Microsatellite stable (MSS) and mismatch repair-proficient (pMMR) metastatic colorectal cancer (mCRC) has shown minimal response to immune checkpoint inhibitors as monotherapy, making combination immunotherapy a key strategy to address this clinical challenge. At the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2025), a multicenter phase II study led by Dr. Rongbo Lin from Fujian Cancer Hospital was selected for the poster abstract session (Abstract #198). This study evaluates the preliminary efficacy and safety of FOLFOXIRI combined with bevacizumab and cadonilimab in pMMR/MSS mCRC patients.  During the conference, a reporter from Oncology Frontier conducted an in-depth interview with Dr. Rongbo Lin to discuss the study findings.

Q1: Could you briefly introduce the background of the SYLT-026 study?

Dr. Rongbo Lin: In recent years, immunotherapy has advanced rapidly, offering new hope to patients across various tumor types. For patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), PD-1 or PD-L1 inhibitors have become the new standard first-line treatment. However, in Chinese colorectal cancer patients, only about 5% belong to the dMMR/MSI-H subgroup, while 95% have microsatellite stable (MSS) or mismatch repair-proficient (pMMR) tumors, which are relatively unresponsive to immune checkpoint inhibitors alone.

Enhancing the efficacy of immunotherapy for pMMR/MSS-type colorectal cancer has become a key research focus. Earlier studies explored various combination strategies. For instance, the CheckMate-9X8 trial tested mFOLFOX6 chemotherapy plus bevacizumab and nivolumab, but failed to improve survival outcomes. In contrast, the phase II Atezo TRIBE study reported that adding atezolizumab to first-line FOLFOXIRI plus bevacizumab significantly improved overall survival (OS) in metastatic colorectal cancer. However, the survival benefit was less pronounced in the pMMR/MSS subgroup.

Cadonilimab (AK104), a humanized bispecific antibody targeting both PD-1 and CTLA-4, has demonstrated promising efficacy in several colorectal cancer studies. It holds potential to enhance the immune response in MSS-type colorectal cancer patients.

Based on these insights, the SYLT-026 study, presented as a poster abstract (Abstract #198) at ASCO GI 2025, investigates the triplet chemotherapy regimen FOLFOXIRI (5-FU + leucovorin + oxaliplatin + irinotecan) combined with bevacizumab and cadonilimab as a first-line treatment for pMMR/MSS mCRC. The study aims to evaluate whether adding cadonilimab to the standard FOLFOXIRI plus bevacizumab regimen can enhance efficacy while maintaining safety in treatment-naïve pMMR/MSS mCRC patients.

Q2: What are the preliminary efficacy results of FOLFOXIRI combined with bevacizumab and cadonilimab in patients with pMMR/MSS metastatic colorectal cancer (mCRC)?

Dr. Rongbo Lin: As of August 30, 2024, a total of 20 patients have been enrolled in the study, with a median age of 65.5 years. Among them, 40% had an ECOG performance status of 1 or 2, 55% had metastases in three or more organs, and 7 patients (35%) carried RAS or BRAF mutations. The median follow-up time was 5.0 months.

At this year’s ASCO GI conference, we reported preliminary results from 15 patients who had undergone at least two imaging evaluations. The results were remarkable, showing a confirmed objective response rate (ORR) of 100% and a disease control rate (DCR) of 100%. These findings are highly encouraging. However, since the follow-up period is still short, data on median progression-free survival (PFS) and overall survival (OS) remain immature, and we are continuing to monitor these outcomes. We anticipate sharing longer-term survival results at ESMO 2025, and we are hopeful for even better results.

Q3: FOLFOXIRI is known for its high efficacy but also significant toxicity, and immunotherapy can also present notable side effects. Could you share your insights on safety management in this study?

Dr. Rongbo Lin: In this study, all 20 patients experienced treatment-related adverse events, but most were grade 1 or 2. Only one patient (5%) discontinued treatment due to immune-mediated colitis. The most common grade 3/4 adverse events included neutropenia (55%), leukopenia (15%), infusion reactions (5%), dermatitis (5%), colitis (5%), anemia (5%), elevated ALT (5%), and diarrhea (5%). No new safety signals were observed.

