Updated 4-year results of the COLUMBUS trial demonstrate a long-term benefit in both median overall survival (OS) as well as progression-free survival (PFS) with the combination of encorafenib (Braftovi®) plus binimetinib (Mektovi®) in patients with BRAFV600–mutated melanoma, as compared to vemurafenib.
Based on improved 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. 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, an updated analysis on OS and other endpoints of the COLOMBUS (Combined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer)- trial was performed. Results of these analyses were recently presented at ASCO 2020.1 Encorafenib is a highly-selective ATP-competitive BRAF inhibitor while binimetinib is a potent, selective allosteric, ATP-non-competitive MEK1/2 inhibitor with a shorter half-life as compared to other MEK1/2 inhibitors.2
In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAFV600-mutant 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 (ENCO300). The study is currently still ongoing.
At data cut-off (November 2019), OS events had occurred in respectively 65%, 59% and 75% of patients in the COMBO450, ENCO300 and VEM arm. 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 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]). Safety results were consistent with the known tolerability profile of COMBO450 and no new safety concerns were noted in this update.
CONCLUSION
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. These results were presented during the poster presentation at the virtual ASCO 2020 meeting.1
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