Array BioPharma Announces Publication of BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) Phase 3 Overall Survival Data in The Lancet Oncology
BOULDER, Colo., Sept. 13, 2018 /PRNewswire/ -- Array BioPharma, Inc.(NASDAQ: ARRY) today announced the publication of detailed overall survival (OS) results from the COLUMBUS trial in The Lancet Oncology. The pivotal Phase 3 trial evaluated the efficacy and safety of the combination of BRAFTOVI®+ MEKTOVI® compared to vemurafenib monotherapy in patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation. BRAFTOVI + MEKTOVI reduced the risk of death compared to treatment with vemurafenib [hazard ratio (HR) of 0.61, (95% CI 0.47-0.79, p <0.0001)] in the planned analysis of OS. Median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. The analysis of OS and updated efficacy and safety data extend findings of previously announced results.
Based on data from the previously reported primary analysis of the COLUMBUS trial, the U.S. Food and Drug Administration (FDA) approved BRAFTOVI capsules in combination with MEKTOVI tablets on June 27, 2018 for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma. Further, on July 16, 2018, Array submitted supplementary New Drug Applications to seek inclusion of OS data from the COLUMBUS trial in the BRAFTOVI and MEKTOVI labels.
Mature median progression-free survival (mPFS) for BRAFTOVI + MEKTOVI was 14.9 months (95% CI 11.0-20.2) compared to vemurafenib with 7.3 months (5.6-7.9), [HR 0.51, (95% CI 0.39-0.67; two-sided p<0.0001)].
"The publication of updated findings from the COLUMBUS trial in The Lancet Oncology underscores the value that BRAFTOVI + MEKTOVI bring to patients with BRAF-mutant melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "Based on the observed efficacy and tolerability, this targeted combination is an important new treatment option for patients with this life-threatening form of melanoma."
Use of post-trial immunotherapy was limited and consistent with other published pivotal trials of BRAF + MEK inhibitors in advanced BRAF-mutant melanoma. The manuscript also noted that the performance of vemurafenib, the control arm, was consistent across efficacy endpoints with its performance in other trials of BRAF + MEK inhibitor combinations where it also served as a control. Finally, the authors conclude the data represent a new benchmark for BRAF + MEK inhibitors in metastatic or unresectable BRAF-mutant melanoma.
With 18 months of additional follow-up relative to the initial publication of COLUMBUS results, the safety profile of the combination remained generally consistent with the prior report. Observed grade 3 or 4 adverse events in more than 5% of patients with BRAFTOVI + MEKTOVI were increased gamma-glutamyltransferase (9%), increased blood creatine phosphokinase (7%) and hypertension (6%). Additional safety information can be found in the manuscript and in the Important Safety Information below.
For more information about treatment of BRAFTOVI in combination with MEKTOVI, visit www.braftovimektovi.com.
The full prescribing information for BRAFTOVI can be found here:
The full prescribing information for MEKTOVI can be found here:
About BRAF-mutant Metastatic Melanoma
About BRAFTOVI + MEKTOVI
Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co, Ltd. exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia (excluding Japan and South Korea) and Latin America.
BRAFTOVI and MEKTOVI are not approved outside of the U.S. The European Medicines Agency (EMA), the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are currently reviewing the Marketing Authorization Applications submitted by Pierre Fabre, and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) is currently reviewing the Manufacturing and Marketing Approval Applications for submitted by Ono Pharmaceutical Co, Ltd.
BRAFTOVI + MEKTOVI Indications and Usage
Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.
BRAFTOVI + MEKTOVI Important Safety Information
Warnings and Precautions
Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or BRAFV600K mutation prior to initiating BRAFTOVI.
Cardiomyopathy: In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal.
Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.
Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.
Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis, was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmic evaluation at regular intervals and for any visual disturbances.
Interstitial Lung Disease (ILD): ILD, including pneumonitis, occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.
Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST). Monitor liver laboratory tests before and during treatment and as clinically indicated.
Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK periodically and as clinically indicated.
QTc Prolongation: In the COLUMBUS trial, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.
Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.
In the COLUMBUS Trial, the most common laboratory abnormalities (≥20%, all Grades) included: increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.
Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information [6,7]. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).
About Array BioPharma
Array BioPharma Forward-Looking Statement
BRAFTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.
MEKTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.
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Company Codes: NASDAQ-NMS:ARRY