Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Abstract

As dermatologists and scientists, we make therapy decisions based on study results in the sense of evidence-based medicine. In particular, in the treatment of advanced metastatic melanoma impressive progress has been documented in recent years. Meanwhile, long-term survival rates from phase III trials have been reported for patients with unresectable metastatic melanoma treated with immune checkpoint inhibition (ICI) using the anti-PD-1 antibodies nivolumab or pembrolizumab and/or the anti-CTLA-4 antibody ipilimumab and for patients with BRAF mutated tumours additionally with targeted therapies (TT) using the BRAF/MEK inhibitors dabrafenib/trametinib, vemurafenib/cobimetinib or encorafenib/binimetinib. In particular, the combination of ipilimumab and nivolumab showed the highest 5-year survival rates documented in a phase 3 study so far and melanoma specific survival rates after 7.5 years of 55% with a significant proportion of complete remissions. Furthermore, long-term survival in this study appears to have plateaued, with only few patients dying of melanoma in the last years of the follow-up period.1 In addition, data from various recent studies, either retrospective or prospective, allow us to conclude that in most cases immune checkpoint inhibition as first-line therapy is the most promising approach. This also applies to patients with BRAF mutation who can be treated with both, immune checkpoint inhibition and targeted therapy, unless there are no limiting underlying conditions (e.g. severe autoimmune disease and organ transplant) or a very symptomatic situation requiring rapid onset of tumour response.2-5 In return, targeted therapy is characterized not only by the highest response rates in first-line therapy, but also by very high response rates in second-line therapy, for example after immune checkpoint blockade. This also applies for the rechallenge situation when a targeted therapy is reintroduced after a switch or interim pause, for example due to toxicity or even due to progression.4, 6 However, the use of combined immune checkpoint inhibition can be accompanied by a high rate of severe side effects, which may be therapy-limiting.1 Thus, for example in patients with limited general condition or with advanced age and with oligometastatic disease, an anti-PD-1 monotherapy may appear to be more appropriate. Even in the presence of brain metastases, which used to be a very critical and survival-limiting situation, impressive responses can be achieved with current therapeutic options. In particular, both immune combination therapy and targeted therapy can achieve intracranial response rates comparable to the response of extracranial metastasis. Even though there are no direct comparative studies, in patients with asymptomatic brain metastases the response seems to last substantially longer with ipilimumab plus nivolumab than with targeted therapy. However, in symptomatic brain metastases, which often require steroid treatment, the situation is much less favourable. Here, remarkable response rates could still be documented with targeted therapies.7, 8 Recently, even in uveal melanoma, which until now was characterized by very limited treatment success in the case of metastatic disease, tebentafusp, an immune-mobilizing T cell receptor against cancer (ImmTAC), has shown for the first time a highly significant improved overall survival compared to comparator therapies in a in a phase III study.9 Since 2022, tebentafusp has been approved in Europe for the treatment of unresectable or metastatic uveal melanoma.10 However, metastatic uveal melanoma remains a very difficult situation to treat. Taken together, long-term survival of more than 5 years which may be achieved in about half of the patients with advanced metastatic cutaneous melanoma is likely to correspond not only to a control or chronofication of the disease but probably also to a cure for many of these patients. Since 2018, these major progresses in the treatment of advanced metastatic melanoma can also be made available to our patients in the adjuvant situation and have documented advantages in both, progression-free survival and distant metastasis-free survival, most recently supplemented by an approval for adjuvant therapy with pembrolizumab already in stage IIB and IIC melanoma.11 Thereby, in contrast to the non-resectable metastatic situation, in the adjuvant situation no advantage for immune checkpoint inhibition compared targeted therapy can be derived from the available study data. Beyond the data from controlled trials, however, real-world data are also are sustainably relevant for the assessment of treatment options in clinical practice. For example, in a recent publication in the Journal of the European Academy of Dermatology and Venereology, a group from 13 skin cancer centres in Germany, Austria and Switzerland examined the real-world situation in current adjuvant melanoma therapy using PD-1 antibodies or BRAF/MEK inhibitors.12 However, the goal of all our efforts is the well-being of our patients. Thus, how does study-based evidence translate into clinical practice and, in particular, into our patients' treatment decisions and experience? In an article of Thiem et al. in this issue of the Journal of the European Academy of Dermatology and Venereology, this question was addressed in a cross-sectional multicentre study including including 13 Germany skin cancer centres evaluating the impact of disease and treatment on the daily life of 414 patients receiving systemic therapy for melanoma in the metastatic and the adjuvant setting.13 Of note, during the study period, the previously discussed evidence was not yet necessarily available to the extent mentioned above, so a treatment decision could well be different today. When it comes to finding the most appropriate treatment option for a patient, our task and obligation as physicians and scientists are to be an advisor to the patient with our experience and our expertise, determined by the available evidence. Ultimately, however, the patient has to make a decision together with us based on our advice and recommendations. Open Access funding enabled and organized by Projekt DEAL. None to declare. KMT received speaker or consultant honoraria and travel support from Bristol-Myers Squibb, Merck Sharp and Dohme, Roche, Novartis, Pierre Fabre, Sun Pharma, Sanofi, Immunocore, LEO, Galderma, Almirall, La Roche-Posay and Candela.