Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial)

**Purpose:** This phase I/II trial aimed to evaluate the efficacy and safety of combining napabucasin with pembrolizumab in treating metastatic colorectal cancer (mCRC).

**Patients and Methods:** The phase I portion of the study focused on determining the recommended phase 2 dose (RP2D) using a dose-escalation design, where napabucasin was administered at doses ranging from 240 to 480 mg twice daily alongside 200 mg of pembrolizumab every three weeks. Phase II involved two cohorts: cohort A (n = 10, with microsatellite instability-high [MSI-H]) and cohort B (n = 40, with microsatellite stable [MSS]). The primary endpoint was the immune-related objective response rate (irORR). Additional assessments included PD-L1 combined positive score (CPS), genomic profiles, and consensus molecular subtypes (CMS) of colorectal cancer.

**Results:** A total of 55 patients were enrolled in the study. In phase I, no BBI608 dose-limiting toxicities were observed, leading to the selection of 480 mg of napabucasin as the RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. Within cohort B, the irORR was 0%, 5.3%, and 42.9% for CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients who showed an objective response tended to have a higher tumor mutation burden compared to those who did not. Among the 18 patients in cohort B who were evaluable for CMS classification, the irORR was 33.3% for CMS1, 0% for CMS2, 33.3% for CMS3, and 33.3% for CMS4. Common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A, and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.

**Conclusions:** The combination of napabucasin and pembrolizumab demonstrated antitumor activity with acceptable levels of toxicity in both MSS and MSI-H mCRC patients, although the primary endpoint was not met. Further investigation into the impact of related biomarkers on efficacy is warranted in future studies with additional cohorts.