IBI363: A Comprehensive Clinical and Scientific Profile of a First-in-Class PD-1/IL-2α-Bias Bispecific Antibody

I. Executive Summary

IBI363 represents a significant advancement in the field of immuno-oncology, engineered as a first-in-class Programmed Death-1 (PD-1)/Interleukin-2 alpha-bias (IL-2α-bias) bispecific antibody fusion protein. Developed independently by Innovent Biologics, this novel agent is designed to overcome the limitations of current immunotherapies by simultaneously addressing two critical pathways of immune regulation.[1] Its core strategic objective is to reactivate the anti-tumor immune response in patients who have developed resistance to standard checkpoint inhibitors and to successfully treat immunologically "cold" tumors, which have historically been unresponsive to such therapies.

The molecular architecture of IBI363 combines a PD-1 blocking antibody with an engineered, α-biased IL-2 cytokine. This dual-action mechanism not only releases the inhibitory "brakes" on T cells via PD-1 blockade but also provides a potent, targeted stimulatory signal through the IL-2 pathway. The key innovation lies in the IL-2α-bias, which directs the cytokine's activity preferentially toward tumor-specific T cells co-expressing PD-1 and the high-affinity IL-2 receptor subunit, IL-2Rα (CD25). This precision targeting is designed to maximize anti-tumor efficacy while mitigating the severe systemic toxicities associated with traditional high-dose IL-2 therapy.

Clinical data from a comprehensive development program have demonstrated compelling efficacy across multiple difficult-to-treat cancers. In heavily pre-treated, immunotherapy-resistant squamous non-small cell lung cancer (NSCLC), IBI363 has achieved objective response rates (ORR) as high as 50.0% and a median progression-free survival (PFS) of 9.3 months at the 3 mg/kg dose, representing a substantial improvement over the current standard of care.[4] In advanced melanoma, particularly the "cold" acral and mucosal subtypes, IBI363 has shown robust activity in both immunotherapy-naïve (ORR of 67.7%) and immunotherapy-resistant settings.[6] Perhaps most notably, in microsatellite stable (MSS) colorectal cancer (CRC)—a classic example of a cold tumor—IBI363 monotherapy has yielded an unprecedented median overall survival (OS) of 16.1 months in a late-line setting, offering new hope for a large patient population with no effective immunotherapy options.[8]

This promising efficacy is complemented by a consistently manageable safety profile. The adverse events are predictable and primarily consist of low-grade, immune-related phenomena such as arthralgia, rash, and thyroid disorders, with low rates of treatment discontinuation.[4] This favorable therapeutic index validates the preclinical hypothesis of the IL-2α-bias engineering.

Reflecting the strength of its clinical profile, IBI363 has received multiple expedited regulatory designations from both the U.S. Food and Drug Administration (FDA) and China's National Medical Products Administration (NMPA), including Fast Track and Breakthrough Therapy Designations for both NSCLC and melanoma.[1] The agent is now advancing into global, pivotal Phase 3 trials, including a head-to-head comparison against docetaxel in NSCLC (MarsLight-11) and against the standard-of-care pembrolizumab in melanoma.[3] These developments position IBI363 as a potential cornerstone of next-generation immuno-oncology and a transformative therapy for patients with advanced malignancies.

II. Scientific Rationale and Mechanism of Action: Engineering a Smarter Cytokine Therapy

The therapeutic strategy underpinning IBI363 is rooted in a sophisticated understanding of tumor immunology and the mechanisms of resistance to first-generation checkpoint inhibitors. By creating a single molecule that addresses both T-cell exhaustion and insufficient T-cell stimulation, Innovent Biologics has engineered a therapy designed to be more potent and broadly applicable than its predecessors.[1]

The Architectural Design of IBI363: A Bispecific Fusion Protein

IBI363 is classified as a bispecific antibody fusion protein. Its structure consists of two functionally distinct components covalently linked into a single therapeutic entity: a humanized monoclonal antibody that specifically targets the PD-1 receptor, and a mutated form of the human cytokine IL-2.[12] This fusion protein design is integral to its function, ensuring that both immunomodulatory actions are delivered simultaneously to the same location within the tumor microenvironment. The molecule was discovered and is being developed solely by Innovent Biologics, a biopharmaceutical company with a growing portfolio of innovative oncology assets.[1]

Dual-Pronged Immunomodulation: A Synergistic Attack on Tumor Evasion

The mechanism of action (MoA) of IBI363 is a coordinated, two-part assault on the tumor's immune evasion strategies. It aims to not only remove immunosuppressive signals but also to actively promote a robust anti-tumor immune response.

1. PD-1 Checkpoint Blockade: The antibody portion of IBI363 binds with high affinity to the PD-1 receptor expressed on the surface of activated T cells.[13] PD-1 is a critical immune checkpoint that, when engaged by its ligands (PD-L1 or PD-L2) on tumor cells or other cells in the microenvironment, delivers an inhibitory signal that dampens T-cell activity. This is a primary mechanism by which tumors evade immune destruction. By physically blocking this interaction, IBI363 effectively "releases the brakes" on the T cell, restoring its ability to recognize and kill cancer cells. This function is analogous to that of established anti-PD-1 therapies like pembrolizumab and nivolumab.[1]
2. IL-2 Pathway Activation: The fused IL-2 component of IBI363 acts as a powerful immunostimulatory agent. IL-2 is a cytokine that plays a central role in T-cell biology, promoting the proliferation, survival, and effector function of cytotoxic T-lymphocytes (CTLs) and Natural Killer (NK) cells, both of which are essential for anti-tumor immunity.[13] By binding to the IL-2 receptor (IL-2R) on these cells, the IL-2 moiety of IBI363 provides a strong activation signal, effectively "stepping on the gas" to expand the army of anti-tumor immune cells.[1]

