Multicenter phase I/II trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial)
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Abstract
Purpose: This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC). Patients and Methods: Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite stable, MSS). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles, and the consensus molecular subtypes (CMS) of colorectal cancer were assessed. Results: A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The 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: Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort. See related commentary by Nusrat, p. 5775
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Positive responses have been reported for CMS4 patients treated with a combination of napabucasin and pembrolizumab.
“(ii) a combination of napabucasin (a STAT3 inhibitor) and pembrolizumab (EPOC1503/SCOOP trial; ref. 64)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [64]
Napabucasin plus pembrolizumab produced an immune-related objective response rate of 33% (2 of 6) in CMS4 patients with metastatic colorectal cancer.
“| Combined STAT3 and PD-1 | Napabucasin + pembrolizumab | Immune-related objective response rate in 33% of patients (2 of 6 CMS4 patients with metastatic colorectal cancer) | (64) |”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [64]
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- Authors
- Kawazoe, A., Kuboki, Y., Shinozaki, E., Hara, H., Nishina, T., Komatsu, Y., Yuki, S., Wakabayashi, M., Nomura, S., Sato, A., Kuwata, T., Kawazu, M., Mano, H., Togashi, Y., Nishikawa, H., & Yoshino, T.
- Affiliations
- National Cancer Centre Japan (JP)
- The Cancer Institute Hospital (JP)
- Saitama Cancer Center (JP)
- Shikoku Cancer Center (JP)
- Hokkaido University Hospital (JP)
- National Cancer Center Hospital East (JP)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-11-13
- Volume
- 26
- Issue
- 22
- Pages
- 5887-5894
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3044842170
- Cited by
- 93
- References
- 27
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 24 · 2023: 18 · 2022: 9 · 2021: 18 · 2020: 2
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dainippon Sumitomo Pharma (NA)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- napabucasin, pembrolizumab, metastatic colorectal cancer, microsatellite instability, PD-L1 combined positive score, tumor mutational burden, consensus molecular subtypes, combination immunotherapy, dose-limiting toxicity, biomarkers
- MeSH terms
- Antineoplastic Agents, Immunological, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzofurans, Female, Humans, Male, Middle Aged, Naphthoquinones, Neoplasm Metastasis, Colorectal Neoplasms, Microsatellite Instability, B7-H1 Antigen, Antibodies, Monoclonal, Humanized, Drug-Related Side Effects and Adverse Reactions
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