Significant Benefit Seen With BRAF/MEK/EGFR Triplet Regimen in mCRC

Scott Kopetz, MD, PhD

Scott Kopetz, MD, PhD

Updated results from an interim analysis of the phase III BEACON CRC trial demonstrated a significant improvement in overall survival (OS) for the triplet regimen of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) compared with cetuximab and irinotecan-containing regimens in patients with previously treatedBRAFV600E—mutant metastatic colorectal cancer (CRC).¹

"It's exciting to see the interim analysis results from the potentially practice-changing BEACON CRC trial, which demonstrated a significant improvement in outcomes compared to available standard of care options for patients withBRAFV600E-mutant metastatic colorectal cancer," lead study author Scott Kopetz, MD, PhD, an associate professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a statement ahead of the presentation at the 2019 ESMO World Congress on Gastrointestinal Cancer.²

Patients treated with the triplet combination had a median OS of 9.0 months compared with 5.4 months in patients treated with standard-of-care treatment (HR, 0.52; 95% CI, 0.39-0.70;P<.0001). Median progression-free survival was 4.3 months compared with 1.5 months for the triplet regimen and cetuximab and irinotecan-containing regimens, respectively (HR, 0.38; 95% CI, 0.29-0.49;P<.0001). Additionally, the objective response rate (ORR) by blinded independent central review (BICR) with the triplet was 26.1% versus 1.9% with standard of care (P<.0001).²

&ldquo;These are very exciting results because we&rsquo;ve been trying to targetBRAF-mutant colorectal cancer for many years. It&rsquo;s encouraging to see such a significant improvement in overall survival and response in patients with such aggressive tumor biology,&rdquo; Kopetz said in a statement. &ldquo;Hopefully, this will soon lead to increased access to this treatment for patients where there is currently such a large unmet need.&rdquo;

Improvements were also seen in the interim analysis for secondary endpoints, including for benefit seen with the combination of encorafenib and cetuximab compared with standard of care. The median OS with the doublet was 8.4 months compared with 5.4 months for the control arm (HR, 0.60; 95% CI, 0.45-0.79;P= .0003). The median PFS for the doublet was 4.2 months versus 1.5 months with the standard-of-care treatment (HR, 0.40; 95% CI, 0.31-0.52;P<.0001). The ORRs per BICR were 20.4% and 1.9% for the BRAF/MEK inhibitor doublet and the cetuximab and irinotecan-containing regimens, respectively (P<.0001).²

A descriptive comparison of the triplet combination to the encorafenib/cetuximab doublet showed a positive trend across endpoints, including ORR and OS (HR, 0.79; 95% CI, 0.59-1.06).

There were no unexpected toxicities noted with the triplet regimen. The safety profile was consistent with prior experiences for each individual agent and with the standard effects of MEK, RAF, and EGFR-directed therapies. Grade &ge;3 adverse events were observed in 58% of patients treated with the triplet, in 50% treated with encorafenib/cetuximab doublet, and in 61% of patients treated with the standard-of-care treatments. Discontinuation due to adverse events was seen in 7%, 8%, and 11% of patients in the triplet, doublet, and control arms, respectively.²

Array BioPharma, the company developing encorafenib and binimetinib, announced that the findings from the BEACON CRC trial would be submitted for potential marketing approval in the second half of the year.

The triplet regimen has already received a breakthrough therapy designation from the FDA in August 2018 for the treatment of patients withBRAFV600E—mutant mCRC as detected by an FDA-approved test, following failure of 1 or 2 prior lines of treatment. The designation, as well as the inclusion in March 2019 of the triplet regimen in the National Comprehensive Cancer Network (NCCN) guidelines for patients with colon and rectal cancer as a category 2A recommended treatment, were based off of findings from the safety lead-in data to the BEACON CRC trial.

&ldquo;This targeted therapy combination should be a new standard of care for this patient group,&rdquo; Kopetz added in a statement.

The open-label, 3-arm, randomized trial enrolled 665 patients withBRAFV600E—mutant metastatic CRC who had previously received 1 or 2 prior treatment regimens in the metastatic setting. Patients were randomized 1:1:1 to receive encorafenib, binimetinib, and cetuximab; encorafenib and cetuximab; or investigator&rsquo;s choice of irinotecan or FOLFIRI (folinic acid, fluorouracil, and irinotecan) and cetuximab. The trial was amended to include an interim analysis of endpoints, including ORR and OS.

The safety lead-in portion of the trial included 30 patients treated with 300 mg of encorafenib, 45 mg twice daily of binimetinib, and standard cetuximab.³

Findings from the safety lead-in showed that at a median follow-up of 18.2 months, the median PFS was 8.0 months with the triplet and the median OS was 15.3 months. The ORR by local assessment was 48% and 3 patients achieved a complete response.

The ongoing ANCHOR-CRC trial (NCT03693170) is examining the use of the triplet regimen in the frontline setting for patients withBRAFV600E—mutant metastatic CRC. &ldquo;Further investigation is needed to determine if this combination may also benefit those with less advanced disease or as a first-line treatment,&rdquo; Kopetz suggested in a statement.

References:

1. Kopetz S, Grothey A, Van Cutsem E, et al. BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E—mutant metastatic colorectal cancer. Presented at: ESMO World Congress on Gastrointestinal Cancer 2019; July 3-6, 2019; Barcelona, Spain. Abstract LBA-006.
2. Array Biopharma. Array Biopharma announces interim analysis results from the BEACON CRC trial of Braftovi + Mektovi + Cetuximab for the treatment of BRAF V600E-mutant metastatic colorectal cancer at the ESMO 21st World Congress on Gastrointestinal Cancer. Press release. http://investor.arraybiopharma.com/news-releases/news-release-details/array-biopharma-announces-interim-analysis-results-beacon-crc. Issued July 6, 2019. Accessed July 9, 2019.
3. 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).J Clin Oncol.2019;37(suppl; abstr 688). doi: 10.1200/JCO.2019.37.4_suppl.688.