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Addition of Vemurafenib to Irinotecan/Cetuximab in Previously Treated Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer


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In a phase II trial (SWOG S1406) reported in the Journal of Clinical Oncology, Scott Kopetz, MD, PhD, and colleagues found that the addition of vemurafenib to irinotecan and cetuximab significantly improved progression-free survival in previously treated patients with BRAF V600E–mutant metastatic colorectal cancer.

As stated by the investigators, “BRAF V600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer. Blockade of BRAF V600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab.”

Scott Kopetz, MD, PhD

Scott Kopetz, MD, PhD

Study Details

In the open-label study, 100 eligible patients were randomly assigned to vemurafenib plus irinotecan/cetuximab (n = 50) or irinotecan/cetuximab (control group, n = 50). Treatment consisted of oral vemurafenib at 960 mg twice daily and irinotecan at 180 mg/m2 and cetuximab at 500 mg/m2 every 2 weeks. The primary endpoint was progression-free survival. At disease progression, patients in the control group were permitted to cross over to receive vemurafenib plus irinotecan/cetuximab.

Progression-Free Survival

Median progression-free survival was 4.2 months in the vemurafenib group vs 2.0 months in the control group (hazard ratio [HR] = 0.50, P = .001), with 9-week rates of 80% vs 39%. Objective response was observed in 17% vs 4% (P = .05), and disease control rates were 65% vs 21% (P < .001). Median overall survival among the randomly assigned groups was 9.6 months vs 5.9 months (HR = 0.77, P = .23). Among 21 patients in the control group who crossed over to receive the vemurafenib combination regimen, median progression-free survival following crossover was 5.4 months, with a response rate of 19% and a disease control rate of 76%.

Among 69 patients with data on circulating tumor DNA, reduction in circulating tumor DNA BRAF V600E variant allele frequency was observed in 87% vs 0% of patients (P < .001). Acquired KRAS mutations were observed in one patient in the vemurafenib group.

RNA sequencing in 71 patients showed that 36 (51%) had consensus molecular subtype (CMS) 1. The progression-free survival benefit of vemurafenib showed little variation with CMS or a previously reported signature of MAPK pathway activation.

KEY POINTS

  • Progression-free survival was significantly improved with vemurafenib plus irinotecan/cetuximab vs irinotecan/cetuximab.
  • Among control group patients crossing over to the vemurafenib combination regimen after disease progression, median progression-free survival following crossover was 5.4 months.

Adverse Events

Grade 3 and 4 adverse events that occurred at a higher incidence in the vemurafenib vs control groups included neutropenia (30% vs 7%), anemia (13% vs 0%), and nausea (19% vs 2%). Adverse events resulted in discontinuation of treatment in 22% vs 8% of patients.

The investigators concluded, “Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF V600E–mutated colorectal cancer.”

Dr. Kopetz, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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