Pucotenlimab (HX008): A Comprehensive Clinical and Scientific Monograph

Executive Summary

Pucotenlimab is a next-generation, recombinant humanized anti-programmed cell death protein 1 (PD-1) monoclonal antibody representing a significant advancement in the field of immuno-oncology. Developed with a "best-in-class" strategic approach, its primary molecular innovation is an engineered Fragment crystallizable (Fc) domain that confers a uniquely prolonged pharmacokinetic half-life, a key differentiator in the competitive landscape of immune checkpoint inhibitors. This report provides a comprehensive analysis of Pucotenlimab's molecular profile, mechanism of action, clinical development program, and regulatory standing, synthesizing data from preclinical studies to late-stage clinical trials.

The drug has secured conditional marketing approvals from China's National Medical Products Administration (NMPA) for two key indications: the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, and for unresectable or metastatic melanoma in patients who have failed prior systemic therapy. These approvals are underpinned by robust clinical evidence, most notably from the pivotal Phase 2 study (NCT03704246) in MSI-H/dMMR tumors. Long-term follow-up from this trial demonstrated not only a high objective response rate of 50.0% but also exceptional durability, with a median progression-free survival of 33.8 months and a median overall survival of 55.9 months in a heavily pre-treated patient population.

Pucotenlimab has consistently demonstrated a manageable and predictable safety profile, characterized by adverse events typical of the anti-PD-1 class, with no new or unexpected safety signals identified during long-term treatment. Its extended half-life, which allows for a convenient every-three-week dosing schedule, combined with strong efficacy and a favorable safety profile, positions it as a formidable therapeutic option. Furthermore, promising data from ongoing trials exploring combination strategies, particularly with antibody-drug conjugates in PD-1 refractory settings, highlight a sophisticated development plan aimed at addressing critical unmet needs in oncology. While currently focused on the Chinese market, where it holds a distinct advantage in Asian-prevalent melanoma subtypes, Pucotenlimab possesses the clinical and pharmacological attributes necessary for potential global expansion.

Molecular Profile and Mechanism of Action

Identification and Nomenclature

Pucotenlimab is a biologic therapeutic agent with a well-defined set of identifiers used across regulatory, clinical, and research domains.

• Generic Name: Pucotenlimab.[1]
• DrugBank ID: DB17552.[1]
• CAS Number: 2403647-03-8.[1]
• Synonyms and Code Names: The drug is widely known by its development code, HX008 or HX-008.[1] In the commercial setting in China, it is marketed under the brand names Puyouheng™ and AiRuiKa.[4] Its detailed chemical synonym is Immunoglobulin G4 (252-theronine,306-proline,432-alanine), anti-(human programmed cell death 1) (human-mus musculus monoclonal hx008.gamma.4-chain), disulfide with human-mus musculus monoclonal hx008.kappa.-chain, dimer.[1]

Structural Characteristics and Engineering

Pucotenlimab is a recombinant, humanized immunoglobulin G4 (IgG4) monoclonal antibody with a kappa light chain, produced in Chinese Hamster Ovary (CHO) cells.[4] Its molecular weight is approximately 144.8 kDa.[8] The design of Pucotenlimab reflects a deliberate strategy to optimize its pharmacological properties and safety profile rather than targeting a novel biological pathway. This is achieved through several key molecular engineering features.

