Xevinapant combined with pembrolizumab in patients with advanced, pretreated colorectal and pancreatic cancer: results of the phase 1b/2 CATRIPCA trial

Abstract Purpose: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers (ICB) by modulating the NF-KB pathway in immune cells. Patients and Methods: Adult patients (pts) with non MSI-H advanced/metastatic PDAC or CRC were enrolled in this phase 1b/2 and received pembrolizumab 200mg q3w, IV and ascending doses of oral xevinapant (100, 150 and 200mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with CRC were enrolled in expansion cohorts to assess preliminary efficacy. Results: Forty-one pts (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose-escalation. The RP2D was identified as xevinapant 200mg/d + pembrolizumab 200mg q3w. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12 % and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin and rash seen in 20, 15 and 15% of patients respectively). The best overall response according to RECIST1.1 was partial response (PR, confirmed) in one (3%) , stable disease (SD) in four (10%) and progressive disease in 35 (88%). Conclusions: Xevinapant combined with pembrolizumab was well tolerated with no unexpected adverse events. However, anti-tumor activity was low.