The IL-2α-Bias: Engineering for Precision and Safety

The most significant innovation in the design of IBI363 is the engineering of its IL-2 component. The IL-2 receptor exists in different forms with varying affinities. The high-affinity receptor is a trimer composed of alpha (IL-2Rα or CD25), beta (IL-2Rβ or CD122), and gamma (IL-2Rγ or CD132) chains. The intermediate-affinity receptor consists of only the β and γ chains. The IL-2 in IBI363 has been specifically mutated to exhibit an "α-bias," meaning it retains a strong affinity for the IL-2Rα subunit while having a markedly reduced affinity for the IL-2Rβ and IL-2Rγ subunits.[1]

This engineering has profound biological and clinical consequences. Scientific evidence has shown that the tumor-specific T cells that are most critical for fighting cancer, but which often become exhausted, are characterized by high co-expression of both PD-1 and CD25.[8] The design of IBI363 masterfully exploits this biological feature. The PD-1 antibody arm acts as a targeting domain, physically guiding the molecule to these key PD-1+ T cells. Once bound, the α-biased IL-2 component then preferentially activates these same cells through CD25. This process, known as "cis-activation," ensures that the powerful IL-2 stimulatory signal is delivered with high precision to the exact T-cell subpopulation that needs to be reinvigorated within the tumor microenvironment.[10]

This targeted delivery system is the key to decoupling efficacy from toxicity. The historical use of high-dose recombinant IL-2 (aldesleukin) was limited by severe, life-threatening toxicities, such as vascular leak syndrome. These toxicities were driven by the non-specific, high-level activation of the intermediate-affinity IL-2Rβγ complex on a wide range of immune cells throughout the body, including NK cells and eosinophils.[1] By reducing binding to IL-2Rβγ, IBI363 is designed to avoid this systemic, off-target activation, thereby minimizing toxicity and creating a much wider therapeutic window. The manageable safety profile observed throughout its clinical development program serves as the clinical validation of this elegant engineering strategy.[4]

Translating Mechanism to Effect: Overcoming Immunotherapy Resistance and "Cold" Tumors

The dual mechanism of IBI363 is purpose-built to address the two major challenges in modern immuno-oncology: acquired resistance and "cold" tumors.

• Overcoming Resistance: Many patients who initially respond to standard PD-1/L1 inhibitors eventually develop resistance. This can occur because the anti-tumor T cells become so profoundly exhausted or depleted that simply blocking PD-1 is no longer sufficient to restore their function. IBI363's mechanism directly counters this; while the PD-1 antibody releases the inhibitory signal, the IL-2 component provides the necessary proliferative and survival signal to expand and rejuvenate the remaining pool of tumor-specific T cells.[1] It does not just release the brakes; it helps rebuild the engine of the immune response. This explains its promising activity in patients who have already progressed on prior immunotherapy.
• Activating "Cold" Tumors: "Cold" tumors are characterized by a non-inflamed tumor microenvironment with a low density of infiltrating T cells. They are often inherently resistant to checkpoint inhibitors because there is no pre-existing immune response to "release." IBI363 has the potential to transform these immunologically barren landscapes into "hot," T-cell-infiltrated environments. By providing a potent IL-2 signal, it can drive the expansion of even a small number of tumor-specific T cells, effectively kick-starting a de novo immune response. This hypothesis is supported by early clinical data showing enrichment of PD-1+CD25+CD8+ cells in the tumors of responding patients and by the drug's notable efficacy in notoriously "cold" tumor types like MSS colorectal cancer and acral/mucosal melanoma.[4]

III. Clinical Development and Efficacy in Non-Small Cell Lung Cancer (NSCLC)

The clinical development program for IBI363 in NSCLC has focused on addressing the significant unmet medical need for patients with advanced disease who have progressed after standard-of-care treatments. The results from this program, particularly in the immunotherapy-resistant squamous cell carcinoma subtype, have been a major driver of the drug's accelerated development.

Overview of the NSCLC Clinical Program

IBI363 is being investigated in a multicenter, first-in-human Phase 1a/1b study (NCT05460767) that includes dose escalation and cohort expansion phases. The trial has enrolled patients with various advanced solid tumors, with a specific focus on NSCLC patients who have failed or were intolerant to prior therapies, including both platinum-based chemotherapy and anti-PD-(L)1 checkpoint inhibitors.[10] This patient population has a poor prognosis and very limited treatment options, making it an ideal setting to demonstrate the unique potential of IBI363.

Efficacy in Immunotherapy-Resistant Squamous NSCLC

Squamous NSCLC represents a key area of success for IBI363, where early clinical data have revealed remarkable and dose-dependent anti-tumor activity.

