Author: By Hannah Kitt, medwireNews Reporter
medwireNews: The 5-year results of the phase III COLUMBUS trial for patients with BRAF V600-mutated advanced melanoma continue to demonstrate a progression-free survival (PFS) gain with encorafenib plus binimetinib versus encorafenib or vemurafenib monotherapy.
Reporting the findings at the 2021 ASCO Annual Meeting, presenting author Reinhard Dummer, from University Hospital in Zürich, Switzerland, said that “this updated analysis demonstrates a continued long-term benefit of encorafenib and binimetinib versus vemurafenib for patients with BRAF-mutant melanoma.”
He added that the trial is the only “head to head comparison” of the two BRAF inhibitors and better survival outcomes “suggest that the pharmacological features of encorafenib translate into improved efficacy” over vemurafenib.
Discussant Sunandana Chandra, from Northwestern University in Chicago, Illinois, USA said that “it is important to know that the statistical design of the study was formerly powered for analysis of survival outcomes of encorafenib and binimetinib versus vemurafenib alone.”
The 577 participants had locally advanced unresectable or metastatic melanoma with a BRAF V600E or V600K mutation and were treatment-naïve or had progressed on first-line immunotherapy. A total of 192 patients were randomly assigned to receive encorafenib 450 mg once a day with binimetinib 45 mg twice a day, 194 to receive encorafenib 300 mg once a day and 191 to receive vemurafenib 960 mg twice a day.
The combination achieved a better 5-year PFS rate than encorafenib alone or vemurafenib, at 22.9%, 19.3% and 10.2%, respectively, and corresponding median PFS durations of 14.9, 9.6 and 7.3 months.
Analysis of the combination and vemurafenib arms showed a significant 49% lower risk of progression or death with the combination.
Reinhard Dummer noted that patients with a baseline lactate dehydrogenase (LDH) level on or below the upper limit derived a greater PFS benefit from encorafenib and binimetinib than those with a higher LDH, with a 5-year PFS rate of 30.9% versus not evaluable and a median PFS of 22.0 versus 5.6 months. This translated into a significant hazard ratio (HR) of 4.22 in favour of the combination, and the presenter emphasized that “all the patients with elevated LDH progressed earlier.”
Furthermore, those with a normal LDH and fewer than three organs involved at baseline (low tumour burden) had a PFS rate of 38.6% and a median PFS of 25.9 months with the combination.
Overall survival (OS) results followed a similar pattern, with 5-year rates of 34.7%, 34.9% and 21.4% in the combination, encorafenib alone or vemurafenib groups, respectively. Patients given the combination were a significant 36% less likely to die than those taking vemurafenib and the greatest OS benefit from the combination was seen in patients with a normal baseline LDH alone or alongside a low tumour burden, with OS rates of 45.1% and 47.7%, respectively, and an identical median duration of 51.7 months.
The objective response rate was 64.1% with the combination versus 51.5% and 40.8% with encorafenib and vemurafenib monotherapies, respectively, and the corresponding median durations of response were 18.6, 15.5 and 12.3 months. Complete responses occurred in 14.1%, 7.7% and 8.4% of patients, respectively, and partial responses in 50.0%, 43.8% and 32.5%. Meanwhile, 28.1%, 32.5% and 40.3% of patients in each treatment arm had stable disease, resulting in disease control rates of 92.2%, 84.0% and 91.2%, respectively.
In safety analyses, 69.8%, 69.8% and 65.6% of patients in the combination, encorafenib alone and vemurafenib alone groups, respectively, had at least one grade 3–4 adverse event, with hypertension being the most common (7.3, 4.6 and 3.8%), followed by pyrexia (3.6, 1.0 and 0.0%), abdominal pain (3.1, 2.1 and 1.1%), diarrhoea (2.6, 2.1 and 2.7%) and vomiting (2.6, 4.7 and 1.1%).
Comparing safety findings for the different dual BRAF/MEK-targeted therapies being trialled for metastatic melanoma, Sunandana Chandra said that “there are some dominant toxicities that stand out, [such as] gastrointestinal toxicities, including nausea, vomiting, diarrhoea, transaminitis, with encorafenib and binimetinib.”
Nevertheless, Sunandana Chandra agreed that “the 5-year survival analysis shows that there’s a long-term benefit for encorafenib and binimetinib in the first-line BRAF-mutated melanoma patient.”
The discussant added: “It is unclear if the increased binding affinity of encorafenib translates into increased efficacy, or whether the shorter half-life of binimetinib leads to rapid resolution of toxicities with drug interruption.”
Reference
Dummer R, Flaherty K, Robert C, et al. Five-year overall survival (OS) in COLUMBUS: A randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma; J Clin Oncol 2021;39(suppl 15; abstr 9507). DOI: 10.1200/JCO.2021.39.15_suppl.9507
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