Date: 2017-05-09
Type of
information: Results
phase: 3
Announcement: results
Company: Array BioPharma (USA - CO) Pierre Fabre (France)
Product: binimetinib and encorafenib
Action
mechanism:
- kinase inhibitor/RAF kinase inhibitor/MEK (MAP kinase) inhibitor. The RAS/RAF/MEK/ERK pathway regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as non-small cell lung cancer, melanoma, colorectal, ovarian and thyroid cancers. Binimetinib is a small molecule MEK inhibitor and encorafenib is a small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Array submitted a New Drug Application (NDA) for binimetinib in NRAS-mutant melanoma to the FDA at the end of June 2016. The FDA accepted the NDA with a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017.
- Array BioPharma is the owner of binimetinib and encorafenib. Pierre Fabre licensed commercial rights to binimetinib and encorafenib for Europe and other global markets from Array in December 2015.
Disease: BRAF-mutant advanced, unresectable or metastatic melanoma
Therapeutic
area: Cancer - Oncology
Country: Argentina, Australia, Brazil, Canada, Colombia, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, Japan, Republic of Korea, Mexico, The Netherlands, Norway, Poland, Portugal, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Turkey, UK, USA
Trial
details:
- The COLUMBUS trial is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of encorafenib plus binimetinib to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the study. Patients were randomized into two parts:
- In Part 1, 577 patients were randomized 1:1:1 to receive the combination of 450mg encorafenib plus 45mg binimetinib, 300mg encorafenib alone, or 960mg vemurafenib alone. The primary endpoint for the COLUMBUS trial was a PFS comparison of the combination versus vemurafenib. PFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Review Committee. Secondary endpoints include a comparison of the PFS of encorafenib monotherapy to that of the combination and a comparison of OS for the combination to that of vemurafenib alone.
In Part 2, 344 patients were randomized 3:1 to receive 300mg encorafenib plus 45mg binimetinib or 300mg encorafenib alone. Part 2 is designed to provide additional data to help evaluate the contribution of binimetinib to the combination.(NCT01909453)
Latest
news:
- • On May 9, 2017, Array BioPharma announced top-line results from Part 2 of the Phase 3 COLUMBUS study evaluating binimetinib and encorafenib in patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The primary analysis of Part 2 compared progression free survival (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. The median PFS 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 adverse events were consistent with COMBO450 results in COLUMBUS Part 1. 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. Further results from Part 2 will be presented at a medical meeting during the second half of 2017. Based on the strength of data from Part 1 and Part 2, Array is on track to file an NDA for COLUMBUS in June or July 2017.
- • On November 9, 2016, Array BioPharma and Pierre Fabre announced new results from the pivotal Phase 3 COLUMBUS trial of binimetinib plus encorafenib treatment in BRAF-mutant melanoma patients 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.
-
|
|
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<0.001 |
|
HR (95% CI): 0.49 (0.37-0.64); P<0.001 |
|
| 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, 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%)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:
• On October 25, 2016, Array BioPharma and Pierre Fabre announced that results from the Phase 3 COLUMBUS trial of binimetinib and encorafenib in BRAF-mutant melanoma will be presented at the 2016 Society for Melanoma Research (SMR) Annual Congress in Boston, Massachusetts on November 9. Abstract 2617508: Results of COLUMBUS Part 1: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) Versus Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma. As reported in late September, 577 patients were randomized 1:1:1 to receive the combination of encorafenib plus binimetinib, encorafenib alone, or vemurafenib alone. In the analysis of the primary endpoint, the median PFS for patients treated with the combination of encorafenib plus binimetinib was 14.9 months versus 7.3 months for patients treated with vemurafenib; HR (0.54), [95% CI 0.41-0.71], p<0.001. Analysis of a secondary endpoint comparing the PFS of patients treated with combination to patients treated with encorafenib showed a median of 14.9 months versus 9.6 months with HR (0.75), [95% CI 0.56-1.00], p=0.051, which did not reach statistical significance. The combination was generally well-tolerated and reported adverse events were overall consistent with previous combination encorafenib plus binimetinib clinical trial results in BRAF-mutant melanoma patients.
- • On September. 26, 2016, Array BioPharma and Pierre Fabre jointly announced top-line results from Part 1 of the Phase 3 COLUMBUS (Combined LGX818 Used with MEK162 in BRAF Mutant Unresectable Skin Cancer) study evaluating LGX818 (encorafenib), a BRAF inhibitor, and MEK162 (binimetinib), a MEK inhibitor, in patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The study met its primary endpoint, significantly improving progression free survival (PFS) compared with vemurafenib, a BRAF inhibitor, alone. In the analysis of the primary endpoint, the median PFS for patients treated with the combination of encorafenib plus binimetinib ("combination") was 14.9 months versus 7.3 months for patients treated with vemurafenib; HR (0.54), [95% CI 0.41-0.71], p<0.001. The combination was generally well-tolerated and reported adverse events were overall consistent with previous combination encorafenib plus binimetinib clinical trial results in BRAF-mutant melanoma patients. Analysis of a secondary endpoint comparing the PFS of patients treated with combination to patients treated with encorafenib showed a median of 14.9 months versus 9.6 months with HR (0.75), [95% CI 0.56-1.00], p=0.051, which did not reach statistical significance. A complete analysis of these results will be provided to global regulatory authorities as part of planned submissions. In addition, data from Part 2 of the COLUMBUS trial are anticipated in mid 2017 and will also be provided to global health authorities as part of planned regulatory submissions for approval of these product candidates.
Further results from Part 1 of the COLUMBUS trial, including objective response rates, disease control rates, safety endpoints, exploratory analyses such as a Part 1 PFS comparison of encorafenib to vemurafenib and pre-specified subgroup analyses including outcomes in patients who received prior treatment with immunotherapy will be presented at an upcoming medical meeting. Analysis of the secondary endpoint of overall survival (OS) was not planned as part of these initial results.
In Part 1, 577 patients were randomized 1:1:1 to receive the combination of 450mg encorafenib plus 45mg binimetinib, 300mg encorafenib alone, or 960mg vemurafenib alone. The primary endpoint for the COLUMBUS trial was a PFS comparison of the combination versus vemurafenib. PFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Review Committee. Secondary endpoints include a comparison of the PFS of encorafenib monotherapy to that of the combination and a comparison of OS for the combination to that of vemurafenib alone.
In Part 2, 344 patients were randomized 3:1 to receive 300mg encorafenib plus 45mg binimetinib or 300mg encorafenib alone. Part 2 is designed to provide additional data to help evaluate the contribution of binimetinib to the combination. While formal statistical analysis of Part 2 is only planned if both the comparison of PFS between combination versus vemurafenib and the combination versus encorafenib achieve statistical significance in Part 1, data from Part 2 are anticipated in mid 2017 and will be provided to global health authorities as part of planned regulatory submissions in 2017.
Is
general: Yes
