In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1, have transformed the treatment landscape of advanced driver gene-negative non-small cell lung cancer (NSCLC). However, resistance to immunotherapy remains inevitable. For patients whose disease progresses following first-line immunotherapy combined with chemotherapy, subsequent treatment options are extremely limited, creating an urgent need for more effective strategies to overcome resistance.At the 2026 European Society for Medical Oncology (ESMO) Congress, Professor Jianya Zhou’s team from the First Affiliated Hospital of Zhejiang University School of Medicine presented the results of a randomized Phase Ib study (Abstract No. 1952RO) investigating the efficacy and safety of IBI363, a first-in-class PD-1/IL-2α-biased bispecific fusion protein, in combination with bevacizumab versus docetaxel. The results showed that, compared with docetaxel, this novel combination significantly prolonged progression-free survival (PFS) and demonstrated a more favorable safety profile, with a lower incidence of myelosuppressive toxicity. These findings suggest a promising new therapeutic paradigm for overcoming immunotherapy resistance. To explore the mechanistic rationale, efficacy and safety findings, and future directions for clinical development, Oncology Frontier invited the study’s principal investigator, Professor Jianya Zhou, to provide an in-depth interpretation.
Study Overview
Study Design and Baseline Patient Characteristics
This was a randomized, 1:1 controlled Phase Ib clinical study (NCT06468098) designed to evaluate the efficacy and safety of the novel combination regimen. Eligible patients had locally advanced or metastatic lung adenocarcinoma (stage IIIB–IV), had previously received at least one systemic treatment regimen (including platinum-based doublet chemotherapy or a PD-1/PD-L1 inhibitor), and had experienced disease progression. Patients had no targetable genomic alterations involving EGFR, ALK, or ROS1.
Patients were stratified according to smoking history and the presence or absence of brain metastases at baseline, then randomized to receive either IBI363 (3 mg/kg every 3 weeks) plus bevacizumab (7.5 mg/kg every 3 weeks; n=45) or docetaxel (75 mg/m² every 3 weeks; n=42). The primary endpoints were safety and PFS, with PFS assessed by investigators according to RECIST v1.1. Baseline characteristics were generally balanced between the two groups.
Key Efficacy Results
As of July 6, 2026, the median follow-up was 8.48 months in the IBI363 combination group and 7.59 months in the docetaxel group. Regarding tumor response, the confirmed objective response rate (cORR) reached 20.0% in the IBI363 combination group, significantly higher than the 7.1% observed in the docetaxel group. The disease control rates (DCRs) were 77.8% and 66.7%, respectively.
In terms of the key survival benefit, median PFS was extended to 4.4 months in the IBI363 combination group, compared with just 2.8 months in the control group, representing a significant 60% reduction in the risk of disease progression or death (HR=0.40, p=0.0006). Particularly noteworthy, the 6-month PFS rate was 40.5% in the combination group, compared with only 4.0% in the control group, demonstrating the regimen’s potential to achieve sustained disease control. Subgroup analyses further confirmed consistent PFS benefits regardless of patients’ PD-L1 expression levels.
Safety Assessment
In terms of safety, the IBI363 combination demonstrated better tolerability than conventional chemotherapy. The incidence of grade ≥3 treatment-related adverse events (TRAEs) was 53.3% in the combination group, lower than the 75.6% reported in the docetaxel group. The most common adverse events in the combination group included arthralgia (53.3%), anemia (48.9%), and rash (46.7%), most of which were mild to moderate events that could be managed with standard clinical interventions. In contrast, the docetaxel group experienced high rates of decreased white blood cell counts (70.7%) and decreased neutrophil counts (65.9%), indicating substantial myelosuppression. In addition, no treatment-related deaths occurred in the combination group, whereas one such death (2.4%) was reported in the docetaxel group.
Study Conclusions
The results indicate that IBI363 plus bevacizumab was well tolerated and associated with a low treatment discontinuation rate. Among patients with immunotherapy-resistant lung adenocarcinoma without targetable genomic alterations, the regimen significantly prolonged PFS compared with docetaxel, demonstrating a promising efficacy signal. These encouraging findings strongly support further development of the combination in NSCLC. A global, multicenter Phase III clinical trial, MarsLight-11, is currently underway.
Investigator’s Perspective
The Clinical Challenge After Immunotherapy Resistance: Unmet Needs and the Safety Limitations of Chemotherapy
Immune checkpoint inhibitors (ICIs) have fundamentally transformed the treatment landscape of advanced driver gene-negative non-small cell lung cancer (NSCLC). However, in real-world clinical practice, resistance to immunotherapy remains inevitable. Studies have shown that the 5-year overall survival (OS) rate following first-line immunotherapy for NSCLC remains below 20%, while patients with low PD-L1 expression continue to face substantial limitations in treatment benefit. For example, patients with PD-L1 tumor proportion score (TPS) <1% have a median OS of only 9.3 months.
