Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: Results from a randomized, open-labeled, phase Ib study.

3505 Background: Immune checkpoint inhibitors have been used in neoadjuvant setting and showed promising clinical benefits in various tumors. Herein, we evaluate IBI310 plus sintilimab as neoadjuvant treatment in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) colorectal cancer (CRC) in a randomized, open-labeled, phase Ib study. Methods: Previously untreated pts with locally advanced (stage IIB-III), resectable, MSI-H/dMMR CRC were enrolled and randomized to receive 1 cycle of IBI310 1mg/kg plus 2 cycles of sintilimab 200 mg Q3W (arm A) or 2 cycles of sintilimab 200 mg Q3W (arm B) as neoadjuvant treatment. The stratification factors were risk evaluation at baseline (high risk: stage T4 or N2 vs low risk: stage T1-3 and N1) and age ( < 55 years vs ≥55 years). Curative resection was scheduled on day 36 to 56 after first dose of neoadjuvant treatment. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included R0 resection rate and safety. Results: As of February 4, 2024, 101 pts were enrolled (males: 55.4%, median age: 56 years, ECOG PS 1: 54.5%, high risk: 76.2%) and randomized into arm A (n = 52) and arm B (n = 49). In arm A, 1 pt had early termination of treatment (withdrawal). In arm B, 4 pts had early termination of treatment (1 withdrawal, 1 died, 2 continued neoadjuvant sintilimab). Scheduled curative resection were performed in 51 (98.1%) pts in arm A and 45 (91.8%) pts in arm B. Postoperative evaluation revealed mismatch repair-proficient (pMMR) in 1 pt each in arm A and arm B. The pCR rates were 80.0% (40/50, 95%CI: 66.3-90.0) in arm A vs 47.7% (21/44, 95%CI: 32.5-63.3) in arm B (p = 0.0007). All pts received surgery had R0 resection. Median time between first dose of neoadjuvant treatment and surgery was 47 days (range: 35-82). Surgery delay occurred in 3 pts including 2 pts in arm A due to grade 2 hypothyroidism (2 days delay) and grade 1 hyperthyroidism (13 days delay), and 1 pt in arm B for other reason (26 days delay). Treatment-emergent adverse events (TEAEs) occurred in 46 pts (88.5%, grade≥3 in 13 pts) in arm A and 39 pts (79.6%, grade≥3 in 9 pts) in arm B. Immune-related adverse events (irAEs) occurred in 22 pts (42.3%) in arm A and 18 pts (36.7%) in arm B. Grade ≥3 irAEs occurred in 3 pts in arm A, including immune-mediated myocarditis, ileus and enteritis, and in 4 pts in arm B, including alanine aminotransferase increased, rash, hypothyroidism and myocarditis. Serious TRAEs occurred in 4 (7.7%) pts in arm A and 3 (6.1%) pts in arm B. TRAE leading to death occurred in 1 pt in arm B (myocarditis). Conclusions: Neoadjuvant IBI310 plus sintilimab significantly improved pCR rate than sintilimab alone in MSI-H/dMMR CRC. The safety profiles were comparable and manageable in both treatment arms. Clinical trial information: NCT05890742 .