Updated data from Phase 1 and Phase 2 clinical studies of IBI363, a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein, presented in an oral presentation during the annual meeting of the American Society of Clinical Oncology (ASCO) held May 30 – June 3, 2025, in Chicago, Illinois, shows breakthrough efficacy in patients with heavily-treated melanoma subtypes (acral and mucosal subtypes) – which are traditionally treatment-resistant “cold” tumors.
Melanoma is a malignant tumor that develops from melanocytes. While it accounts for only 3% of all skin cancers, it has the highest mortality rate and is the most prone to metastasis.
In China, both the incidence and mortality rates of melanoma are rising annually. Based on tumor location, melanoma is classified into cutaneous, acral, and mucosal subtypes. Melanoma in Chinese populations differs significantly from that in Caucasian populations in Europe and the United States with regard to pathogenesis, biological behavior, histological morphology, treatment methods, and prognosis.[4]
For patients with advanced cutaneous and acral melanoma with BRAF V600 mutation, a combination of BRAF and MEK inhibitors is the preferred treatment. For those without this mutation, chemotherapy combined with anti-angiogenic drugs is often considered as first-line treatment. Although Pembrolizumab (Keytruda®; Merck & Co/MSD) was approved in September 2024 for first-line treatment of melanoma, the clinical benefit of PD-1 inhibitors in this setting remains modest.
In second-line treatment, agents different from those used in the first line are generally preferred. For patients not previously treated with a PD-1 inhibitor, it can be considered as a second-line option. In advanced mucosal melanoma, median PFS for patients without prior immunotherapy is only about 3 months. Given the limited efficacy of current treatments for non-cutaneous melanomas, especially mucosal subtypes, which are more prevalent in China, there is an urgent need for more effective therapies.
IBI363 (PD-1/IL-2 α-bias bispecific antibody fusion protein
IBI363 is the world’s first PD-1/IL-2α-bias bispecific fusion protein independently developed by Innovent Biologics. This investigational drug integrates two key functions: blockade of the PD-1/PD-L1 pathway and activation of the IL-2 signaling pathway.
The IL-2 arm of IBI363 has been engineered to retain affinity for IL-2 Rα while reducing binding to IL-2Rβ and IL-2Rγ, thereby minimizing toxicity. The PD-1 binding arm enables simultaneous PD-1 blockage and selective delivery of IL-2. This differential targeting strategy exploits the fact that newly activated tumor-specific T cells co-express PD-1 and IL-2α, which allows for more precise and efficient targeting and activation of this T cell subset. In preclinical and early clinic studies IBI363 not only showed good anti-tumor activity in a variety of tumor-bearing pharmacological models but also showed prominent anti-tumor efficacy in PD-1 resistance and metastasis models.
Clinical development
IBI363, which is being developed by Innovent Biologics, is included in clinical studies (NCT05460767, NCT06081920) in China, the United States, and Australia to explore the efficacy and safety of IBI363 for multiple tumor indications, including immune resistance, cold tumors, and front-line treatments
At this year’s ASCO meeting, IBI363 reported encouraging Phase 1/2 clinical data in the first three indications explored—non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and melanoma—focusing on IO-resistant and cold tumors.
The data demonstrated a robust tumor response to long-term survival benefits. These findings provide strong support of the drug’s novel mechanism of action translating effectively into clinical outcomes, and imply its potential for broader clinical development, offering new hope in areas of immunotherapy where treatment options remain limited.
As of April 7, 2025, a total of 31 patients with unresectable, locally advanced or metastatic acral and mucosal melanoma who had previously received immunotherapy were enrolled and treated at the dosage of 1 mg/kg Q2W, and 64.5% of them had ≥2 lines of prior treatment.
Breakthrough efficacy of IBI363 monotherapy has been achieved in patients with “immune-cold” melanoma, with notable durable response and prolonged survival benefit:
- In patients with at least one post-baseline tumor assessment (n=30), the confirmed objective response rate (cORR) was 23.3%, including 25.0% for mucosal type and 20.0% for acral type. The disease control rate (DCR) reached 76.7%, with 85.0% in mucosal type and 60.0% in acral type.
- In patients treated with 1 mg/kg Q2W with confirmed responses (n=7),a durable response was observed with a median duration of response (DoR) of 14.0 months and events of 42.9%.
- In patients treated with 1 mg/kg Q2W (n = 31) had a median progression-free survival (PFS) of 5.7 (2.7, 6.8) months, which was significantly longer than data from previous studies (PFS less than 3 months.[1]) The median follow-up time was 14.7 months, the median overall survival (OS) was 14.8 (9.9, NC) months, and the median OS of patients with mucosal subtype was 19.3 (9.9, NC) months. The overall 12-month OS rate was 61.5%.
