Encorafenib Plus Binimetinib vs Vemurafenib or Encorafenib in Patients With BRAF-Mutant Melanoma
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma.
METHODS
COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600Eor BRAFV600Kmutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either 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). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately.
FINDINGS
Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator.
INTERPRETATION
Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.
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Additional Info
Disclosure statements are available on the authors' profiles:
Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF-Mutant Melanoma (COLUMBUS): A Multicentre, Open-Label, Randomised Phase 3 Trial
Lancet Oncol 2018 Mar 21;[EPub Ahead of Print], R Dummer, PA Ascierto, HJ Gogas, A Arance, M Mandala, G Liszkay, C Garbe, D Schadendorf, I Krajsova, R Gutzmer, V Chiarion-Sileni, C Dutriaux, JWB de Groot, N Yamazaki, C Loquai, LA Moutouh-de Parseval, MD Pickard, V Sandor, C Robert, KT FlahertyFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
COLUMBUS is a two-part, randomized, open-label phase III trial exploring the efficacy and safety of encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, vs vemurafenib in patients with advanced BRAF V600–mutant melanoma. Encorafenib effectively suppresses the MAPK pathway in tumor cells that express several mutated forms of BRAF kinase (V600-E, -K, and -D); in addition, its longer dissociation half-life (>30 h) than that of other BRAF inhibitors seems to enable sustained target inhibition and enhanced anti-tumor activity, while reducing paradoxical activation of MAPK pathway in normal tissues.
This study was originally designed to compare the efficacy of encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, with encorafenib given at 300 mg once daily (its maximum tolerated dose as monotherapy) or vemurafenib given at its clinically indicated dose. At the request of the FDA, the study protocol was amended in November 2014 to add a second phase to better understand and characterize the contribution of binimetinib to the combination therapy, and this was done by comparing encorafenib 300 mg plus binimetinib 45 mg against encorafenib 300 mg alone. The results of phase II will be published separately.
Between December 30, 2013, and April 10, 2015, 1345 patients were assessed, of whom 177 were randomly assigned 1:1:1 to receive either encorafenib 450 mg once daily plus binimetinib 45 mg twice daily (n = 192), or encorafenib given at 300 mg once daily (n = 194), or vemurafenib given at 960 mg twice daily (n = 191). Patients had extensive disease, with 64% overall having stage M1c disease and 45% having three or more organs involved. One-third of patients previously had and progressed on first-line immunotherapy. The primary endpoint of the study was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib.
At a median follow-up of 16.7 months (95% CI, 14.8–16.9), median progression-free survival was longer for patients in the combination group (14.9 months) than for those in the vemurafenib group (7.3 months) or encorafenib monotherapy group (9.6 months). This was translated to a significant reduction in the risk of progression or death for encorafenib plus binimetinib versus vemurafenib (HR, 0.54; 95% CI 0.41–0.71; two-sided P < .0001). The key secondary comparison of progression-free survival by blinded independent central review showed a median of 14.9 (95% CI, 11.0–18.5) months in the encorafenib plus binimetinib group and 9.6 (7.5–14.8) months in the encorafenib alone group (HR, 0.75; 95% CI, 0.56–1.00; two-sided P = .051), indicating a larger treatment effect for the combination therapy versus encorafenib monotherapy.
Grade 3/4 adverse events were reported in 58% of patients in the encorafenib plus binimetinib group, compared with 66% in the encorafenib group and 63% in the vemurafenib group. The most common grade 3/4 adverse events seen in more than 5% of patients treated with combination therapy were increased γ-glutamyltransferase (9%), increased creatine phosphokinase (7%), and hypertension (6%). By comparison, palmoplantar erythrodysesthesia syndrome (14%), myalgia (10%), and arthralgia (9%) were seen most frequently in the encorafenib group; and arthralgia (6%) in the vemurafenib group. Serious adverse events occurred in 34% of patients in the encorafenib plus binimetinib group, a rate that was fairly similar to that in the encorafenib (34%) and vemurafenib (37%) monotherapy groups. The most common serious adverse events by treatment group were pyrexia (in 6 patients [3%]) in the encorafenib plus binimetinib group, vomiting and nausea (each in 6 patients [3%]) in the encorafenib group, and deterioration of general physical health (in 6 patients [3%]) in the vemurafenib group. Of note, pyrexia occurred in 35 (18%) of 192 patients in the encorafenib plus binimetinib group, 30 (16%) of 192 patients in the encorafenib group, and 55 (30%) of 186 patients in the vemurafenib group.
In this study, pyrexia episodes were generally of a lower grade, not recurrent, and most often associated with concurrent illness or progressive disease. Serous retinopathy occurred in 38 (20%) patients in the encorafenib plus binimetinib group, 4 (2%) patients in the encorafenib group, and 3 (2%) patients in the vemurafenib group. Most of the events in the encorafenib plus binimetinib group were grade 1 (12%) or grade 2 (5%) and resulted in dose interruption or adjustment in 11 (6%) patients but did not result in treatment discontinuation. Left ventricular dysfunction occurred in 15 (8%) patients in the encorafenib plus binimetinib group and was grade 1 in 4 (2%) patients, and grade 2 in 8 (4%). This led to dose interruption or adjustment in 12 patients (6%), was generally reversible, and did not result in treatment discontinuations. Photosensitivity was seen in 30% of patients in the vemurafenib group, 5% in the encorafenib plus binimetinib group, and 4% in the encorafenib alone group.
Overall, these data suggest that and encorafenib in combination with binimetinib is an effective treatment option for BRAF-mutant metastatic melanoma with a progression-free survival of 14.9 months. Overall survival data and the results of the phase II study will provide additional insight into the efficacy of this combination. Additionally, the treatment seems to be well-tolerated, with a different toxicity profile from other combinations of BRAF- and MEK-inhibitors and lower frequencies of pyrexia and photosensitivity.