Pharmacokinetic/pharmacodynamic data indicated linear dose exposure and ≥2-fold activation of plasma caspase 3/7.<h4>Conclusions</h4>In heavily pretreated patients with GI tumors, BI 905711 monotherapy or with FOLFIRI plus bevacizumab displayed a manageable safety profile and limited clinical activity.<h4>Significance</h4>Translating preclinical activity of TRAILR2 agonists into the clinic has been hampered by severe hepatotoxicity. Here, TNFRSF10B is linked to digestive system neoplasm.