CASTRES, France, November 9, 2016 /PRNewswire/ --
- Binimetinib plus encorafenib
meets primary endpoint
with statistically significant advantage on median
PFS of 14.9 months versus 7.3 months
for vemurafenib monotherapy
- Additional PFS, ORR and durability data support
primary endpoint result
Detailed safety and drug exposure data presented;
combination of binimetinib plus
encorafenib demonstrates a
favorable tolerability profile
-
Pierre Fabre today announced
first results from the pivotal Phase 3 COLUMBUS trial of
binimetinib plus encorafenib (bini/enco) 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.
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"The results presented today from the COLUMBUS trial 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 a potential, 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.
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 or photographs,
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.
mPFS BICR mPFS Local Review
Bini/Enco Vemurafenib Bini/Enco Vemurafenib
Bini/Enco vs. 14.9 months 7.3 months 14.8 months 7.3 months
Vemurafenib HR (95% CI):0.54 (0.41-0.71); HR (95% CI): 0.49 (0.37-0.64);
P<0.001 P<0.001
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
response, high median dose intensity and consistent activity in
patients with prior immunotherapy as well as an advantage in terms
of maintening 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%)
- 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 (EORTC Quality of Life
Questionnaire Core 30 and Functional Assessment of Cancer Therapy
Melanoma Scale Score) 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 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%).
Frédéric Duchesne, Chief Executive Officer Pharmaceutical
Division, Pierre Fabre remarked, "We
are very pleased with the promising results and look forward to the
possibility that, if approved, the combination of encorafenib plus
binimetinib could offer a new treatment option for patients
suffering from this devastating disease."
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
bini/enco of 45mg binimetinib plus 450mg encorafenib, 300mg
encorafenib alone, or 960mg vemurafenib alone. The primary endpoint
for the COLUMBUS trial was a PFS comparison of bini/enco versus
vemurafenib. PFS is determined based on tumor assessment (RECIST
version 1.1 criteria) by a Blinded Independent Central Review.
Secondary endpoints include a comparison of the PFS of encorafenib
monotherapy to that of bini/enco and a comparison of overall
survival (OS) for bini/enco to that of vemurafenib alone.
- 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 bini/enco. While
formal statistical analysis of Part 2 is only planned if both the
comparison of PFS between bini/enco versus vemurafenib and
bini/enco 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.
Binimetinib and encorafenib are investigational medicines and
are not currently approved in any country.
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 recently initiated Phase
3 BEACON CRC trial that will study encorafenib in combination with
cetuximab with or without binimetinib in patients with BRAF
V600E-mutant colorectal cancer. In September 2016, the FDA accepted Array
BioPharma's New Drug Application (NDA) for binimetinib in
NRAS-mutant melanoma with a target action date under the
Prescription Drug User Fee Act (PDUFA) of June 30, 2017. Also, the binimetinib Marketing
Authorization Application (MAA) submitted by Pierre Fabre was validated and is currently
under evaluation by the Committee for Medicinal Products for Human
Use (CHMP). This file has also been submitted to SwissMedic the
31th of October 2016.
Array BioPharma retains exclusive rights to binimetinib and
encorafenib in 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.
For more information on Array, please go to
http://www.arraybiopharma.com/.
To find out more about Pierre
Fabre, please go to
http://www.pierre-fabre.com