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Randomized phase 2 study of pegylated SN‐38 (EZN‐2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer
Author(s) -
Garrett Christopher R.,
BekaiiSaab Tanios S.,
Ryan Theresa,
Fisher George A.,
Clive Sally,
Kavan Petr,
ShachamShmueli Einat,
Buchbinder Aby,
Goldberg Richard M.
Publication year - 2013
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.28358
Subject(s) - irinotecan , cetuximab , medicine , colorectal cancer , kras , gastroenterology , oxaliplatin , cancer
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) and arm C (9.1 months; 95% CI, 6.0‐13.0 months). CONCLUSIONS EZN‐2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression‐free survival were similar in the cetuximab plus irinotecan arm and the EZN‐2208 arm. Cancer 2013;119:4223–4230 . © 2013 American Cancer Society .