Encorafenib (LGX818)
Target: BRAF | Indications: Melanoma and Colorectal Cancer
Introduction / Brief Description
Encorafenib is a late-stage small molecule BRAF inhibitor which targets key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer (CRC). Encorafenib is being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.
In September 2017, Array announced that the U.S. Food and Drug Administration (FDA) has accepted for review its New Drug Applications (NDAs) to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (COMBO450) for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the FDA informed Array that based on their preliminary review of the applications they have not identified any potential review issues, and that they are not currently planning to hold an advisory committee meeting to discuss these NDAs. Array completed its NDA submissions at the end of June 2017 based on findings from the pivotal Phase 3 COLUMBUS trial.
COLUMBUS Results
In February 2018, Array announced results of the planned analysis of overall survival (OS) from the COLUMBUS trial. Treatment with COMBO450 reduced the risk of death compared to treatment with vemurafenib 960 mg daily [hazard ratio (HR) of 0.61, [95% CI 0.47, 0.79, p <0.001]. Median OS was 33.6 months for patients treated with COMBO450, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. At the time of the planned analysis comparing COMBO450 to vemurafenib monotherapy, a preliminary analysis of OS in patients treated with 300 mg encorafenib alone daily (ENCO 300), demonstrated a median OS of 23.5 months.
As presented at the 2016 Society for Melanoma Research Annual Congress, results from Part 1 of the COLUMBUS study showed that COMBO450 significantly extend PFS in patients with advanced BRAF-mutant melanoma, with a PFS of 14.9 months compared with 7.3 months observed with vemurafenib [HR of 0.54, (95% CI 0.41-0.71, P<0.001)]. As part of the trial design, the primary analysis was based on a Blinded Independent Central Review (BICR) of patient scans, while results by local review at the investigative site were also analyzed. The table below outlines the median PFS (mPFS) results, as determined by both assessments, for COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:
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mPFS BICR |
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mPFS Local Review |
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COMBO450 vs. Vemurafenib |
|
COMBO450 |
Vemurafenib |
COMBO450 |
Vemurafenib |
|
|
14.9 months |
7.3 months |
14.8 months |
7.3 months |
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HR (95% CI): 0.54 (0.41-0.71); P |
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HR (95% CI): 0.49 (0.37-0.64); P |
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|
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COMBO450 vs. Encorafenib |
|
COMBO450 |
Encorafenib |
COMBO450 |
Encorafenib |
|
|
14.9 months |
9.6 months |
14.8 months |
9.2 months |
||
|
HR (95% CI): 0.75 (0.56-1.00); P=0.051 |
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HR (95% CI): 0.68 (0.52-0.90); P=0.006 |
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Encorafenib vs. Vemurafenib |
|
Encorafenib |
Vemurafenib |
Encorafenib |
Vemurafenib |
|
|
9.6 months |
7.3 months |
9.2 months |
7.3 months |
||
|
HR (95% CI): 0.68 (0.52-0.90); P=0.007 |
|
HR (95% CI): 0.70 (0.54-0.91); P=0.008 |
In this study, COMBO450 was generally well-tolerated, with a median duration of treatment of 51 weeks and median relative dose intensity for encorafenib and binimetinib of 100% and 99.6%, respectively. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving COMBO450 were increased blood creatine phosphokinase (CK) (9%), increased gamma-glutamyltransferase (GGT) (7%) and hypertension (6%). The incidence of any grade of AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO450 included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.
BRAF-mutant Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma
BEACON CRC Safety Lead-In Results
In January 2018, Array announced updated results from the 30 patient safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, binimetinib, and cetuximab, an anti-EGFR antibody, in patients with BRAF-mutant metastatic CRC whose disease has progressed after one or two prior regimens. The data were presented at the ASCO 2018 Gastrointestinal Cancers Symposium.
