Cadonilimab, a bispecific anti–PD-1/CTLA-4 antibody, for patients with dMMR/MSI-H metastatic colorectal cancer after progression on anti–PD-(L)1 therapy: A multicenter, single-arm, phase 2 trial (CSWOG-C03).

3577 Background: Immune checkpoint blockade targeting PD-1 is the standard of care for patients with mismatch repair–deficient or microsatellite instability–high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, approximately 37%–45% of patients experience disease progression within 1 year when treated with anti-PD-1 monotherapy, and effective subsequent treatment options remain undefined. The CSWOG-C03 study evaluated the efficacy and safety of cadonilimab, a bispecific anti-PD-1/CTLA-4 antibody, in patients with dMMR/MSI-H mCRC after progression on prior anti-PD-(L)1 therapy. Methods: This multicenter, single-arm, phase 2 study enrolled patients with centrally confirmed dMMR/MSI-H mCRC and iRECIST-defined disease progression after prior anti-PD-(L)1 monotherapy or anti-PD-(L)1-based combination therapy. Patients received intravenous cadonilimab at 6 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was the 12-month progression-free survival (PFS) rate, assessed by RECIST v1.1. Results: A total of 24 patients were enrolled and received study treatment. The median age was 54 years; 29% were female, 17% had Lynch syndrome, 92% had peritoneal metastases, and 33% had liver metastases. Overall, 63% of patients had received ≥2 prior lines of systemic therapy; all had prior exposure to anti-PD-(L)1 therapy, 71% had received fluoropyrimidines and oxaliplatin, and 29% had received irinotecan. The best response to prior anti-PD-(L)1 therapy was partial response in 2 patients, stable disease in 17, and progressive disease in 5. With a median follow-up of 14.8 months at data cutoff (January 22, 2026), the 12-month PFS rate was 44.6% (95% CI, 23.4–63.9), meeting the prespecified primary endpoint of 40%. Median PFS was 6.1 months (95% CI, 2.2–10.1). Median overall survival (OS) was not reached and the 12-month OS rate was 68.6% (95% CI, 42.5–84.7). The confirmed objective response rate (ORR) was 20.8% (95% CI, 7.1–42.2), and the disease control rate (DCR) was 75.0% (95% CI, 53.3–90.2). One patient completed the protocol-specified 2-year treatment without progression, and 7 remained on study treatment. Treatment-related adverse events of any grade occurred in 15 patients (63%), with grade 3 events observed in 3 patients (13%). Conclusions: Cadonilimab provided meaningful disease control with modest antitumor activity and a manageable safety profile in patients with dMMR/MSI-H mCRC after progression on prior anti-PD-(L)1 therapy. Clinical trial information: NCT05426005 . N=24 12-month PFS rate 44.6% (95% CI, 23.4–63.9) Best overall response PR 5 (21) SD 13 (54) PD 5 (21) NE 1 (4) Objective response rate 20.8% (95% CI, 7.1–42.2) Disease control rate 75.0% (95% CI, 53.3–90.2)