• Efficacy at the 3 mg/kg Dose: At the dose of 3 mg/kg administered every three weeks (Q3W), IBI363 has demonstrated compelling efficacy. An early analysis of 18 patients with at least 12 weeks of follow-up showed an impressive ORR of 50.0% (95% CI, 26.0%-74.0%) and a disease control rate (DCR) of 88.9% (95% CI, 65.3%-98.6%).[4] More mature data from a larger cohort of 31 patients at this dose confirmed a high level of activity, with a confirmed objective response rate (cORR) of 36.7% (95% CI, 19.9%-56.1%) and a DCR of 90.0% (95% CI, 73.5%-97.9%).[4] The durability of these responses was also notable, with a median PFS of 9.3 months (95% CI, 6.2-11.7). The median OS had not been reached at the time of analysis, but the 12-month OS rate was a promising 70.9%.[4]
• Efficacy at Lower Doses: In comparison, patients treated at lower doses of 1 mg/kg or 1.5 mg/kg (n=28) showed a cORR of 25.9% (95% CI, 11.1%-46.3%) and a DCR of 66.7% (95% CI, 46.0%-83.5%). The survival outcomes were also less favorable, with a median PFS of 5.5 months (95% CI, 1.5-8.3) and a median OS of 15.3 months.[4]

The clear dose-response relationship observed in these data is a critical finding. The substantially improved efficacy metrics at the 3 mg/kg dose, coupled with a manageable safety profile at this level (as detailed in Section VI), established a clear and compelling therapeutic window. This provided high confidence for the selection of the 3 mg/kg dose for late-stage development, as it appears to maximize the drug's therapeutic potential without introducing prohibitive toxicity, thereby significantly de-risking the program. The observed efficacy is particularly significant given the patient population. For patients with squamous NSCLC who have progressed on both chemotherapy and immunotherapy, the standard second-line option is typically docetaxel, which historically yields an ORR in the range of 6-9% and a median PFS of only 3-4 months. The results for IBI363 represent a potential paradigm shift in treatment outcomes for this population.

Performance in Non-Squamous NSCLC (Adenocarcinoma) and Across PD-L1 Strata

IBI363 has also demonstrated meaningful activity in non-squamous NSCLC. In a cohort of 25 patients with adenocarcinoma lacking actionable genomic alterations who were treated at the 3 mg/kg dose, the cORR was 24.0% (95% CI, 9.4%-45.1%) and the DCR was 76.0%. The median PFS in this group was 5.6 months.[5] While more modest than in the squamous population, these results are still highly encouraging in a heavily pre-treated setting.

A crucial finding that validates the drug's unique mechanism of action is its potent activity irrespective of tumor PD-L1 expression, a key biomarker for first-generation checkpoint inhibitors. In the squamous NSCLC cohort, patients whose tumors had a PD-L1 tumor proportion score (TPS) of less than 1%—a classic feature of an immunologically "cold" tumor—achieved a remarkable ORR of 45.5% (n=22 across all dose levels).[10] Similarly, in the adenocarcinoma cohort with TPS <1%, the ORR was

29.4% (n=17).[10] This ability to generate responses in PD-L1-negative tumors suggests that the IL-2 component of IBI363 can effectively stimulate an anti-tumor immune response even when the PD-1/PD-L1 axis is not the dominant immunosuppressive pathway, a key differentiator from standard anti-PD-1 monotherapy.

The table below provides a comparative summary of the key efficacy data for IBI363 in different NSCLC cohorts.

Table 1: Comparative Efficacy of IBI363 in Advanced NSCLC (Phase 1/2 Data)

Histology	Dose Level	N	Confirmed ORR (%)	DCR (%)	Median PFS (months)	Median OS (months)
Squamous	1 or 1.5 mg/kg	28	25.9	66.7	5.5	15.3
Squamous	3 mg/kg Q3W	31	36.7	90.0	9.3	Not Reached
Adenocarcinoma	0.6, 1, or 1.5 mg/kg	30	13.8	62.1	2.7	17.5
Adenocarcinoma	3 mg/kg Q3W	25	24.0	76.0	5.6	Not Reached

Data compiled from sources [4], and.[10]

The MarsLight-11 Study: The Path to Registration

Based on the strength of these Phase 1/2 results, Innovent has received Investigational New Drug (IND) application clearance from the U.S. FDA to initiate a global, multi-regional, randomized Phase 3 trial designated MarsLight-11.[5] This pivotal study is designed to confirm the superiority of IBI363 over the current standard of care.

• Trial Design: MarsLight-11 will enroll approximately 600 patients globally. It is designed as a head-to-head comparison of IBI363 monotherapy (at the 3 mg/kg Q3W dose) versus docetaxel chemotherapy.[5]
• Patient Population: The study will enroll patients with unresectable, locally advanced, or metastatic squamous NSCLC whose disease has progressed during or after treatment with both platinum-containing chemotherapy and an anti-PD-1 or anti-PD-L1 immunotherapy.[5]
• Endpoints: The primary endpoint of the trial is Overall Survival (OS), with secondary endpoints including PFS, ORR, and safety.[11]

The design of this trial reflects a highly astute clinical and commercial strategy. Rather than entering the crowded and competitive first-line NSCLC market, Innovent is positioning IBI363 to become the new, undisputed standard of care in the second- or third-line setting for squamous NSCLC. This targets a large and growing patient population for whom the current standard, docetaxel, offers minimal benefit. By aiming to replace a weak incumbent in an area of high unmet need, Innovent has charted a more direct and capital-efficient path to market, seeking to establish IBI363 as the essential therapy for patients after the failure of first-line treatments like Keytruda.

IV. Clinical Efficacy in Advanced Melanoma

The clinical development of IBI363 in advanced melanoma has been strategically focused on subtypes with significant unmet medical needs and on demonstrating potential superiority over the established standard of care. The program has yielded impressive results in both immunotherapy-resistant and immunotherapy-naïve patient populations.

