Long-term benefit with encorafenib/binimetinib in patients with BRAFV600-mutated melanoma
In order to get a better understanding of the proportion of patients with advanced BRAFV600-mutated melanoma who benefit the most from the encorafenib/binimetinib combination, Gogas et al. presented a four-year updated analysis on overall survival (OS) and progression-free survival (PFS) of the COLUMBUS study. In this landmark analysis, encorafenib plus binimetinib demonstrated an improved overall and progression-free survival compared to vemurafenib at years 1, 2, 3 and 4. This benefit was consistently seen across a broad range of patient subgroups.
Introduction
Based on improved overall survival (OS) and a manageable tolerability relative to BRAF inhibitor monotherapy, combined BRAF/MEK inhibition has become the standard of care for patients with BRAFV600-mutated locally advanced or metastatic melanoma. The phase III COLUMBUS study compared encorafenib plus binimetinib versus encorafenib or vemurafenib in patients with BRAFV600E/K-mutated melanoma. In previous reports of this trial, the combination of encorafenib and binimetinib was shown to significantly prolong the median PFS compared to vemurafenib (14.9 versus 7.3 months). Similarly, also the median OS was significantly extended with the combination therapy (33.6 versus 16.9 months). At ASCO 2020, a 4-year updated, post-hoc analysis with additional follow-up from the COLUMBUS trial was presented to get a better view on the proportion of patients who derive a long-term benefit and their patient’s characteristics.
In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAFV600E/K-mutated melanoma were included who were untreated or who progressed after first-line immunotherapy. Enrolled patients were randomly assigned (1:1:1) to encorafenib 450 mg once daily in combination with binimetinib 45 mg twice daily (COMBO450), vemurafenib 960 mg twice daily or encorafenib 300 mg once daily. All patients had an ECOG performance status of 0-1. Baseline characteristics were well balanced between treatment groups and consistent with advanced/metastatic BRAFV600-mutated melanoma.
Results
At data cut-off (November 2019), OS events had occurred in 65%, 59% and 75% of patients, with PFS events in 62%, 60% and 62% of patients in the COMBO450, encorafenib and vemurafenib treatment arms, respectively. After a median follow-up of 60.6 months, the median OS for patients in the COMBO450 arm was 33.6 months, as compared to 23.5 months for patients in the encorafenib arm and 16.9 months for patients treated with vemurafenib. As compared to vemurafenib, the combination of encorafenib and binimetinib decreased the risk of death by 38% (HR [95%CI]: 0.62 [0.49-0.79]). A landmark analysis demonstrated a higher rate of OS for COMBO450 at each year analysed, with 4-year OS rates of 39%, 37% and 26% for patients in the COMBO450, encorafenib and vemurafenib arm, respectively. The overall response rate, as confirmed by blinded independent central review, was 64% for patients in the COMBO450 arm, 52% for encorafenib and 41% for vemurafenib. The OS benefit of COMBO450 compared to vemurafenib, was consistently seen across all subgroups, including sex, age, BRAF mutation status, lactate dehydrogenase above or below the upper limit of normal, ECOG performance status, tumour stage and number of organs involved at baseline.
The updated median PFS was 14.9 months for patients treated with COMBO450, 9.6 months for encorafenib and 7.3 months for patients in the vemurafenib arm. The 4-year PFS rate was 26% for patients in the COMBO450 arm, 22% for patients treated with encorafenib only and 12% for patients in the vemurafenib arm. As compared to vemurafenib, the combination of encorafenib and binimetinib reduced the risk of disease progression or death by 48% (HR [95%CI]:0.52 [0.40-0.67]). The median duration of exposure was 51 weeks for patients in the COMBO450 arm, 31 weeks for patients in the encorafenib arm and 26 weeks for patients in the vemurafenib arm. Safety results were consistent with the known tolerability profile of COMBO450 and no new safety concerns were noted in this update. The most common side effects of all grade in the COMBO450 arm were nausea (44%), diarrhoea (39%), vomiting (32%), fatigue (30%) and arthralgia (29%).
Conclusions
In the COLUMBUS trial, the updated OS and PFS data with the combination of encorafenib and binimetinib continue to demonstrate the long-term benefits with this regimen in patients with BRAFV600-mutated melanoma. Landmark analyses showed an improved OS and PFS for COMBO450 versus vemurafenib at years 1, 2, 3 and 4.
Reference
Gogas H, Ascierto PA, Flaherty K, et al. Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600-mutant melanoma. Presented at ASCO 2020; Abstract 10012.
