Serplulimab (4.5 mg/kg) plus HLX04 (15 mg/kg) plus chemotherapy (pemetrexed and carboplatin).

Group B (Triplet)

Serplulimab plus chemotherapy plus a placebo for HLX04.

Group C (Control)

Chemotherapy plus placebos for both serplulimab and HLX04.

The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent central review (BICR) per RECIST version 1.1. Stratification factors included PD-L1 expression levels, smoking history, and the presence of brain metastases.

Key Findings: Efficacy and Survival Outcomes

The study reached its primary endpoint, demonstrating a clear superiority of immunotherapy-containing regimens over chemotherapy alone.

Superiority of Serplulimab Triplet over Chemotherapy

In the intention-to-treat population, patients receiving serplulimab plus chemotherapy (Group B) experienced a median PFS of 11.0 months (95% CI 8.4-12.7), compared to 5.6 months (95% CI 4.8-6.8) in the chemotherapy-only group (Group C). This represents a 45% reduction in the risk of disease progression or death (Hazard Ratio [HR] 0.55; 95% CI 0.43-0.69; p < 0.0001).

The Impact of Adding HLX04

Interestingly, the addition of the bevacizumab biosimilar (Group A) resulted in a numerical increase in median PFS to 12.6 months (95% CI 8.7-14.0). However, when compared directly to the serplulimab-chemotherapy triplet (Group B), the hazard ratio was 0.86 (95% CI 0.67-1.11), with a p-value of 0.25. Consequently, the study did not find a statistically significant benefit for the quadruplet therapy over the triplet therapy.

Safety and Adverse Events

The safety profile was consistent with the known toxicities of the individual agents. Treatment-related serious adverse events (SAEs) occurred in 39% of patients in Group A, 37% in Group B, and 24% in Group C.

Grade 3 or worse treatment-related adverse events (TRAEs) were reported in 71% of Group A and 66% of Group B, compared to 57% in Group C. The most common high-grade toxicities were related to hematological suppression (neutropenia, anemia) and immune-related effects. Notably, treatment-related adverse events leading to death occurred in 5% of patients in the quadruplet group, 2% in the triplet group, and 3% in the chemotherapy group.

Expert Commentary: Interpreting the Data

The results of ASTRUM-002 solidify the role of serplulimab as a potent first-line option for non-squamous NSCLC. The significant PFS benefit over chemotherapy alone aligns with findings from other major PD-1/PD-L1 trials, such as KEYNOTE-189.

However, the lack of statistical significance for the quadruplet regimen (Group A) raises important questions about patient selection and biological redundancy. While some previous trials, like IMpower150, suggested a benefit for the addition of bevacizumab to atezolizumab and chemotherapy, that benefit was most pronounced in specific subgroups, such as those with liver metastases or EGFR mutations. In ASTRUM-002, the broad non-squamous population may not have derived enough incremental benefit from VEGF inhibition to overcome the statistical threshold, or perhaps the potency of serplulimab alone reached a therapeutic plateau in this unselected cohort.

Clinicians must weigh the marginal numerical gain in PFS (1.6 months) against the increased risk of high-grade toxicities and the added cost of quadruplet therapy. For the majority of patients, the triplet of serplulimab and chemotherapy currently offers the most favorable benefit-to-risk ratio.

Conclusion

The ASTRUM-002 trial successfully demonstrates that serplulimab plus chemotherapy provides a robust and clinically meaningful improvement in progression-free survival for patients with advanced non-squamous NSCLC. While the addition of the bevacizumab biosimilar HLX04 did not meet the criteria for statistical superiority over the immunotherapy-chemotherapy triplet, serplulimab emerges as a validated and effective first-line treatment option. Future research should focus on identifying biomarkers that might predict which subset of patients could truly benefit from the intensified quadruplet approach.

Funding and Trial Registration

This study was funded by Shanghai Henlius Biotech. ClinicalTrials.gov Identifier: NCT03952403.

References

Wang L, Hao X, Hao Y, et al. First-line serplulimab plus chemotherapy with or without HLX04 versus chemotherapy in locally advanced or metastatic non-squamous non-small-cell lung cancer (ASTRUM-002): a randomised, double-blind, multicentre phase 3 trial. Lancet Respir Med. 2026 Feb;14(2):117-128. doi: 10.1016/S2213-2600(25)00263-2. Epub 2025 Dec 4. PMID: 41354044.