Encorafenib/Binimetinib-based Triplet Added to NCCN Guidelines for BRAF+ CRC

Scott Kopetz, MD, PhD, FACP, associate professor of oncology and urology at Johns Hopkins Medicine

Scott Kopetz, MD, PhD, FACP

The NCCN has updated their clinical practice guidelines for the treatment of patients with colorectal cancer (CRC) to include the regimen of encorafenib (Braftovi) and binimetinib (Mektovi) plus EGFR inhibition with either cetuximab (Erbitux) or panitumumab (Vectibix) as a Category 2a treatment recommendation for patients with BRAF V600E—mutant metastatic colorectal cancer (CRC), after failure of 1 or 2 lines of therapy for metastatic disease.

Array BioPharma Inc, the manufacturer of encorafenib and binimetinib, reported in a press release that the NCCN based its recommendation on data from the BEACON CRC trial. Data reported at the 2019 Gastrointestinal Cancers Symposium from the safety lead-in (SLI) phase of the trial showed that clinical outcomes with the BRAF inhibitor encorafenib, the MEK inhibitor binimetinib, and cetuximab exceeded historic data in patients with BRAF V600E-mutant metastatic CRC.

Results from 30 patients showed an estimated median progression-free survival (PFS) of 8.0 months and an estimated median overall survival (OS) of 15.3 months with a median duration of follow-up of 18.2 months. The overall response rate (ORR) was 48% by local assessment, with 3 patients achieving a complete response (CR).

"With no current FDA-approved therapies for BRAF CRC, this combination represents an important treatment option for this patient population," BEACON trial lead author Scott Kopetz, MD, PhD., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a statement.

"Historical published benchmarks in BRAF V600E—mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy, are an overall response generally between 4% to 8%, a median progression-free survival of 2 to 3 months, and median overall survival of 4 to 6 months. The NCCN recommendation underscores the potential for this triplet combination to benefit these patients in critical need."

BEACON CRC is a randomized open-label 3-arm phase III study evaluating the triplet compared with irinotecan-based chemotherapy plus cetuximab and encorafenib plus cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer after 1 or 2 prior lines of treatment in the metastatic setting. Enrollment was completed in 2018. BEACON SLI was conducted to evaluate safety and efficacy of the triplet prior to randomizing patients to the phase III portion.

The primary endpoint of BEACON CRC is OS associated with the triplet combination compared with the control arm.

Previously, as reported at the 2018 Gastrointestinal Cancers Symposium, the triplet combination was generally well-tolerated in the SLI. Of the 2 patients who discontinued treatment due to adverse events, 1 was considered related to treatment. The most common grade ≥3 adverse events were fatigue (n = 4), urinary tract infection (n = 3), an increase in the level of aspartate aminotransferase (n = 3), and an increase in the level of blood creatine kinase (n = 3). At that report, in the 29 patients with a BRAF V600E mutation, the estimated median PFS was 8 months and the confirmed ORR was 48%, with 3 patients achieving complete responses.²

The 30 patients treated in the SLI portion of the study received encorafenib at 300 mg daily, binimetinib at 45 mg twice daily, and cetuximab at the standard weekly dose of 400 mg/m², then 250 mg/m² once weekly. Of the 30 patients, 29 had a BRAF V600E mutation. Median patient age was 59 years. Sixty percent had received 1 prior line of therapy and 40% received 2 prior lines. Forty-three percent received prior irinotecan. At the data cutoff of September 2, 2018, 6 patients remained on treatment.

Efficacy was evaluated in the 29 patients with BRAF V600E mutations, who were on study treatment for a median of 7.9 months. The confirmed 48% ORR by local assessment consisted of 3 CRs, 11 (38%) partial responses (PRs), and 13 (45%) with stable disease (SD). The 41% ORR by central assessment included 2 CRs, 10 (34%) PRs, and 13 (45%) with SD. The median duration of response was 5.5 months by local assessment and 8.2 months by central assessment. The duration of response estimate was ≥6 months in 43% of the responders by local assessment and 73% by central assessment.

When response was stratified by number of previous lines of therapy, the ORR by local assessment was 59% with 1 previous line (8 PRs and 2 CRs) and 33% (3 PRs and 1 CR) with 2 previous lines, and by central assessment, the ORR was 53% (8 PRs and 1 CR) with 1 previous line of therapy and 25% (2 PRs and 1 CR) with 2 previous lines.

The 6-month OS was 86.2% and the 12-month OS was 62.1%. Adverse events (AEs) were similar to those previously reported with BRAF, MEK, and EGFR inhibitors. The most common grade 3/4 AEs were fatigue (n = 4), anemia, increased level of creatine kinase, asthenia, and urinary tract infection (n = 3 for each AE); dyspnea (n = 2); and gastrointestinal toxicities such as nausea, vomiting, decreased appetite (n = 2 for each). Six patients (20%) had at least 1 drug discontinued due to AEs, 1 of whom discontinued all 3 drugs due to grade-2 fatigue.

"Patients with BRAF V600E—mutant mCRC are in great need of effective treatment options," Ron Squarer, CEO of Array, said in a press release. "Based on data from the safety lead-in portion of the BEACON CRC phase III trial, the FDA granted breakthrough therapy designation in August 2018 for Braftovi, in combination with Mektovi and cetuximab for the treatment of patients with BRAF V600E—mutant mCRC as detected by an FDA-approved test, after failure of 1 to 2 prior lines of therapy for metastatic disease. We look forward to the interim analysis of the randomized portion of the trial in the first half of this year."

References

1. Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 688.
2. Van Cutsem, E, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in in patients with BRAF V600E metastatic colorectal cancer. Presented at: 2018 Gastrointestinal Symposium; January 18-20; San Francisco, CA. Abstract 627.