Array BioPharma Announces Positive Top-Line Results from Par
May 9, 2017 20:05:32 GMT
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Post by mhat on May 9, 2017 20:05:32 GMT
Array BioPharma Announces Positive Top-Line Results from Part 2 of the Phase 3 COLUMBUS Study of Binimetinib and Encorafenib for BRAF-Mutant Melanoma
Last update: 09/05/2017 1:01:01 pm
- Median PFS for patients on combination of binimetinib (45mg) plus encorafenib (300mg) was 12.9 months versus 9.2 months for patients on encorafenib (300mg) -
BOULDER, Colo., May 9, 2017 /PRNewswire/ -- Array BioPharma (Nasdaq: ARRY) today announced top-line results from Part 2 of the Phase 3 COLUMBUS study evaluating binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, 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.
"The totality of the COLUMBUS results, including estimated progression free survival, objective response rate, dose intensity and tolerability of the combination, provide a strong and consistent theme across multiple endpoints, underscoring the promise of binimetinib plus encorafenib as an attractive treatment option for patients diagnosed with BRAF-mutant melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and Professor of Medicine, Harvard Medical School.
Ron Squarer, Chief Executive Officer at Array BioPharma noted: "The robust PFS benefit and tolerability observed with binimetinib plus encorafenib in COLUMBUS Part 2 once again demonstrates the combination represents a potentially important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma. The results of Part 2 confirm the contribution of binimetinib to the combination."
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.
About the Phase 3 COLUMBUS Study
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of binimetinib plus encorafenib 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 45mg binimetinib
plus 450mg encorafenib (COMBO450), 300mg encorafenib alone, or 960mg
vemurafenib alone. The dose of encorafenib in the combination arm is 50%
higher than the single agent maximum tolerated dose of 300mg. A higher
dose of encorafenib was possible due to improved tolerability when
combined with binimetinib. The primary endpoint for the COLUMBUS trial
was a PFS comparison of COMBO450 versus vemurafenib. PFS is determined
based on tumor assessment (RECIST version 1.1 criteria) by a Blinded
Independent Central Review (BICR). Secondary endpoints include a
comparison of the PFS of encorafenib monotherapy to that of COMBO450 and
a comparison of overall survival (OS) for COMBO450 to that of vemurafenib
alone.
In November 2016, results from Part 1 were presented at the Society for Melanoma Research Annual Congress. The study met its primary endpoint, with COMBO450 significantly improving PFS compared with vemurafenib alone. In the analysis of the primary endpoint, the mPFS for patients treated with COMBO450 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 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 COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:
mPFS BICR mPFS Local Review
---------------------------- -----------------------------
COMBO450 COMBO450 Vemurafenib COMBO450 Vemurafenib
vs.
Vemurafenib
14.9 months 7.3 months 14.8 months 7.3 months
HR (95% CI): 0.54 HR (95% CI): 0.49
(0.41-0.71); P<0.001 (0.37-0.64); P<0.001
COMBO450 COMBO450 Encorafenib COMBO450 Encorafenib
vs.
Encorafenib
14.9 months 9.6 months 14.8 months 9.2 months
HR (95% CI): 0.75 HR (95% CI): 0.68
(0.56-1.00); P=0.051 (0.52-0.90); P=0.006
Encorafenib Encorafenib Vemurafenib Encorafenib Vemurafenib
vs.
Vemurafenib
9.6 months 7.3 months 9.2 months 7.3 months
HR (95% CI): 0.68 HR (95% CI): 0.70
(0.52-0.90); P=0.007 (0.54-0.91); P=0.008
COMBO450 was generally well-tolerated and reported adverse events (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 percent of patients receiving COMBO450 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 COMBO450 included: rash (23 percent), pyrexia (18 percent), retinal pigment epithelial detachment (13 percent) and photosensitivity (5 percent).
-- In Part 2, 344 patients were randomized 3:1 to receive 45mg binimetinib
plus 300mg encorafenib or 300mg encorafenib alone. Part 2 is designed to
provide additional data to help evaluate the contribution of binimetinib
to the combination of binimetinib and encorafenib. As the comparison of
COMBO450 to encorafenib in Part 1 did not achieve statistical
significance, the statistical analysis conducted in Part 2 is
descriptive.
About 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. 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.
About Binimetinib & Encorafenib
MEK and BRAF are key protein kinases 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, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Binimetinib and encorafenib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial with encorafenib in combination with cetuximab with or without binimetinib in patients with BRAF V600E-mutant colorectal cancer.
