In-Depth Analysis of Hengrui Pharmaceuticals' PD-L1/TGF-β Bispecific Antibody SHR-1701: Approval and Clinical Controversies

Based on the collected information, I will prepare a detailed analysis report for you.

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Hengrui Pharmaceuticals’ independently developed

is a bifunctional fusion protein targeting PD-L1/TGF-βRII, belonging to the category of bispecific antibody innovative drugs [0]. This drug aims to overcome the immunosuppressive state in the tumor microenvironment by simultaneously blocking the PD-L1 immune checkpoint pathway and the TGF-β signaling pathway [1].

From the perspective of mechanism of action, SHR-1701 has the following characteristics:

• High Affinity
  : High affinity binding ability to PD-L1, TGF-β1, and TGF-β3 [2]
• Target Occupancy
  : Preclinical studies show that PD-L1 target occupancy reaches 71% [2]
• Dual Mechanism
  : Can promote the activation of effector T cells while improving the immunoregulatory effect of the tumor microenvironment [1]

According to data released at the 2024 European Society for Medical Oncology (ESMO) Congress, SHR-1701 achieved breakthrough results in the Phase III clinical trial for

[1]:

Indicator	SHR-1701 + Chemotherapy Group	Chemotherapy-only Group	Difference
Median Overall Survival (OS)	16.8 months	10.4 months	+6.4 months
Mortality Risk Reduction	-	-	47%
Applicable Population	PD-L1 CPS≥5	PD-L1 CPS≥5	-

In the clinical trial for

, the regimen of SHR-1701 combined with nab-paclitaxel and gemcitabine also showed good anti-tumor activity [1]:

• Objective Response Rate (ORR)
  : 32.1%
• Disease Control Rate (DCR)
  : 78.6%

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There are several controversial points in the clinical trial design of the PD-L1/TGF-β bispecific antibody field. These issues not only affect SHR-1701 but also relate to the scientificity and ethical compliance of the entire technical route [1].

: Should the control group be set to chemotherapy-only or the standard treatment regimen?

According to the disclosed clinical trial design, the control group of SHR-1701’s Phase III trial is chemotherapy-only. However, the first-line standard treatment regimen for advanced gastric cancer has gradually evolved from chemotherapy-only to chemotherapy combined with immunotherapy (such as PD-1 inhibitor combined with chemotherapy) [1]. This raises the following questions:

• Does the control group treatment represent the current optimal standard in clinical practice?
• Will using chemotherapy as the control lead to an overestimation of SHR-1701’s efficacy?
• Against the background of approved immunotherapies, is there an ethical issue with using only chemotherapy as the control?

The trial’s enrolled population is limited to patients with

[1]. This selection is based on:

• CPS (Combined Positive Score) ≥5 is generally considered a population sensitive to immunotherapy
• Helps enrich patients who may benefit from the treatment

However, there are also controversies:

• Should TGF-β-related biomarkers be considered simultaneously?
• Does dual-target therapy require the development of combined predictive factors?
• Can single PD-L1 expression accurately predict the efficacy of bispecific antibodies?

The primary endpoint of the clinical trial is

, which is a clinically meaningful hard endpoint. However, the controversies are:

• Should Progression-Free Survival (PFS) also be used as a primary endpoint?
• For bifunctional antibodies, should changes in the tumor microenvironment be included as a biomarker endpoint?
• How to ensure the completeness of long-term follow-up data?

It is worth noting that Hengrui Pharmaceuticals is not the only company facing such challenges in the PD-L1/TGF-β bispecific antibody field:

Drug	Developer	Status	Control Group Design Issues
Bintrafusp alfa	GSK/Merck	Phase III Terminated	Controversies over control group setup and data interpretation
M7824	Merck	Phase III Terminated	Efficacy failed to meet expectations
SHR-1701	Hengrui Pharmaceuticals	Phase III Ongoing	Successful Phase III trial for gastric cancer
JS201	Junshi Biosciences	Phase I	Early R&D stage

GSK’s Bintrafusp alfa terminated development after failing to meet primary endpoints in multiple Phase III clinical trials, which cast a shadow over the entire PD-L1/TGF-β technical route [1]. The success of Hengrui Pharmaceuticals’ SHR-1701 in gastric cancer provides important positive evidence for this technical route.

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The clinical trial data of SHR-1701 comes from multiple clinical centers, and the following need to be verified:

• Consistency of efficacy data among different centers
• Efficacy differences between East Asian and non-East Asian populations (if applicable)
• Efficacy differences among different pathological types of gastric cancer

It is recommended that an independent Data Monitoring Committee (DMC) conduct the following:

• Re-analysis of raw data
• Blinded review to reduce bias
• Sensitivity analysis to evaluate the robustness of results

After drug approval, conduct a prospective real-world registry study:

• Patient Population
  : Include a broader range of real-world patients (including those with poor PS scores and multiple comorbidities)
• Data Collection
  : Systematically collect efficacy, safety, and quality of life data
• Control Setup
  : Use external controls or propensity score matching

Analyze through real-world databases:

• Compare the actual use of SHR-1701 and standard treatment
• Evaluate efficacy in special populations (such as elderly patients, those with hepatic or renal insufficiency)
• Analyze the correlation between treatment patterns and efficacy

Establish a comprehensive pharmacovigilance system:

• Active monitoring and reporting of adverse reactions
• Identification of rare adverse events
• Tracking of long-term safety signals

