Editorial Note: From January 23 to 25, 2025, the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) was held in San Francisco, showcasing significant advancements in gastrointestinal cancer treatment. The Peking University Cancer Hospital presented a series of cutting-edge findings, contributing to global progress in digestive tract oncology. On the first day of the conference, Dr. Zhi Peng from Peking University Cancer Hospital delivered an oral presentation on the latest findings from a Phase III clinical study evaluating the domestically developed PD-L1/TGF-βRII bispecific fusion protein SHR-1701 in first-line treatment for HER2-negative gastric and gastroesophageal junction adenocarcinoma (G/GEJA). Building upon the efficacy improvements previously reported at the European Society for Medical Oncology (ESMO) Congress, the latest data presented at ASCO GI suggests that SHR-1701 combined with chemotherapy may mitigate chemotherapy-induced bone marrow suppression, offering a more effective and safer treatment option for G/GEJA.

During the conference, Dr. Lin Shen from Peking University Cancer Hospital connected with Dr. Zhi Peng at the ASCO GI venue for an in-depth discussion on the clinical implications of this study. Below is a summary of their conversation.

• Dr. Lin Shen: On the first day of ASCO GI, you delivered an oral presentation on the bone marrow suppression-related findings from our multi-center, Phase III clinical study investigating the PD-L1/TGF-βRII bispecific fusion protein SHR-1701, with or without CAPOX, as a first-line treatment for HER2-negative advanced G/GEJA. The primary results of this study were previously presented at the 2024 ESMO Congress, and ASCO GI focused specifically on SHR-1701’s impact on bone marrow suppression.

To begin, could you provide a brief overview of the study design and key findings, along with the latest results presented at ASCO GI?

• Dr. Zhi Peng: Thank you, Professor Shen. At the 2024 ESMO Congress, we reported the primary results of this study. This was a nationwide, multi-center, two-phase, Phase III clinical trial. In the first phase, we explored and confirmed the recommended dose of SHR-1701 as 30 mg/kg administered every three weeks (Q3W) and evaluated its safety and tolerability in combination with CAPOX (oxaliplatin plus capecitabine). The second phase was a randomized, double-blind, placebo-controlled trial conducted across multiple centers in China, specifically targeting patients with HER2-negative advanced gastric cancer. This phase aimed to assess the efficacy and safety of SHR-1701 combined with CAPOX in first-line treatment.

The previously reported results demonstrated significant benefits in both progression-free survival (PFS) and overall survival (OS) for patients receiving SHR-1701 plus CAPOX compared to those receiving CAPOX alone, particularly in patients with a PD-L1 CPS ≥5 and in the intent-to-treat (ITT) population. In the PD-L1 CPS ≥5 population, median OS was 16.8 months for SHR-1701 plus CAPOX versus 10.4 months for CAPOX alone, with a hazard ratio (HR) of 0.53 (95% CI: 0.40-0.68, P < 0.0001). In the ITT population, median OS was 15.8 months for SHR-1701 plus CAPOX versus 11.2 months for CAPOX alone, with an HR of 0.66 (95% CI: 0.53-0.81, P < 0.0001). Median PFS in the PD-L1 CPS ≥5 population was 7.6 months for SHR-1701 plus CAPOX versus 5.5 months for CAPOX alone. In the ITT population, median PFS was 7.0 months for SHR-1701 plus CAPOX versus 5.5 months for CAPOX alone.

At ASCO GI, we presented new findings on SHR-1701’s potential to mitigate chemotherapy-induced bone marrow suppression. With a median follow-up of 13.6 months, our data showed that the SHR-1701 plus CAPOX regimen significantly reduced the incidence of chemotherapy-induced adverse events, including thrombocytopenia, neutropenia, and leukopenia, compared to CAPOX alone.

