Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-line Therapy for Advanced Colorectal Adenocarcinoma: The Phase II DeFianCe Trial

作者：Zev A. Wainberg, Keun‐Wook Lee, Jong Gwang Kim, Craig Devoe, John H. Strickler, Jason Baum, Calvin Jia, Michael H. Kagey, Cynthia A. Sirard, Alexander Stein, Aaron J. Scott, Meredith Pelster, Markus Moehler, Sae‐Won Han · 发表于：Clinical Cancer Research · 年份：2026 · DOI：10.1158/1078-0432.ccr-26-1456 · 研究领域：Colorectal Cancer Treatments and Studies、HER2/EGFR in Cancer Research、Colorectal Cancer Surgical Treatments

PURPOSE: DeFianCe was a randomized phase 2 study evaluating sirexatamab, a Dickkopf-related protein 1 (DKK1)-neutralizing antibody, plus chemotherapy and bevacizumab as second-line therapy for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC and progression, during or after 1 prior systemic therapy line were randomized 1:1 to investigator's-choice FOLFIRI or mFOLFOX6 plus bevacizumab, with or without intravenous sirexatamab. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Baseline plasma DKK1 was a prespecified candidate biomarker. RESULTS: In Part B, 188 patients were randomized. Median PFS was 9.2 months with sirexatamab versus 8.3 months with control (HR, 0.84; 95% CI, 0.58-1.21; one-sided p=0.1712); the primary endpoint was not met. Median OS was not reached in either arm (HR, 0.83; 95% CI, 0.46-1.48; one-sided p=0.2632), and ORR was 35.1% versus 26.6% (one-sided p=0.1009). The final analysis included 119 investigator-assessed PFS events versus 145 planned events. Safety was generally comparable between arms. In exploratory baseline plasma DKK1 analyses, greater treatment benefit was observed in patients with DKK1 above the median for PFS (HR, 0.61; 95% CI, 0.37-1.00), OS (HR, 0.42; 95% CI, 0.19-0.91), and ORR (38.0% vs 23.7%). CONCLUSIONS: Sirexatamab plus chemotherapy and bevacizumab did not improve PFS in the intent...