Phase 3 Trial Initiated for Novel Bispecific Antibody in NSCLC

The US FDA has cleared an investigational new drug (IND) application to begin a global phase 3 clinical trial of IBI363, a novel bispecific antibody, in patients with immunotherapy (IO)-resistant squamous non–small cell lung cancer (NSCLC).¹ This marks the first global phase 3 study for the agent, which is a PD-1/IL-2α-biased bispecific antibody fusion protein. The trial will evaluate IBI363 as a monotherapy for patients who have experienced disease progression after receiving prior platinum-based chemotherapy and anti–PD-1/PD-L1 immunotherapy.

"Lung cancer remains the most prevalent malignant tumor worldwide, with particularly high incidence and mortality rates globally. Non-small cell lung cancer constitutes the majority of these cases. Although immunotherapy has significantly improved survival outcomes for some patients, those who do not respond to such treatments and lack driver gene mutations have limited therapeutic options, underscoring the urgent need for enhanced clinical interventions,” said Roy S. Herbst, MD, PhD, deputy director and chief of Medical Oncology and Hematology for Yale Cancer Center and Smilow Cancer Hospital, Ensign Professor of Medicine (Medical Oncology), and professor of pharmacology at Yale School of Medicine, in a press release.

“Clinical research of the PD-1/IL-2α-biased bispecific molecule IBI363 has revealed encouraging findings.Preliminary trials have demonstrated that IBI363 not only induces tumor remission in a subset of patients but also achieves disease stability in the majority of patients, indicating durable anti-tumor activity. In comparison to traditional chemotherapy, IBI363 appears to offer potential advantages in both objective response rate [ORR] and progression-free survival [PFS], providing new hope for patients diagnosed with lung cancer,” Herbst continued.

The multiregional, randomized, controlled study, known as MarsLight-11, will enroll approximately 600 patients across various countries, including China, the US, Canada, the UK, and Japan. The primary end point of the trial is overall survival.

This IND clearance follows a recent end-of-phase 2 (EOP2) meeting with the FDA, where key aspects of the phase 3 program, including dose selection and study design, were aligned upon. The agent has also received a fast track designation from the FDA and a breakthrough therapy designation from China's National Medical Products Administration (NMPA) for this indication.

About IBI363

IBI363 is designed to activate a dual-immune response by simultaneously blocking the PD-1/PD-L1 pathway and stimulating the IL-2 pathway. The IL-2 arm of the molecule has been engineered to selectively bind to IL-2Rα while minimizing binding to IL-2Rβ and IL-2Rγ, a modification intended to reduce the systemic toxicity often associated with IL-2-based therapies. The PD-1 binding arm of the bispecific antibody serves a dual purpose: it blocks the PD-1 checkpoint and delivers IL-2 directly to tumor-specific T cells that co-express PD-1 and IL-2α. This mechanism is intended to achieve more precise and effective T-cell stimulation.

Preliminary data from phase 1b/2 studies presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated encouraging clinical activity in populations with a high unmet need, including patients with IO-resistant lung cancer, acral and mucosal melanoma, and microsatellite stable (MSS) colorectal cancer. These findings support the agent’s dual-immune activation mechanism and its potential applicability across difficult-to-treat malignancies.

The efficacy data from a phase 1 trial (NCT05460767) in squamous NSCLC patients who had received prior immunotherapy were particularly notable.² In a cohort of 18 patients treated with a 3 mg/kg dose of IBI363, an ORR of 50.0% and a disease control rate (DCR) of 88.9% were observed at a minimum of 12 weeks of follow-up. The median PFS was not reached (NR) in this group at the time of the analysis. Importantly, the agent demonstrated antitumor activity regardless of PD-L1 expression levels, suggesting a potential advantage in a broader patient population, including those with "cold tumors" that express low or no PD-L1.

The initiation of the global phase 3 trial for IBI363 in IO-resistant squamous NSCLC represents a significant step forward in addressing the limited treatment options available for this patient population. If successful, the trial could lead to a new treatment modality that leverages a dual-mechanism approach to potentially improve long-term outcomes for patients worldwide. The ongoing clinical program reflects a comprehensive strategy to maximize the agent's therapeutic potential across various difficult-to-treat cancers.

This article was generated with assistance from Google Gemini. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. Innovent Biologics Announces U.S. FDA IND Approval for the First Global MRCT Phase 3 Study (MarsLight-11) of IBI363 (PD-1/IL-2α-bias) in Squamous Non-Small Cell Lung Cancer. News release. Innovent Biologics. August 24, 2025. Accessed August 25, 2025. https://tinyurl.com/ak9p7a5c

2. Zhou J, Bai X, Chen Y, et al. First-in-class PD-1/IL-2 bispecific antibody IBI363 in patients (Pts) with advanced immunotherapy-treated non-small cell lung cancer (NSCLC). J Clin Oncol. Volume 43, Number 16_suppl10.1200/JCO.2025.43.16_suppl.850