COLUMBUS part 1–7-year results for encorafenib and binimetinib in BRAF V600-mutant melanoma

ABSTRACT

This summary presents 7-year results from COLUMBUS part 1, which tested encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®) (COMBO group), against encorafenib alone (ENCO group), or vemurafenib (ZELBORAF®) alone (VEMU group) as a treatment for a skin cancer called advanced or metastatic BRAF V600-mutant melanoma.

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1. COLUMBUS 7-year follow-up audio interview transcript

1.1. Let’s talk about COLUMBUS

The COLUMBUS study is a randomized, two-part, multicenter, open-label, active-controlled, phase III study. In part 1, patients with advanced or metastatic BRAF V600E/K-mutant melanoma received encorafenib plus binimetinib, or encorafenib monotherapy, in comparison with vemurafenib monotherapy. Results from the previously published primary analysis, which led to the approval of the combination in this patient population, and 5-year analysis have demonstrated that treatment with encorafenib plus binimetinib is associated with improved and continued long-term benefits compared to vemurafenib in this patient population. This 7-year analysis presents updated efficacy and safety results for the combination compared with vemurafenib or monotherapy using encorafenib, including a first report of melanoma-specific survival data and insights on long-term responders in this study. To our knowledge, this is the longest follow-up study from a phase III randomized trial of a combination of BRAF and MEK inhibitors in such a patient population.

1.2. What did the efficacy results show after 7 years of follow-up?

The updated results show prolonged PFS and OS with encorafenib plus binimetinib in comparison to both monotherapy arms. Seven-year PFS rates were 21% with the combination, 6.4% with vemurafenib, and 15.8% with encorafenib monotherapy. Seven-year OS rates were 27.4% with encorafenib plus binimetinib, 18.2% with vemurafenib, and 31.7% with encorafenib monotherapy. Overall response rate was 64% with enco(rafenib) plus bini(metinib), 41% with vemurafenib, and 51.5% with encorafenib monotherapy. Thirty-four long-term responders, patients with ongoing complete or partial response, were reported at 7 years and were identified across all arms. Median melanoma-specific survival was 36.8 months for the combination, 19.3 months in the vemurafenib arm, and 24.2 months in the encorafenib monotherapy arm. Seven-year melanoma-specific survival rates were 32% with enco/bini (encorafenib plus binimetinib), 20% with vemurafenib, and almost 34% with encorafenib monotherapy.

1.3. What was the safety profile after 7 years of follow-up?

Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib, and grade 3/4 adverse events (AEs) occurred in roughly 70% of patients who received enco (encorafenib) plus bini (binimetinib), in roughly 66% of patients who received vemurafenib, and 70% who received encorafenib monotherapy. AEs leading to treatment discontinuation occurred in roughly 20% of patients who received encorafenib plus binimetinib, 17.7% in patients who received vemurafenib, and in 16% of patients who received enco(rafenib) monotherapy. Most treatment-related adverse events of special interest occurred within the first year of treatment in the combination arm.

1.4. What types of anticancer treatments did people take after stopping the study treatments?

After drug discontinuation, roughly 46% of patients from the enco/bini (encorafenib plus binimetinib) arm received treatment, roughly 69% from the vemurafenib arm, and close to 60% from the encorafenib monotherapy arm received subsequent anticancer systemic treatment. Looking at which kind of first subsequent antineoplastic systemic treatment was given, immunotherapy (anti-CTLA-4 and/or anti-PD-1/ligand 1), targeted therapies (either BRAF inhibitor or in combination with MEK inhibitor), or chemotherapy were given, and the percentage of patients with a least one immunotherapy as the first antineoplastic systemic treatment after study treatment was 32.8%, 32.5%, and 29.4% in the three arms, respectively. The percentage of patients with at least one targeted therapy as the first antineoplastic systemic treatment after study treatment was 8.3% versus 27.7% and 20.6%, respectively. The percentage of patients with at least one chemotherapy as the first antineoplastic systemic therapy after study treatment was low, in the range of 4.2%, 7.9%, and 9.3%, respectively.

