1. Fuerst, Mark L.

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SAN FRANCISCO-The innovative combination of cetuximab, encorafenib, and binimetinib continues to show potential as a new treatment option for patients with BRAF V600E metastatic colorectal cancer (mCRC), according to a new study.

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BRAF mutations are detected in 10-15 percent of mCRC patients and confer a poor prognosis, with a progression-free survival (PFS) of approximately 2 months, objective response rates (ORRs) generally less than 10 percent, and an overall survival (OS) of less than 6 months after failure of first-line therapy.


In a phase II study in patients with BRAF V600E mCRC, treatment with the anti-EGFR antibody cetuximab plus the BRAF inhibitor encorafenib led to a median PFS of 4.2 months, an ORR of 22 percent, and a median OS of more than 1 year, substantially improving outcomes relative to historical data for this population.


Results from the study led to the initiation of the BEACON CRC phase III study. The MEK inhibitor binimetinib was added into the treatment regimen because it has shown to improve efficacy and tolerability over BRAF inhibition alone in several tumor settings, including mCRC, reported Eric Van Cutsem, MD, Head of Digestive Oncology at the University Hospitals Gasthuisberg Leuven in Leuven, Belgium, at the 2018 ASCO Gastrointestinal Cancers Symposium, held Jan. 18-20 (Abstract 627).


Study Details

BEACON CRC is a 3-arm multicenter, randomized, phase III study evaluating the triplet combination of binimetinib, encorfenib, and cetuximab compared with investigator's choice of irinotecan standard biweekly dose plus cetuximab or folinic acid/5-fluorouracil/irinotecan (FOLFIRI) plus cetuximab and to the doublet combination of encorfenib and cetuximab in patients with BRAF V600E mCRC whose disease has progressed after one or two prior regimens in the metastatic setting.


A safety lead-in study for this triplet combination led to a preliminary analysis that showed, in addition to the 41 percent of patients with BRAF V600E tumors who responded, an additional 31 percent had extended stable disease of 6 or more months.


Van Cutsem reported updated results from the trial with approximately 3 months of additional follow-up as well as analyses exploring the association of CEA and CA19-9 changes while on treatment with clinical outcomes.


All 30 patients were treated with the single starting dose of encorafenib 300 mg once daily plus binimetinib 45 mg twice daily plus cetuximab at the standard weekly dose of 400 mg/m2 as initial dose, then 250 mg/m2 once weekly administered in 28-day cycles.


A BRAF V600E mutation was identified in 29 patients; one treated patient was determined to have a non-V600 BRAF mutation. Of the 29 patients with a BRAF V600E mutation, the median time on study treatment was 7.9 months, and one-third of patients remained on study treatment.


In patients with BRAF V600E mCRC, confirmed ORR was seen in 14/29 (48%) of patients, including a complete response in 3/29 (10%) patients. The ORR in patients with one previous line of therapy was 62 percent (10/16 patients), including eight partial responses (PR) and two complete responses (CR). In patients with two previous lines of therapy, it was 31 percent (4/13 patients), including three PRs and one CR.


The majority of responses were observed at first tumor assessment at 6 weeks, and the median duration of response was 5.4 months. Responses were ongoing in six of 14 responding patients (43%). In addition, the remaining 15 patients all achieved stable disease as their best response, and among them, nine patients (60%) had prolonged stable disease of 6 or more months.


Of the 28 patients with a BRAF V600E mutation and a post-baseline tumor assessment, tumor regressions were observed in all but one patient.


Preliminary estimate of median PFS is 8 months, with seven of 29 patients (24%) still in follow-up and progression-free. PFS was similar between patients who had one versus two previous regimens (median 7.6 vs. 8.1 months, respectively).


One-third of the patients were still on treatment and two-thirds had discontinued treatment. The median time on study treatment was 7.8 months. One patient (without the BRAF V600E mutation) died while on treatment and four additional patients died within 30 days of the last dose of study drug, all due to disease progression.


Grade 3/4 adverse events reported in 10 percent or more patients were fatigue (four patients), urinary tract infection (three patients), increased aspartate aminotransferase (AST) (three patients), and increased blood creatine phosphokinase (three patients). Of these, all were grade 3 except for a grade 4 AST increase in one patient.


The only grade 3/4 skin-related adverse event reported was rash (grade 3) in one patient (3%). The rate of severe skin toxicities (grade 3/4) was lower than generally observed for cetuximab alone or in combination with standard chemotherapy for mCRC.



"This triple combination continues to be generally well-tolerated with additional follow-up," Van Cutsem said. "Only one patient discontinued because of a treatment-related adverse event. Common adverse events were those associated with BRAF, MEK, and EGFR inhibitors and included gastrointestinal and skin toxicities." Severe skin adverse events were observed less frequently in the combination than reported rates for cetuximab monotherapy, he noted.


"The triplet combination continues to show promising antitumor activity, with additional responses, as well as additional CRs with further follow-up. Both ORR and PFS were substantially improved over historical standards of care, which generally have an ORR of less than 10 percent and a median PFS of approximately 2 months," said Van Cutsem.


Reduction in tumor markers CEA and CA19-9 were similar between patients with prolonged stable disease and objective response. "Changes in tumor markers indicate a biological effect on the disease and support a treatment effect leading to the observed clinical benefit in patients with prolonged stable disease," he concluded, noting that prolonged stable disease was observed in nine of 15 (60%) patients without a confirmed objective response.


Mark L. Fuerst is a contributing writer.