Triplet Combination Demonstrates Promise for Frontline Treatment of BRAF V600E–mutant CRC

Doublet and triplet chemotherapy-based therapies are standard treatment options for patients with BRAF V600–mutant metastatic colorectal cancer.

Doublet and triplet chemotherapy-based therapies are standard treatment options for patients with BRAF V600–mutant metastatic colorectal cancer (CRC). However, this population of patients have traditionally poor outcomes with chemotherapy-based regimens, yet BRAF inhibitors alone are not effective enough to overcome the feedback activation of EGFR.1

Investigators of the ANCHOR-CRC trial (NCT03693170) hypothesized that targeting multiple nodes in the MAPK pathway may elicit better responses for patients and fill an urgent unmet need for patients whose disease harbors BRAF V600 mutations.2 Specifically, the study was designed to examine the efficacy of the triplet combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in the first-line setting.

Updated data analysis presented at the 2021 European Society of Medical Oncology Virtual World Congress on Gastrointestinal Cancer demonstrated that the trial met its primary end point of observed confirmed objective response rate (cORR). In total 92 patients were evaluable and the investigator-assessed cORR was 47.8% (95% CI, 37.3%-58.5%); all responses were partial responses for a disease control rate of 88%. Progressive disease was reported in 5.4% of patients.2

The analysis combined 41 patients enrolled to stage 1 of the study with an additional 54 patients enrolled to stage 2. At the time of presentation 6 patients (15%) from stage 1 and 14 patients (26%) from stage 2 remained on treatment. For the 75 patients who discontinued therapy, the cited reasons included progressive disease (64%), adverse effects (AEs; 21%), investigator decision (8%), and other (7%).

Patients with treatment-naïve mCRC and a confirmed BRAF V600E mutation were treated with oral encorafenib (300 mg daily), oral binimetinib (45 mg orally twice daily), and intravenous cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 weekly for the first 28 weeks, followed by 500 mg/m2 once every 2 weeks).

At baseline evaluation, the median age was 65 years (range, 30-84) with median time since initial diagnosis of 66 days. Most patients (60%) had right-side or transverse primary tumors and the remaining (40%) had either left-side tumors or tumors located in the rectum. In terms of metastases, most patients (75.8%) had greater than 2 organs involved including the liver (54.7%), lymph node (51.6%), peritoneum/omentum (48.4%), and lung (36.8%).

Secondary end points of the study were progression-free survival (PFS), overall survival (OS), safety, quality of life, and pharmacokinetics.

At median follow-up of 4.8 months the median PFS was 5.8 months (95% CI, 2.6-6.4) for patients treated with the triplet. At a median follow-up of 14.4 months, the median OS was 17.2 months (95% CI, 14.1-21.1). For 95 patients included in the OS analysis the OS rates at 12, 18, and 24 months were 65%, 49%, and 29%, respectively.

Investigators noted that most patients were able to receive active subsequent therapies. The median time to subsequent therapy was 6.9 months (range, 5.9-8.4). Specifically, 43.2% of patients went on to receive antineoplastic therapy of either oxaliplatin-based doublet with or without bevacizumab (Avastin), FOLFOXIRI with or without bevacizumab, or immunotherapy.

In terms of safety, the results reported for the triplet combination were similar with those reported for recommended chemotherapy-based regimens. The most common all-grade AEs were diarrhea (67.4%), nausea (45.3%). dermatitis acneiform (40%), rash (40%), and vomiting (37.9%). The most common grade 3 or higher AEs were anemia (10.5%), increased lipase levels (10.5%), diarrhea (9.5%), and nausea (8.4%).

Further, the most frequent serious AEs of grade 3 or higher were intestinal obstruction (14.7%), renal failure (7.4%), nausea (5.3%), and abdominal pain (4.2%). Investigators also noted that no meaningful changes in patient reported outcomes.

Eric Van Cutsem, MD, who reported the data at the conference noted that these results were “encouraging” and “support exploring the combination of encorafetinib plus cetuximab with chemotherapy in the first line setting.” Van Cutsem is the division head of clinical digestive oncology at University of Leuven and University Hospitals Gasthuisberg, Leuven, Belgium.

Investigators of the ongoing BREAKWATER study (NCT04607421) will evaluate the efficacy of encorafetinib plus cetuximab with or without FOLFOX or FOLFIRI vs the control of physician’s choice of either FOLFOX, FOLFIRI, FOLFOXFIRI, or CAPEOX with or without anti-VEGF therapy. Patients who received prior systemic therapy in the metastatic setting are not eligible for enrollment. The primary end points of the study are PFS for arm A vs control and arm B vs control by blinded independent central review. Key secondary end points are OS for arm A vs control and arm B vs control. Other end points include incidence of dose-limited toxicities, AEs, dose modifications and drug-drug interactions.2,3

In April 2020, the combination of encorfenib and cetuximab was approved for the treatment of patients with metastatic CRC with a confirmed BRAF V600E mutation who experienced disease progression after 1 or 2 prior lines of therapy based on results of the BEACON CRC trial (NCT02928224).4 Investigators of the trial examined outcomes of the doublet regimen as well as the triplet regimen of encorafenib, binimetinib, and cetuximab against the control of investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI.

Although the triplet combination group outperformed the doublet therapy group against the control arm, respectively, the trial was not powered to compare the 2 experimental arms.1


  1. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075
  2. Van Cutsem E, Tabernero J, Taieb J, et al. ANCHOR CRC: results from a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E–mutant metastatic colorectal cancer. Ann Oncol. 2021;32(suppl 3):S222. doi:10.1016/j.annonc.2021.05.014
  3. BRAF V600E-mutant colorectal cancer study of encorafenib taken with cetuximab plus or minus chemotherapy (BREAKWATER). Updated July 12, 2021. Accessed July 28, 2021.
  4. Braftovi. Prescribing information. Array BioPharma Inc; 2020. Accessed July 28, 2021.