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 November 2016, new results from the pivotal Phase 3 COLUMBUS trial were presented at the Society for Melanoma Research Annual Congress. The study met its primary endpoint, with the combination of bini/enco significantly improving progression free survival (PFS) compared with vemurafenib, a BRAF inhibitor, alone. The combination of bini/enco was generally well-tolerated and reported adverse events (AEs) were overall consistent with previous published clinical trial results for the bini/enco combination in BRAF-mutant melanoma patients. 

In the analysis of the primary endpoint, the median PFS (mPFS) for patients treated with the combination of bini/enco was 14.9 months versus 7.3 months for patients treated 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 chart below outlines the mPFS results, as determined by both assessments, for the combination of bini/enco versus vemurafenib, bini/enco versus encorafenib, and encorafenib versus vemurafenib:

   

mPFS BICR

 

mPFS Local Review

Bini/Enco vs. 
Vemurafenib 

 

Bini/Enco

Vemurafenib

 

Bini/Enco

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

 

Bini/Enco vs. 
Encorafenib 

 

Bini/Enco

Encorafenib

 

Bini/Enco

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 

The combination of bini/enco also demonstrated an improvement in confirmed overall response rate (ORR; complete response plus partial response), as well as favorable median duration of exposure, high median dose intensity and consistent activity in patients with prior immunotherapy treatment as well as an advantage in terms of maintaining quality of life for patients.

 

Confirmed ORR BICR

Confirmed ORR Local Review

Bini/Enco

63% (95% CI:  56-70%)

75% (95% CI:  68-81%)

Vemurafenib 

40% (95% CI:  33-48%)

49% (95% CI:  42-57%)

Encorafenib 

51% (95% CI:  43-58%)

58% (95% CI:  50-65%)

  • Median duration of exposure was approximately 51 weeks for patients receiving bini/enco, versus 31 weeks and 27 weeks for the encorafenib and vemurafenib monotherapy arms, respectively
  • Median dose intensity for patients treated with bini/enco was 100% (encorafenib) and 99.6% (binimetinib)
  • 5% of bini/enco patients had received prior treatment with check-point inhibitors, including ipilimumab, anti-PD-1 and/or anti-PD-L1 therapies, and the observed clinical activity for these patients was consistent with that of bini/enco patients who had not received prior immunotherapy
  • The Quality of Life (QoL) measures were consistent between two scales and showed an advantage in terms of maintaining quality of life for patients receiving bini/enco compared to patients treated with either encorafenib or vemurafenib single agent therapy. The QoL scales used were the EORTC Quality of Life Questionnaire Core 30 and FACT-Melanoma Scale Score (Functional Assessment of Cancer Therapy).

The combination of bini/enco was generally well-tolerated and reported AEs were overall consistent with previous bini/enco combination clinical trial results in BRAF-mutant melanoma patients.

  • Grade 3/4 AEs which occurred in more than 5% of patients receiving bini/enco included increased gamma-glutamyltransferase (GGT), increased blood creatine phosphokinase (CK), and hypertension
  • The incidence of AEs of special interest (toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments), for patients receiving bini/enco included (% of patients): rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%)

Updated results from a Phase 2 study of the combination of encorafenib and cetuximab, with or without alpelisib, in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC) were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract No. 3544). BRAFm CRC represents a difficult-to-treat subtype of colorectal cancer that impacts 8 to 15 percent of patients.  Data from this study suggest that median overall survival (OS) for these patients may exceed one year which is more than double historical published benchmarks for this population. 

In the Phase 2 study, 102 patients with BRAFm CRC who had progressed after one or more prior therapies were randomized to receive the doublet regimen of encorafenib and cetuximab (ENCO 200 mg PO QD and CETUX per label; n=50) or the triplet regimen of encorafenib, cetuximab and alpelisib (ENCO, CETUX and ALP 300 mg PO QD; n=52). The Phase 2 analysis for these treatment regimens demonstrated promising clinical activity in patients:

  • Median OS was 12.4 and 13.1 months for the doublet and triplet regimens, respectively.
  • Median progression-free survival (PFS) was 4.2 and 5.4 months for the doublet and triplet regimens, respectively.
  • Overall response rate (ORR) was 22 percent and 27 percent for the doublet and triplet regimens, respectively.
  • Grade 3 or 4 adverse events (AEs) occurring in greater than 10 percent of patients included anemia, hyperglycemia and increased lipase. 

Historical published median PFS and median OS results after first-line treatment range from 1.8 to 2.5 months and four to six months, respectively, and published overall response rates from various studies in this population range between 6 percent to 8 percent.

BRAF-mutant Colorectal Cancer

Colorectal cancer is the second most common cancer among men and third most common cancer among women in the United States, with more than 135,000 new cases and more than 50,000 deaths from the disease projected in 2017. 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. 

BRAF-mutant Melanoma

Melanoma is the fifth most common cancer among men and the sixth most common cancer among women in the United States, with more than 87,000 new cases and over 9,700 deaths from the disease expected in 2017. Novel therapies that target the RAS-RAF-MEK-ERK pathway have a strong scientific rationale for activity in this disease, as up to 50 percent of patients with metastatic melanoma have activating BRAF mutations, the most common gene mutation in this patient population. Current marketed MEK/BRAF combination agents have a run rate approaching $1 billion in annual worldwide sales.

Clinical Trials

Trial Data
Trial Title
Program: Encorafenib (LGX818)
Phase: 3
Status: Active, not recruiting
Disease: BRAF V600 mutant melanoma
Sponsor: Novartis
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.