Determination of the recommended phase II dose of birinapant in combination with pembrolizumab: Results from the dose-escalation phase of BPT-201.

Abstract

2506 Background: Birinapant is a bivalent SMAC mimetic targeting cIAP1. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models. Based on these observations, a clinical trial with birinapant and pembrolizumab was initiated (NCT02587962). Methods: Patients ≥18 years with advanced solid tumors without further suitable standard therapeutic options were eligible for inclusion. Birinapant (5.6-22 mg/m2) was administered IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle until disease progression using standard 3+3 dose-escalation. The primary objective was to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab. Secondary and exploratory objectives included antitumor activity assessed by RECIST 1.1 and iRECIST, pharmacokinetics and assessment of biomarkers including serum cytokines, cIAP1, PD-L1 expression and tumor infiltrating lymphocytes. Results: Nineteen patients were enrolled at 4 dose levels of 5.6 (n = 3), 11 (n = 3), 17 (n = 6) and 22 (n = 7) mg/m2. Most common tumors were pancreatic (n = 5), colorectal (n = 4), ovarian (n = 3) and sarcoma (n = 3). Median prior therapies were 4 (0-12). The most common AE related to any of the study drugs was rash occurring in 3 patients. Ten patients had 17 SAE's of which only one (stomatitis) was judged related to birinapant. Increased ALT/AST (G3/G2) leading to missed day 8 dose constituted a DLT at 22 mg/m2. Grade 2 lipase increases were seen in 2 patients. No cases of Bell’s palsy were detected. ORR by RECIST 1.1 was 5.6% (n = 1) in 18 evaluable patients. The responding patient had microsatellite stable colorectal carcinoma (MSS-CRC)) and remains on therapy 13+ months after first dose. By iRECIST, ORR was 11.1%. CBR (PR+SD) by RECIST was 22.2%. The exposure to birinapant generally increased with dose. The RP2D was determined to be 22 mg/m2. Conclusions: Birinapant and pembrolizumab is a safe and tolerable combination that has shown encouraging signals of efficacy. A phase 2 study evaluating efficacy of this combination in MSS-CRC is ongoing. Clinical trial information: NCT02587962.