Targeted therapy: “real world” data on encorafenib plus binimetinib

The BERING-Melanoma multicenter study is monitoring the use of encorafenib with binimetinib in the first- and second-line setting* in patients with advanced BRAFV600-mutated malignant melanoma in everyday care in Germany, Austria, and Switzerland [4 –10]. Over the next several years, this study will provide further insight into the efficacy and tolerability of this therapeutic option.

*  i.e., following a prior line of treatment with advanced stage checkpoint inhibition.

Deferred medical appointments during the Corona pandemic raise concerns for more cases in malignant melanoma, including stage IV [1,2]. But questions remain about the therapy. “The preparation of evidence-based guidelines takes time, so not all current data can be taken into account. Especially in the important question of the therapy sequence, the guidelines cannot yet give us an answer,” emphasized Prof. Dr. med. Axel Hauschild, University Dermatology Clinic Kiel, on the occasion of the German Skin Cancer Congress of the Arbeitsgemeinschaft Dermatologische Onkologie (ADO). Data on the sequence of different lines of therapy and patient subgroups as well as on the combination of different substances would be desirable. A look at the reality of care can be revealing, he and Prof. Dr. med. Dirk Schadendorf, University Hospital Essen, and Prof. Dr. med. Erika Richtig, Medical University of Graz [16] explained. It is becoming apparent that targeted therapy -especially when remission pressure is high- can play an important role in the first-line setting [3]. Initial real-world data on encorafenib plus binimetinib in nonresectable or metastatic melanoma with a BRAFV600 mutation support first- and second-line use [6–15].

MORSE: high remission pressure favors first-line targeted therapy

Information on the reality of care in Germany, Austria, and Switzerland between 2016 and 2018 is provided by the retrospective cross-sectional study MORSE (“Melanoma Online Retrospective Evaluation”), which is based on anonymized data from 242 documented first-, second-, and third-line treatment lines and investigated the reasons for treatment selection [3]. It was notable that targeted therapies (50.7%) and immunotherapies (49.3%) were used equally in the first-line setting in this population during the period studied [3]. Second-line results were 50.0% for targeted therapy and 45.9% for immunotherapy [3]. Other classes of therapy, such as chemotherapy, would usually be used in later lines of treatment [3]. In the third-line setting, decision makers relied predominantly on targeted therapy (67.9%; immunotherapy 28.6%) [3].

The main reason for choosing first-line targeted therapy from the perspective of decision makers in MORSE was predominantly high remission pressure (70%), whereas immunotherapy was primarily used based on physician preference (54%) [3]. Other reasons, such as safety profile or patient preference, were less frequently reported as the main reason for the treatment decision [3]. Prof. Schadendorf added: “Earlier use of targeted therapy may be warranted when the goal is to achieve a rapid response. However, patients with low tumor burden also benefit from targeted therapy in the advanced stage in the long term.”

BERING melanoma: first data confirm use under routine conditions

The BERING-Melanoma study (“Binimetinib plus Encorafenib Real life Investigation of Next Generation Melanoma treatment”) is monitoring the use of encorafenib with binimetinib in the first and second line in approximately 750 patients with advanced BRAFV600 mutated malignant melanoma from 80 centers in Germany, Austria and Switzerland [4,5]. “Fortunately, 230 patients have already been enrolled in the non-interventional study,” Prof. Schadendorf reported. “It is interesting to note that combination therapy has been documented here predominantly (65.2%) in the first-line setting to date. It should be noted, of course, that this is a first interim analysis of a data set that is in flux. We look forward to the results of subsequent analyses.” [10]. Compared to the phase III COLUMBUS study, the patient population of this first interim analysis with n=89 patients in the main analysis set shows
^#
a worse prognostic configuration in terms of elevated LDH levels and the proportion of patients with brain metastases at baseline[10–15]. Nevertheless, the median treatment duration of 12.7 months observed to date and the tolerability profile are broadly comparable to the results of the COLUMBUS trial (median follow-up: 8.1 months) [10–15]. No new safety signals were observed [10].

^# COLUMBUS Part I Study Design: Part I of the randomized, open-label, active-controlled phase III COLUMBUS study compared the efficacy and safety of combination therapy with encorafenib plus binimetinib to BRAF inhibitor monotherapies vemurafenib and encorafenib, respectively.
 

A patient case from the BERING-Melanoma study was presented by Prof. Dr. Erika Richtig, Medical University of Graz. The 61-year-old patient with stage IV BRAFV600E mutation and metastases to lymph nodes, lung, liver, and brain benefited long-term from encorafenib plus binimetinib after previous discontinuation of first-line ipilimumab plus nivolumab therapy due to toxicities. “It is always amazing the rapid response we can achieve in stage IV, even in the second line, with the combination of encorafenib plus binimetinib,” Prof. Richtig concluded.

Literature:

1. Asai Y, et al: Impact of the COVID-19 pandemic on skin cancer diagnosis: A population-based study. PLoS ONE 2021; 16(3): e0248492.
2. Gisondi P, et al: Impact of the COVID-19 pandemic on melanoma diagnosis. J Eur Acad Dermatol Venereol 2021; https://doi.org/10.1111/jdv.17493 (last accessed Oct 13, 2021).
3. Pierre Fabre data on file (DE/AT data published in: Haferkamp S et al. Patients with BRAFMutant Advanced/Metastatic Melanoma: Original Research on the Treatment Reality in Germany and Austria in the Era of Choice. Adv Ther 2020; 37(8): 3619-3629)
4. BERING-Melanoma NIS – ObsPlan DE/AT – V2.0 – 2019-10-28; https://clinicaltrials.gov/ct2/show/NCT04045691 (last call 10-13-2021).
5. BERING melanoma NIS – ObsPlan CH – V2.0 – 2020-03-23; URL: https://clinicaltrials.gov/ct2/show/NCT04045691 (last accessed 10-13-2021).
6. Specialist information BRAFTOVI® at https://www.ema.europa.eu/en/medicines/human/EPAR/braftovi (last accessed: 13.10.2021)
7. Technical information MEKTOVI® at https://www.ema.europa.eu/en/medicines/human/EPAR/mektovi (last accessed: 13.10.2021)
8. Professional information BRAFTOVI® at www.swissmedicinfo.ch, (last accessed: 10/13/2021).
9. Technical information MEKTOVI® at www.swissmedicinfo.ch, (last accessed: 13.10.2021)
10. Right E, et al. Encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma: First data of the multicenter, multinational, prospective, non-interventional longitudinal study BERINGMELANOMA. ASCO2021: Abstract #9555 and Poster
11. Dummer R, 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): 603-615.
12. Dummer R, 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): 1315-1327.
13. Ascierto PA, et al: Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer 2020; 126: 33-44.
14. Gogas H, 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: 116-128.
15. Dummer R, 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 BRAFV600-mutant melanoma. ASCO 2021: Abstract and Presentation #9507
16. “Targeting therapy in stage IV BRAFV600 melanoma: Real-world data on encorafenib plus binimetinib provide new insights,” Pierre Fabre, October 14, 2021.

DERMATOLOGY PRACTICE 2021; 31(6): 36-37