Journal article
Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial.
- Dummer R Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch.
- Ascierto PA Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy.
- Gogas HJ Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece.
- Arance A Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
- Mandala M Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
- Liszkay G Department of Dermatology, National Institute of Oncology, Budapest, Hungary.
- Garbe C Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
- Schadendorf D Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany.
- Krajsova I Department of Dermato-oncology, University Hospital Prague and Charles University First Medical Faculty, Prague, Czech Republic.
- Gutzmer R Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
- Chiarion Sileni V Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy.
- Dutriaux C Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux Cédex, France.
- de Groot JWB Department of Medical Oncology, Isala, Zwolle, Netherlands.
- Yamazaki N Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
- Loquai C Department of Dermatology, University Medical Center Mainz, Mainz, Germany.
- Moutouh-de Parseval LA Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland.
- Pickard MD Array BioPharma, Boulder, CO, USA.
- Sandor V Array BioPharma, Boulder, CO, USA.
- Robert C Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif Cedex, France.
- Flaherty KT Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
- 2018-09-17
Published in:
- The Lancet. Oncology. - 2018
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Benzimidazoles
Biomarkers, Tumor
Carbamates
Disease Progression
Female
Genetic Predisposition to Disease
Humans
Male
Melanoma
Middle Aged
Mutation
Phenotype
Progression-Free Survival
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
Skin Neoplasms
Sulfonamides
Time Factors
Vemurafenib
Young Adult
English
BACKGROUND
Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.
METHODS
COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAFV600E or BRAFV600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.
FINDINGS
Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.
INTERPRETATION
The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAFV600-mutant melanoma.
FUNDING
Array BioPharma, Novartis.
Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.
METHODS
COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAFV600E or BRAFV600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.
FINDINGS
Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.
INTERPRETATION
The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAFV600-mutant melanoma.
FUNDING
Array BioPharma, Novartis.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1016/S1470-2045(18)30497-2
- PMID 30219628
- Persistent URL
- https://sonar.ch/global/documents/258630
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