Pierre Fabre and Its Partner Array BioPharma Announce Additional Median Overall Survival Results of Encorafenib and Binimetinib in Patients with Braf-Mutant Advanced Melanoma

Pierre Fabre and its partner Array BioPharma Inc. today announced updated results from the Phase 3 COLUMBUS trial in BRAF-mutant advanced melanoma. The results showed median overall survival (mOS) was 33.6 months for patients treated with the combination of encorafenib and binimetinib compared with 16.9 months for patients treated with vemurafenib as a monotherapy. The combination reduced the risk of death compared with vemurafenib monotherapy (hazard ratio [HR] of 0.61 [95% CI: 0.47–0.79], p<0.0001]. The observed efficacy of vemurafenib in the control arm is also consistent with historical data, providing an additional benchmark for validating the patient population and results observed in COLUMBUS.^1,2 Further, the two-year OS with the combination therapy was 58%. These results will be part of an oral presentation today at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois, and have been selected for the “Best of ASCO” program.

Importantly, the presentation included data showing limited use of post-trial immunotherapy, which is consistent with other published pivotal trials of BRAF and MEK inhibitors in BRAF-mutant advanced melanoma.^1,3

“These data indicate that regardless of treatment group, the use of subsequent immunotherapies was similar, and therefore indicate that post-trial treatments are unlikely to have contributed to the OS results we’ve seen,” said Professor Reinhard Dummer, University of Zurich, lead author and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland. “We’re pleased to present this data at ASCO which builds upon previous analyses of the COLUMBUS data and further support our belief that encorafenib and binimetinib could be a promising new treatment option for patients with BRAF-mutant advanced melanoma.”

Additionally, the updated median progression-free survival (mPFS) results for patients treated with the combination of encorafenib and binimetinib remained consistent with what was previously reported: 14.9 months versus 7.3 months for patients treated with vemurafenib (HR=0.51 [95% CI 0.39–0.67]; p<0.0001).

As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. Grade 3–4 adverse events (AEs) that occurred in more than 5% of patients receiving the combination were increased gamma-glutamyltransferase (GGT; 9%), increased blood creatine phosphokinase (CK; 7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available BRAF+MEK inhibitor treatments, for patients receiving the combination of encorafenib and binimetinib included: rash (22%), serous retinopathy including retinal pigment epithelial detachment (20%), pyrexia (18%) and photosensitivity (5%). Full safety results of COLOMBUS Part 1 were published in The Lancet Oncology.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.^4,5 There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma.^4,6,7,8

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open-label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared with 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 trial. Patients were randomized into two parts:

• In Part 1, 577 patients were randomized 1:1:1 to receive encorafenib 450 mg daily + binimetinib 45 mg twice daily (COMBO450); encorafenib 300 mg daily (ENCO 300); or vemurafenib 960 mg twice daily as a monotherapy. The dose of encorafenib in the combination arm is 50% higher than the single-agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was a median progression-free survival (mPFS) comparison of the COMBO450 arm versus vemurafenib. mPFS 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 mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial previously published in The Lancet Oncology earlier this year (online March 2018, print May 2018), showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib (HR 0.54 [95% CI 0.41-0.71], p<0.0001). In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months (HR 0.75 [95% CI 0.56-1.00], p=0.051).
• In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg daily plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.

As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol-specified analysis of OS is descriptive.

About Encorafenib and Binimetinib
BRAF and MEK 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, including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 COLUMBUS trial and the Phase 3 BEACON CRC trial.

Pierre Fabre has exclusive rights to commercialize encorafenib and binimetinib in Europe, Asia, Latin America and Australia. Pierre Fabre’s development partner, Array BioPharma, has exclusive rights in the U.S. and Canada, and has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea. Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

References
[1] Ascierto PA, et al. Lancet Oncol. 2016;17:1248-1260.
[2] Robert C, et al. Eur J Cancer. 2015;51:S663-S664.
[3] Long GV, et al. Ann Oncol. 2017;28:1631-1639.
[4] Melanoma Skin Cancer. American Cancer Society. Available at: https://www.cancer.org/cancer/melanoma-skin-cancer.html. Accessed May 2018.
[5] A Snapshot of Melanoma. National Cancer Institute. Available at: https://seer.cancer.gov/statfacts/html/melan.html. Accessed May 2018.
[6] Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed May 2018.
[7] Klein O, et al. Eur J Cancer, 2013.
[8] American Cancer Society. What Causes Melanoma Skin Cancer? 2016. https://www.cancer.org/cancer/melanoma-skin-cancer/causes-risks-prevention/what-causes.html. Accessed May, 2018.

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Contact information

Pierre Fabre
Valérie Roucoules, (33) 1 49 10 83 84
valerie.roucoules@pierre-fabre.com