First, the selection of the IgG4 isotype is intentional. IgG4 antibodies exhibit minimal effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).[9] This is a critical safety feature for an antibody targeting an immune cell receptor like PD-1, as it avoids the unintended killing of the very T cells the therapy is designed to activate.[9] To further enhance stability, the antibody incorporates a serine-to-proline substitution at position 228 (S228P) in the hinge region, a standard modification for IgG4 therapeutics that prevents Fab-arm exchange and maintains the integrity and bivalent binding capacity of the antibody.[9]

The most significant innovation in Pucotenlimab's structure is its engineered Fc domain. It contains three specific amino acid substitutions—S254T, V308P, and N434A—designed to enhance its binding affinity to the neonatal Fc receptor (FcRn).[9] The FcRn plays a crucial role in salvaging IgG antibodies from lysosomal degradation, thereby extending their circulating half-life. By increasing this binding affinity, these mutations significantly prolong the persistence of Pucotenlimab in the bloodstream, a feature that distinguishes it from first-generation anti-PD-1 agents.[12] This combination of a silenced effector function with a stabilized and pharmacokinetically enhanced Fc region exemplifies a sophisticated bioengineering approach aimed at creating a "best-in-class" molecule with superior dosing convenience and a favorable safety profile. The full amino acid sequences for the heavy and light chains of Pucotenlimab have been elucidated.[14]

Pharmacodynamics: Mechanism of Action

Pucotenlimab is an immune checkpoint inhibitor that functions as a potent and specific antagonist of the PD-1 receptor (also known as PDCD1 or CD279).[3] The PD-1 pathway is a critical negative regulatory axis in the immune system. PD-1 is expressed on the surface of activated T cells, and its engagement by its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), delivers an inhibitory signal that dampens T-cell activation and effector functions.[3]

Many tumor cells exploit this natural checkpoint mechanism to evade immune surveillance. They achieve this by upregulating the expression of PD-L1 on their cell surface, which then engages PD-1 on tumor-infiltrating T cells, effectively "switching them off" and creating an immunosuppressive tumor microenvironment that permits unchecked tumor growth.[5]

Upon intravenous administration, Pucotenlimab binds with high affinity to the PD-1 receptor on T cells.[8] This binding physically obstructs the interaction between PD-1 and its ligands, PD-L1 and PD-L2.[4] By blocking this inhibitory signal, Pucotenlimab effectively "releases the brakes" on the T cells. This restores their activation, proliferation, and cytotoxic functions, leading to the reinvigoration of T-cell-mediated antitumor immune responses.[3] The reactivated T cells can then recognize and eliminate cancer cells, resulting in potent and often durable antineoplastic activity.[5]

Pharmacokinetics

The pharmacokinetic (PK) profile of Pucotenlimab is a cornerstone of its clinical value proposition, largely defined by its engineered extended half-life.

• Absorption and Distribution: As an intravenously administered monoclonal antibody, Pucotenlimab achieves immediate and complete bioavailability in the systemic circulation. Pharmacokinetic modeling from its Phase I study demonstrated rapid distribution followed by a slow terminal elimination phase.[5]
• Metabolism and Excretion: Consistent with other protein-based therapeutics, Pucotenlimab is not metabolized by hepatic cytochrome P450 enzymes. Instead, it is expected to be catabolized into smaller peptides and amino acids through general protein degradation pathways, a process typical for biologics.[18]
• Half-Life and Dosing: The engineered Fc domain is highly effective, resulting in a mean terminal half-life of approximately 17.1 to 23.5 days after a single dose [9], and a mean half-life of 21.8 days (single dose) to 38.2 days at steady-state.[12] This extended half-life is a primary pharmacological differentiator from earlier anti-PD-1 antibodies and provides strong support for the approved dosing regimen of 200 mg administered every 3 weeks (Q3W).[12] This prolonged persistence ensures sustained target engagement and offers a significant convenience advantage for patients by reducing the frequency of clinic visits.
• Dose Proportionality and Immunogenicity: The Phase I study established that Pucotenlimab exhibits dose-proportional pharmacokinetics, with both maximum serum concentration (Cmax​) and area under the curve (AUC) increasing proportionally with dose escalations from 1 mg/kg to 10 mg/kg. Steady state was achieved by the sixth treatment cycle. The risk of immunogenicity appears low; in the initial study, only one patient developed anti-drug antibodies, and these did not have a discernible impact on the drug's PK profile, safety, or efficacy.[9]