Addressing Unmet Needs in "Cold" Melanoma Subtypes

A primary focus of the melanoma program has been on acral and mucosal melanoma. These are rare subtypes that are more common in Asian populations and are considered immunologically "cold" due to their low tumor mutational burden and lack of T-cell infiltration. Consequently, they have historically demonstrated poor responses to standard PD-1 checkpoint inhibitors.[7]

In a combined analysis from the Phase 1 (NCT05460767) and Phase 2 (NCT06081920) studies, IBI363 monotherapy showed significant and durable activity in a heavily pre-treated cohort of 91 patients with advanced acral or mucosal melanoma who had already progressed on prior immunotherapy. In this challenging setting, the overall ORR was 26.4% (95% CI, 17.6-37.0), and the DCR was 64.4% (95% CI, 53.4-74.4).[7]

Further analysis of the cohort treated at the 1 mg/kg Q2W dose (n=30) provided more detailed insights into the durability of response and survival benefit. In this group, the median PFS was 5.7 months (95% CI, 3.6-6.7), and the median OS was 14.8 months (95% CI, 9.9-NC).[7] For patients with the mucosal subtype, the median OS was even longer at

19.3 months.[24] The 12-month OS rate for the overall group was

61.5%. The median duration of response (DoR) was a notable 14.0 months.[7] These survival outcomes are particularly meaningful, as the historical median PFS in this post-immunotherapy setting is typically less than three months, highlighting the substantial clinical benefit offered by IBI363.[24]

Efficacy in IO-Naïve Patients and Strategic Implications

While demonstrating efficacy in the refractory setting is crucial, the performance of IBI363 in immunotherapy-naïve patients has been even more striking and has informed a bold late-stage development strategy. In an analysis of 31 evaluable IO-naïve patients with advanced melanoma (including mucosal, acral, and cutaneous subtypes), IBI363 monotherapy achieved an overall ORR of 67.7% (95% CI, 50.1-81.4) and a DCR of 87.1% (95% CI, 71.1-94.9).[6] In the specific subgroup of 20 patients with mucosal melanoma, the ORR was

60.0% (95% CI, 38.7-78.1) and the DCR was 85.0%.[6]

These exceptionally high response rates in a first-line setting prompted Innovent to pursue a high-risk, high-reward strategy. The company has initiated a pivotal, randomized, open-label Phase 2 study designed to directly challenge the global standard of care. This trial will compare IBI363 monotherapy head-to-head against pembrolizumab (Keytruda) in approximately 180 IO-naïve patients with unresectable mucosal or acral melanoma.[2] The primary endpoint is PFS, and the trial is powered to demonstrate the superiority of IBI363 over pembrolizumab.[23]

This strategic decision signals immense confidence from the developer in the mechanistic superiority of IBI363. Instead of taking a safer path of demonstrating non-inferiority, Innovent is aiming to prove that IBI363 can deliver better outcomes than the world's leading checkpoint inhibitor in these specific "cold" melanoma subtypes. A successful outcome in this trial would not only lead to regulatory approval but could immediately redefine the standard of care for these patients, representing a major clinical and commercial victory. Furthermore, demonstrating superiority over pembrolizumab in these archetypal "cold" tumors would serve as the most powerful clinical proof-of-concept for IBI363's foundational scientific premise: its ability to transform non-inflamed tumor microenvironments. Such a result would have positive implications for its development across a wide range of other "cold" tumors.

The table below summarizes the efficacy of IBI363 in the key melanoma patient populations studied.

Table 2: Efficacy of IBI363 in Advanced Melanoma

Patient Population	N	ORR (%)	DCR (%)	Median PFS (months)	Median OS (months)
IO-Treated Acral/Mucosal	91	26.4	64.4	5.7*	14.8*
IO-Naïve Advanced	31	67.7	87.1	Not Mature	Not Mature

*PFS and OS data are from the n=30 cohort treated at 1 mg/kg Q2W.

Data compiled from sources 6, and.7

V. Therapeutic Potential in Colorectal Cancer and Other Malignancies

Beyond its lead indications in NSCLC and melanoma, IBI363 has demonstrated highly promising activity in colorectal cancer (CRC) and other solid tumors, suggesting a broad therapeutic potential that could establish it as a "pipeline in a product."

Breaking New Ground in Microsatellite Stable (MSS) CRC

The vast majority of metastatic colorectal cancer cases—approximately 85%—are classified as microsatellite stable (MSS) or proficient in mismatch repair (pMMR).[11] These tumors are notoriously immunologically "cold" and have proven almost completely unresponsive to standard anti-PD-1/L1 checkpoint inhibitors, representing one of the largest unmet needs in oncology.

IBI363 has produced unprecedented signals of efficacy in this difficult-to-treat population. In a Phase 1 study cohort of 68 heavily pre-treated patients with advanced CRC (the majority of whom were MSS/pMMR), IBI363 administered as a monotherapy achieved an ORR of 12.7% (95% CI, 5.6-23.5).[8] While this response rate is modest, the survival outcome was truly remarkable. With a median follow-up of 20.1 months, the median OS reached

16.1 months.[9] This represents a potential step-change improvement over the historical median OS of 6-9 months for standard-of-care therapies like regorafenib or trifluridine/tipiracil in this late-line setting.[9] This survival benefit was observed in patients both with and without liver metastases, which are typically associated with a poorer prognosis.[9]

