Global Melanoma Research Report - April

Global Melanoma Research Report - April

6 April 2017

Welcome to our Global Research Report – our quarterly update of selected research from around the world and here at Melanoma Institute Australia (MIA) that is making a difference to the lives of melanoma patients now and in the future.

Finding new options for NRAS-mutant melanoma

Approximately one in four melanoma patients in Australia has NRAS-mutant melanoma, a highly aggressive form of the disease. There are currently no specific therapies for patients diagnosed with NRAS-mutant melanoma. The Phase III clinical trial, known as NEMO, assessed the safety and efficacy of the MEK inhibitor (binimetinib) compared to the chemotherapy (dacarbazine) in patients with advanced NRAS-mutant melanoma.

The study found that binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Although statistically significant, the results are not as ground-breaking as anticipated.

“We’re used to seeing much greater advances over dacarbazine [with other treatments],” says study author and MIA’s Conjoint Medical Director, Professor Georgina Long. “But what this does tell us is that biologically, a MEK inhibitor may have a role in treating NRAS-mutant melanoma. Although it’s not a cure, these findings are a good and important foundation for us to now build upon.”

Research is already underway to investigate combining MEK inhibitors, like binimetinib, with other treatments to improve patient survival.

“We’ve conducted a Phase I clinical trial at MIA that combines a MEK inhibitor with a CDK46 inhibitor, and we’re seeing higher response rates than with binimetinib alone,” says Professor Long.

“In addition, we will be opening a trial shortly to investigate combining a MEK inhibitor with immunotherapy, specifically a PDL-1 inhibitor. We eagerly anticipate how this will affect survival rates in patients with NRAS-mutant melanoma,” she said.

This research was published in Lancet Oncology.

Predicting long-term survival after dabrafenib and trametinib combination treatment  

Studies have shown that advanced melanoma patients (BRAF-mutant) who are treated with dabrafenib and trametinib have greater survival than those patients treated with a single BRAF-inhibitor. However, in many patients the disea­­se still progresses, leading to death. With many treatment options now available, it is important to identify which factors will predict long-term response and survival.

This research aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma.

The longest one-year and two-year progression-free and overall survival were observed in patients with normal lactate dehydrogenase (LDH) concentrations and fewer than three metastatic sites.

This research was published in Lancet Oncology.

Nivolumab combined with ipilimumab or nivolumab alone improves survival in patients with advanced melanoma

Previous research has shown the benefit of nivolumab plus ipilimumab or nivolumab alone in delaying progression of advanced melanoma compared to ipilimumab alone. But new data from the CheckMate 067 trial, recently presented at the American Association for Cancer Research Annual Meeting, has shown patients treated with nivolumab plus ipilimumab or nivolumab alone had significantly improved overall survival and progression-free survival compared to patients treated with ipilimumab alone. This is the first Phase III trial to evaluate overall survival with the combination of anti-PD-1 therapies (like nivolumab) and anti-CTLA-4 therapies (like ipilimumab).

Although the study was not powered to compare the two nivolumab containing arms, the one-year overall survival was similar between them (74% for nivolumab alone and 73% for nivolumab plus ipilimumab), but the two-year overall survival showed some numerical difference (59% for nivolumab alone and 64% for nivolumab plus ipilimumab). The combination arm was more toxic, with 59% of patients experiencing grade 3 and 4 adverse event, as opposed to only 21% in the nivolumab arm. Patients with little or no PD-L1 expression in their tumours seemed to benefit the most from the combination.

“These findings confirm the superior benefit of nivolumab over ipilimumab in terms of patient survival, and further follow up is awaited to see what the long-term survival is for patients treated with either nivolumab or nivolumab plus ipilimumab,” comments Professor Georgina Long from MIA who is involved in the CheckMate 067 trial. “The long-term survival for patients with advanced melanoma is continuing to improve, and I am confident some people may even be cured.  We have come a long way in the last decade, when previously, less than 15% of patients would be alive at two years.”

This research will be published in the near future.

Unexpected mutation burden patterns in acral and skin melanoma

Typically cutaneous (skin) melanoma has a lot of genetic mutations caused by ultraviolet (UV) radiation and acral melanoma (on the hands and feet) doesn’t show any. However, new research from MIA has found a handful of cases that don’t behave in this typical fashion.