Table 1: Pucotenlimab Key Identifiers and Properties

Property	Detail
Generic Name	Pucotenlimab
Brand Names (China)	Puyouheng™, AiRuiKa
Development Code	HX008, HX-008
DrugBank ID	DB17552
CAS Number	2403647-03-8
UNII	CGA81G3KR5
Type	Biotech / Protein-Based Therapy
Class	Humanized IgG4, kappa Monoclonal Antibody; Immune Checkpoint Inhibitor
Target	Programmed cell death protein 1 (PD-1/PDCD1/CD279)
Molecular Weight	~144.8 kDa
Key Structural Features	Engineered Fc domain (S254T/V308P/N434A mutations) for extended half-life; S228P hinge stabilization.

Clinical Efficacy in Approved and Investigational Indications

The clinical development program for Pucotenlimab is extensive, spanning multiple solid tumor types and lines of therapy. Its efficacy has been most robustly demonstrated in MSI-H/dMMR solid tumors and advanced melanoma, leading to its first regulatory approvals.

Pivotal Trial in MSI-H/dMMR Solid Tumors (NCT03704246)

The cornerstone of Pucotenlimab's clinical validation comes from a single-arm, multicenter, open-label, Phase 2 study (NCT03704246). This trial was designed to evaluate the efficacy and safety of Pucotenlimab monotherapy (200 mg Q3W) in patients with previously treated, unresectable or metastatic solid tumors confirmed to be MSI-H or dMMR.[19] The study enrolled 100 patients, with colorectal cancer (CRC, n=71) and gastric cancer (n=10) being the most prevalent tumor types.[19]

The long-term results from this study, with a median follow-up of 43.8 months, are particularly compelling and underscore the drug's capacity for inducing durable responses.[21] The primary goal of immunotherapy in this advanced, refractory setting is not merely to shrink tumors, but to achieve long-term disease control and extend survival. The data from this trial indicate that Pucotenlimab successfully achieves this objective for a substantial portion of patients.

• Objective Response Rate (ORR): The Independent Review Committee (IRC)-assessed ORR for the total population was 50.0% (95% CI: 39.8-60.2), which included an impressive 12% rate of complete responses (CR).[21] The response was even more pronounced in the large CRC cohort, where the ORR reached 57.7%.[21]
• Progression-Free Survival (PFS): The median PFS was 33.8 months (95% CI: 7.1-Not Reached), a remarkably long duration for a second-line or later therapy. The 36-month (3-year) PFS rate was 49.7%, suggesting that nearly half of the patients remained free of disease progression at three years.[21]
• Overall Survival (OS): The median OS was 55.9 months (95% CI: 55.9-Not Reached). The estimated 60-month (5-year) OS rate was 46.3%, indicating a significant potential for long-term survival benefit.[21]
• Duration of Response (DoR): The median DoR was not reached, highlighting the profound durability of the responses. The 36-month DoR rate was 81.1%, meaning that over 80% of patients who responded were still in response three years later.[21]

These results demonstrate that when a response to Pucotenlimab occurs in this patient population, it is highly likely to be deep and sustained, transforming the clinical outlook from a terminal prognosis to one of potential long-term, chronic disease management.

Advanced Melanoma (NCT04749485)

Pucotenlimab was also evaluated in a Phase 2 study (NCT04749485) involving 119 Chinese patients with locally advanced or metastatic melanoma who had progressed on prior standard therapy.[22] This trial is notable because its population was enriched for melanoma subtypes—acral (52.1%) and mucosal (19.3%)—that are more common in Asian populations and are historically considered less responsive to immunotherapy compared to the cutaneous melanoma prevalent in Western populations.[22]

• Efficacy Results: The study met its primary endpoint, showing an IRC-assessed ORR of 20.17% (95% CI: 13.37-28.51).[22] The median OS was 16.59 months, and the median PFS was 2.89 months.[22]

This performance is clinically significant. The observed ORR of over 20% is numerically superior to the historical response rates of 12-13% typically seen with immune monotherapy in these challenging subtypes.[24] This provides strong, evidence-based support for Pucotenlimab's use in the Chinese and broader Asian melanoma patient population, addressing a specific demographic and clinical need that may be underrepresented in pivotal trials conducted primarily in the West.