The potential of IBI363 in CRC is further enhanced when used in combination therapy. A cohort of the Phase 1 trial evaluated IBI363 in combination with bevacizumab (Avastin), an anti-VEGF antibody known to have immunomodulatory effects. In 32 efficacy-evaluable patients, this combination achieved an ORR of 21.9% (with a cORR of 15.6%), a DCR of 65.6%, and a median PFS of 4.1 months.[16] The median DoR was 8.1 months.[25] Efficacy was observed across various subgroups, including patients with liver metastases, those with prior immunotherapy exposure, and those with RAS mutations.[16]

The data in MSS CRC may represent the most significant long-term value driver for IBI363. While the NSCLC and melanoma markets are large, they are already well-served by existing immunotherapies. The MSS CRC market, by contrast, is an enormous, untapped "blue ocean" for immuno-oncology. The ability of IBI363 to more than double the expected overall survival with monotherapy in a late-line setting is a potentially practice-changing finding. If these results can be replicated in larger, registrational trials, IBI363 could become the first broadly effective immunotherapy for the vast majority of patients with colorectal cancer, addressing a profound unmet need and capturing a multi-billion-dollar market with little to no IO competition.

Pan-Tumor Signals

Early data from the dose-escalation phase of the NCT05460767 study have indicated that the activity of IBI363 is not limited to its three lead indications. In a cohort of 24 patients with a variety of other solid tumors, promising signals of efficacy were observed.[18] Among 18 efficacy-evaluable patients, the overall ORR was

22.2% and the DCR was 77.8%.[18]

This cohort included patients with refractory tumors such as biliary tract cancer (BTC), where the DCR was 90.9%, as well as immunotherapy- or platinum-resistant tumors like cervical cancer (CC) and ovarian cancer (OC).[18] The observation of durable disease control and tumor regressions in such a diverse and heavily pre-treated group of patients suggests that the fundamental mechanism of IBI363—reinvigorating exhausted, tumor-specific T cells—is applicable across a wide range of histological contexts. This pan-tumor activity strongly supports the concept of IBI363 as a "pipeline in a product," with the potential for a long product lifecycle driven by label expansions into numerous other IO-resistant cancer settings.

VI. Comprehensive Safety and Tolerability Assessment

A critical component of the value proposition for any novel IL-2-based therapy is its safety profile. The primary goal of the sophisticated molecular engineering behind IBI363 was to uncouple the potent efficacy of IL-2 from its historical, often prohibitive, toxicity. The comprehensive safety data collected from hundreds of patients across multiple clinical trials indicate that this goal has been successfully achieved.

Characterization of the Adverse Event Profile

Across the entire clinical program, encompassing various tumor types and dose levels, IBI363 has demonstrated a manageable and predictable safety profile that is consistent with its dual mechanism of action.[1]

• Most Common Adverse Events: The most frequently reported Treatment-Emergent Adverse Events (TEAEs) are generally low-grade (Grade 1 or 2) and reflect the known effects of both PD-1 inhibition and cytokine stimulation. These consistently include arthralgia (joint pain), rash, hyperthyroidism, hypothyroidism, and anemia.[4]
• Incidence of Severe Events and Discontinuations: The rates of severe adverse events and treatment discontinuations have been clinically acceptable and relatively consistent across the different patient populations studied.
• In the overall NSCLC cohort (n=136), Grade ≥3 TEAEs occurred in 42.6% of patients. Importantly, TEAEs led to permanent discontinuation of IBI363 in only 6.6% of patients.[10]
• In the IO-treated advanced melanoma cohort (n=91), the rate of Grade ≥3 TEAEs was lower at 29.7%, with an even lower treatment discontinuation rate of 3.3%.[7]
• In the advanced CRC monotherapy cohort (n=68), Grade ≥3 Treatment-Related Adverse Events (TRAEs) were observed in 23.5% of patients, and only 2.9% of patients discontinued treatment due to a TRAE.[8]

Dose-Dependent Safety and Management

A crucial observation from the clinical program is that the enhanced efficacy seen at higher doses of IBI363 does not come at the cost of unmanageable toxicity. In the cohort of 57 NSCLC patients treated at the 3 mg/kg Q3W dose—the dose selected for the pivotal Phase 3 trial—the safety profile was particularly favorable. The rate of Grade ≥3 TRAEs in this group was 17.5%, and the discontinuation rate due to TRAEs was 5.3%.[4] The fact that the rate of severe events at this highly effective dose is manageable and not substantially higher than the rates seen in the overall population underscores the drug's favorable therapeutic index.

The overall safety profile of IBI363 stands as the ultimate clinical validation of its IL-2α-bias engineering. The notable absence of the severe, systemic toxicities like high-grade vascular leak syndrome or cytokine release syndrome that plagued first-generation IL-2 therapy is the most important safety finding. The low rates of treatment discontinuation across all major cohorts indicate that the observed adverse events, while common, are generally manageable with standard supportive care and do not require most patients to stop a potentially life-extending therapy. This favorable safety profile is what makes the potent dual-action mechanism of IBI363 clinically viable and provides it with a significant competitive advantage over less-targeted immunocytokines.

The table below summarizes the key safety findings across the three main indications.

