IBI363 Plus Bevacizumab Improves PFS in Immunotherapy-Resistant Lung Adenocarcinoma

IBI363 (TAK-928) plus bevacizumab (Avastin) significantly prolonged progression-free survival (PFS) compared with docetaxel in patients with locally advanced or metastatic lung adenocarcinoma without actionable genomic alterations whose disease was resistant to immunotherapy, according to findings from a randomized phase 1b study (NCT06468098) presented at the 2026 ESMO Congress.¹

At a data cutoff of July 6, 2026, findings showed the median PFS was 4.4 months (95% CI, 4.0-8.2) in the IBI363 arm (n = 45) vs 3.4 months (95% CI, 2.6-4.1) in the docetaxel arm (n = 42; HR, 0.40; 95% CI, 0.23-0.68; P = .0006). The confirmed objective response rate (ORR) was 20.0% (95% CI, 9.6%-34.6%) with the combination and 7.1% (95% CI, 1.5%-19.5%) with docetaxel.

"IBI363 plus bevacizumab was well tolerated with low discontinuation rates," study author Jianya Zhou, MD, a professor at The First Affiliated Hospital, Zhejiang University School of Medicine in Hangzhou, China, said during the presentation. "The combination demonstrated a significantly longer PFS compared with docetaxel in patients with [immunotherapy-resistant] lung adenocarcinoma."

What is the mechanism of action of IBI363?

IBI363 is an investigational bispecific fusion protein that pairs PD-1 inhibition with interleukin-2 signaling biased toward the alpha subunit of the receptor. By lifting checkpoint-driven suppression, the agent is intended to expand and activate tumor-specific T cells while keeping peripheral immune activation in check. Bevacizumab was added with the goal of complementing this immune activity through VEGF inhibition.

How was the trial designed?

The randomized, open-label phase 1b cohort is part of a larger study evaluating IBI363-based combination regimens.² Eligible patients had stage IIIB to IV lung adenocarcinoma that was locally advanced and unresectable or metastatic. Patients were required to have experienced disease progression on or after at least 1 previous line of systemic therapy, which could include platinum-based doublet chemotherapy or a PD-1/PD-L1 inhibitor.

Patients also needed an ECOG performance status of 0 or 1 and could not have known actionable EGFR, ALK, or ROS1 alterations or brain metastases that were uncontrolled or unstable. Every patient in the analyzed population had received prior immunotherapy.

Per the registry for the broader study, patients also had to be aged 18 to 75 years, have at least 1 measurable lesion by RECIST v1.1, and have a life expectancy of 3 months or longer.

In total, 87 patients were randomly assigned 1:1 to receive IBI363 plus bevacizumab (n = 45) or docetaxel (n = 42), with stratification by smoking history and by whether brain metastases were present at baseline.¹

In the experimental arm, patients were given IBI363 at 3 mg/kg and bevacizumab at 7.5 mg/kg, both every 3 weeks; those in the control arm received docetaxel at 75 mg/m² every 3 weeks.

Median follow-up was 8.48 months (range, 2.1-15.1) in the combination arm and 7.59 months (range, 0.2-14.8) in the docetaxel arm. Because 1 patient randomly assigned to docetaxel withdrew before receiving treatment, the safety populations included 45 and 41 patients, respectively.

Safety and investigator-assessed PFS per RECIST 1.1 criteria served as the primary end points of the randomized cohort.¹ Other efficacy measures included confirmed and unconfirmed ORR, disease control rate (DCR), duration of response (DOR), and overall survival (OS).

Secondary outcomes include pharmacokinetic parameters (maximum plasma concentration, area under the concentration-time curve, half-life, clearance, and volume of distribution) as well as immunogenicity, assessed by anti-IBI363 antibodies.²

The mean age in the randomized cohort was 62.7 years in the IBI363 arm and 63.2 years in the docetaxel arm, and all patients were Asian.¹ Men made up 73.3% and 90.5% of the respective arms, and 24.4% vs 14.3% had never smoked.

All patients in the combination arm had stage IV disease, compared with 95.2% of those in the docetaxel arm. Brain metastases were present at baseline in 24.4% vs 23.8% of patients. Among patients with available data, 88.9% vs 85.4% had an ECOG performance status of 1.

PD-L1 expression was below 1% in 51.1% of patients in the combination arm vs 38.1% of those in the docetaxel arm and at least 1% in 28.9% vs 40.5%; PD-L1 status was unavailable for 20.0% vs 21.4%.

Patients in the 2 arms had received 1 (57.8% vs 54.8%), 2 (24.4% vs 23.8%), or at least 3 (17.8% vs 21.4%) prior lines of therapy. In addition to universal prior immunotherapy exposure, 86.7% vs 92.9% had previously received platinum-based therapy.

What additional efficacy findings were reported?

The unconfirmed ORR was 26.7% (95% CI, 14.6%-41.9%) with IBI363 plus bevacizumab vs 11.9% (95% CI, 4.0%-25.6%) with docetaxel, and the DCRs were 77.8% (95% CI, 62.9%-88.8%) and 66.7% (95% CI, 50.5%-80.4%), respectively. DOR and OS data were not yet mature.

In exploratory analyses by PD-L1 tumor proportion score (TPS), patients with a TPS of at least 1% had a median PFS of 8.1 months with the combination (n = 13) vs 2.8 months with docetaxel (n = 17; HR, 0.152; 95% CI, 0.047-0.490).

In patients with a TPS below 1%, median PFS was 4.2 months (n = 23) vs 3.8 months (n = 16), respectively (HR, 0.541; 95% CI, 0.242-1.213). Although the HRs in both subgroups numerically favored the combination, the confidence interval crossed 1 in the TPS-below-1% subgroup, and these exploratory analyses included small numbers of patients.

What safety findings were reported?

Treatment-emergent adverse effects (TEAEs) of any grade occurred in all treated patients, and grade 3 or higher TEAEs occurred in 62.2% of patients in the IBI363 arm vs 78.0% of those in the docetaxel arm. Treatment-related AEs (TRAEs) were reported in 97.8% vs 100% of patients, respectively, including grade 3 or higher TRAEs in 53.3% vs 75.6%.

Serious TEAEs occurred in 57.8% vs 39.0% of patients, and serious TRAEs occurred in 46.7% vs 36.6%. TRAEs led to treatment discontinuation in 8.9% vs 7.3% of patients. No treatment-related deaths occurred in the combination arm; 1 occurred in the docetaxel arm.

The most common TRAEs with the combination included arthralgia (53.3%), anemia (48.9%), hypothyroidism (46.7%), rash (46.7%), proteinuria (42.2%), and hyperthyroidism (42.2%); grade 3 or higher rash occurred in 11.1% of patients. In the docetaxel arm, grade 3 or higher decreases in neutrophil and white blood cell counts were observed in 58.5% and 51.2% of patients, respectively.

No new safety signals were identified, and the investigators concluded that the data support continued evaluation of IBI363 in non–small cell lung cancer, including in the ongoing phase 3 MarsLight-11 trial (NCT07217301).

References

1. Zhou J. IBI363 (TAK-928) plus bevacizumab (Bev) vs docetaxel (DTX) in patients with locally advanced or metastatic immunotherapy-resistant lung adenocarcinoma without actionable genomic alterations: a randomized phase Ib study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 1952RO
2. A study of IBI363 in subjects with advanced malignancies. ClinicalTrials.gov. Accessed October 26, 2026. https://clinicaltrials.gov/study/NCT06468098