Ipilimumab for advanced metastatic melanoma

Keywords::

• CTLA-4
• immune system
• ipilimumab
• melanoma
• metastasis
• T lymphocyte

The June issue of Expert Opinion on Biological Therapy (EOBT) contains a review article entitled ‘Ipilimumab in the Treatment of Melanoma' [1]. I highly recommend this excellent paper to all colleagues interested in the treatment of patients with metastatic melanoma, because it provides detailed information without neglecting open questions in a field where rapid change is just taking place and where new orientation is urgently needed.

Among the white population, malignant melanoma is one of the malignancies with the currently highest increase in incidence worldwide, and even adolescents and young adults are more and more involved. Despite enormous efforts over many decades, the prognosis of stage IV melanoma remained very poor until 2010, characterized by median survival periods of about half a year and 2-year survival rates around 10%.

Now, the struggle against melanoma has entered a new era. This was highlighted by two presentations about new therapies of advanced melanoma during the plenary session of the ASCO annual meeting 2011 in Chicago. Vemurafenib, a selective BRAF inhibitor, has become an option for about 50% of advanced melanoma patients, namely for those with V600 mutations of the BRAF gene in their metastatic melanoma cells [2]. Ipilimumab, a monoclonal antibody binding to the cytotoxic T-lymphocyte antigen 4, successfully pioneers the immunotargeted therapy for advanced melanoma [3,4]. The same strategy, namely blocking negative regulators of immune activity, appears to be as well successful in early trials with programmed death 1 antibodies not only in the fight against metastatic melanoma, but also against other advanced malignancies [5]. Interestingly, the breakdown of immune tolerance appears to result in more efficient anti-tumor therapies than previous attempts to stimulate the immune system with vaccinations or with cytokines [6-8]. Regarding ipilimumab, two successful phase-III trials brought both the approval of the FDA in the U.S.A. and that of the EMA in Europe for the treatment of stage-4 and of unresectable stage-3 melanoma. In Europe, however, this approval is reserved for the second-line therapy following the failure of another first-line treatment. At the first glance, this restriction seems to be hardly tolerable for patients, who urgently need an efficient therapy and who may not have good alternatives to ipilimumab.

On the other hand, ipilimumab is efficient only for a minority of melanoma patients. These patients, who indeed tend to have long-term benefits, can unfortunately not yet be identified a priori. On the contrary, it may take 4 months, until such benefits—or the failure—of this highly expensive therapy become apparent, and even the detection of an increased T-cell infiltrate in a melanoma metastasis during the treatment is not a reliable predictor of clinical success [9]. Furthermore, severe adverse events resulting from the activation of auto-immunity, cannot be disregarded in the competition of ipilimumab with other therapeutic options for the priorities how to treat patients with advanced melanoma [10]. But is not a combination of therapies better than competition in the desperate situation of these patients? The combination of ipilimumab with gp100 vaccine and that with dacarbazine are not more attractive than ipilimumab alone, because the therapeutic efficacy of both combinations is obviously not superior, and ipilimumab combined with dacarbazine results in a higher risk of hepatotoxicity in comparison with each drug alone [3,4]. Combinations of ipilimumab with vemurafenib are just being tested in a recently initiated phase I/II trial (NCT01400451) for patients with metastatic melanoma and a V600 BRAF mutation. Final results are expected in 2015.

Expert opinion

Immunotargeted therapy with antibodies such as ipilimumab imply a change of paradigm in the treatment of advanced melanoma present now, and other metastasized malignancies will probably follow soon. Thus, ipilimumab is the prototype of a new class of anti-tumor drugs, which transform fatally aggressive cancers into chronic diseases by reversing the escape of malignant cells from the control of the immune system. Ipilimumab does achieve this benefit, but unfortunately only for a subset of patients with advanced melanoma, and at the price of immune-related adverse events, some of them life-threatening.

It remains a challenge for the future to find out patient and tumor profiles that help to predict the benefit and also the risks of the anti-cytotoxic T-lymphocyte antigen 4 therapy for individual patients. Further issues in discussion or in trial are the optimal dose and duration of ipilimumab treatment, and the potential toxicities resulting from combination therapies. Answers to these questions will be decisive for the permanent integration of ipilimumab in the rapidly growing orchestra of anti-melanoma therapies, which promises the treatment of future patients with individually optimized combinations or sequences of single therapeutic elements.

Back in the present time, we all find ourselves in a learning phase how to utilize ipilimumab in the concert with the current therapeutic options for the best benefit of each individual patient. In this situation, it is extremely helpful if we share our key experiences with each other, and the current issue of EOBT is starting in the pole position for this goal.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.