FOLFIRI plus dulanermin (rhApo2L/TRAIL) in a patient with BRAF-mutant metastatic colon cancer.

Abstract

Colorectal cancer patients with BRAF-mutant tumors have a more aggressive, rapidly progressing disease that is in critical need of novel therapeutic approaches. Indeed, whereas the median overall survival (OS) of colorectal cancer (CRC) patients receiving standard-of-care therapy is approximately two years or more if their tumors express wild-type BRAF and wild-type KRAS, median OS is less than twelve months with tumors expressing V600E-mutant BRAF and wild-type KRAS. Pro-apoptotic receptor agonists are a class of biologic agents under development to induce tumor-specific apoptosis and are being combined with classical chemotherapy or targeted agents in clinical trials. Herein, we present the case of a patient with bulky V600E-mutant BRAF hepatic flexure colon carcinoma, treated initially with FOLFOX plus bevacizumab neoadjuvant therapy and surgery. The patient had a rapid tumor relapse with metastatic disease to the liver and lung, and was enrolled in a phase 1b open-label clinical study, where he received the FOLFIRI regimen in combination with the pro-apoptotic receptor agonist dulanermin (rhApo2L/TRAIL). The patient maintained stable disease through 25 doses administered every two weeks before his disease progressed. After coming off study, the patient underwent surgical debulking and received intraperitoneal hyperthermic chemotherapy. He subsequently relapsed and was treated with FOLFIRI plus cetuximab. At the time of this report, the patient remains on active treatment. It is unclear what effect dulanermin may have had on the course of his disease, but it is noteworthy that the patient remained on FOLFIRI plus dulanermin therapy for a period that exceeded the median OS for patients with advanced, aggressive BRAF-mutant CRC. It is also noteworthy that at the time of this report the patient's overall survival since diagnosis has exceeded 30 months, which is beyond what is generally observed even for patients with CRC harboring wild-type BRAF and wild-type KRAS.

• Authors: Bora Lim, Angelique Scicchitano, Cheryl Beachler, Niraj Gusani, Nabeel Sarwani, Zhaohai Yang, Kevin Staveley-O'Carroll, Avi Ashkenazi, Chia Portera, Wafik S El-Deiry
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 14 Issue 8 Pg. 711-9 (Aug 2013) ISSN: 1555-8576 [Electronic] United States
• PMID: 23792567 (Publication Type: Case Reports, Journal Article)

Chemical References

• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Colorectal Neoplasms (drug therapy, enzymology, genetics, pathology)
• Fluorouracil (administration & dosage)
• Humans
• Leucovorin (administration & dosage)
• Male
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Proto-Oncogene Proteins B-raf (genetics)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage)