Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.

Abstract

3530 Background: The anti–PD-1 antibody pembrolizumab provided an objective response rate of 28-57% in patients (pts) with Microsatellite Instability–High (MSI-H) metastatic colorectal cancer (mCRC) vs 0% in pts with Non-MSI-H. The WNT/β-catenin signaling has been reported to prevent anti-tumor immunity and promote resistance of anti-PD-1/PD-L1 antibodies. Furthermore, STAT3 has been known to be a key driver of the immune evasion. This study investigates efficacy and safety of the combination of BBI608, which blocks phosphorylated STAT3 and downregulates WNT/β-catenin signaling, with pembrolizumab in pts with mCRC. BBI608 480mg BID with pembrolizumab was determined as RP2D in the phase I part (Kawazoe A, et al. ASCO-GI 2018). Here, we present the preliminary results of the ongoing phase II part. Methods: Phase II part was composed of Cohort A (MSI-H) and Cohort B (Non-MSI-H). The main eligibility criteria was pts with mCRC not responded or intolerant to standard chemotherapies. Primary endpoint was Immune-related objective response rate (irORR) determined by irRECIST. Sample size for Cohort A with 10 pts was determined in an exploratory manner. In Cohort B, according to a null hypothesis and alternative hypothesis; irORR = 5% and 20%, estimating required sample size was 40 pts with a one-sided alpha of 5% and power of 90%. Results: From Feb 2017 to January 2018, 10 pts were enrolled in Cohort A, and 37 pts in Cohort B. As of October 2017, tumor response was evaluated in 3 pts of Cohort A and 25 pts of Cohort B, respectively. Two out of the 3 pts in Cohort A showed confirmed partial response. Among 12pts with right-sided colon in Cohort B, one patient showed confirmed partial response with remarkable decline of CEA level, and two pts showed stable disease lasting more than 16 weeks. Immunohistochemistry before treatment demonstrated the high expressions of PD-L1, CD8, and MHC-class I in the tumor samples from the patient with partial response. No severe or unexpected adverse events occurred up to the present. Conclusions: BBI608 with pembrolizumab showed preliminary efficacy signals with acceptable toxicity for MSI-H as well as Non-MSI-H mCRC pts with right-sided primary. Clinical trial information: NCT02851004.