Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.

Abstract

In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.

SIGNIFICANCE:

Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.

• Authors: David S Hong, Van K Morris, Badi El Osta, Alexey V Sorokin, Filip Janku, Siqing Fu, Michael J Overman, Sarina Piha-Paul, Vivek Subbiah, Bryan Kee, Apostolia M Tsimberidou, David Fogelman, Jorge Bellido, Imad Shureiqi, Helen Huang, Johnique Atkins, Gabi Tarcic, Nicolas Sommer, Richard Lanman, Funda Meric-Bernstam, Scott Kopetz
• Journal: Cancer discovery (Cancer Discov) Vol. 6 Issue 12 Pg. 1352-1365 (12 2016) ISSN: 2159-8290 [Electronic] United States
• PMID: 27729313 (Publication Type: Clinical Study, Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Indoles
• Sulfonamides
• Vemurafenib
• Irinotecan
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Cetuximab
• Camptothecin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives, therapeutic use)
• Cell Line, Tumor
• Cetuximab (administration & dosage, therapeutic use)
• Colorectal Neoplasms (drug therapy, genetics)
• Disease-Free Survival
• Drug Administration Schedule
• Female
• Humans
• Indoles (administration & dosage, therapeutic use)
• Irinotecan
• Male
• Mice
• Mutation
• Neoplasm Metastasis
• Proto-Oncogene Proteins B-raf (genetics)
• Sulfonamides (administration & dosage, therapeutic use)
• Survival Analysis
• Treatment Outcome
• Vemurafenib
• Xenograft Model Antitumor Assays