From January 23 to 25, 2025, the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2025) was held in San Francisco, USA. At this prestigious event, Cadonilimab, the world's first bispecific antibody developed in China, achieved multiple breakthroughs in the treatment of gastrointestinal cancers.Several research teams, including Professors Jing Huang and Wang Qu from the Cancer Hospital Chinese Academy of Medical Sciences, Professor Rongbo Lin from Fujian Cancer Hospital, and Professor Wan He from Shenzhen People's Hospital, presented the latest research findings on Cadonilimab in the treatment of advanced esophageal squamous cell carcinoma (ESCC), mismatch repair-proficient/microsatellite-stable (pMMR/MSS) metastatic colorectal cancer (mCRC), and locally advanced rectal cancer (LARC). These studies demonstrated the potential of Cadonilimab-based combination therapies to enhance anti-tumor efficacy, prolong survival, and improve safety, laying the foundation for a new era of bispecific antibody therapy in gastrointestinal cancers.

Oncology Frontier invited the principal investigators of these three studies to share their findings and discuss their implications for clinical practice and future research directions.

AK104-IIT-014 Study: Sustained Benefits of Cadonilimab Plus Chemotherapy as First-Line Therapy for ESCC

Professor Jing Huang：Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). Studies such as KEYNOTE-590 and CheckMate-648 have demonstrated that PD-1 inhibitors plus chemotherapy achieve an overall response rate (ORR) of approximately 50% and a median progression-free survival (mPFS) of 5 to 6 months, indicating room for improvement.

Currently approved immune checkpoint inhibitors primarily target a single immune checkpoint, whereas Cadonilimab, the world’s first bispecific antibody targeting both PD-1 and CTLA-4, offers a synergistic effect that enhances anti-tumor activity while maintaining a favorable safety profile. Based on the COMPASSION-03 trial, Cadonilimab monotherapy has already been recommended in the 2023 edition of the Chinese Guidelines for Radiotherapy in Esophageal Cancer and the 2024 Chinese Society of Clinical Oncology (CSCO) Guidelines for Esophageal Cancer as a second-line treatment for advanced ESCC.

Building on this foundation, the AK104-IIT-014 study explored Cadonilimab-based first-line therapy for advanced ESCC. Following previous presentations at ESMO IO 2023 and ASCO 2024, the latest updates at ASCO GI 2025 continue to show that Cadonilimab plus chemotherapy provides numerical improvements in ORR and PFS compared to single-target immune checkpoint inhibitors. Notably, its efficacy appears independent of PD-L1 CPS scores, and it consistently demonstrates encouraging anti-tumor activity with manageable safety.

Furthermore, this study identified a correlation between DNA methylation levels and clinical response, offering a potential biomarker for patient selection. We look forward to further data releases from this trial, which may broaden treatment options and improve outcomes for patients with advanced ESCC.

SYLT-026 Study: Remarkable Efficacy of Cadonilimab-Based First-Line Therapy in pMMR/MSS mCRC

Professor Rongbo Lin：The prognosis for patients with metastatic colorectal cancer (mCRC) remains poor, with a five-year survival rate of only 14% for stage IV CRC patients. Currently, systemic therapy remains the primary treatment approach, with chemotherapy regimens such as FOLFOX and FOLFIRI combined with targeted agents like bevacizumab or cetuximab serving as the standard first-line treatment.

The AtezoTRIBE study demonstrated that adding atezolizumab to FOLFOXIRI plus bevacizumab improved PFS and OS, though the benefits were limited in the pMMR/MSS population. Since Cadonilimab, a bispecific antibody targeting both PD-1 and CTLA-4, has previously shown activity in CRC, we hypothesized that it could further enhance the efficacy of immunotherapy in pMMR/MSS mCRC patients, a group that traditionally shows poor response to immune checkpoint inhibitors.

To explore this, we designed the SYLT-026 study, combining Cadonilimab with FOLFOXIRI plus bevacizumab as first-line therapy for pMMR/MSS mCRC patients. The results were striking, with both DCR and ORR reaching 100%, confirming that this approach may be a promising new treatment strategy for this population. While further validation is required, these findings highlight the potential and value of this regimen. The study is still ongoing, and survival data will be presented at ESMO 2025. Stay tuned for further updates.

NeoCaCRT Study: Promising Outlook for SCRT Followed by Cadonilimab Plus Chemotherapy as Neoadjuvant Treatment for pMMR/MSS LARC

Professor Wan He：For pMMR/MSS locally advanced rectal cancer (LARC), the 2024 Chinese Society of Clinical Oncology (CSCO) Guidelines for Colorectal Cancer recommend preoperative chemoradiotherapy (CRT) followed by surgery. While this approach achieves approximately 20% complete tumor regression, many patients still do not experience sufficient tumor shrinkage, making sphincter preservation particularly challenging for low rectal cancer. Additionally, there is a 30% risk of distant metastasis, which negatively impacts both survival outcomes and quality of life. Recent studies suggest that adding PD-1/PD-L1 inhibitors to CRT can increase pCR rates in neoadjuvant therapy.

Based on this concept, we conducted the Phase II NeoCaCRT study, leveraging SCRT to enhance tumor antigen release, followed by sequential treatment with Cadonilimab plus mFOLFOX6, a combination designed to achieve a synergistic immune effect. This approach has demonstrated promising outcomes in pMMR/MSS LARC patients, a group that has historically responded poorly to immunotherapy. The study showed significant improvements in surgical resection rates, pCR rates, and cCR rates, offering new hope for improved prognosis in these patients.

The NeoCaCRT study represents a new frontier for immune-based neoadjuvant therapy in pMMR/MSS LARC. Not only does it introduce a novel preoperative treatment strategy, but it also paves the way for further refinement of treatment protocols. Additionally, we are actively investigating potential biomarkers to enable precision medicine approaches for identifying the most responsive patient populations. As research continues and more data become available, we anticipate that this strategy will play a greater role in future clinical practice, ultimately improving outcomes for patients with pMMR/MSS LARC.