Table 3: Summary of Key Treatment-Related Adverse Events (TRAEs)

Indication	N	Most Common TRAEs (All Grades, %)	Grade ≥3 TRAEs (%)	TRAEs Leading to Discontinuation (%)
NSCLC	136	Arthralgia (51.5), Anemia (43.4), Rash (38.2)	20.1*	6.0*
Melanoma (IO-Treated)	91	Arthralgia (59.3), Rash (42.9), Anemia (42.9)	29.7**	3.3**
CRC (Monotherapy)	68	Arthralgia (35.3), Anemia (32.4), Pyrexia (22.1)	23.5	2.9

*Data for NSCLC (n=134) from source.[4]

**Data for Melanoma represents TEAEs, not specifically TRAEs.

Data compiled from sources 4, and.7

VII. Strategic Analysis and Future Outlook

IBI363 is not only a scientifically innovative molecule but is also being advanced through a sophisticated and aggressive global development and regulatory strategy. This positions the drug to potentially address multiple areas of high unmet need and achieve significant commercial success.

Regulatory Trajectory and Milestones: A Global Expedited Path

The strength of the early clinical data for IBI363 has been recognized by the world's leading regulatory agencies, granting the program multiple designations that can accelerate its path to market.

• U.S. Food and Drug Administration (FDA): IBI363 has received two separate Fast Track Designations from the FDA. The first is for the treatment of patients with unresectable, locally advanced, or metastatic squamous NSCLC who have progressed on prior anti–PD-(L)1 therapy and platinum-based chemotherapy. The second is for the treatment of advanced melanoma that has progressed after one or more prior lines of systemic therapy.[1]
• China National Medical Products Administration (NMPA): Similarly, the Center for Drug Evaluation (CDE) of the NMPA has granted IBI363 two Breakthrough Therapy Designations for the same two indications: advanced melanoma and immunotherapy-resistant squamous NSCLC.[1]

Securing these four key expedited pathway designations from the world's two largest pharmaceutical markets is a powerful endorsement of the drug's transformative potential. These designations facilitate more frequent and collaborative interactions with regulators, provide guidance on efficient drug development, and open the possibility of priority review and accelerated approval, potentially shortening the time to market by years. This dual-track success enables Innovent to pursue a more harmonized and efficient global clinical development program, such as the MarsLight-11 trial, which is designed to generate data acceptable to multiple regulatory bodies simultaneously.

Competitive Landscape and Market Positioning

IBI363 is being strategically positioned not as a direct competitor to first-generation immunotherapies in all settings, but as a superior solution for specific, well-defined patient populations with high unmet needs.

• In NSCLC: The drug is being developed to become the new standard of care after the failure of current standards. The pivotal trial directly compares it to docetaxel, a weak incumbent, in the post-chemo, post-immunotherapy setting for squamous NSCLC. Success here would position IBI363 as the go-to second- or third-line agent for a large and growing patient population.
• In Melanoma: The strategy is twofold. In the IO-refractory setting, it offers a much-needed salvage therapy. In the IO-naïve setting for acral and mucosal subtypes, it is being positioned to displace the current standard of care, pembrolizumab, by demonstrating superiority in a head-to-head trial.
• In CRC: IBI363 is positioned to create an entirely new market for immunotherapy. By showing a significant survival benefit in the vast MSS population, it has the potential to become the first broadly effective immunotherapy in a disease where checkpoint inhibitors have thus far failed.

Compared to other investigational agents, IBI363's status as a first-in-class, clinically validated PD-1/IL-2α-bias bispecific gives it a substantial first-mover advantage. While other cytokine-based therapies and novel bispecific antibodies are in development, few have demonstrated such a compelling combination of efficacy and manageable safety across multiple tumor types in advanced-stage clinical trials.

Future Development and Commercial Potential

Innovent Biologics is pursuing a comprehensive and ambitious global development plan to maximize the value of IBI363, reflecting a high degree of confidence in the asset.

• Development Strategy: Beyond the ongoing pivotal trials in NSCLC and melanoma and a planned registration strategy in CRC, the company is actively exploring IBI363 in a multitude of other settings. These include combination therapies (e.g., with bevacizumab in CRC, with the TKI lenvatinib in other tumors), earlier lines of treatment (e.g., first-line NSCLC and CRC), and additional tumor types such as platinum-resistant ovarian cancer and in the neoadjuvant setting.[11] This broad "pipeline-in-a-product" approach is designed to secure multiple label expansions and a long product lifecycle.[11]
• Market Potential: The target markets for IBI363 are substantial. The global NSCLC therapeutics market is valued in the tens of billions of dollars annually, with various analyses projecting it to reach between $36.9 billion and $66.2 billion by the early 2030s.[29] The global melanoma therapeutics market is also a multi-billion-dollar opportunity, projected to exceed $10 billion to $17 billion by the same period.[33] The global cancer immunotherapy market for colorectal cancer was valued at nearly $9 billion in 2023 and is projected to grow significantly.[37] By successfully targeting the large, underserved immunotherapy-resistant segments of these major oncology markets, IBI363 has a clear path to becoming a multi-billion-dollar blockbuster therapy.

The scale of investment, the aggressive nature of the clinical trial designs, and the global scope of the development program all indicate that Innovent views IBI363 as its flagship asset. It is the cornerstone of the company's strategy to transition from a regional leader to a global biopharmaceutical innovator.[2] The clinical and regulatory success of IBI363 will likely be a defining factor in the company's trajectory on the world stage.

VIII. Conclusion

IBI363 has emerged as a highly promising, first-in-class immuno-oncology agent with the potential to address some of the most significant challenges in modern cancer therapy. Its innovative design as a PD-1/IL-2α-bias bispecific antibody fusion protein provides a novel, dual-action mechanism that has been validated through extensive clinical investigation. By simultaneously blocking the PD-1 checkpoint and delivering a targeted IL-2 stimulatory signal to tumor-specific T cells, IBI363 is uniquely equipped to overcome resistance to existing immunotherapies and activate immunologically "cold" tumors.

