Randomized phase 2 study of pegylated SN‐38 (EZN‐2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer
Abstract
Background Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines. Methods Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m(2) on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m(2) loading dose on day 1 followed by 250 mg/m(2) weekly starting on day 8 [arm B]) or irinotecan 125 mg/m(2) on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C). Results The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) a…
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EZN-2208 was generally well tolerated across multiple early-phase clinical studies in solid malignancies.
“Across these studies, EZN-2208 was generally well tolerated.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [329]
In advanced colorectal cancer, combination therapy with EZN-2208 and cetuximab did not confer a survival advantage compared with irinotecan plus cetuximab.
“In contrast, in advanced colorectal cancer, combination therapy with EZN-2208 and cetuximab did not confer a survival advantage compared with irinotecan plus cetuximab, indicating limited efficacy in this setting [329].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [329]
Cites
Cunningham, D., Pyrhönen, S., James, R. D., Punt, C. J., Hickish, T. F., Heikkila, R., Johannesen, T. B., Starkhammar, H., Topham, C. A., Awad, L., et al. (1998) · The Lancet · doi:10.1016/s0140-6736(98)02309-5 · Cited by 1,259 · see citing works
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HIF Inhibitors: Status of Current Clinical Development
Fallah, J., & Rini, B. I. (2019) · Current Oncology Reports · doi:10.1007/s11912-019-0752-z · Cited by 308 · see citing works
Kao, T.-W., Bai, G.-H., Wang, T.-L., Shih, I.-M., Chuang, C.-M., Lo, C.-L., Tsai, M.-C., Chiu, L.-Y., Lin, C.-C., & Shen, Y.-A. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02724-y · Cited by 89 · see citing works
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
“In contrast, in advanced colorectal cancer, combination therapy with EZN-2208 and cetuximab did not confer a survival advantage compared with irinotecan plus cetuximab, indicating limited efficacy in this setting [329].”
- Authors
- Garrett, C. R., Bekaii‐Saab, T. S., Ryan, T., Fisher, G. A., Clive, S., Kavan, P., Shacham‐Shmueli, E., Buchbinder, A., & Goldberg, R. M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- NYU Langone Health (US)
- Stanford Medicine (US)
- Edinburgh Cancer Research (GB)
- Jewish General Hospital (CA)
- Tel Aviv Sourasky Medical Center (IL)
- Enzon Pharmaceuticals (United States) (US)
- Corresponding author
- Goldberg, Richard M.
- ORCID
- Venue
- Cancer
- Publisher
- Wiley
- Published
- 2013-09-16
- Volume
- 119
- Issue
- 24
- Pages
- 4223-4230
- ISSN
- 0008-543X (ISSN-L)
- 1097-0142
- OpenAlex
- W1516980941
- Cited by
- 62
- References
- 1
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 4 · 2020: 1 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 3
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA016086)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- irinotecan, cetuximab, advanced colorectal cancer, metastatic colorectal cancer, KRAS mutation, EGFR inhibition, combination chemotherapy, progression-free survival, drug toxicity
- MeSH terms
- Cetuximab, Irinotecan, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Antineoplastic Agents, Phytogenic, Camptothecin, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Recurrence, Local, Polyethylene Glycols, Proto-Oncogene Proteins, Genes, ras, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Disease-Free Survival, ras Proteins, Cell Line, Tumor, Young Adult, Antibodies, Monoclonal, Humanized
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