Encorafenib (LGX818)

Target: BRAF | Indications: Melanoma and Colorectal Cancer

Introduction / Brief Description

Encorafenib is a novel oral small molecule kinase inhibitor with potent and selective inhibitory activity against mutant BRAF kinase, a member of the RAF/MEK/ERK pathway, which plays a prominent role in controlling several key cellular functions including growth, proliferation and survival. There are two Phase 3 trials with encorafenib in advanced cancer patients:  COLUMBUS (encorafenib in combination with binimetinib in BRAF-mutant melanoma) and BEACON CRC [encorafenib, binimetinib and Erbitux® (cetuximab) in BRAF-mutant colorectal cancer].  

In June 2017, Array submitted two NDAs to the FDA 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 submissions are supported by data from the pivotal Phase 3 COLUMBUS study, which showed that patients who received binimetinib and encorafenib had a significantly longer progression free survival (PFS) compared to patients receiving vemurafenib.  

COLUMBUS Results

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 [hazard ratio (HR) 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:

 

 

mPFS BICR

 

mPFS Local Review

COMBO450 vs. Vemurafenib 

 

COMBO450

Vemurafenib

 

COMBO450

Vemurafenib

 

14.9 months

7.3 months

 

14.8 months

7.3 months

 

HR (95% CI): 0.54 (0.41-0.71); P

 

HR (95% CI): 0.49 (0.37-0.64); P

 

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 

 

HR (95% CI): 0.68 (0.52-0.90); P=0.006 

 

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.

COLUMBUS Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. In COLUMBUS Part 2, the primary analysis compared PFS in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (COMBO300) to patients treated with encorafenib 300mg daily as a single agent.  Top-line results showed the mPFS for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with HR of 0.77 [95% CI 0.61-0.97, p=0.029]. COMBO300 was generally well-tolerated and reported dose intensity and AEs were consistent with COMBO450 results in COLUMBUS Part 1. Further results from COLUMBUS Part 2 will be presented at the 2017 ESMO Congress.

In addition to these registration trials, early-stage studies have been initiated or announced to evaluate binimetinib in numerous solid tumors and hematologic malignancies.  

BRAF-mutant Melanoma 

Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease. 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 

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 135,430 patients will be diagnosed with cancer of the colon or rectum in 2017, and approximately 50,000 are estimated to die of their disease. There is wide variation in 5-year survival rates across the globe, with 5-year survival expected to be around 65% in the developed world and dropping to around 20% in some developing countries. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients.  

Clinical Trials

Trial Data
Trial Title
Program: Encorafenib (LGX818)
Phase: 3
Status: Active, not recruiting
Disease: BRAF V600 mutant melanoma
Sponsor: Array BioPharma
Trial Information: NCT01909453
Trial Title: Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)
Program: Encorafenib (LGX818)
Phase: 3
Status: Recruiting
Disease: BRAF-mutant colorectal cancer
Sponsor: Array BioPharma
Trial Title: Study evaluating the efficacy and safety of binimetinib, encorafenib and Erbitux in BRAFm metastatic CRC (BEACON CRC)
Program: Encorafenib (LGX818)
Trial Information: ClinicalTrials.gov
Trial Title: Other clinical Trials

Publications

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

Keith T. Flaherty, M.D., et al.

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

J. Tabernero, et al.

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)

J. Tabernero, et al.

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

E. Elez, et al.

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

R. Sullivan, et al.

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

C. Krepler, et al.