Results from the multicenter phase I/II SCOOP trial exploring the combination of the stemness inhibitor napabucasin (BBI608) and the PD-1 inhibitor pembrolizumab (Keytruda) demonstrated an acceptable safety profile in patients with metastatic colorectal cancer (mCRC).
Phase I, which was presented during the 2018 Gastrointestinal (GI) Cancers Symposium, was designed to determine the recommended phase II dose. The phase II portion will explore the efficacy of the combination.
In the phase I portion, investigators established 480 mg twice daily of napabucasin as the recommended phase II dose along with 200 mg every 3 weeks of pembrolizumab. Investigators also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections.
Five patients were enrolled at the level 1 dose (240 mg twice daily), and 3 patients at level 2 (480 mg twice daily). All patients had microsatellite stable (MSS) mCRC, 7 of whom were included in the safety analyses. Two patients at level 1 were excluded from the dose-limiting toxicity (DLT) analysis because of disease progression.
Enrollment criteria for the trial included ECOG performance status of 0 or 1, histologically-confirmed colon or rectal adenocarcinoma, and verification of the KRAS codon 12 and 13 status by RAS gene testing.
Regarding safety, absence of DLTs and grade 3 treatment-related adverse events (TRAEs) were reported in both levels. Grade 1/2 TRAEs included diarrhea (57%), hyperthyroidism (14%), hypothyroidism (14%), and fever (14%). One patient at the level 2 dose displayed a tumor shrinkage over a 12-week span for lung and lymph node metastases with substantial decline of carcinoembryonic antigen levels.
In an interview with OncLive
during the GI Symposium, lead investigator Akihito Kawazoe, MD, of the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, discussed the study of napabucasin plus pembrolizumab in mCRC.
OncLive: Can you please provide some background on napabucasin?
We know that pembrolizumab showed an objective response rate (ORR) of 40% in microsatellite instability-high (MSI-H) CRC. On the other hand, it showed an ORR of 0% in patients with MSS CRC. It has been reported that WNT/β-catenin signaling has been involved in the elimination of lymphocyte infiltration and resistance to anti–PD-1. CRC is a tumor in which we need better catenin signaling activation. Preclinical models show that napabucasin in combination with anti–PD-1 shows antitumor activity. Thus, we initiated a phase I/II study of napabucasin in combination with pembrolizumab for CRC.
The study has 2 cohorts. Cohort A is MSI-H CRC, and the target number is 10. Cohort B is MSS CRC, with a target number of 40.
What did you find?
The safety profile is tolerable and expected with no DLTs. We decided to recommend a phase II dose of napabucasin at 480 mg per day with pembrolizumab at a fixed dose. One patient on 480 mg per day of napabucasin showed remarkable shrinkage. Also, a biomarker analysis showed that [there was] CD8 infiltration inside the tumor; this was observed by immunohistochemistry and flow cytometry.
What impact could this study have on clinical practice for mCRC?
There are unmet medical needs for MSS CRC in the development of immunotherapy. We will have those promising results in this study, so that we can [hopefully] change the [state of] immunotherapy in MSS CRC by this combination of napabucasin and pembrolizumab.
What do you predict to be the next steps of this combination?
We can show the promising result in this phase I/II trial, so then [we can begin] the phase III trial for MSS CRC of this combination in the future.
Kawazoe A, Kuboki Y, Komatsu Y, et al. Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503. J Clin Oncol. 2018;36(suppl 4S; abstr 760).