For patients whose disease progresses following first-line immunotherapy combined with chemotherapy, there is not only a lack of standardized second-line treatment options, but also a cumulative burden of toxicities associated with conventional chemotherapy, such as docetaxel, including myelosuppression, nausea and vomiting, and neurotoxicity. Against this background, there is an urgent need to explore novel therapeutic strategies that can overcome resistance while offering a more favorable safety profile.
Exploring the Mechanistic Rationale for the Combination Strategy: Dual-Target Synergy and Remodeling of the Tumor Immune Microenvironment
To address the challenge of immunotherapy resistance, several previous randomized controlled trials have explored combination approaches involving VEGF-targeted agents, TAM kinase inhibitors, and novel immune checkpoint monoclonal antibodies. However, most have failed to achieve significant improvements in survival. The present study adopts a mechanistically innovative approach, combining a bispecific fusion protein with an antiangiogenic agent.
IBI363 is a PD-1/IL-2α-biased bispecific fusion protein. Its molecular design retains high affinity for IL-2Rα while reducing its binding capacity to IL-2Rβ and IL-2Rγ, with the aim of minimizing systemic toxicity and selectively activating tumor-specific T cells. Bevacizumab, the combination partner, can improve the immunosuppressive tumor microenvironment by blocking VEGF signaling and promoting effector T-cell infiltration. This combination strategy is designed to achieve synergistic effects through two complementary mechanisms: relieving immunosuppression within the tumor microenvironment and precisely activating T cells, while avoiding the severe myelosuppressive toxicity associated with conventional chemotherapy.
Key Efficacy Findings: Significant PFS Improvement and Benefits Across PD-L1 Subgroups
Regarding efficacy, the cORR in the IBI363 combination group was 20.0%, higher than the 7.1% observed in the docetaxel group. Although the absolute cORR suggests that the proportion of patients achieving substantial tumor shrinkage was relatively limited, the PFS results demonstrated significant statistical and clinical benefits. Median PFS was extended to 4.4 months in the combination group, compared with 2.8 months in the control group, corresponding to a 60% reduction in the risk of disease progression or death (HR=0.40, p=0.0006). Particularly important, the 6-month PFS rate reached 40.5% in the combination group, compared with only 4.0% in the control group. This suggests that the regimen can achieve durable disease stabilization in a considerable proportion of patients with immunotherapy-resistant disease.
Furthermore, subgroup analyses showed consistent PFS benefits regardless of patients’ PD-L1 expression levels. These findings suggest that the antitumor activity of this dual-targeted regimen may not be entirely dependent on PD-L1 expression status in tumor cells, offering a new therapeutic approach for patients with low or negative PD-L1 expression who have traditionally derived limited benefit from immunotherapy.
Safety Profile: Reducing the Risk of Myelosuppression and Supporting Treatment Continuity
In the later-line treatment of advanced cancer, a drug’s toxicity profile directly affects patient tolerability and the number of treatment cycles that can be delivered. This study showed that the incidence of grade ≥3 TRAEs was 53.3% in the IBI363 combination group, lower than the 75.6% observed in the docetaxel group. Adverse events in the combination group were primarily non-myelosuppressive events, including arthralgia (53.3%), anemia (48.9%), rash (46.7%), and hypothyroidism (46.7%), for which relatively well-established clinical management strategies are available. In contrast, myelosuppression was predominant in the docetaxel group, particularly decreased white blood cell counts (70.7%) and decreased neutrophil counts (65.9%). In addition, no treatment-related deaths occurred in the combination group, compared with one in the control group.
The predominantly non-myelosuppressive toxicity profile of this regimen may help avoid dose adjustments or treatment interruptions caused by severe hematologic toxicity, thereby supporting sustained exposure to antitumor immunotherapy.
Study Limitations and Future Perspectives: From Early Validation to Precision Biomarker Exploration
Objectively, as a randomized controlled Phase Ib study, this trial had a relatively limited sample size, and the current overall survival (OS) data remain immature. Whether the PFS benefit will ultimately translate into prolonged OS requires longer follow-up. In addition, the mechanisms of immunotherapy resistance involve a complex network of factors, including tumor metabolism, antigen escape, and the tumor microenvironment. Although the current regimen has demonstrated efficacy in the overall population, identifying the patients most likely to derive the greatest benefit remains an unresolved challenge.
Looking ahead, dynamic biomarker monitoring and adaptive treatment strategies will be essential. The integration of dynamic indicators such as circulating tumor DNA (ctDNA) may enable more precise assessment of patients’ immune status. The global, multicenter Phase III clinical trial MarsLight-11 has now been initiated to further confirm the efficacy and safety of this combination regimen.
Professor Jianya Zhou
