Triplet Combo Improves Survival for BRAF V600E-Mutant mCRC

Scott Kopetz, MD, PhD

Updated findings from the safety lead-in (SLI) phase of the BEACON CRC trial showed an estimated survival time beyond historic controls from treatment with a triplet combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) for patients with BRAFV600E-mutant metastatic colorectal cancer.

Findings presented at the 2019 Gastrointestinal Cancers Symposium covered 30 patients, who demonstrated a 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.¹

The overall response rate (ORR) was 48% by local assessment, with 3 patients achieving a complete response (CR). Up to 15% of patients with metastatic colorectal cancer haveBRAFV600E mutations, which confer poor prognosis.

“We know that these patients have very poor survival; their median survival from the diagnosis is about 12 months,” said presenter Scott Kopetz, MD, PhD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, Texas. “The ORR of 48% is substantially better than historic controls, and encouraging that our OS is a median of 15 months with reasonably mature data. This is encouraging because these were patients who were received either second- or third-line treatment, and we’re seeing survivals that would exceed even what a first-line population would expect. This sets the stage for the phase III BEACON CRC results.”

Standards of care, generally with a cetuximab-based regimen, have historically demonstrated ORRs <10%, median PFS rates of about 2 months, and median OS rates of only 4 to 6 months, he noted.

The rationale for the triplet is the minimal effectiveness of BRAF inhibitors alone in colorectal cancer, &ldquo;due in part to feedback through growth factor receptors such as epidermal growth factor receptor (EGFR),&rdquo; Kopetz said. &ldquo;The EGFR inhibitor is blunting that feedback. That feedback results in MAP kinase pathway activation. Importantly, when we look at patients who are progressing on BRAF/EGFR inhibition we&rsquo;re seeing reactivation of the MAP kinase pathway through acquired alterations, including upstream. The addition is binimetinib, which is a MEK inhibitor that&rsquo;s also in the MAP kinase pathway, and you get optimal pathway inhibition and blunt at least some of the mechanisms of potential acquired resistance that could occur.&rdquo;

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 withBRAFV600E-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 &ge;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 aBRAFV600E 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/m²once weekly. Of the 30 patients, 29 had a&nbsp;BRAFV600E 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 withBRAFV600E 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 &ge;6 months in 43% of the responders by local assessment and 73% by central assessment.

&ldquo;We&rsquo;re encouraged by the durability of the regimen, acknowledging that durability with doublets is on the shorter side,&rdquo; said Kopetz.

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.

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.