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Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406)
Scott Kopetz, Shannon L McDonough, Van Karlyle Morris, Heinz-Josef Lenz, Anthony Martin Magliocco, Chloe Evelyn Atreya, et al.
J Clin Oncol 35, 2017 (suppl 4S; abstract 520)
Editorial comment from Prof. Florian Lordick:
Survival outcomes for patients with BRAF-mutated metastatic colorectal cancers are much worse than for patients with BRAF wildtype tumors. BRAFinhibition alone was not shown to be effective in previous studies. This randomized controlled studyshows that dual inhibition of the EGFR and BRAF dependent pathway by combining cetuximab,vemurafenib in addition to standard chemotherapy with irinotecan is an effective treatment for thismolecular subtype of colorectal cancer. This confirms previous observation from uncontrolled smallertrials and may eventually lead to a new treatment option for patients who failed on previouschemotherapy.
RAFV600 mutations are associated with rare objective responses to the mutatedBRAF inhibitor vemurafenib in patients with mCRC. Blockade of BRAFV600 by vemurafenibcauses feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab.In murine models of BRAFV600 mCRC, the combination of irinotecan, cetuximab, and vemurafenib leads to greater anti-tumor activity, as suggested by a prior Phase 1B study.
Patients (pts) with BRAFV600 mutated and extended RAS wild-type mCRC wererandomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14days) with or without vemurafenib (960 mg PO twice daily). Patients had received 1 or 2 priorregimens, with no prior anti-EGFR agents, although prior irinotecan was allowed. Crossoverfrom the control arm to the experimental arm was allowed after documented progression. Theprimary endpoint was progression-free survival (PFS, investigator assessed), with 90% power todetect a HR of 0.5, with two-sided type 1 error of 5%.
106 patients were enrolled (54 in the experimental arm) from 12/2014 to 4/2016, with ECOG PS ≤ 1. Median age of 62 years, 59% female, and prior irinotecan therapy in 39%. PFS was improved with the addition of vemurafenib (HR = 0.42, 95% confidence interval [CI] of0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI: 3.6 – 5.7) months vs 2.0 (95% CI: 1.8– 2.1). Response rate was 16% vs 4% (P = 0.09), with disease control rate of 67% vs 22% (P <0.001). Grade 3/4 adverse events higher in the experimental arm included neutropenia (28% vs7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity orfatigue. No new safety signal was observed. Approximately 50% of patients in the control aimcrossed over at the time of progression. Overall survival and efficacy at cross-over data remainimmature.
The addition of vemurafenib to the combination of cetuximab and irinotecanresulted in a prolongation of progression-free survival and a higher disease control rate,indicating that simultaneous EGFR and BRAF inhibition is effective in BRAFV600 mutated CRC.Clinical trial information: NCT02164916.
All content © 2017 American Society of Clinical Oncology. All rights reserved.