Treatment of melanoma makes headway

An educational session held yesterday, which focused on the the diagnosis and management of advanced melanoma, revealed the extraordinary progress made in the past few years.

Professor Boris Bastian from the University of California San Francisco (UCSF), California, USA, provided an overview of the latest insights into melanoma patho-biology. Melanoma gene discovery, he said, has occurred in ‘an era of massive parallel sequencing’, with over eight genotype phenotypes now identified in primary melanomas.

The susceptibility hypothesis holds that BRAF dependent melanomas develop in younger patients, whereas independent mutations develop in older patients. However, other significant mutations have now been identified, including NRAS, TP53, PTEN, PPP6C, CDKN2A, MAP2KI, SNX31, STK19, RAC1 and TACCC1.

“Melanomas are a genetically and phenotypically diverse group of biologically distinct entities. Integrating molecular and phenotypic features would lead to an improved, more clinically relevant taxomy,” said Professor Bastian.

Professor Reinhard Dummer, from the University of Zurich, Switzerland, informed delegates that for over 30 years, the standard of care for patients with advanced melanoma has been single-agent dacarbazine (DTIC) which in trials has displayed response rates of 7 15%. But the discovery of BRAF mutations in 66% of melanomas has resulted in the development of BRAF inhibitors, with vemurafenib leading the way. The Phase 3 trial showed that vemurafenib was associated with a 63% reduction in the risk of death compared to DTIC.

Professor Dirk Schadendorf from the University Hospital Essen, Germany, explored the new approach to immunotherapy. Melanoma immunotherapy, he said, has a ceiling response in the order of 10 – 20% of patients.

“While responses can take time, once there is a response it tends to be durable and some patients are seemingly cured,” said Professor Schadendorf. Clinical features associated with increased response rates include skin, in-transit and nodal metastasis, low levels of low-density lipoprotein (LDL), and pre-existing or induced autoimmune phenomenon.

Current immunological approaches include specific immunization and unspecific immunostimulation. Specific approaches have included vaccination of melanoma patients with peptide or tumour lysate- pulsed dendritic cells, while unspecific approaches include iplimumab.

Ipilimumab, he explained, is an antibody that activates the immune system to fight melanoma cells by inhibiting the cytotoxic T lymphocyte- associated antigen 4 (CTLA-4) molecule found on T cells.

Recent studies have shown that in patients with brain metastases, ipilimumab nearly doubled the one and two year survival rates and resulted in prolonged survival. Most strikingly, said Professor Schadendorf, 26% of patients were alive at two years.

In the future, biomarkers will need to be found that identify patients who have the potential to respond, he concluded.