- In terms of safety, IBI363 was generally well tolerated. Among the subjects treated with 1 mg/kg Q2W (n = 31), the treatment-related adverse events (TRAEs) with an incidence > 30% were arthralgia, rash, and hyperthyroidism, most of which were Grade 1 or 2. The overall incidence of Grade ≥ 3 TRAEs was 29.0%, and only 3.2% of subjects discontinued treatment due to TRAEs. Overall safety was manageable, and no new safety risks were found.
Trial in progress update
Innovent Biologics announced a trial in progress (TiP) for a randomized, open-label, multi-center Phase 2 study evaluating the efficacy and safety of IBI363 monotherapy compared to pembrolizumab in patients with unresectable, locally advanced or metastatic mucosal and acral melanoma who have not received prior systemic treatment.
As the first pivotal registration trial of IBI363, this study is designed to directly compare IBI363 monotherapy with pembrolizumab in this patient population. A total of 180 patients are planned to be enrolled and randomized in a 1:1 ratio. The primary endpoint is progression-free survival (PFS) assessed by an Independent Review Committee (IRC).
The first patient was dosed in March 2025, marking a significant step in advancing IBI363’s development in melanoma. Additional studies exploring IBI363 in combination therapies across other cancer types are also ongoing.
“Although melanoma is a relatively rare malignant tumor in China, it has a high mortality rate, and its incidence continues to rise each year. Historically, patients with melanoma who have not received immunotherapy have had a median PFS of only about 3 months, which highlights a significant unmet clinical need,” noted Professor Guo Jun from Peking University Cancer Hospital and the Principal Investigator of Melanoma Studies on IBI363
“Notably, non-cutaneous melanoma (especially mucosal melanoma) accounts for a large proportion of cases in China and is considered a ‘cold tumor’, typically unresponsive to traditional immunotherapy. In these cases, the response rate to PD-1 monotherapy is often below 15%, offering limited clinical benefit. More effective treatments are urgently needed. [2] IBI363 addresses this challenge by transforming ‘cold tumors’ into ‘hot tumors’ through dual activation of the PD-1 and IL-2 pathways. The data presented in this study showed that IBI363 delivers significantly improved efficacy compared to previous studies in cold tumor subtypes and standard of care therapies, while maintaining a favorable safety profile. IBI363 has the potential to become a new standard in immunotherapy for malignant melanoma in China, providing a long-needed treatment option for patients with acral and mucosal malignant melanoma,” Jun added.
Unmet medical need
“At present, there is a huge unmet clinical need for the treatment of unresectable, locally advanced or metastatic mucosal and acral melanoma in China. Approved PD-1 therapies have not substantially improved first-line outcomes in melanoma, and the clinical benefits remain limited,[3] said Dr. Zhou Hui, Senior Vice President of Innovent Biologics.
“IBI363 is leading the evolution of next-generation immunotherapy. By leveraging a dual-mechanism of ‘PD-1 blockade + IL-2 directed activation’, IBI363 enhances T cell function and expands T cell populations to reshape the tumor immune microenvironment. IBI363 has shown excellent efficacy and safety results in the treatment of patients with immune-cold melanoma subtypes. A Phase 2 pivotal registrational study is currently underway. Positive results in patients with mucosal and acral melanoma are highly anticipated, offering hope for a more effective treatment option. Meanwhile, we are accelerating the global development of IBI363 across multiple tumor types, with the goal of making this innovative treatment accessible to patients around the world,” he concluded.
Regulatory status
IBI363 has been granted two fast track designations by the FDA for the treatment of advanced squamous non-small cell lung cancer and melanoma, respectively. IBI363 has also been granted Two Breakthrough Therapy Designations by the National Medical Products Administration (NMPA) for the treatment of advanced melanoma and squamous NSCLC.
Clinical trials
Safety, Tolerability and Preliminary Efficacy of IBI363 in Subjects With Advanced Solid Tumors or Lymphoma
ClinicalTrials.gov ID NCT05460767
A Study of IBI363 in Subjects With Advanced Melanoma – ClinicalTrials.gov ID NCT06081920
Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Reference
[1]. Cui C, Yan X, Li B, et al. Real-world clinical outcomes of anticancer treatments and prognostic factors in patients with advanced melanoma in China. International Journal of Surgery Oncology. 2020; 5. e97-e97. doi:10.1097/IJ9.0000000000000097.
[2]. Cui C, Chen Y, Luo Z, et al. Safety and efficacy of Pucotenlimab (HX008) – a humanized immunoglobulin G4 monoclonal antibody in patients with locally advanced or metastatic melanoma: a single-arm, multicenter, phase II study. BMC Cancer. 2023;23(1):121. Published 2023 Feb 6. doi:10.1186/s12885-022-10473-y
[3]. Si L, Zhang X, Shu Y, et al. A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151).Transl Oncol. 2019;12(6):828-835. doi:10.1016/j.tranon.2019.02.007
[4]. Diagnostic and Therapeutic Guidelines for Melanoma (2022 Edition)
Featured image: ASCO Annual Meeting/ Photo courtesy © 2016 – 2025 ASCO/David Eulitt. Used with permission.
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