Research

A multicentre phase III randomised control trial, compared the Delcath Chemosaturation procedure (percutaneous hepatic perfusion with melphalan, or PHP-Mel) with the best alternative care (BAC). Primary BAC treatment strategies included systemic chemotherapy and embolization. Patients enrolled into the trial between February 2006 and April 2009.

A total of 93 patients were involved, with respectively 44 and 49 receiving PHP-Mel or BAC. All of the patients had cutaneous or ocular melanoma that had predominantly spread to the liver. The allocation of the treatment that patients received was random, but over half of those receiving BAC switched over to PHP-Mel eventually, due to liver cancer progression. In general, this group of patients had extensive liver disease, with 51% of them having at least 5 or more liver lesions. 

The trial aimed to investigate:

• Progression free survival: the length of time during and after the treatment of cancer that a patient lives with the disease but it does not get worse. This can be overall, or hepatic.
• Hepatic objective response: the percentage of patients whose cancer shrinks or disappears after treatment.
• Overall Survival: the length of time from either the date of diagnosis or the start of treatment for a cancer that patients diagnosed with the cancer are still alive.

The results demonstrated the effectiveness of the chemosaturation (PHP-Mel) procedure. The average hepatic progression free survival (hPFS) was 7 months for PHP-Mel compared to 1.6 months for BAC, while average overall progression free survival (oPFS) was 5.4 months for PHP-Mel and 1.6 months for BAC. The hepatic objective responses (hOR) were respectively 36.4% and 2% for the PHP-Mel and BAC.

The average overall survival (OS) was not significantly different between the two groups, probably due to the crossover of many patients from the BAC to PHP-Mel. Nearly all of the patients receiving PHP-Mel experienced adverse effects, the most common including neutropenia, thrombocytopaenia and anaemia. Three deaths were attributed to the PHP-Mel treatment.

A retrospective analysis of the data of 51 patients receiving PHP-Mel between 2008 and 2016 was also performed. 

All of the patients had metastatic uveal melanoma that had progressed to the liver. Compared to the initial phase III randomised trial, a lower number of procedures were administered per patient, yet the hOR was similar to the initial trial at 49%. The average hPFS in this study was 9.1 months, and the OS rates was 64% at one year, compared to 38% in the previous trial.

This improvement could be due to differences in patient selection; in this retrospective study compared to the clinical trial, less patients had extra-hepatic melanoma which is associated with worse outcomes. If they did, it was treatable or resected between PHP-Mel procedures. It could also be due to many patients receiving immunotherapy after completing a course of PHP-Mel. This was not available during the original trial. Patients participating in this study also were selected at an earlier stage of the disease.

Finally, in this retrospective study, toxicity rates were comparable with the earlier clinical trial, and there were no treatment related deaths. This improved outcome could be due to strict patient selection criteria, increased melphalan extraction during the procedure and fewer cycles of PHP-Mel being administered.

Immunotherapy is also being investigated for treatment of metastatic uveal melanoma (MUM). The drug Ipilimumab has been shown to be effective in cutaneous melanoma but has varying degrees of success for uveal melanoma. As a checkpoint inhibitor, it blocks proteins that stop the immune system from attacking cancer cells.

One phase II trial of treatment-naïve MUM patients showed promising results after a follow up at 5.5 months. However, another multi-centre phase II trial in treatment naïve and pre-treated MUM patients reported an average PFS and OS of 2.8 months and 6.8 months respectively.

Other checkpoint inhibitors, such as nivolumab or pembrolizumab, have been used in uveal melanoma alone, or in conjunction with Ipilimumab. Although there have been some mixed results, one study on previously untreated patients showed that nivolumab is more effective used by itself, or in conjunction with Ipilimumab than Ipilimumab alone.

Another recent study showed a significant number of MUM patients experiencing prolonged periods of disease stabilisation after treatment with pembrolizumab. 28% of patients managed to maintain disease control for more than 6 months. This study also showed that pembrolizumab has an acceptable toxicity profile and can be used safely as treatment for uveal melanoma. 

However, it is worth noting that immune checkpoint inhibitors can lead to the development of adverse events and toxicities. These are more frequent in combined therapies than in therapies alone. In a phase III trial, grade 3 or 4 immune related adverse effects occurred in 55% of the combination group and 16% and 27%, respectively, for nivolumab and ipilimumab alone.

IMCgp100 is a bi-specific antibody. This means it binds to two proteins at the same time, triggering a process that kills melanoma cells. A phase I clinical trial has shown that it is safe in low doses- and can trigger long-lasting responses in patients with eye and skin melanoma.

Another phase I clinical trial is being used to investigate IMCgp100 specifically for uveal melanoma. The toxicity of IMCgp100 will hopefully be reduced so that its effectiveness can be maximised. 

An interim analysis of 19 patients showed that patients experienced a prolonged response to treatment and longer survival times compared to other treatments. 73% of patients survived a year after treatment, as opposed to 25-40% with other treatments.

This finding has led to the introduction of a Phase II trial of IMCgp100 in previously untreated Uveal Melanoma. IMCgp100 could be a future treatment option for uveal melanoma.

A Single-arm, Multi-national, Multi-center, Open-Label Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients with Hepatic-Dominant Ocular Melanoma.

The FOCUS Trial is currently being conducted at 22 leading cancer institutes worldwide and Southampton is the lead centre in Europe.