In the COMBI-d and COMBI-v trials, first-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation [3]. More than a decade ago, the diagnosis of metastatic melanoma was still a death knell: long-term survival was non-existent, only 3% of patients survived for 5 years [4]. “The first glimmers of hope were seen in 2010, with the publication of data on ipilimumab and vemurafenib,” said Prof. Garbe. With the arrival of immunotherapy and targeted therapy, long-term survival was still rare in about 10-20% of patients [5,6]. The modern era of melanoma therapy started with combination therapy [3,7]. With the combination of encorafenib and binimetinib, 39% of patients survived 5 years [7]. However, as Prof. Garbe pointed out, this is by no means the end of the story: even more effective combinations are yet to come.
BRAF inhibition is known to increase T cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti-PD-1 therapy. This was the rationale to assess therapy with the anti-PD-1 antibody spartalizumab in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma. [8]. In the COMBI-i trial, the triple therapy showed a promising and durable overall response rate of 75% with a CR in 33% of patients. With more than 15 months of follow-up, median progression-free survival was not reached. The safety profile was manageable.
“With these sophisticated multimodal combinations, we will probably reach long-term survival rates of 60 to 79%,” concluded Prof. Garbe.
When to stop therapy?
Prof. Caroline Robert (Institute Gustave Roussy, France) discussed the question whether therapy can be halted after patients reach CR [9]. With immunotherapy, this is obviously the case, as was shown by the long-term results of the KEYNOTE-001 study in patients who experienced CR with pembrolizumab [10]. Of 655 treated patients, 105 (16.0%) achieved CR after a median follow-up of 43 months. Therapy with pembrolizumab was discontinued by 91 patients (86.7%). The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR. The low incidence of relapse after approximately 2 years from discontinuation provides hope for a cure–at least in some patients.
Unfortunately, this is different with targeted therapy. In a published case series of 12 patients with metastatic melanoma who achieved a CR and then ceased BRAF inhibitor-based therapy, 6 patients subsequently relapsed, and there were no predictors for disease recurrence [11]. However, all patients were suitable for subsequent therapy, including recommencing BRAF/MEK inhibitors with at least 2 out of 3 responding.
- Garbe C. 24th World Congress of Dermatology, 12 June 2019, Milan, Italy.
- Garbe C. 24th World Congress of Dermatology, 13 June 2019, Milan, Italy.
- Robert C, et al. N Engl J Med 2019 Jun 4; epub ahead of print.
- Korn EL, et al. J Clin Oncol 2008;26:527-34.
- Hodi FS, et al. N Engl J Med 2010;363:711–23.
- Sosman JA, et al. N Engl J Med 2012;366:707-14.
- Liszkay G, et al. J Clin Oncol 2019;37suppl: Abstract 9512.
- Long GV, et al. J Clin Oncol 2019;37suppl: Abstract 9531.
- Robert C. 24th World Congress of Dermatology, 10-15 June 2019, Milan, Italy.
- Robert C, et al. J Clin Oncol 2018;36:1668-1674.
- Carlino MS, et al. Br J Cancer 2016;115:1280-1284.
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Table of Contents: WCD 2019
Featured articles
Letter from the Editor
Insights into pathogenesis of AD define novel therapeutic targets
Treating Psoriasis in 2019
Choosing the right biologic in psoriasis
Registries – an important research tool in biologics
Atopic Dermatitis – What is New
Insights into pathogenesis of AD define novel therapeutic targets
Combinations are hot in AD treatment
Dermal Reactions to Systemic Drugs
Cutaneous adverse events due to EGFR inhibitors
Management strategies for drug-induced mucositis
Skin toxicity of immune checkpoint inhibitors
Lupus Erythematosus Today
New targets and biologics for cutaneous lupus erythematosus
Novel lupus classification will aid future research
Hidradenitis Suppurativa
Various guidelines with much overlap
Antibiotics in hidradenitis suppurativa
Biologicals beyond TNF blockade
Small Molecules – What to Expect
Novel treatment options for many dermatologic indications
Long awaited oral therapy for moderate-to-severe AD
Novel treatment options in alopecia areata and vitiligo
Optimising the Management of Keloids
Keloids: a faulty switch in wound healing?
What the future of keloid treatment could hold
Malignant Melanoma – Advances in Management
Will malignant melanoma become a curable disease?
Best of the Posters
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