Re: Ashley M. Hopkins, Ganessan Kichenadasse, Christos S. Karapetis, et al. Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab. Clin Cancer Res. In press. https://doi.org/10.1158/1078-0432.CCR-20-1876

Vollständiger Abstract

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<h4>Purpose</h4>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).<h4>Patients and methods</h4>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.<h4>Results</h4>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%).<h4>Conclusions</h4>Sirexatamab plus chemotherapy and bevacizumab did not improve PFS in the intent-to-treat population but was generally well tolerated. However, the consistent association between higher baseline plasma DKK1 and greater sirexatamab benefit suggests that DKK1-directed therapy may require biomarker-selected evaluation rather than all-comer development in mCRC.

Abstract: PubMed · Datensatz