Combining the investigational oral cancer stem cell pathway inhibitor napabucasin (BBI608) with the PD-1 inhibitor pembrolizumab (Keytruda) showed a signal of efficacy in the first 8 patients enrolled in a multicenter phase I/II trial of patients with metastatic colorectal cancer (mCRC).
One patient in phase I at dose level 2 (480 mg twice daily) had shrinkage of lung and lymph node metastases lasting >12 weeks with a “remarkable” decline in carcinoembryonic antigen (CEA) level, lead investigator Akhito Kawazoe, MD, said at the 2018 Gastrointestinal Cancers Symposium. This dose was determined as the recommended phase II dose. Analysis of repeated tumor sampling from this responder demonstrated infiltration of CD8+ T cells inside the tumor by immunohistochemistry and flow cytometry.
Napabucasin blocks phosphorylated STAT3 and downregulates β-catenin and PD-L1, explained Kawazoe, a resident, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Japan. “Recently, the WNT/β-catenin signaling pathway has been reported to prevent antitumor immunity and promote resistance of anti-PD-1/PD-L1 antibodies,” he said. Further, STAT3 is a key driver of this immune evasion.
For these reasons, the investigators initiated a phase I/II study to assess the efficacy and safety of combining oral napabucasin with IV pembrolizumab, using a 3+3 cohort-based dose escalation of napabucasin. Dosage level 1 of napabucasin was 240 mg twice daily and dosage level 2 was 480 mg twice daily. Pembrolizumab was administered as 200 mg/kg every 3 weeks.
The hope was that the napabucasin/pembrolizumab combination would show antitumor activity, even in microsatellite-stable (MSS) mCRC tumors, he said. In mouse models of mCRC, the combination produced tumor regression and an influx of tumor infiltrating lymphocytes.
All patients were treated previously with 1 or more standard chemotherapy regimens for mCRC, and were either refractory or intolerant. Cohort A includes a planned 10 patients with microsatellite instability-high mCRC and cohort B (phase II) will include 40 patients with MSS disease. So far, 37 patients have been enrolled in cohort B. Phase I results from 8 patients with MSS were reported here, 5 enrolled at dose level 1 and 3 in at dose level 2.
The primary site of the responder mentioned previously was the cecum, and this patient had lung, lymph node, liver, and peritoneal metastases and had been treated with 7 prior regimens. He had MSS and a mutation in RAS
. One additional patient experienced a decline in CEA level.
Two patients at dose level 1 were excluded from evaluation of dose-limiting toxicity (DLT) because of disease progression. Of the 8 patients in the DLT evaluation, the primary site was the right side of the colon in 2 and the left side in 6; all had metastases to the liver, 5 to the lung, and 6 to the lymph nodes. Five were RAS
wild type and 3 had RAS
-mutant mCRC. Six of the 8 had ≥3 lines of palliative chemotherapy; all 8 were refractory to fluoropyrimidine, oxaliplatin, irinotecan, an angiogenesis inhibitor, and an anti-EGFR inhibitor. Two had received prior regorafenib (Stivarga).
Treatment-emergent adverse events of any grade that appeared in ≥20% of patients included diarrhea in 4, fever in 3, anorexia in 2, weight loss in 2, and pain in 2. There were no treatment-emergent or treatment-related grade 3 or grade 4 adverse events, and there were no treatment-related study discontinuations. One patient developed hyperthyroidism.
The napabucasin/pembrolizumab combination showed “an efficacy signal and might evoke immunity in MSS mCRC, which will be confirmed by the ongoing phase II part,” the investigators concluded.
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. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 760.