COLUMBUS study: Five-year follow up

Research summary edited by Pierre Fabre from:
COLUMBUS 5-year update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma.

COLUMBUS study: Five-year follow up on efficacy and safety of the BRAF inhibitor encorafenib (Braftovi) plus the MEK inhibitor binimetinib (Mektovi) in patients with BRAF V600-mutant melanoma

Abstract

The phase III COLUMBUS study showed that combination treatment with the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib results in longer progression free survival and overall survival compared to the BRAF inhibitor vemurafenib, while also producing a positive impact on perceived health status for patients with advanced BRAF V600-mutant melanoma. The recently published 5-year update on the COLUMBUS study showed continued long-term benefits and a consistent safety profile of encorafenib plus binimetinib in patients with unresectable or metastatic BRAF V600-mutant melanoma.

Introduction

Almost 50% of melanomas contain BRAF V600 mutations that lead to constitutive activation of the mitogen activated protein kinase pathway and increased cell growth and proliferation. Combination treatment with inhibitors of BRAF and the mitogen activated protein kinase kinase (MEK) is now a part of the European Society for Medical Oncology (ESMO) recommendations for treating BRAF V600-mutant locally advanced or metastatic melanoma.1

The COLUMBUS study assigned 577 patients with unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first line immunotherapy, in a 1:1:1 ratio: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. Baseline characteristics were similar among groups.2,3 Results on progression free survival (PFS), overall survival (OS) and quality of life have been published;2–4 treatment with encorafenib plus binimetinib extended PFS compared to vemurafenib (14.9 vs 7.3 months; hazard ratio [HR], 0.51; 95% CI, 0.39 – 0.67).5 Combination treatment also extended median OS compared to vemurafenib (33.6 vs 16.9 months; HR, 0.61; 95% CI, 0.48 – 0.79).5 Further, treatment with encorafenib plus binimetinib improved quality of life compared to vemurafenib, as shown by the results of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) and the European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) questionnaires; postbaseline scores were 3.03 points higher (P<0.0001) for FACT-M and 5.28 points higher for (P=0.0042) for EORTC QLQ-C30.4

Main results:

At the 5-year follow up cutoff, 13% were still receiving encorafenib plus binimetinib treatment compared to 2.1% for vemurafenib. Of the 87% who discontinued treatment in the encorafenib plus binimetinib group, 55.2% was due to progression of disease and 12% due to adverse events (AE).5

PFS rates were higher with encorafenib plus binimetinib at each yearly landmark: encorafenib plus binimetinib vs. vemurafenib (HR 0.51; 95% CI 0.40 – 0.67; P<0.0001).5,6 The PFS for encorafenib plus binimetinib at 5 years was 23% compared to 10% for vemurafenib (Figure 1).5

OS rates for encorafenib plus binimetinib were higher at each yearly landmark compared to vemurafenib (HR, 0.64; 95% CI 0.50 – 0.81; P<0.001).5,6 At 5 years the OS rate for encorafenib plus binimetinib was 35% compared to 21% for vemurafenib (Figure 2).5

Central review showed that 92% of patients treated with encorafenib plus binimetinib achieved disease control, with a median duration of response of 18.6 months (95% CI 12.7 to 27.6). Complete response was achieved in 14.1% of patients in the encorafenib plus binimetinib group compared to 8.4% for the vemurafenib group. The most common first subsequent therapy after study treatment in both arms were anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) or anti-programmed cell death protein 1 (anti-PD-1) as monotherapy or in combination.5

The safety profile observed at the 5-year follow up was consistent with previous reports,2,3 with grade 3–4 AEs occurring in 70% and 66% of patients in the encorafenib plus binimetinib and vemurafenib groups, respectively. In the encorafenib plus binimetinib group AEs that led to dose adjustment or interruption were gastrointestinal disorders (17%), eye disorders (12%), pyrexia (6%), decreased ejection fraction (5%) and increased gamma-glutamyl transferase (5%). On-treatment deaths were 13% and 11% in the encorafenib plus binimetinib and vemurafenib groups, respectively; most were due to underlying disease.5

Conclusion

While analyses of the 5-year follow up are post hoc and descriptive, results from the COLUMBUS study demonstrated continued long-term benefits of combined encorafenib plus binimetinib treatment for patients with unresectable or metastatic BRAF V600-mutant melanoma. After 5 years 35% of patients treated with encorafenib plus binimetinib in COLUMBUS were alive, with 23% remaining progression-free and 14.1% having achieved complete response. At each yearly landmark PFS and OS rates were higher in the encorafenib plus binimetinib treatment group compared to the vemurafenib group. AEs with encorafenib plus binimetinib were consistent with previous reports and no new safety signals were observed in this 5-year follow up.

 

Figures

Figure 1. Kaplan-Meier analysis of progression free survival (PFS) in all patients. The 5-year PFS rates for encorafenib plus binimetinib was 23% compared to 10% for vemurafenib; the median follow up was 40.8 months. HR, hazard ratio; CI, confidence interval. Figure adapted from Dummer et al.5

 

Figure 2. Kaplan-Meier analysis of overall survival (OS) in all patients. The 5-year OS rates for encorafenib plus binimetinib was 35% compared to 21% for vemurafenib; median follow up was 70.4 months. HR, hazard ratio; CI, confidence interval. Figure adapted from Dummer et al.5

 

 

Viktig sikkerhetsinformasjon

Viktig sikkerhetsinformasjon Braftovi® (enkorafenib) og Mektovi® (binimetinib)

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Oppdatert: 7 november, 2022
Referanser
1 Keilholz U, Ascierto PA, Dummer R, et al. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol 2020;31(11):1435–48.
2 Dummer R, Ascierto PA, Gogas HJ, et al. 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;19(5):603–15.
3 Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19(10):1315–27.
4 Gogas H, Dummer R, Ascierto PA, et al. Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). Eur J Cancer 2021;152:116–28.
5 Dummer R, Flaherty KT, Robert C, et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600–Mutant Melanoma. J Clin Oncol 2022;JCO.21.02659.
6 Altman DG, Bland JM. How to obtain the P value from a confidence interval. BMJ [Internet] 2011;343. Available from: https://www.bmj.com/content/343/bmj.d2304
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