The clinical data generated to date are compelling. IBI363 has demonstrated robust and durable anti-tumor activity in heavily pre-treated patient populations across multiple major cancer types, including immunotherapy-resistant squamous NSCLC, "cold" acral and mucosal melanoma, and, most notably, microsatellite stable colorectal cancer. In each of these settings, the efficacy signals, particularly regarding objective response and overall survival, represent a potential step-change improvement over current standards of care.

Critically, this potent efficacy is paired with a manageable and predictable safety profile. The successful engineering of the IL-2α-bias has effectively mitigated the severe systemic toxicities that limited the utility of earlier IL-2-based therapies, resulting in a favorable therapeutic index that allows for effective dosing with acceptable tolerability.

Supported by multiple expedited regulatory designations from both the U.S. FDA and China's NMPA, IBI363 is now advancing rapidly through a well-defined and ambitious global pivotal trial program. With its unique mechanism, strong clinical data, and sophisticated development strategy, IBI363 is poised to become a transformative therapy for patients with difficult-to-treat cancers and a cornerstone of the next generation of immuno-oncology.

Works cited

1. Innovent's IBI363 (PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) Receives Second NMPA Breakthrough Therapy Designation for Immuno-resistant Squamous Non-Small Cell Lung Cancer - BioSpace, accessed September 12, 2025, https://www.biospace.com/press-releases/innovents-ibi363-pd-1-il-2%CE%B1-bias-bispecific-antibody-fusion-protein-receives-second-nmpa-breakthrough-therapy-designation-for-immuno-resistant-squamous-non-small-cell-lung-cancer
2. Innovent Receives NMPA Breakthrough Therapy Designation for IBI363 (PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) in Melanoma - PR Newswire, accessed September 12, 2025, https://www.prnewswire.com/news-releases/innovent-receives-nmpa-breakthrough-therapy-designation-for-ibi363-pd-1il-2-bias-bispecific-antibody-fusion-protein-in-melanoma-302415173.html
3. Innovent's IBI363 (PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) Receives Second NMPA Breakthrough Therapy Designation for Immuno-resistant Squamous Non-Small Cell Lung Cancer - PR Newswire, accessed September 12, 2025, https://www.prnewswire.com/news-releases/innovents-ibi363-pd-1il-2-bias-bispecific-antibody-fusion-protein-receives-second-nmpa-breakthrough-therapy-designation-for--immuno-resistant-squamous-non-small-cell-lung-cancer-302473851.html
4. FDA Grants Fast Track Designation to IBI363 in Pretreated ..., accessed September 12, 2025, https://www.cancernetwork.com/view/fda-grants-fast-track-designation-to-ibi363-in-pretreated-squamous-nsclc
5. FDA Clears IND for IBI363 in Squamous Non–Small Cell Lung Cancer - CancerNetwork, accessed September 12, 2025, https://www.cancernetwork.com/view/fda-clears-ind-for-ibi363-in-squamous-non-small-cell-lung-cancer
6. 1502 Efficacy and safety results of first-in-class PD-1/IL-2 α-bias bispecific antibody fusion protein IBI363 in patients with immunotherapy-naïve advanced melanoma, accessed September 12, 2025, https://jitc.bmj.com/content/12/Suppl_3/A1730
7. Efficacy and safety results of a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein IBI363 in patients (pts) with immunotherapy-treated, advanced acral and mucosal melanoma. | Journal of Clinical Oncology - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2502
8. First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with advanced colorectal cancer: Safety and efficacy results from a phase I study. - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3593
9. 2025 ASCO Oral Presentation: Innovent Biologics Announces Updated Date of IBI363 (First-in-class PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) from Phase 1 Clinical Studies in Advanced Colorectal Cancer - PR Newswire, accessed September 12, 2025, https://www.prnewswire.com/news-releases/2025-asco-oral-presentation-innovent-biologics-announces-updated-date-of-ibi363-first-in-class-pd-1il-2-bias-bispecific-antibody-fusion-protein-from-phase-1-clinical-studies-in-advanced-colorectal-cancer-302470217.html
10. First-in-class PD-1/IL-2 bispecific antibody IBI363 in patients (Pts) with advanced immunotherapy-treated non-small cell lung cancer (NSCLC). - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8509
11. Innovent Biologics Announces U.S. FDA IND Approval for the First ..., accessed September 12, 2025, https://www.prnewswire.com/news-releases/innovent-biologics-announces-us-fda-ind-approval-for-the-first-global-mrct-phase-3-study-marslight-11-of-ibi363-pd-1il-2-bias-in-squamous-non-small-cell-lung-cancer-302537159.html
12. IBI-363 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 12, 2025, https://synapse.patsnap.com/drug/f581eae8e33c446e9c4d2213385b6b24
13. Definition of anti-PD-1/IL-2 bispecific antibody fusion protein IBI363 - NCI, accessed September 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-pd-1-il-2-bispecific-antibody-fusion-protein-ibi363
14. Innovent Receives NMPA Breakthrough Therapy Designation for IBI363 (PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) in Melanoma - FirstWord Pharma, accessed September 12, 2025, https://firstwordpharma.com/story/5945993
