Ono Pharmaceutical Co., Ltd. (Osaka, Japan; President, Representative Director, Gyo Sagara; “ONO”) announced today that ONO has obtained an approval of BRAFTOVI® (generic name: encorafenib) Capsule (“BRAFTOVI”), a BRAF inhibitor, and MEKTOVI® (generic name: binimetinib) Tablet (“MEKTOVI”), a MEK inhibitor, in Japan for an additional indication of unresectable advanced or recurrent BRAF-mutant colorectal cancer that has progressed after chemotherapy, in triplet combination therapy with BRAFTOVI, MEKTOVI and cetuximab, an anti-human EGFR monoclonal antibody, and in doublet combination therapy with BRAFTOVI and cetuximab. This approval is based on results of a global randomized, open label Phase 3 study (BEACON CRC study...

The NCCN Panel recommends three drug combinations as subsequent treatment options for patients with mCRC that harbors the BRAF V600E mutation:...3) encorafenib, binimetinib, and cetuximab or panitumumab.

Pts with BRAF V600E mutations with high VAF had significantly (P≤0.0001) increased ORR (95% CI) in the triplet and doublet arms (27.3% [19.5–36.8] and 15.9% [9.7–25.0], respectively) compared with control (0% [0.0–4.3]). Similar response trends were observed in pts with BRAF V600E mutations with low VAF (triplet: 28.9% [20.8–38.9]; doublet: 25.3% [17.7–34.6]; control: 5.3% [2.1–12.8])....Increased response rates were observed in pts treated with triplet or doublet therapy compared with control, independent of VAF.

BEACON CRC is a randomized, phase 3 study which evaluated the triplet of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) and the doublet of ENCO + CETUX vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC)...Median OS was 9.3 months (95% confidence interval [CI]:8.2, 10.8) for triplet and 5.9 months (95% CI:5.1-7.1) for control (hazard ratio [HR] (95% CI): 0.60 (0.47-0.75)). Median OS for doublet was 9.3 months (95% CI: 8.0-11.3) (HR vs. control: 0.61 (0.48-0.77). Confirmed ORR was 26.8% (95% CI: 21.1%-33.1%) for triplet, 19.5% (95% CI: 14.5%-25.4%) for doublet, and 1.8% (95% CI: 0.5%-4.6%) for control.

In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAFV600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens.

Array BioPharma Inc...today announced it has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for encorafenib (BRAFTOVI), in combination with binimetinib (MEKTOVI) and cetuximab for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E-mutant mCRC...In 29 patients with BRAF V600E-mutant tumors (one patient had a non-BRAF V600E-mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months)...

A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation.

...Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory...

The objective response rate under e/c+/-b was 32% and the disease control rate was 71%, all lines combined. Median PFS under e/c+/-b was 4.4 months (95% CI 3.9-5.6) and median OS was 9.1 months (95% CI 7.8-10.8). In multivariate analysis, the factors associated with a shorter PFS under e/c+/-b were the presence of liver metastases (HR: 1.6, p=0.02)...This real-world study showed that in patients with BRAF V600E mutated mCRC treated with encorafenib + cetuximab +/- binimetinib, efficacy data are very similar to those reported in the BEACON CRC registration trial.

The clinical outcomes of the BEACON triplet regimen in the Japanese patients with BRAF V600E-mutant mCRC were consistent with those in the BEACON CRC study. These results support that the BEACON triplet regimen is one of the standard treatment for pretreated Japanese patients with BRAF V600E-mutant mCRC.

Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses….With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months....The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile.

...BRAF-V600E mutated metastatic colorectal cancer (mCRC) treated with encorafenib-cetuximab +/-binimetinib (E-C+/-B)...Of note, women treated with the triplet showed a clear trend towards better mOS (20 vs 9 months, HR 3.22 95%CI 0.91-11.41 p 0.07) and mPFS (8.44 vs 5.72 months, HR 1.44 95%CI 0.49-4.24 p 0.5)….Among BRAF-V600E mt treated with E-C+/-B women seem to achieve greater clinical benefit particularly with the triplet combination but with an increased toxicity cost.

Among the 76 pts with target lesions, 21 pts were responders, and the confirmed ORR was 27.6%. Stable disease was observed in 42 pts, resulting in a disease control rate of 82.9%....These results support the triplet regimen as a new standard-of-care treatment option in the second- or third-line treatment of pts with BRAF V600E-mutant mCRC in the Japanese population...

ANCHOR CRC is an open-label, single-arm, two-stage design, phase 2 study in patients with BRAFV600E-mutant mCRC…Patients received ENCO 300 mg orally QD + BINI 45 mg orally BID and CETUX IV weekly...in this study, almost half of the patients responded and most had disease control, with a median PFS of 5.8 months and a median OS of 17.2 months.

...59 BRAFV600E mutated mCRC patients from Vall d'Hebron and Università della Campania L. Vanvitelli, Naples that received encorafenib-cetuximab +/- binimetinib...Overall, median PFS was 5.2 months (m) (CI 95% 4.1-8.5) and median OS (mOS) was 10.3 m (CI 95% 6.5-20.2)...

Forty-one BRAFV600E-mutant mCRC patients with a median age of 67 years old (61% of the patients were ≥ 65 years old) were enrolled in Stage 1 and received the triplet combination as first line metastatic treatment…The investigator measured median PFS was 4.9 months (95% CI, 4.4-8.1)...Adverse events were consistent with those observed in prior studies with this triplet combination...The ANCHOR CRC study is the first prospective study using a BRAF inhibitor-based therapy in first line BRAFV600E-mutant mCRC.

A 55-year-old woman with BRAF V600E-mutated transverse colon NEC...Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.

A 76-year-old woman was diagnosed with left-sided transverse colon cancer...Preoperative diagnosis was cT4b(SI)N2aM1c(H3, P1), cStage Ⅳc, harboring BRAF V600E mutation….Because of CEA elevating after 5-FU plus LV plus BEV as maintenance therapy was changed, the regimen was switched to encorafenib plus binimetinib plus cetuximab as the second-line chemotherapy....Eight months after the start of the second- line, the patient has been administered with triple therapy and had stable disease status.