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Triplet Therapy Poses a Triple Threat to BRAF-Mutated Colorectal Cancers


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Triplet therapy that inhibits the BRAF, MEK, and epidermal growth factor receptor (EGFR) pathways appears promising in BRAF-mutated colorectal cancer, a malignancy that typically does not respond to BRAF inhibition alone. Early results from the BEACON CRC study showed a 48% response rate and an estimated median progression-free survival of 8.0 months in patients receiving encorafenib, binimetinib, and cetuximab (Erbitux).1

BRAF mutations are detected in 10% to 15% of metastatic colorectal cancer cases. These patients have a poor prognosis after the failure of first-line therapy, with a median progression-free survival of about 2 months and overall survival of less than 6 months, said the study’s senior author, Axel Grothey, MD, PhD, of the Mayo Clinic, Rochester.

Axel Grothey, MD, PhD

Axel Grothey, MD, PhD

“In BRAF-mutated colorectal cancer, the RAS, MEK, and MAP kinase pathways are all activated. While a BRAF inhibitor plus a MEK inhibitor can produce long-term survival in melanoma, it doesn’t work as well in colon cancer because of feedback activation of the EGFR, which is upstream and not present on the surface of melanoma cells,” he explained in an interview. 

“When you block the BRAF pathway, there’s a feedback loop up to EGFR, which is then activated, so it overrides the pathway,” he said. It is thought that in colon cancer, targeting the EGFR pathway may overcome resistance to BRAF and MEK inhibitors. 

BEACON CRC Details

At the 2018 Gastrointestinal Cancers Symposium, Eric Van Cutsem, MD, PhD, of the University Hospital Gasthuisberg in Leuven, Belgium, reported the results of the safety lead-in to the BEACON CRC phase III trial. The trial evaluated the safety and efficacy of the combination of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib, given with the anti-EGFR antibody cetuximab, in patients with BRAF V600E–mutant metastatic colorectal after one or two prior regimens. 

The study also measured levels of carcinoembryonic antigen (CEA) and CA 19-9, tumor markers widely used to monitor the effectiveness of systemic therapies. Researchers evaluated the association of changes in these markers with clinical outcomes. 

Eric Van Cutsem, MD, PhD

Eric Van Cutsem, MD, PhD

The randomized phase III portion of the study is currently enrolling 615 patients to one of three arms: the targeted triplet, a doublet of encorafenib plus cetuximab, or a chemotherapy-based control arm of FOLFIRI (leucovorin, fluorouracil, irinotecan) plus cetuximab or irinotecan plus cetuximab. Patients will be treated until disease progression. 

In the phase I dose-determining, dose-expansion study, 30 patients received the following starting doses: encorafenib at 300 mg daily plus binimetinib at 45 mg twice a day plus cetuximab at 400 mg/m2 (initial dose) then 250 mg/m2 -weekly in 28-day cycles.

Efficacy results in 29 patients showed that 14 patients (48%) responded, including 10 (62%) after 1 prior regimen and 4 (31%) after 2 regimens. The 48% response rate included 3 (10%) complete responses. A total of 13 patients (45%) had stable disease.

“We saw that none of the BRAF V600E–mutated -patients had progressive disease as their best response,” Dr. Grothey noted. 

The median duration of response was 5.4 months. Responses were ongoing in 6 of 14 responding patients (43%) at data cutoff. In the remaining 15 patients, 9 (60%) had stable disease for at least 6 months (range, 7–12 months). 

Tumor regression was observed in all except 1 patient, among the 28 patients with postbaseline tumor assessments. This contrasts with results achieved with standard-of-care therapies, the researchers noted.

The preliminary estimate of median progression-free survival is 8.0 months, with 7 (24%) still in follow-up and progression-free. Median progression-fee survival is similar between patients who had one vs two previous regimens.

The authors noted that both response rate and progression-free survival were substantially improved over historical standards of care, which generally produce responses in < 10% of patients and a median progression-free survival of about 2 months.

“Historically, median overall survival is about 5 to 6 months for patients [with metastatic colorectal cancer] in the second- and third-line settings. Here, median progression-free survival was more than 8 months,” Dr. Grothey said. 

Triplet Well Tolerated 

Grade 3/4 adverse events reported in more than 10% of patients included fatigue (n = 4), urinary tract infection (n = 3), increased aspartate aminotransferase levels (n = 3), and increased blood creatine phosphokinase levels (n = 3). One patient had a grade 3 rash, and one patient discontinued therapy because of treatment-related fatigue.

The observed adverse events were consistent with known BRAF, MEK, and EGFR inhibitor toxicities. The rate of grade 3/4 skin toxicities was lower than is generally observed for cetuximab alone or in combination with standard chemotherapy for metastatic colorectal cancer, the researchers noted. 

Tumor Markers

All patients whose CEA and CA 19-9 levels were elevated at baseline showed decreases in these tumor markers. There were no notable differences in percentage change in either CEA or CA 19-9 levels from baseline to nadir between patients with a confirmed response and those with prolonged stable disease. 

“The changes in tumor markers indicate a biologic effect on the disease and support a treatment effect leading to the observed clinical benefit in patients with prolonged stable disease,” the investigators noted. ■

DISCLOSURE: Dr. Grothey has had a consulting or advisory role with Amgen, Array BioPharma, Bayer, Boston Biomedical, Bristol-Myers Squibb, Genentech/Roche, Guardant Health, and Lilly; has received institutional research funding from Bayer, Boehringer Ingelheim, Boston Biomedical, Eisai, Genentech/Roche, Lilly, Pfizer, and Sanofi; and has received travel and accommodation expenses from Amgen, Bayer, Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, Genentech/Roche, and Merck Sharp & Dohme. Dr. Van Cutsem has had a consulting or advisory role with Bayer, Lilly, Roche, and Servier and has received institutional research funding from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck, Merck KGaA, Novartis, Roche, Sanofi, and Servier.

REFERENCE

1. Van Cutsem, E, Cuyle P-J, Huijberts S, et al: BEACON CRC study safety lead-in in patients with BRAFV600E metastatic colorectal cancer. 2018 Gastrointestinal Cancers Symposium. Abstract 627. Presented January 20, 2018.


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