ERBITUX® is an epidermal growth factor receptor (EGFR) antagonist indicated for treatment of...BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)...in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

encorafenib (Braftovi) is accepted for use within NHSScotland...In combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy.

Encorafenib is indicated:...in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy

For BRAF V600E-mutated, pre-treated mCRC patients, encorafenib–cetuximab is recommended as the best option in second line...

Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E–mutant mCRC that has progressed after at least one previous line of therapy.

Encorafenib plus cetuximab is recommended, within its marketing authorisation, as an option for treating BRAF V600E mutation-positive metastatic colorectal cancer in adults who have had previous systemic treatment.

...Pierre Fabre today announced that the National Institute for Health and Care Excellence (NICE) has issued a Final Appraisal Determination (FAD) recommending BRAFTOVI®q(encorafenib) plus cetuximab, within its marketing authorisation, as an option for treating BRAFV600E mutation-positive metastatic colorectal cancer (mCRC), in adults who have had previous systemic treatment.

...the panel believes that evidence increasingly suggests that BRAF V600E mutation makes response to panitumumab or cetuximab, as single agents or in combination with cytotoxic chemotherapy, highly unlikely, unless given as part of a BRAF-inhibitor regimen (eg, encorafenib plus cetuximab or panitumumab)....

...the ongoing Ph 3 BREAKWATER study (NCT04607421) is evaluating EC ± chemo vs standard-of-care chemo in BRAF V600E mCRC….Preliminary promising antitumor activity was seen in 1L and 2L BRAF V600E mCRC...PR...EC + mFOLFOX6...13 (68.4)...

Median OS was 9.3 (encorafenib + cetuximab) versus 5.9 months (ACT/control) (stratified hazard ratio (HRstrat): 0.61 [95% confidence interval: 0.48-0.77]). Time-to-response (TTR) showed a statistically significant advantage for encorafenib + cetuximab compared to ACT/control (HRstrat [95% CI]: 10.46 [3.75; 29.15]; P < .0001). Median progression-free survival 2, ie, PFS after initiation of subsequent treatment after completion of study treatment, was 8.3 (dual blockade) versus 5.3 months (ACT/control), representing a statistically significant benefit for the dual blockade (HRstrat [95% CI]: 0.62 [0.48; 0.78]; P < .0001). In the HTA, the German G-BA granted a "hint for a considerable additional benefit" of encorafenib + cetuximab compared to the ACT in BRAFV600E-mutant mCRC patients.

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.

In the BEACON CRC study, pts treated with the doublet for BRAF V600E-mutant mCRC demonstrated similar OS regardless of prior therapies or duration of prior therapy use.

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.

...we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer...Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group)...The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001).

...the median follow-up time for survival was 18.2 mo and median exposure was 7.8 mo (range 0.5-21.4 mo). The confirmed ORR and median PFS remain unchanged from the previous report (ORR, 48% [95% CI, 29.4-67.5]; PFS, 8.0 mo [95% CI, 5.6-9.3 mo]). Mature median OS is 15.3 mo (95% CI, 9.6 mo not reached).

...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 ORR and disease control rate was 33.8 % (CI 95% 23.4-45.5) and 68.8 (CI 95% 57.3 – 78.9) respectively. One (1.2%) pt achieved complete response...This study provides real-world data of BRAFV600E mCRC pts treated with EC combination in routine clinical practice in Spain. EC effectiveness and safety were consistent with the results obtained in clinical trials.

Twenty-five BRAFm mCRC patients were enrolled...these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC...

...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)...

In this open-label, phase III trial, 665 patients with BRAF V600E–mutant mCRC...Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75])....In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy.

A 68-year-old woman was diagnosed with ascending colon cancer and multiple para-aortic lymph node metastases. After primary tumor resection, molecular genetic testing of the primary tumor revealed a BRAF V600E mutation. She was treated with FOLFOXIRI plus bevacizumab as first-line chemotherapy. After disease progression, the regimen was changed to encorafenib plus cetuximab, and the metastatic lesions shrank. She underwent para-aortic lymph node dissection as conversion surgery, and pathology revealed complete response of the lymph nodes. She achieved long-term survival.

The patient was then treated with the RAF/EGFR inhibitor combination of encorafenib and cetuximab and experienced a dramatic drop in the CEA tumor marker levels after initiating therapy, suggesting an overall decrease in tumor burden (Fig. 2A). The patient also experienced a decrease in two of three target lesions by RECIST (Fig. 2B)...WES revealed that the post-progression specimen retained the original BRAF V600E mutation.

We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination….Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control....These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.

Antitumor activity of either FOLFIRI or E+C was better in first-line as compared to second-line…We performed a series of in vivo studies using BRAFV600EmCRC tumor xenografts. Mice were randomized to receive: 5-fluoruracil, irinotecan or oxaliplatin regimens (FOLFIRI or FOLFOX), encorafenib plus cetuximab (E+C) or the combination....These results support the combination of cytotoxic chemotherapy and molecular targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.

Our study showed across all 4 models both FOLFOX and FOLFIRI, each in combination with encorafenib plus cetuximab, having greater efficacy than encorafenib plus cetuximab or either chemotherapy alone....We performed an in vivo study using human BRAFV600E CRC cell line-derived xenografts in nude mice. We evaluated the efficacy of encorafenib (E) + cetuximab (C), FOLFOX, and FOLFIRI, both as individual regimens and in combinations.