Conduct long-term follow-up of clinical trial subjects:

• Evaluate sustained response rate and duration of response
• Monitor updated overall survival data
• Analyze the mechanism of acquired resistance

Verify the mechanism of action through translational research:

• Immunohistochemical analysis of tumor biopsy samples before and after treatment
• Evaluation of T cell infiltration and functional status
• Molecular evidence of TGF-β signaling pathway inhibition

Develop more precise efficacy prediction tools:

• Composite score combining PD-L1 and TGF-β-related indicators
• Relationship between Tumor Mutational Burden (TMB) and efficacy
• Predictive value of Microsatellite Instability (MSI) status

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As a leading domestic pharmaceutical innovation enterprise, Hengrui Pharmaceuticals has a strong R&D pipeline in the anti-tumor field [0]:

Product	Target/Mechanism	Indication	Development Stage
SHR-1701	PD-L1/TGF-β Bispecific Antibody	Gastric cancer, pancreatic cancer	Phase III/Phase II
SHR-A1811	HER2 ADC	Breast cancer	Phase III
Camrelizumab	PD-1	Multiple cancer types	Launched
Adebelimab	PD-L1	Extensive-stage small cell lung cancer	Launched
Dalpiciclib	CDK4/6	Breast cancer	Launched

1. First-Mover Advantage
   : Hengrui Pharmaceuticals is in a leading domestic position in the PD-L1/TGF-β bispecific antibody field
2. Positive Clinical Data
   : Successful Phase III trial for gastric cancer with significantly prolonged OS
3. Broad Indication Coverage
   : Covers multiple treatment areas such as gastric cancer and pancreatic cancer

1. Technical Route Risk
   : The failure of similar products from GSK/Merck has cast a shadow
2. Intensified Competition
   : Companies such as Junshi Biosciences are also laying out this target
3. Medical Insurance Negotiation Pressure
   : Uncertainties in innovative drug pricing and medical insurance access

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1. Clinical Breakthrough
   : The successful Phase III trial of SHR-1701 for gastric cancer provides important verification for the technical route
2. Market Space
   : Both gastric cancer and pancreatic cancer are high-incidence malignant tumors with huge treatment demand
3. R&D Capability
   : Hengrui Pharmaceuticals has presented research results at the American Society of Clinical Oncology (ASCO) Annual Meeting for 15 consecutive years, and its R&D capability has been internationally recognized [3]

1. Control Group Controversy
   : Controversies over clinical trial design may affect regulatory approval and academic recognition
2. Safety Risk
   : Bifunctional antibodies may bring new safety challenges
3. Changing Competitive Landscape
   : Competition from similar drugs and the emergence of alternative therapies

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Hengrui Pharmaceuticals’ PD-L1/TGF-β bispecific antibody SHR-1701 has achieved encouraging data in the Phase III trial for gastric cancer (median OS 16.8 months vs 10.4 months in the control group, 47% reduction in mortality risk), providing important positive evidence for this innovative technical route [1]. However, the controversies surrounding the clinical trial control group design still deserve attention, mainly involving issues such as whether the control group treatment regimen represents the current optimal standard and whether biomarker selection is sufficient.

Verifying the real-world efficacy of SHR-1701 requires:

• Ensuring the reliability of clinical trial results through independent data review and cross-validation
• Conducting prospective real-world registry studies and retrospective cohort studies
• Establishing a comprehensive pharmacovigilance and long-term follow-up system
• Carrying out in-depth translational research to verify the mechanism of action and develop predictive biomarkers

For investors, the successful development of SHR-1701 will significantly enhance Hengrui Pharmaceuticals’ competitiveness in the tumor immunotherapy field, but attention should also be paid to regulatory and commercial risks that may arise from the clinical trial design controversies.

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[0] Jinling AI - Hengrui Pharmaceuticals Company Profile Data (January 2026)

[1] PatSnap Drug Intelligence Database - Hengrui’s PD-L1-TGF-β Bispecific Antibody: Successful Phase III Trial for Gastric Cancer, First Release of Pancreatic Cancer Data (December 2025) (https://synapse.zhihuiya.com/blog/)

[2] Nature - A phase 1b/2 study of first-line anti-PD-L1/TGF-βRII fusion protein SHR-1701 (https://www.nature.com/articles/s41392-025-02530-2)

[3] Hengrui Pharmaceuticals Official Website - Led by 11 Oral Presentations! Hengrui Pharmaceuticals’ Numerous Anti-Tumor Studies Debut on the International Stage (https://www.hengrui.com/media/detail-865.html)

[4] Xinhua News - 70 Anti-Tumor Research Results from 15 Innovative Drugs of Hengrui Pharmaceuticals Debut at the 2025 ASCO Annual Meeting (http://www.news.cn/health/20250601/)

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Note on the figure: The left panel shows the comparison of median OS between the SHR-1701 + chemotherapy group and the control group in the Phase III gastric cancer trial; the right panel shows the objective response rate and disease control rate data from the Phase Ib/II pancreatic ductal adenocarcinoma trial

Note on the figure: From top-left to bottom-right, it shows: Global PD-L1/TGF-β bispecific antibody competition landscape, analysis of controversial elements in clinical trial design, evaluation of real-world efficacy verification methods, and value score of Hengrui Pharmaceuticals’ core anti-tumor pipeline