EORTC Completes Patient Recruitment to Study of Treatment for unresectable or metastatic melanoma

Brussels, August 05, 2022 – The European Organisation for Research and Treatment of Cancer (EORTC) has finished patient recruitment for the EORTC-1612-MG trial in patients with unresected or metastatic melanoma. The randomised trial will study the effect of combined targeted therapy (encorafenib and binimetinib) followed by combined immunotherapy (ipilimumab and nivolumab) as compared to immediate combined immunotherapy, in patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Systemic therapy options for metastatic melanoma currently depend on whether the patient’s tumour expresses the so-called BRAF mutation. Activating mutations in the BRAF gene (a protein kinase) occur in 40-60% of patients, the most common mutations being V600E, followed by V600K.  In recent years, the approval of immunomodulatory agents and targeted agents for treatment of advanced or metastatic melanoma has dramatically changed the landscape and is leading to a potential broad range of applications for combination therapies.

To date, there is no consensus on the optimal first line treatment for patients with BRAF mutant metastatic melanoma.

Evidence suggests that targeted agents can provide not only additive effects to immunotherapy but can also sensitise the tumour cells to immune attacks (by increasing antigen expression) and improve the effector function of immune cells. Pre-clinical data support the rationale for intermittent regimens with BRAF inhibitors, showing that the development of resistance could be delayed with intermittent therapy. The hypothesis is that a sequential approach could merge the high response rate of target therapy with the peculiarity of immunotherapy to achieve long-term durable responses, prior to secondary resistance to the targeted therapy occurring.

Recruitment to the EORTC-1612-MG trial started in November 2018. Completion of recruitment marks a crucial milestone for the trial.

‘I would like to sincerely thank all the persons who made this study possible in spite of the difficulties we went through in this troubled period. We will finally soon be in a position to answer the important questions that we wanted to address with this study’, says Professor Caroline Robert from the Gustave Roussy Cancer Institute, Villejuif, France and Coordinator of this trial for the EORTC Melanoma Group.

This is a multicentre, 2-arm open-label, randomised comparative phase II study. Its primary objective is to prospectively assess whether a sequential treatment approach with an induction period of 12 weeks with targeted therapy drugs encorafenib + binimetinib, followed by an immunotherapy combination with immunomodulatory agents nivolumab + ipilimumab, improves Progression Free Survival (PFS) compared to a nivolumab + ipilimumab immunotherapy combination alone as first line treatment, in patients with BRAF V600 mutation–positive unresectable or metastatic melanoma.

A total of 270 patients with unresectable or metastatic (stage IV) (as per AJCC Cancer Staging Manual, 7^th edition) melanoma were randomised to receive either one of the two treatments:

Treatment arm A: nivolumab 3 mg/kg once every 3 weeks + ipilimumab 1 mg/kg once every 3 weeks or 4 infusions followed by nivolumab 480 mg intravenously once every 4 weeks until completion of 2 years total treatment or disease progression. Then treatment will be left at the investigator choice and continued until the second progression.

Treatment arm B: encorafenib 450 mg once a day + binimetinib 45 mg twice a day orally for 12 weeks followed, after a week of pause, by nivolumab 3 mg/kg once every 3 weeks + ipilimumab 1 mg/kg once every 3 weeks for 4 infusions, followed by nivolumab 480 mg intravenously once every 4 weeks until completion of 2 years total treatment or disease progression. Then patients will be rechallenged with encorafenib 450 mg once a day + binimetinib 45 mg twice a day orally continuously until the second progression.

This is an academic trial supported by the EORTC Melanoma Group, and a restricted educational grant from Pierre Fabre and Bristol Myers Squibb, who supply encorafenib & binimetinib and nivolumab & ipilimumab, respectively, for the duration of the trial.

First results from the trial are expected around mid-2023.

Melanoma is the deadliest form of skin cancer. Historically, melanoma was a rare cancer, but in the last 50 years its incidence has risen faster than almost any other cancer ^[1] making it the 19^th most commonly occurring cancer worldwide,^[2] with over 320,000 new cases and over 55,000 deaths, in 2020.^[3] After Australia and New Zealand, European countries have highest rates of melanoma incidence. According to GLOBOCAN, in Europe there are approximately 144.000 cases diagnosed per year and 27.000 deaths related.^[4] By 2025, the number of cases is expected to increase to over 340,000.^[5] Approximately half of the cases diagnosed have BRAF mutations, a key target in the treatment of metastatic melanoma.^[6-8]

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours.^[9] Starting from pigment-producing cells (melanocytes) in the skin, melanoma spreads to other parts of the body through metastasis.

Before the development of immune checkpoint inhibitors and anti-BRAF-targeted therapy, patients with metastatic melanoma had a median OS of less than 12 months. Both targeted therapy (anti-BRAF + anti-MEK) ^[11] and immunotherapy (anti-PD1 +/- anti-CTLA-4) have significantly prolonged the OS of patients with BRAF mutant metastatic melanoma.^[11]

1. Matthews NH, Li WQ, Qureshi AA, et al. Epidemiology of Melanoma. In: Ward WH, Farma JM, editors. Cutaneous Melanoma: Etiology and Therapy [Internet]. Brisbane (AU): Codon Publications; 2017 Dec 21. Chapter 1. Available from: https://www.ncbi.nlm.nih.gov/books/NBK481862/ doi: 10.15586/codon.cutaneousmelanoma.2017.ch1
2. WCRF International, Cancer trends – Skin cancer statistics; https://www.wcrf.org/cancer-trends/skin-cancer-statistics/
3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 2021;71:209–249. https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21660
4. Melanoma Patient Network Europe, Melanoma – the facts. http://www.melanomapatientnetworkeu.org/melanoma.html
5. Melanoma UK. 2020 Melanoma Skin Cancer Report. https://www.melanomauk.org.uk/2020-melanoma-skin-cancer-report
6. American Cancer Society. What Causes Melanoma Skin Cancer. https://www.cancer.org/cancer/melanoma-skin-cancer/causes-risks-prevention/what-causes.html
7. International Agency for Research on Cancer. Melanoma of skin. https://gco.iarc.fr/today/data/factsheets/cancers/16-Melanoma-of-skin-fact-sheet.pdf
8. Klein O, et al. Eur J Cancer 2013;49:1073–1079.
9. 2016;63(4):510-7. doi: 10.4149/neo_2016_40
10. Zeynep Eroglu, Antoni Ribas. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol. 2016; 8(1): 48–56. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699264/
11. Anand Rotte. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. Journal of Experimental & Clinical Cancer Research 2019; 38:255. https://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1259-z

The Melanoma Group aims to improve the clinical care of patients suffering with cutaneous, mucosal, or ocular melanoma, and to increase knowledge about melanoma acquisition and progression. Group sub-committees focus on topics including epidemiology, early-stage melanoma, surgery, pathology, and systemic therapy (adjuvant and for advanced disease).

The European Organisation for Research and Treatment of Cancer (EORTC) is a non-governmental, non-profit organisation, which unites clinical cancer research experts, throughout Europe, to define better treatments for cancer patients to prolong survival and improve quality of life. Spanning from translational to large, prospective, multi-centre, phase III clinical trials that evaluate new therapies and treatment strategies as well as patient quality of life, its activities are coordinated from EORTC Headquarters, a unique international clinical research infrastructure, based in Brussels, Belgium.

For further information, please visit www.eortc.org.

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