Emerging Indications and Combination Therapies

Lepu Biopharma is pursuing a broad and sophisticated development strategy for Pucotenlimab, moving beyond monotherapy to explore its potential in combination regimens and new indications.

• Metastatic Triple-Negative Breast Cancer (mTNBC): A Phase 1b study combined Pucotenlimab with standard chemotherapy (gemcitabine and cisplatin) for the first-line treatment of mTNBC. The results were highly promising, with an ORR of 80.6% and a median PFS of 9.0 months, suggesting strong synergistic activity.[10]
• Overcoming Immunotherapy Resistance: A Phase I/II study is evaluating Pucotenlimab in combination with MRG003, an antibody-drug conjugate (ADC) targeting the epidermal growth factor receptor (EGFR).[27] This trial focuses on patients with EGFR-positive solid tumors, such as nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (SCCHN). The preliminary data are striking: in the Phase II cohort of NPC patients who had already progressed on a prior PD-1 inhibitor-containing regimen, the combination of Pucotenlimab and MRG003 achieved an ORR of 77.8%, including two complete responses.[27] This result points toward a forward-thinking strategy to tackle the major clinical challenge of acquired resistance to immunotherapy, potentially by using the ADC to induce immunogenic cell death and re-sensitize the tumor microenvironment to PD-1 blockade.
• Broad Development Pipeline: Pucotenlimab is in late-stage development for gastrointestinal cancer (Phase III) and non-small cell lung cancer (Phase II/III). It is also being investigated in Phase II trials for bladder cancer, breast cancer, and liver cancer, demonstrating a significant investment in expanding its clinical utility.[4]

Biomarker Analysis

Exploratory analyses from the clinical trials have begun to identify potential predictive biomarkers for response to Pucotenlimab. In the MSI-H/dMMR study, a higher likelihood of response was correlated with a baseline neutrophil-to-lymphocyte ratio (NLR) below 4, a high tumor mutational burden (TMB) of at least 32.5 mutations per megabase, and the presence of mutations in the KMT2D gene.[19] In the melanoma trial, specific cytokine levels, such as Eotaxin (CCL11) and MCP-1 (CCL2), were associated with response, while elevated TNF-α and VEGF were linked to treatment failure, suggesting a complex interplay within the tumor microenvironment.[22]

Table 2: Overview of Pucotenlimab Clinical Development Program

Indication	Highest Development Phase	Key Trial(s) / Status
MSI-H/dMMR Solid Tumors	Approved (China)	NCT03704246 (Pivotal Phase 2)
Malignant Melanoma	Approved (China)	NCT04749485 (Pivotal Phase 2)
Gastrointestinal Cancer	Phase III	Ongoing
Non-Small Cell Lung Cancer (NSCLC)	Phase II/III	Ongoing
Triple-Negative Breast Cancer (mTNBC)	Phase Ib/II (Combination)	CTR20191353 (Combination with Chemotherapy)
Nasopharyngeal Cancer (NPC)	Phase II (Combination)	NCT05688605 (Combination with EGFR-ADC)
Bladder Cancer	Phase II	NCT04738630
Liver Cancer	Phase II	Ongoing
Head & Neck Squamous Cell Carcinoma (HNSC)	Phase II	Ongoing
Endometrial Cancer	Phase II (Neoadjuvant)	NCT06561308

Safety and Tolerability Profile

Across its extensive clinical program, Pucotenlimab has demonstrated a safety profile that is both manageable and consistent with the known toxicities of the anti-PD-1 drug class. No new or unexpected safety signals have emerged, even with long-term follow-up.