Binimetinib and encorafenib are investigational medicines and are not currently approved in any country. Array BioPharma retains exclusive rights to binimetinib and encorafenib in key markets including the U.S., Japan, Canada, Korea and Israel. Pierre Fabre will have exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America.
Last update: 09/05/2017 1:01:01 pm
- Median PFS for patients on combination of binimetinib (45mg) plus encorafenib (300mg) was 12.9 months versus 9.2 months for patients on encorafenib (300mg) -
BOULDER, Colo., May 9, 2017 /PRNewswire/ -- Array BioPharma (Nasdaq: ARRY) today announced top-line results from Part 2 of the Phase 3 COLUMBUS study evaluating binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, 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.
"The totality of the COLUMBUS results, including estimated progression free survival, objective response rate, dose intensity and tolerability of the combination, provide a strong and consistent theme across multiple endpoints, underscoring the promise of binimetinib plus encorafenib as an attractive treatment option for patients diagnosed with BRAF-mutant melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and Professor of Medicine, Harvard Medical School.
Ron Squarer, Chief Executive Officer at Array BioPharma noted: "The robust PFS benefit and tolerability observed with binimetinib plus encorafenib in COLUMBUS Part 2 once again demonstrates the combination represents a potentially important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma. The results of Part 2 confirm the contribution of binimetinib to the combination."
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.
About the Phase 3 COLUMBUS Study
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of binimetinib plus encorafenib 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 45mg binimetinib
plus 450mg encorafenib (COMBO450), 300mg encorafenib alone, or 960mg
vemurafenib alone. The dose of encorafenib in the combination arm is 50%
higher than the single agent maximum tolerated dose of 300mg. A higher
dose of encorafenib was possible due to improved tolerability when
combined with binimetinib. The primary endpoint for the COLUMBUS trial
was a PFS comparison of COMBO450 versus vemurafenib. PFS is determined
based on tumor assessment (RECIST version 1.1 criteria) by a Blinded
Independent Central Review (BICR). Secondary endpoints include a
comparison of the PFS of encorafenib monotherapy to that of COMBO450 and
a comparison of overall survival (OS) for COMBO450 to that of vemurafenib
alone.
In November 2016, results from Part 1 were presented at the Society for Melanoma Research Annual Congress. The study met its primary endpoint, with COMBO450 significantly improving PFS compared with vemurafenib alone. In the analysis of the primary endpoint, the mPFS for patients treated with COMBO450 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 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 COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:
mPFS BICR mPFS Local Review
---------------------------- -----------------------------
COMBO450 COMBO450 Vemurafenib COMBO450 Vemurafenib
vs.
Vemurafenib
14.9 months 7.3 months 14.8 months 7.3 months
HR (95% CI): 0.54 HR (95% CI): 0.49
(0.41-0.71); P<0.001 (0.37-0.64); P<0.001
COMBO450 COMBO450 Encorafenib COMBO450 Encorafenib
vs.
Encorafenib
14.9 months 9.6 months 14.8 months 9.2 months
HR (95% CI): 0.75 HR (95% CI): 0.68
(0.56-1.00); P=0.051 (0.52-0.90); P=0.006
Encorafenib Encorafenib Vemurafenib Encorafenib Vemurafenib
vs.
Vemurafenib
9.6 months 7.3 months 9.2 months 7.3 months
HR (95% CI): 0.68 HR (95% CI): 0.70
(0.52-0.90); P=0.007 (0.54-0.91); P=0.008
COMBO450 was generally well-tolerated and reported adverse events (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 percent of patients receiving COMBO450 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 COMBO450 included: rash (23 percent), pyrexia (18 percent), retinal pigment epithelial detachment (13 percent) and photosensitivity (5 percent).
-- In Part 2, 344 patients were randomized 3:1 to receive 45mg binimetinib
plus 300mg encorafenib or 300mg encorafenib alone. Part 2 is designed to
provide additional data to help evaluate the contribution of binimetinib
to the combination of binimetinib and encorafenib. As the comparison of
COMBO450 to encorafenib in Part 1 did not achieve statistical
significance, the statistical analysis conducted in Part 2 is
descriptive.
About 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. 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.
About Binimetinib & Encorafenib
MEK and BRAF are key protein kinases 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, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Binimetinib and encorafenib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial with encorafenib in combination with cetuximab with or without binimetinib in patients with BRAF V600E-mutant colorectal cancer.
Binimetinib and encorafenib are investigational medicines and are not currently approved in any country. Array BioPharma retains exclusive rights to binimetinib and encorafenib in key markets including the U.S., Japan, Canada, Korea and Israel. Pierre Fabre will have exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America.
