Tislelizumab plus cetuximab and irinotecan in relapsed/refractory RAS/BRAF wild-type and microsatellite stable metastatic colorectal cancer: A randomized, controlled, multicenter study (TEC2).

3530 Background: Under suboptimal efficacy and safety of current third-line standard-of-care (SoC), several single-arm studies have demonstrated that anti-PD-(L)1 antibodies plus EGFR inhibitors with or without chemotherapy may be valuable for relapsed/refractory RAS/BRAF wild-type and microsatellite stable metastatic colorectal cancer (R/R RAS/BRAF WT and MSS mCRC). This study aimed to compare tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan as third- or later-line therapy versus investigator-selected SoC for R/R RAS/BRAF WT and MSS mCRC. Methods: This was a randomized controlled, open-label, multicenter study (NCT05278351). Eligible patients were aged ≥18 years with histologically confirmed RAS/BRAF WT and MSS metastatic colorectal adenocarcinoma who failed ≥2 prior lines of systemic therapy. Patients were randomly assigned (2:1) to receive intravenous tislelizumab (200 mg) plus cetuximab (500 mg/m 2 ) and irinotecan (180 mg/m 2 ) on days 1 and 15 or investigator-selected SoC (fruquintinib, regorafenib, or TAS-102) in a 4-week cycle until disease progression, unacceptable toxicity, or other protocol-defined reasons. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, disease control rate, duration of response, overall survival, and safety. Results: Eighty-seven patients (median age, 62.0 years; 59 [67.8%] men) were enrolled between July 2022 and March 2024, randomized, and assessed for efficacy; one patient did not receive the triplet regimen and was removed from the safety population. With median follow-up of 26.1 months (95% confidence interval [CI]: 22.4-28.4) by data cutoff (June 30, 2025), median PFS was 4.4 months (95% CI, 3.8-6.6) in the tislelizumab-cetuximab-irinotecan group and 2.0 months (95% CI, 1.9-5.4) in the SoC group (Breslow-Gehan P =0.009). Landmark analysis at a cutoff point of 10 months showed a significantly extended PFS with tislelizumab plus cetuximab and irinotecan versus SoC (HR 0.37 [95% CI, 0.21-0.64]; p<0.001). Grade ≥3 treatment-related adverse events (TRAEs) occurred at comparable frequencies in the two groups (15.8% vs 17.2%). No TRAEs led to death. Conclusions: Tislelizumab plus cetuximab and irinotecan as third- or later-line therapy appeared feasible and safe for patients with R/R RAS/BRAF WT and MSS mCRC. Clinical trial information: NCT05278351 . Tislelizumab-cetuximab-irinotecan (n=58) SoC (n=29) Best response Complete response 0 0 Partial response 12 (20.7) 1 (3.4) Stable disease 32 (55.2) 12 (41.4) Disease progression 11 (19.0) 16 (55.2) Not evaluable 3 (5.2) 0 Objective response 12 (20.7) 1 (3.4) Disease control 44 (75.9) 13 (44.8) 6-month PFS rate, % (95% CI) 38.2 (27.3-53.5) 20.4 (9.6-43.7)