• Dr. Lin Shen: What do you believe is the underlying mechanism by which SHR-1701 reduces chemotherapy-induced bone marrow suppression?
• Dr. Zhi Peng: SHR-1701 is a PD-L1/TGF-βRII bispecific fusion protein that simultaneously inhibits PD-L1 and TGF-βRII. Our findings suggest that its ability to reduce bone marrow suppression may be linked to the TGF-β signaling pathway. TGF-β is known to suppress hematopoietic stem cell differentiation, and by inhibiting this pathway, SHR-1701 may prevent chemotherapy-induced bone marrow suppression. In our study, we observed a clear reduction in thrombocytopenia, neutropenia, and leukopenia, reinforcing the potential of SHR-1701 as a bone marrow-protective agent when combined with chemotherapy. Interestingly, another PD-L1/TGF-β bispecific fusion protein, M7824, has also demonstrated bone marrow protective effects in clinical trials. We are currently conducting further research to better understand this phenomenon, which could provide valuable insights for future clinical applications.
• Dr. Lin Shen: Thank you for your detailed explanation. SHR-1701 is the first PD-L1/TGF-βRII bispecific antibody developed in China to enter clinical trials. In clinical practice, PD-1 inhibitors alone have shown limited efficacy, and research has identified additional immune escape mechanisms beyond PD-1, such as TGF-β, TIM-3, and CTLA-4. Studies have further confirmed that tumor-derived TGF-β plays a critical role in resistance to immune checkpoint inhibitors. By incorporating TGF-β inhibition alongside PD-L1 blockade, SHR-1701 may enhance tumor suppression and improve therapeutic outcomes.

The clinical performance of SHR-1701 reflects these mechanistic advantages. Our study demonstrated that SHR-1701 combined with CAPOX offers significant survival benefits over placebo plus CAPOX in patients with locally advanced or metastatic HER2-negative G/GEJA while also mitigating chemotherapy-induced bone marrow suppression. With accumulating evidence from clinical trials, SHR-1701 has the potential to reshape the first-line treatment landscape for HER2-negative G/GEJA.

Beyond gastric and gastroesophageal junction adenocarcinoma, SHR-1701 is also being explored in lung cancer, rectal cancer, nasopharyngeal carcinoma, and cervical cancer. Given its ability to alleviate chemotherapy-induced bone marrow suppression, SHR-1701 holds promise for broader application in combination therapies, offering new treatment possibilities across multiple cancer types.

Expert Profiles

• Director of the Department of Gastrointestinal Oncology and Phase I Clinical Trials Unit, Peking University Cancer Hospital
• Former Vice President of Peking University Cancer Hospital
• Former Deputy Director of the Beijing Institute for Cancer Prevention and Treatment
• Beijing Scholar
• Chair, Chinese Anti-Cancer Association (CACA) Committee on Precision Oncology
• Founding Chair, CACA Committee on Clinical Research of Anticancer Drugs
• Chair, Clinical Research Expert Committee, Chinese Society of Clinical Oncology (CSCO)
• Chair-elect, CSCO Gastric Cancer Expert Committee
• Vice Chair, CACA Colorectal Cancer Committee
• Chair, Clinical Oncology Committee, Chinese Female Physicians Association

• Chief Physician, Peking University Cancer Hospital
• Doctoral Supervisor
• National Young Talent Awardee
• Member, CACA Gastric Cancer Committee
• Member, CACA Tumor Metastasis Committee
• Member, CACA Precision Oncology Committee
• Member, CSCO Gastric Cancer Expert Committee
• Member, CSCO Oncology Nutrition Committee
• Member, Clinical Immunology Subcommittee, Chinese Society of Immunology
• Vice Chair, Beijing Cancer Prevention Society Committee on Precision Gastrointestinal Cancer Treatment
• Secretary General, Beijing Cancer Prevention Society Gastric Cancer Committee
• Editorial Board Member, Chinese Medical Journal, Electronic Journal of Integrated Oncology
• Recipient of First Prize, Chinese Medical Association Award, CACA Young Scientist Award, and CACA First Prize