1.5. Does the type of anticancer treatment people took after stopping the study medications affect outcomes?

So, among the patients who received subsequent treatment, the median OS since start of the first antineoplastic systemic treatment following study drug discontinuation was 17.2 months for patients initially in the enco(rafenib) plus (bini)metinib arm, 11.6 months for patients initially in the vemurafenib arm, and 12.3 months for patients initially in the encorafenib monotherapy arm. Patients initially in the combination arm, for those, the median OS since start of the first subsequent therapy was 38.3 months for the 16 patients who received at least one subsequent targeted therapy; 17.1 months for the 63 patients who received at least one subsequent immunotherapy; and 12.3 months for the eight patients who received at least one subsequent chemotherapy.

1.6. What is meaningful about COLUMBUS and its 7-year follow-up?

This 7-year update of COLUMBUS part 1 further supports the long-term survival benefit of the combination of encorafenib plus binimetinib for patients with unresectable or metastatic BRAF V600E/K-mutant melanoma. PFS and OS were prolonged with the combination in comparison with both monotherapy arms and PFS and OS Kaplan–Meier curves began to plateau after around 4 years, which suggests that patients may continue (to) derive long-term survival benefit, similar to survival plateaus observed with immune checkpoint inhibitors. Melanoma-specific survival, reported here for the first time, was (also) longer for the combination of enco/bini (encorafenib plus binimetinib) in comparison with both monotherapy arms. Fewer patients in the enco(rafenib) plus bini(metinib) arm received next-line anticancer therapy after study drug discontinuation compared to both monotherapy arms, and among patients who received subsequent antineoplastic systemic treatment, OS was better in the combination arm in comparison to both monotherapy arms. Of note, among patients originally in the encorafenib monotherapy arm who went on to receive subsequent therapy, approximately one-third received a BRAF inhibitor or a combination of BRAF/MEK inhibitors as first subsequent treatment. This 7-year analysis adds to the body of evidence from previous studies, such as SECOMBIT and DREAMseq, suggesting that BRAF plus MEK inhibition is effective both in the first-line setting and in patients who previously received immunotherapy. While immunotherapy is effective in the first-line setting, a subset of patients may benefit from targeted therapy in the first line or as a lead-in to immunotherapy. AEs in the combination arm were generally manageable, and no new safety signals were observed. The proportion of patients with adverse events was similar across arms. Overall, the most common adverse events with the combination were nausea, diarrhea, vomiting, arthralgia, and fatigue. The majority of treatment-related adverse events of special interest occurred during the first year of treatment and, of note, fewer patients in the combination arm had dose interruptions compared with those in the vemurafenib and encorafenib monotherapy (arms). To our knowledge, this analysis is the longest follow-up from a phase III trial of a BRAF/MEK inhibitor for the treatment of unresectable or metastatic BRAF V600E/K-mutant melanoma. Thank you for your attention.

Funding Statement

This study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Author contributions

Study conception and design: Dirk Schadendorf

Provision of study materials or patients: Dirk Schadendorf

Collection and assembly of data: Dirk Schadendorf

Data analysis and interpretation: Dirk Schadendorf

Content writing/reviewing: Dirk Schadendorf

Final approval: Dirk Schadendorf

Accountable for all aspects of the work: Dirk Schadendorf

Disclosure statement

Dirk Schadendorf. Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, Replimune. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, MSD, Pierre Fabre, Sanofi/Regeneron. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing support was provided by Blaise Low, PhD, and Eleanor Porteous, MSc, of Nucleus Global, an Inizio company, and was funded by Pfizer.

Reviewer disclosures

A reviewer on this manuscript has disclosed “I was a local principal investigator for the COLUMBUS clinical trial and recruited patients who participated in it.” Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Original European Journal of Cancer publication title

Schadendorf R, et al. COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma. Eur J Cancer. 2024;204:114073; https://doi.org/10.1016/j.ejca.2024.114073.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2025.2536459.