This study provides high-level, class I evidence for first-line treatment of non-squamous NSCLC, clearly demonstrating the survival benefit of PD-1 inhibitor combined with chemotherapy, while suggesting that the addition of anti-VEGF therapy may not offer further advantage. It has significant implications for the design of clinical immunotherapy regimens.
Literature Overview
The article titled 'Serplulimab Plus Chemotherapy, with or without HLX04, versus Chemotherapy as First-Line Treatment for Nonsquamous NSCLC: Final Survival Analysis of the Phase III ASTRUM-002 Study,' published in Cancer Communications, systematically investigates the efficacy and safety of the PD-1 inhibitor serplulimab combined with chemotherapy ± the anti-VEGF biosimilar HLX04 (bevacizumab) in patients with advanced non-squamous non-small cell lung cancer (nsq-NSCLC). Based on the final overall survival (OS) analysis of a phase III randomized controlled trial, this study further validates the long-term survival benefits of immunotherapy combined with chemotherapy and evaluates the incremental benefit of the triplet regimen. The findings have direct translational value for clinical practice in non-squamous NSCLC.Background Knowledge
Non-squamous NSCLC accounts for more than 75% of all NSCLC cases, with most patients diagnosed at an advanced stage. For patients without EGFR or ALK/ROS1 driver mutations, platinum-based doublet chemotherapy combined with PD-1/PD-L1 inhibitors has become the standard first-line treatment. However, whether adding anti-angiogenic agents (such as VEGF inhibitors) to dual immunotherapy-chemotherapy regimens can further improve outcomes remains controversial. The IMpower150 study previously showed that atezolizumab plus bevacizumab plus chemotherapy improved OS, but subsequent studies such as IMpower151 and APPLE failed to confirm this benefit, suggesting that patient heterogeneity and treatment context may influence results. Moreover, most studies use bevacizumab plus chemotherapy as the control arm, lacking direct comparisons with PD-1 inhibitor plus chemotherapy. The HARMONi-6 study suggested potential synergy between VEGF and PD-1 dual blockade, but this involved a bispecific antibody. Therefore, high-quality evidence is urgently needed to clarify the efficacy hierarchy of PD-1 inhibitors plus chemotherapy with or without VEGF-targeted therapy in real-world settings. This study was specifically designed to fill this critical evidence gap.
Research Methods and Experiments
The study employed a multicenter, randomized, double-blind, three-arm design, enrolling 636 treatment-naïve patients with advanced nsq-NSCLC, who were randomly assigned in a 1:1:1 ratio to three groups: Group A (serplulimab + HLX04 + chemotherapy), Group B (serplulimab + placebo + chemotherapy), and Group C (dual placebo + chemotherapy). All patients received pemetrexed plus carboplatin, with treatment continuing up to 2 years or until disease progression. The primary endpoint was progression-free survival (PFS) assessed by independent blinded central review (BICR), with overall survival (OS) as a key secondary endpoint. Survival data were analyzed using Kaplan-Meier methods and Cox regression models, with a two-stage model and RPSFTM applied to adjust for crossover from Group C, providing a more accurate reflection of treatment effects. Baseline characteristics were well balanced, ensuring comparability across groups.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides clear evidence-based medicine support for first-line treatment of non-squamous NSCLC, endorsing PD-1 inhibitor plus chemotherapy as a cornerstone regimen. Its results may influence future guideline updates and limit the widespread use of triplet regimens. Future research should explore biomarkers (e.g., PD-L1 expression, TMB) to further refine patient stratification and identify subpopulations that may benefit from triplet therapy. Additionally, since HLX04 is a biosimilar, the findings indirectly support the accessibility and effectiveness of biosimilars in combination therapies, potentially reducing treatment costs and improving global access.
Conclusion
The final survival analysis of the ASTRUM-002 study provides pivotal evidence for first-line treatment of non-squamous NSCLC. The results clearly demonstrate that serplulimab plus chemotherapy significantly extends overall survival, reinforcing the standard role of immunotherapy combined with chemotherapy. However, the addition of the anti-VEGF agent HLX04 did not yield additional survival benefit, challenging the broad applicability of triplet regimens. These findings have important clinical implications: for patients without driver mutations, dual immunotherapy-chemotherapy should be preferred to avoid overtreatment. The study also highlights the necessity of high-quality RCTs in evaluating incremental benefits of combination strategies. Future efforts should integrate biomarkers such as PD-L1 and TMB to further personalize treatment pathways and achieve precision oncology. From bench to bedside, this study not only validates mechanistic hypotheses but also directly optimizes therapeutic decision-making, laying a solid foundation for improving patient quality of life and healthcare efficiency.