In patients with the BRAFV600E mutation, the estimated mPFS at the time of analysis was 8 months. The confirmed overall response rate (ORR)* in patients with the BRAFV600E mutation was 48%, and 3 patients achieved complete responses (CR). Further, the ORR was 62% in the 16 patients (10/16) who received only one prior line of therapy. These data represent substantial improvements compared to several separate historical published ORR and mPFS benchmarks in this patient population using standard of care regimens which range between 4% to 8% and 1.8 and 2.5 months, respectively.
In the safety lead-in, the triplet combination was generally well-tolerated. Two patients discontinued treatment due to AEs with only one of these considered related to treatment. The most common grade 3 or 4 AEs seen in at least 10% of patients were fatigue (4/30), urinary tract infection (3/30), increased aspartate aminotransferase (AST; 3/30) and increased blood CK (3/30).
In addition to these registration trials, early-stage studies have been initiated or announced to evaluate encorafenib in numerous solid tumors and hematologic malignancies.
BRAF-mutant Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Of these, nearly 750,000 were diagnosed in men, and 614,000 in women. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. In the U.S. alone, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease. In the U.S., BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients. Based on recent prospective historical data, the prevalence of MSI-H in tumors from patients with metastatic BRAF-mutant CRC ranged from 14% in a recent Phase 1b/2 trial (NCT01719380) (Array, data on file) to 18% in a recent Southwestern Oncology Group (SWOG) randomized phase 2 trial.
Clinical Trials
Phase: 3
Status: Active, not recruiting
Disease: BRAF V600 mutant melanoma
Sponsor: Array BioPharma
Trial Information: NCT01909453
Phase: 3
Status: Recruiting
Disease: BRAF-mutant colorectal cancer
Sponsor: Array BioPharma
Trial Information: NCT02928224
Publications
Binimetinib and Encorafenib
03/21/2018
The Lancet Oncology
Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial
Binimetinib and Encorafenib
01/20/2018
2018 Gastrointestinal Cancers Symposium (ASCO GI)
BEACON CRC Study Safety Lead-in (SLI) in Patients With BRAFV600E Metastatic Colorectal Cancer (mCRC): Efficacy and Tumor Markers
Binimetinib and Encorafenib
09/09/2017
European Society for Medical Oncology Congress
RESULTS OF COLUMBUS PART 2: A Phase 3 Trial of Encorafenib Plus Binimetinib Versus Encorafenib in BRAF-Mutant Melanoma
Binimetinib and Encorafenib
11/09/2016
2016 Society for Melanoma Research (SMR) Annual Congress
Results of COLUMBUS Part 1: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) Versus Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma
Encorafenib / Cancer
07/01/2016
ESMO World Congress of Gastrointestinal Cancer
Combination of Encorafenib and Cetuximab With or Without Alpelisib in Patients With Advanced BRAF-Mutant (BRAFm) Colorectal Cancer: Phase 2 Results
Encorafenib / Cancer
06/01/2016
American Society of Clinical Oncology Meeting
Phase 2 results: encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC)
Encorafenib / Cancer
07/04/2015
ESMO World Congress of Gastrointestinal Cancer
Phase 1b/2 Study of the Selective BRAF V600 Inhibitor Encorafenib (LGX818) Combined With Cetuximab With or Without the α‐Specific PI3K Inhibitor Alpelisib (BYL719) in Patients With Advanced BRAF‐Mutant Colorectal Cancer
Encorafenib / Cancer
05/30/2015
American Society of Clinical Oncology Meeting
A Phase 1/b2 Study of BRAF Inhibitor (BRAFi) Encorafenib (ENCO) Plus MEK Inhibitor (MEKi) Binimetinib (BINI) in Cutaneous Melanoma Patients Naive to BRAFI Treatment
Encorafenib / Cancer
04/20/2015
American Association for Cancer Research Annual Meeting
Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models of melanoma identify c-Met as an effective second line combination therapy target
Continuing Medical Education / Grant Requests
Array BioPharma Guidelines for the Support of Independent Medical Education.pdf
CME@arraybiopharma.com