Case 1: BRAF-Mutated Metastatic Colorectal Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDShubham Pant, MD:Thank you for joining us for thisTargeted Oncology^™Expert Perspective Virtual Tumor Board^®focused on metastatic colorectal cancer. Throughout this presentation, my colleagues and I will review strategies for managing 4 clinical cases based on recent evidence as demonstrated in clinical trials.

I’m Dr Shubham Pant, an associate professor in the Department of Investigational Cancer Therapeutics and an associate professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer and Medicine, at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Also joining us in this discussion are Dr Richard Kim, associate member of the Gastrointestinal Oncology Department at Moffitt Cancer Center and associate professor of oncology at the South Florida College of Medicine in Tampa, Florida; Dr Michael Morse, a professor of medicine and professor in the Department of Surgery and a member of the Duke Cancer Institute in Durham, North Carolina; and Dr Gregory Riedlinger, assistant professor of pathology in the Division of Translational Pathology at Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School—Rutgers University in New Brunswick, New Jersey. Thank you for joining us. Let’s get started with our first case.

Our first case looks at a patient withBRAF-mutant metastatic colorectal cancer. This is the history and physical: A 73-year-old Caucasian male sought medical attention after experiencing bloody diarrhea. His past medical history is remarkable for hypertension, which was managed with losartan. He’s active and can perform daily activities without restriction. A colonoscopy showed a fungating mass in the descending colon, which was biopsied.

The pathology findings for this patient revealed invasive, poorly differentiated adenocarcinoma. Molecular testing showedKRASandNRASwild-type disease, but it wasBRAFV600E—mutant and was microsatellite stable.

The CEA [carcinoembryonic antigen] was 6.4 ng/mL. The CT [computed tomography] of his chest, abdomen, and pelvis showed a 9.5-cm mass in the descending colon, small bilateral lung nodules, and a 3-cm mass in the right lobe of the liver. His surgical consult for metastasectomy indicated unresectable disease.

First-line treatment with FOLFIRI [folinic acid, fluorouracil, and irinotecan] and bevacizumab was initiated. Imaging at 3 months showed stable disease in the liver and lung nodules. After 6 months of therapy, the patient complained of increased fatigue, requiring the need for frequent rest. A CT scan showed an increase in the size of the liver nodule and the appearance of 4 new small liver lesions.

I’m going to go through some of the data related toBRAF-mutant metastatic colorectal cancer. The first was presented by Scott Kopetz—SWOG S1406. The SWOG S1406 trial was a randomized trial in patients withBRAFV600E—mutant colorectal cancer. The arms were cetuximab with irinotecan, which is considered the standard of care. This was with or without vemurafenib as an add-on in the treatment arm. This was, again, for patients with a PS [performance status] of 0/1. The important thing to mention is that these patients had received 1 or 2 prior systemic therapies for metastatic or locally advanced unresectable disease. We saw a median progression-free survival benefit of 4.4 months versus 2 months with a hazard ratio of 0.42. ThePvalue was statistically significant: .0002. The overall response rate was 16% versus 4%, and there was a better disease control rate: 67% versus 22%.

The other trial, which is a precursor to the new trial that is going on, is the COLUMBUS trial. This looked atBRAF-mutant melanoma with a combination of encorafenib and binimetinib, which is also relevant in colorectal cancer, as the next few slides will show us.

This looked at the progression-free survival of encorafenib plus binimetinib versus vemurafenib in melanoma, and this combination has been approved by the FDA forBRAFV600E patients with metastatic melanoma. This is relevant to our patients with colorectal cancer because of the BEACON trial that is currently ongoing, which we saw earlier results on at this year’s ASCO [American Society of Clinical Oncology] Gastrointestinal Cancers Symposium.

This is a phase III randomized controlled trial of patients withBRAFV600E—positive metastatic colorectal cancer and progression on 1 or 2 prior regimens of therapy. This is a combination of encorafenib, which is a BRAF inhibitor; binimetinib, which is a MEK inhibitor; and cetuximab, which is an EGFR inhibitor, versus irinotecan/cetuximab or FOLFIRI/cetuximab.

The presentation was on the trial safety lead-in of 30 patients. Even in these patients, there was an overall response rate of 48% and a median progression-free survival of 8 months. Most of the grade 3/4 adverse events were fatigue, UTI [urinary tract infection], increased AST [aspartate aminotransferase], and increased blood creatine phosphokinase. About 3% of patients had grade 3/4 rash.

Transcript edited for clarity.