Overview of Treatment-Related Adverse Events (TRAEs)

The overall safety profile of Pucotenlimab monotherapy is favorable.

• In the pivotal MSI-H/dMMR study (NCT03704246), long-term follow-up showed that Grade 3 or higher TRAEs occurred in 24.0% of patients.[21] The most common TRAEs of any grade were laboratory abnormalities, including increased aspartate aminotransferase (AST, 28%), increased alanine aminotransferase (ALT, 26%), and anemia (24%).[21]
• In the melanoma study, TRAEs of any grade were reported in 77.3% of patients, with the incidence of Grade 3 or higher TRAEs being lower, at 15.1%. Importantly, no treatment-related deaths were reported in this study.[22]
• When used in combination with chemotherapy for mTNBC, the incidence of severe adverse events was higher, as expected. Grade 3 or higher TRAEs were reported in 74.2% of patients, driven primarily by the known hematological toxicities of the gemcitabine and cisplatin backbone, such as neutropenia (74.1%), anemia (35.5%), and thrombocytopenia (32.3%).[25]

Immune-Related Adverse Events (irAEs)

As a therapy designed to augment the immune response, Pucotenlimab can lead to a range of inflammatory side effects known as immune-related adverse events (irAEs), which can affect any organ system.[5]

• Commonly reported irAEs are generally mild to moderate and include fatigue, rash, pruritus (itching), and diarrhea.[5]
• Less frequent but more severe irAEs that require clinical vigilance include pneumonitis (inflammation of the lungs), colitis (inflammation of the colon), hepatitis (inflammation of the liver), and various endocrinopathies, such as hypothyroidism and hyperthyroidism.[5]
• Data from the mTNBC study showed that irAEs were mostly low-grade; reported events included hypothyroidism (32.3%), skin reactions (25.8%), and hyperthyroidism (16.1%), nearly all of which were Grade 1 or 2 in severity.[28]

Management, Contraindications, and Drug Interactions

The management of irAEs is a critical component of administering immune checkpoint inhibitors safely.

• Management: Prompt recognition of irAEs is essential. Mild events can often be managed symptomatically. However, moderate to severe (Grade 2 or higher) irAEs typically necessitate withholding the drug and initiating systemic corticosteroid therapy (e.g., prednisone 1-2 mg/kg/day or equivalent) to suppress the inflammatory response. In corticosteroid-refractory cases, other immunosuppressive agents may be required.[5]
• Contraindications: Pucotenlimab should be used with caution in patients with pre-existing autoimmune diseases. Patients with active, serious infections, such as tuberculosis or hepatitis, should have these conditions addressed before starting treatment.[5]
• Drug Interactions: The most significant potential drug interaction is with other immunosuppressive medications. Concurrent use of systemic corticosteroids (at doses higher than physiological replacement) can dampen the T-cell activation induced by Pucotenlimab, potentially counteracting its therapeutic efficacy. Therefore, their use should be avoided unless medically necessary to manage irAEs.[5]

Regulatory and Commercial Landscape

Global Regulatory Status

Pucotenlimab's regulatory journey has been centered in China, where it has achieved key approvals, while its development continues for potential entry into Western markets.

• China (NMPA): Pucotenlimab has received two conditional marketing approvals from the National Medical Products Administration.

1. July 2022: First approval for the treatment of patients with unresectable or metastatic MSI-H/dMMR advanced solid tumors who have progressed on prior therapy.[4]
2. September 2022: Second approval for the treatment of unresectable or metastatic melanoma after the failure of previous systemic therapy.[4]

• United States (FDA): Pucotenlimab is not currently approved for marketing in the United States.[30] It remains an investigational agent. Lepu Biopharma received Investigational New Drug (IND) clearance from the FDA in January 2022, allowing for the initiation of clinical trials in the US to evaluate the drug in advanced solid tumors.[12]
• Europe (EMA): Pucotenlimab does not currently hold a marketing authorisation from the European Medicines Agency and is not approved for use in the European Union.[32]

Corporate Development and Manufacturing

The development of Pucotenlimab is a case study in strategic collaboration within the modern biopharmaceutical ecosystem, leveraging the distinct strengths of multiple organizations.