15. www.cancer.gov, accessed September 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-pd-1-il-2-bispecific-antibody-fusion-protein-ibi363#:~:text=Upon%20administration%2C%20anti%2DPD%2D,immune%20responses%20against%20tumor%20cells.
16. Innovent Announces Clinical Data of IBI363 (First-in-class PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) Combined with Bevacizumab in Advanced Colorectal Cancer at the 2024 ESMO Congress - PR Newswire, accessed September 12, 2025, https://www.prnewswire.com/news-releases/innovent-announces-clinical-data-of-ibi363-first-in-class-pd-1il-2-bias-bispecific-antibody-fusion-protein-combined-with-bevacizumab-in-advanced-colorectal-cancer-at-the-2024-esmo-congress-302250106.html
17. IL-2Rα-biased agonist enhances antitumor immunity by invigorating ..., accessed September 12, 2025, https://pubmed.ncbi.nlm.nih.gov/37550516/
18. First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with other solid tumors: Safety and efficacy results from a phase I study. - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e14593
19. First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with other solid tumors: Safety and efficacy results from a phase I study. - ASCO, accessed September 12, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT463030
20. FDA Grants Fast Track Designation to IBI363 for Squamous NSCLC, accessed September 12, 2025, https://www.onclive.com/view/fda-grants-fast-track-designation-to-ibi363-for-squamous-nsclc
21. Study Details | NCT05460767 | Safety, Tolerability and Preliminary ..., accessed September 12, 2025, https://clinicaltrials.gov/study/NCT05460767
22. Safety, Tolerability and Preliminary Efficacy of IBI363 in Subjects With Advanced Solid Tumors or Lymphoma - larvol clin, accessed September 12, 2025, https://clin.larvol.com/trial-detail/NCT05460767
23. A multicenter, randomized, controlled, open-label, phase 2 study of the PD-1/IL-2α-bias bispecific antibody fusion protein IBI363 in mucosal and acral melanoma. - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS9594
24. ASCO 2025 Oral Presentation: Innovent Biologics Announces ..., accessed September 12, 2025, https://www.prnewswire.com/news-releases/asco-2025-oral-presentation-innovent-biologics-announces-updated-data-of-ibi363-first-in-class-pd-1il-2--bias-bispecific-antibody-fusion-protein-from-phase-1-and-2-clinical-studies-on-immunotherapy-treated-advanced-malignant--302470081.html
25. Innovent Announces Clinical Data of IBI363 (First-in-class PD-1/IL-2α-bias Bispecific Antibody Fusion Protein) Combined with Bevacizumab in Advanced Colorectal Cancer at the 2024 ESMO Congress - PR Newswire, accessed September 12, 2025, https://www.prnewswire.com/apac/news-releases/innovent-announces-clinical-data-of-ibi363-first-in-class-pd-1il-2-bias-bispecific-antibody-fusion-protein-combined-with-bevacizumab-in-advanced-colorectal-cancer-at-the-2024-esmo-congress-302250527.html
26. ESMO: Innovent ties cytokine fusion protein to colorectal cancer responses, accessed September 12, 2025, https://synapse.patsnap.com/article/esmo-innovent-ties-cytokine-fusion-protein-to-colorectal-cancer-responses
27. ESMO: Innovent links cytokine to colorectal cancer responses - Fierce Biotech, accessed September 12, 2025, https://www.fiercebiotech.com/biotech/esmo-innovent-links-cytokine-fusion-protein-responses-colorectal-cancer
28. Study Details | NCT06081907 | The Efficacy and Safety of IBI363 in Solid Tumors | ClinicalTrials.gov, accessed September 12, 2025, https://clinicaltrials.gov/study/NCT06081907
29. Non Small Cell Lung Cancer Therapeutics Market Size, 2032 - Fortune Business Insights, accessed September 12, 2025, https://www.fortunebusinessinsights.com/industry-reports/non-small-cell-lung-cancer-therapeutics-market-100484
30. Non-small Cell Lung Cancer Therapeutics Market Report 2030 - Grand View Research, accessed September 12, 2025, https://www.grandviewresearch.com/industry-analysis/non-small-cell-lung-cancer-nsclc-therapeutics-market
31. Non-small Cell Lung Cancer Therapeutics Market Size to Hit USD 66.20 Billion by 2033, accessed September 12, 2025, https://www.biospace.com/press-releases/non-small-cell-lung-cancer-therapeutics-market-size-to-hit-usd-66-20-billion-by-2033
32. Non Small Cell Lung Cancer Market Size & Research By 2031, accessed September 12, 2025, https://www.alliedmarketresearch.com/non-small-cell-lung-cancer-market
33. Global Malignant Melanoma Treatment Market $9.3 Billion by 2033, accessed September 12, 2025, https://www.ihealthcareanalyst.com/global-malignant-melanoma-treatment-market/
34. Melanoma - Cancer immunotherapy market outlook - Grand View Research, accessed September 12, 2025, https://www.grandviewresearch.com/horizon/statistics/cancer-immunotherapy-market/application/melanoma/global
35. Melanoma Therapeutics Market Size & Share Report, 2030 - Grand View Research, accessed September 12, 2025, https://www.grandviewresearch.com/industry-analysis/melanoma-therapeutics-market
36. Melanoma Therapeutics Market Size To Hit USD 17.93 Bn By 2034 - Precedence Research, accessed September 12, 2025, https://www.precedenceresearch.com/melanoma-therapeutics-market
37. Colorectal Cancer immunotherapy market outlook, accessed September 12, 2025, https://www.grandviewresearch.com/horizon/statistics/cancer-immunotherapy-market/application/colorectal-cancer/global