As part of the Australian Melanoma Genome Project, researchers have for the first time proven that, although rare, acral melanoma can be caused by UV radiation damage and that skin melanomas can have no UV radiation damage. 

“Studies on nail beds show that UV doesn’t penetrate them, so it is a surprising find that a small percentage (9%) of our cases exhibit UV damage in acral melanoma,” says lead author and MIA Fellow, Dr Robert Rawson. “We need to investigate further to find out why.”

“In the non-UV radiation cutaneous samples, we found that pathologically they had high-risk features and the patients’ prognoses were worse than UV-related melanoma,” comments Dr Rawson. “We don’t understand the cause of them at the moment, but the Melanoma Genome Project is investigating this further.”

This research was published in Laboratory Investigation.

Bim biomarker

Researchers around the globe are trying to predict how patients will response to treatments before they are given them. One such biomarker, called Bim, has recently been shown to help predict if a melanoma patient will respond well to anti-PD-1 therapy (like Keytruda) before treatment begins.

New research from Cancer Research Institute showed that by measuring levels of Bim—a protein made by cancer-fighting T cells—via a simple blood test, doctors could predict which metastatic melanoma patients would benefit from anti-PD-1 therapy.

What does this mean for patients? “If they have increased levels of Bim in their T cells, [checkpoint blockade immunotherapy] may be an optimal choice of treatment,” noted investigator, Dr Haidong Dong.

Furthermore, by monitoring Bim levels after treatment, doctors could determine if the immunotherapy was working. Researchers hope these findings will be used to provide smarter, safer, and more effective treatment for patients with all types of cancer.

MIA is actively investigating the importance of Bim in melanoma treatment. Research in Professor Peter Hersey’s lab has identified that the level of Bim in the melanoma cells themselves is an  important indicator for how many therapies work. They are working with a number of drugs that will increase Bim with the aim of killing the melanoma cells more efficiently.

This research was published in JCI Insight.

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Insights provide possible new targets for personalised treatments

Cancer tumours are voracious. Once they’ve consumed oxygen and nutrients at the original site, they travel to other parts of the body, or metastasize, to find more nourishment. National Institutes of Health researchers have identified genes and genetic pathways involved in this process that could give researchers new targets for developing personalised treatments for melanoma. They discovered 40 new genes that are either turned on or off by HIF1α (a protein that acts as a sensor for oxygen and nutrients in many types of cancer) and 10 genes that were associated with the amount of time it took the melanoma to move from the original tumour to the rest of the body.

In addition, gene expression (whether they are turned on or off) could be used in the future to predict how and when the cancer cells will spread to other parts of the body and how fast they will grow. 

This research was published in Pigment Cell & Melanoma Research.

Mucosal melanoma hope

Patients with a rare form of melanoma, known as mucosal melanoma, have very few treatment options. New clinical trial research presented at the European Cancer Congress 2017 suggests that pembrolizumab (Keytruda) may help some patients, offering a new hope. 

“Immunotherapy for melanoma has revolutionized treatment of the disease,” said researcher Dr Marcus Butler from Princess Margaret Cancer Centre in Canada. “Some patients with mucosal melanoma have had complete responses to pembrolizumab and essentially return to a normal life. Some, of course, have less spectacular responses, but they still benefit from therapy.”

“The data presented here is important because it proves that patients with mucosal melanoma can benefit from anti-PD-1 therapy and should not be excluded from this treatment,” said Dr Butler. “At this stage, we don’t know why some mucosal melanoma patients responded to pembrolizumab while others did not. This is an important question and research is ongoing.”

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Melanoma mutation likes fat for fuel

Early research suggests that melanoma driven by the BRAF V600E gene mutation grows faster with a high-fat diet.

When researchers fed mice a diet with more than 90 percent of its calories from fat, grafted tumours derived from V600E melanoma cells grew faster (twice as large over four weeks) than in mice fed a normal diet.

Further investigation is needed but this supports our understanding of the role that obesity plays in many cancers, and is yet another reason why a healthy diet is so important.

This research was published in Cell Metabolism.

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