• Originator/Discoverer: The antibody was initially discovered and developed through a collaboration between HanX Biopharmaceuticals, Inc. and Akeso Biopharma.[15] HanX Biopharmaceuticals is credited with the innovative molecular design, including the engineering for a prolonged half-life.[13]
• Developer/License Holder: Lepu Biopharma Co., Ltd. acquired the rights and has spearheaded the late-stage clinical development and commercialization of Pucotenlimab.[4] Lepu Biopharma's focus on oncology therapeutics and its capabilities in conducting large-scale clinical trials were instrumental in bringing the drug to market in China.[35] This partnership model allows an R&D-focused entity like Akeso to monetize its discovery through milestones and royalties while a development-focused company like Lepu Biopharma builds its commercial portfolio.[34]
• Manufacturing: To ensure a robust and scalable supply chain for commercial launch, Lepu Biopharma partnered with Chime Biologics, a leading global contract development and manufacturing organization (CDMO). Chime Biologics successfully executed the technology transfer, process validation, and scaled-up cGMP production, culminating in the successful manufacture of 12 commercial batches and passing the NMPA's pre-approval inspection. This partnership de-risks the manufacturing process, a critical step for any biologic's commercial success.[37]

Strategic Analysis and Future Outlook

Comparative Clinical Assessment vs. Standard of Care

Pucotenlimab enters a market with well-established standards of care. Its clinical value and potential for uptake must be assessed relative to these incumbents, primarily other PD-1 inhibitors.

• MSI-H/dMMR Solid Tumors: The current standard of care for previously treated MSI-H/dMMR solid tumors includes Pembrolizumab (Keytruda) and Dostarlimab (Jemperli).[38] A cross-trial comparison, while subject to inherent limitations, provides valuable context. The long-term data from Pucotenlimab's NCT03704246 trial (ORR 50.0%, mPFS 33.8 months, mOS 55.9 months) [21] appear highly competitive and numerically favorable to the pivotal pooled data for Pembrolizumab in a similar second-line setting (ORR 33.3%, median DoR 63.2 months).[38] The rate of severe (Grade ≥3) TRAEs for Pucotenlimab (24.0%) [21] is also in line with that of its competitors. This suggests that Pucotenlimab is, at a minimum, a non-inferior option with potentially superior efficacy metrics in this indication.
• Advanced Melanoma: In advanced melanoma, the treatment landscape includes PD-1 monotherapy (Nivolumab, Pembrolizumab) and more potent dual immunotherapy combinations (Nivolumab/Ipilimumab, Nivolumab/Relatlimab).[40] As a second-line monotherapy, Pucotenlimab's ORR of 20.17% [22] is clinically meaningful and compares favorably to the historical 16-17% ORRs cited for other PD-1 inhibitors in Chinese patients with acral and mucosal subtypes.[24] While its efficacy is not expected to match that of first-line dual checkpoint blockade combinations (e.g., Nivolumab/Ipilimumab ORR ~58%) [42], it establishes Pucotenlimab as a strong and validated option for patients who have progressed on prior therapy, particularly within the Asian demographic.

Market Positioning and Unmet Needs

Pucotenlimab is strategically positioned for significant impact, initially within the Chinese market.

