Metastatic colorectal cancer (mCRC) remains a significant clinical challenge, particularly in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors, which tend to respond poorly to immunotherapy. The AtezoTRIBE phase II trial previously demonstrated that adding Atezolizumab to the standard FOLFOXIRI plus Bevacizumab regimen resulted in improved overall survival (OS), but the benefit in the pMMR/MSS subgroup was limited. Given the need for more effective treatment strategies in this population, there is increasing interest in exploring novel immunotherapeutic agents.Cadonilimab, a humanized bispecific antibody targeting both PD-1 and CTLA-4, has shown potential in other malignancies by enhancing antitumor immune responses. The SYLT-026 study was designed to evaluate whether the addition of Cadonilimab to FOLFOXIRI plus Bevacizumab could improve clinical outcomes while maintaining an acceptable safety profile in treatment-naïve patients with pMMR/MSS mCRC.Methods
The SYLT-026 trial is a multicenter, single-arm phase II study enrolling treatment-naïve patients diagnosed with pMMR/MSS mCRC. Eligible patients were between 18 and 75 years old, had at least one measurable lesion per RECIST 1.1 criteria, an ECOG performance status (PS) of 0 to 2, and adequate organ function. Patients with dMMR/MSI-H tumors or prior exposure to immunotherapy were excluded.
Participants received a combination regimen consisting of FOLFOXIRI, which included irinotecan at 165 mg/m², oxaliplatin at 85 mg/m², leucovorin at 200 mg/m², and fluorouracil at 2400 mg/m² administered as a 48-hour infusion. Bevacizumab was given at 5 mg/kg, while Cadonilimab was administered at 6 mg/kg. The treatment was delivered in 14-day cycles for up to 12 cycles, followed by a maintenance regimen comprising fluoropyrimidine, Bevacizumab, and Cadonilimab for up to 52 weeks or until disease progression, unacceptable toxicity, or withdrawal of consent.
Patients were evenly distributed based on the presence of liver metastases, with ten having liver involvement and ten without. The primary endpoint of the study was the objective response rate (ORR) as assessed by RECIST 1.1.
Results
As of August 30, 2024, a total of 20 patients had been enrolled, with a median age of 65.5 years, ranging from 33 to 74. Among these patients, 40 percent had an ECOG PS of 1 or 2, while 55 percent presented with three or more metastatic organs. Additionally, seven patients, accounting for 35 percent of the cohort, had RAS or BRAF mutations. The median follow-up duration was 5.0 months.
Fifteen patients underwent at least two imaging assessments, demonstrating a confirmed ORR of 100 percent, with all 15 patients responding to treatment. The disease control rate (DCR) was also 100 percent. However, median progression-free survival (PFS) and overall survival (OS) data were not yet mature at the time of analysis.
All 20 patients experienced treatment-emergent adverse events, though the majority were mild, classified as grade 1 or 2. One patient, representing 5 percent of the cohort, discontinued treatment due to immune-mediated colitis. The most frequently observed grade 3 or 4 adverse events included neutropenia in 55 percent of patients, leukopenia in 15 percent, infusion reactions in 5 percent, dermatitis in 5 percent, colitis in 5 percent, anemia in 5 percent, elevated ALT in 5 percent, and diarrhea in 5 percent. Importantly, no new safety signals were identified, indicating that the regimen was generally well-tolerated.
Discussion
The results from the SYLT-026 study suggest that the addition of Cadonilimab to FOLFOXIRI plus Bevacizumab may significantly improve response rates in pMMR/MSS mCRC patients. The observed ORR and DCR of 100 percent in this cohort are particularly promising, given that pMMR/MSS tumors have historically exhibited limited responsiveness to immunotherapy. These findings indicate that dual PD-1/CTLA-4 blockade in combination with chemotherapy and anti-angiogenic therapy may be a viable strategy for overcoming resistance mechanisms in this patient population.
The safety profile of the regimen appears to be manageable, with adverse events aligning with expectations for this combination approach. While one patient discontinued treatment due to immune-mediated toxicity, no unexpected or severe safety concerns emerged. The high incidence of hematologic toxicities, including neutropenia and leukopenia, suggests that proactive management strategies should be incorporated into future trials.
Conclusion
The findings from this phase II study demonstrate that Cadonilimab in combination with FOLFOXIRI and Bevacizumab exhibits promising efficacy and a manageable safety profile as a first-line treatment for patients with pMMR/MSS mCRC. While these early results are encouraging, further investigation in larger, randomized trials is necessary to validate these outcomes and assess long-term survival benefits.
Future Directions
To establish the role of Cadonilimab in mCRC treatment, future studies should expand patient enrollment to confirm the robustness of efficacy and safety data. Comparative trials evaluating this regimen against standard treatment approaches will be critical in determining its clinical utility. Additionally, biomarker-driven analyses may help identify patient subgroups that are most likely to benefit from this novel combination strategy. If further clinical validation is achieved, this approach could redefine the first-line treatment paradigm for pMMR/MSS mCRC and provide new hope for patients with limited immunotherapy options.