Our center was one of the earliest in China to implement the FOLFOXIRI triplet regimen. Since the publication of a phase III multicenter randomized controlled trial in J Clin Oncol (2007) showing that FOLFOXIRI significantly improved response rates compared to FOLFIRI (60% vs. 34%, P<0.0001) in first-line mCRC treatment, we have routinely adopted this regimen. Currently, over 95% of our patients receive FOLFOXIRI, with only elderly patients being treated more cautiously. We have played a key role in promoting FOLFOXIRI nationwide and have gained extensive experience in managing treatment-related toxicities.

Over the past decade, we have developed a systematic toxicity management approach, including patient education, physical activity guidance, and nutritional support, effectively minimizing adverse effects. Physicians visiting our center often find that FOLFOXIRI administration here is as manageable as standard doublet chemotherapy.

However, long-term immunotherapy use presents additional side effects, particularly endocrine-related toxicities that can cause severe fatigue and may require long-term hormone replacement therapy. To address this, we are actively exploring ways to optimize treatment regimens to maximize efficacy while minimizing toxicity.

Given that triplet chemotherapy enhances tumor antigen release and immune microenvironment remodeling, we hope to achieve the following objectives with this combination approach: improving treatment efficacy for advanced patients, extending overall survival by integrating immunotherapy with the possibility of achieving functional cure, and increasing the pathological complete response (pCR) rate, which is crucial in colorectal cancer treatment. We have already observed cases of complete tumor disappearance (pCR) in advanced colorectal cancer patients receiving this regimen, offering promising early signals of success.

Q4: Based on the preliminary results, what are your future research plans? Do you intend to conduct larger clinical trials to further validate the efficacy and safety of this regimen?

Dr. Rongbo Lin: Our study has yielded promising results, and we plan to continue discussions with pharmaceutical companies to pursue larger randomized controlled trials.

Beyond cadonilimab (AK104), we are also exploring another PD-1/CTLA-4 bispecific antibody, QL1706. QL1706 is a combination of two monoclonal antibodies: ipafricept (IgG4) targeting PD-1 and tovorolimab (IgG1) targeting CTLA-4. Both CTLA-4 and PD-1 pathways negatively regulate T-cell immune responses, and by blocking both pathways simultaneously, QL1706 enhances anti-tumor immune activity while reducing CTLA-4-associated toxicity.

We have already completed the study protocol for QL1706, and we plan to launch further comparative studies to evaluate its safety and efficacy. These findings will help lay the groundwork for a future phase III clinical trial.

Dr. Rongbo Lin

Fujian Cancer Hospital

Dr. Rongbo Lin is a Chief Physician in the Department of Medical Oncology at Fujian Cancer Hospital. He serves as the Vice Chair of the Tumor Comprehensive Assessment Committee of the Chinese Anti-Cancer Association and the Chair of the Cancer Pain Committee of the Fujian Anti-Cancer Association.

He is a board member of the fifth CSCO (Chinese Society of Clinical Oncology) and a member of the CSCO Gastric Cancer Expert Committee, where he contributed as a lead author of the CSCO Gastric Cancer Treatment Guidelines. Additionally, he holds standing committee positions in the Chinese Anti-Cancer Association’s Targeted Therapy, Cancer Pain Integrated Treatment, Neuroendocrine Tumors (Integrative Medicine), Cancer Rehabilitation and Palliative Care, and Integrative Oncology Committees.

Professor Lin is also a standing committee member of the Oncology Palliative Care Division of the Chinese Medical Health International Exchange Promotion Association, as well as the Vice Chair of the Fujian Anti-Cancer Association’s Psycho-Oncology Committee and the Vice Chair of the Digestive System Diseases Committee of the Fujian Association of Integrative Medicine.

As a member of the Fujian Cancer Translational Medicine Key Laboratory, he has been actively involved in advancing cancer research and treatment. From 2012 to 2015, he participated in an international medical assistance program at Princess Marina Hospital in Botswana, further expanding his clinical expertise and contributions to global oncology care.