• Primary Market Focus: With two NMPA approvals and strong data in Asian-prevalent melanoma subtypes, its immediate commercial focus is China. Its performance provides a compelling reason for adoption by clinicians in the region.
• Key Differentiator: The primary competitive advantage is its extended pharmacokinetic half-life. The convenience of a Q3W dosing schedule, with the potential for even less frequent administration, reduces the treatment burden on both patients and healthcare systems. This practical advantage, coupled with a favorable safety profile, could be a powerful driver of market penetration against competitors requiring more frequent infusions.
• Global Prospects: Entering the saturated US and EU markets will be a significant challenge, given the entrenched market leadership of Pembrolizumab and Nivolumab. A viable path to global expansion will likely require either demonstrating superiority in a head-to-head trial or, more strategically, succeeding in areas of high unmet need, such as in patients who have become refractory to first-line PD-1 inhibitors.

Future Research Directions

The future development of Pucotenlimab will likely focus on expanding its use into new settings and patient populations.

• Combination Therapies: The highly encouraging preliminary results from combination studies with chemotherapy (in mTNBC) and ADCs (in NPC) represent the most promising avenue for growth. Pursuing these strategies in larger, randomized Phase 3 trials is essential to establish new standards of care and move Pucotenlimab into earlier lines of therapy.
• Neoadjuvant and Adjuvant Settings: A major trend in immuno-oncology is the move into early-stage disease to prevent recurrence. Initiating trials in the neoadjuvant (pre-surgical) and adjuvant (post-surgical) settings, such as the ongoing NCT06561308 trial in endometrial cancer [43], is a critical long-term strategy to maximize the drug's clinical impact and market potential.
• Biomarker-Driven Development: Further validation of potential predictive biomarkers like KMT2D mutations, TMB, and NLR could enable a more personalized approach to treatment. Identifying which patients are most likely to achieve the exceptional, durable responses seen in clinical trials would optimize its use and solidify its value proposition.

Table 3: Summary of Efficacy and Safety from the NCT03704246 Trial (MSI-H/dMMR Solid Tumors)

Endpoint	All Patients (N=100)	Colorectal Cancer Subgroup (N=71)
Median Follow-up	43.8 months	43.8 months
ORR (IRC)	50.0% (95% CI: 39.8-60.2)	57.7% (95% CI: 46.8-70.7)
Complete Response (CR)	12.0%	Not Reported
Median PFS (IRC)	33.8 months (95% CI: 7.1-NR)	Not Reached
36-month PFS Rate	49.7% (95% CI: 39.2-59.3)	52.5% (95% CI: 39.9-63.7)
Median OS	55.9 months (95% CI: 55.9-NR)	55.9 months (95% CI: 55.9-NR)
60-month OS Rate	46.3% (95% CI: 19.1-69.9)	44.3% (95% CI: 10.7-74.3)
Median DoR (IRC)	Not Reached	Not Reached
36-month DoR Rate	81.1% (95% CI: 66.7-89.7)	Not Reported
Safety Summary	All Patients (N=100)
Common TRAEs (Any Grade)	AST increased (28%), ALT increased (26%), Anemia (24%)
Grade ≥3 TRAEs	24.0%
Source: 21

Table 4: Cross-Trial Comparison of PD-1 Inhibitors in Second-Line MSI-H/dMMR Solid Tumors

Metric	Pucotenlimab (NCT03704246)	Pembrolizumab (KEYNOTE-164/158 Pooled)
Patient Population	N=100 (71 CRC)	N=504 (124 CRC)
Line of Therapy	≥2nd Line	≥2nd Line
ORR (Overall)	50.0%	33.3%
ORR (CRC only)	57.7%	34%
Median PFS	33.8 months	Not Reported in Pooled Analysis
Median OS	55.9 months	Not Reported in Pooled Analysis
Median DoR	Not Reached	63.2 months
Grade ≥3 TRAEs	24.0%	Not explicitly stated for pooled data
Sources: Pucotenlimab 21; Pembrolizumab 38
Disclaimer: Data are from separate, non-randomized trials and cannot be directly compared due to potential differences in patient populations and study conduct. This table is for informational purposes only.

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