Écrit par Pierre Fabre | 09 Novembre 2016

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

Castres, France (November 9, 2016) -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.

"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.

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 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%)

• 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 BRAF-Mutant Melanoma

Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and over 10,000 deaths from the disease expected in 2016. Novel therapies that target the RAS-RAF-MEK-ERK pathway have a strong scientific rationale for activity in this disease, as up to 50% 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 forecasted to approach $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 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.

About Array BioPharma

Array BioPharma Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer. Five registration studies are currently advancing related to three cancer drugs. These programs include binimetinib (MEK162), encorafenib (LGX818) and selumetinib (AstraZeneca). For more information on Array, please go to http://www.arraybiopharma.com/.

About Pierre Fabre

Pierre Fabre is a French private pharmaceuticals and dermo-cosmetics company founded in 1962 by Mr.

Pierre Fabre. Its turnover reached over 2.2 billion Euros in 2015, spread over 130 countries. The company is structured around two divisions: Pharmaceuticals (prescription drugs, consumer health care)

and Dermo-cosmetics (including Pierre Fabre Dermatologie, one of the most comprehensive portfolio of Rx dermatology worldwide, and Eau Thermale Avène, a global market-leading brand in dermo-cosmetics).

Pierre Fabre employs some 13,000 people worldwide and owns subsidiaries in 43 countries. In 2015, the company allocated 16% of its pharmaceuticals sales to R&D with a focus on 4 therapeutic areas: oncology, dermatology, CNS and consumer health care.

Pierre Fabre Oncology, a business unit of the Pierre Fabre company, is supported by over 1,000 employees with a strong focus on European markets. In 2015, worldwide annual sales of Pierre Fabre

Oncology products surpassed $200 million on the strength of the Oral Navelbine, Javlor and Busilvex brands.

Through the Group's controlling company Pierre Fabre Participations, Pierre Fabre is 86% owned by the

Pierre Fabre Foundation, a recognized public-interest organization since 1999. Up to 8% of the remaining shares are held by the company's employees and the remaining balance is held as treasury stock.

To find out more about Pierre Fabre, please go to www.pierre-fabre.com