Survival in Melanoma Ups Further: 'We Have Cure in Our Sights'

Zosia Chustecka

November 20, 2014

ZURICH, Switzerland — "Can we now cure an incurable disease in some of our patients with metastatic melanoma?" This was the questioned posed here at the end of the Society for Melanoma Research International Congress 2014 meeting.

Posing the question was Grant McArthur, MB, BS, PhD, FRAC, consultant medical oncologist at the University of Melbourne and director of the skin and melanoma service at the Peter MacCallum Cancer Centre in Melbourne, Australia, who was summing up the meeting, and said that after hearing some "outstanding" data that had been presented, he was feeling "upbeat."

Dr McArthur summarized the avalanche of new drug approvals for metastatic melanoma and outlined how each new development has pushed survival rates ever higher.

The recap began in 1975, when the chemotherapeutic dacarbazine was approved for use in melanoma. Recent data shows that about a third of patients with advanced melanoma will still be alive after a year of treatment with this drug.

Dacarbazine has long been the standard of care for metastatic melanoma, but it is now clear that it is being replaced, he said.

A hint of the potential for treatment via the immune system came from some of the responses seen with interleukin-2 (aldesleukin; Proleukin, Prometheus Laboratories), which was approved in 1988. However, for most patients it offered little improvement over dacarbazine, Dr Grant commented, with one-year survival rates of 46%. But he added that interleukin-2 was a "really important drug, as it really laid down the basis for our interest in durable long-term complete responses with immunomodulator agents."

The first of these, the immune checkpoint inhibitor acting on CTLA4, was ipilimumab (Yervoy, Bristol-Myers Squibb), approved in 2011.

2011 also saw the approval of the first targeted agent, the BRAF inhibitor vemurafenib (Zelboraf, Plexxikon/Roche) for patients with BRAF mutant tumors (about 50% of melanoma patients).

With both of these agents, around half of the patients are still alive after a year of therapy, Dr McArthur noted, listing one-year survival rates as 47% with ipilimumab and 56% with vemurafenib.

Another BRAF inhibitor followed two years later, with the 2013 approval of dabrafenib (Tafinlar, GlaxoSmithKline), which increased one-year survival rates up to 70%.

2014 has been a "fantastic" year for melanoma, Dr McArthur said, and has seen the one-year survival rates increased still further, up to 80%, with the combination of dabrafenib with the MEK-inhibitor trametinib (Mekinist, GlaxoSmithKline). This combination of dabrafenib and trametinib has been approved in the United States and is awaiting approval elsewhere.

2014 has also seen the launch in the US of a new immune checkpoint inhibitor, the programmed death inhibitor, pembrolizumab (Keytruda, Merck & Co), with one-year survival rate of 69%.

"This is such a big improvement from where we were prior to 2011," Dr Grant emphasized.

Looking ahead to 2015, he foresees early approvals for nivolumab (Opdivo, Bristol-Myers Squibb), which has reported one-year survival rates of 73%, and for another combination of a BRAF inhibitor with a MEK inhibitor, vemurafenib with cobimetinib, with a one-year survival rate of 83%.

So, survival is clearly improving, Dr Grant concluded, but what we really need to focus on now is long-term survival.

Follow-up data show that there is a plateau in the survival curve, he said — the data on ipilimumab out to five years show that about 20% of patients become long-term survivors, while the data out to three years with the targeted agent dabrafenib show that about 30% of patients are long-term survivors, and likely to be higher with the combinations of BRAF and MEK inhibitors.

"So I think we need to concentrate on these long-term survivors," Dr Grant said, "because we can move towards more patients being cured.

"I think that we have cure in our sights for this disease, which has long been considered incurable," he said. "I still sign insurance forms for patients to say they have a terminal illness, but pleasingly, I am getting increasingly nervous about whether this is the right thing to do."

Dr McArthur reports serving as a consultant for Celgene and Pfizer.


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