Melanoma 2014: Another Banner Year

Antoni Ribas, MD, PhD; Nancy Terry


December 18, 2014

Editor's Note: An avalanche of drugs and drug approvals, new combination therapies, and clear improvement in survival rates made 2014 an exciting year in melanoma. Primarily on the basis of Medscape Oncology coverage and input from melanoma experts, Antoni Ribas, MD, PhD, professor of medicine, David Geffen UCLA School of Medicine, Los Angeles, California, and Nancy Terry, editorial director for Medscape Oncology, compiled a review of the notable advances in melanoma from the past year.

In 2012, the New England Journal of Medicine published a number of key studies[1,2,3] on melanoma immunotherapy, prompting some experts to quip that the venerable publication should be renamed the New England Journal of Melanoma. In 2013, Science declared cancer immunotherapy the breakthrough of the year,[4] and recent headlines in the popular press illustrate the extent to which immunotherapy is transforming all fields of oncology.[5]

In 2014, treatment in melanoma has never been so promising, and immunotherapies are delivering durable benefit. Among the melanoma abstracts presented at the 2014 meeting of the American Society of Clinical Oncology (ASCO) were six on immuno-oncology and three on targeted therapies. "That tells us where the field is going," commented Jeffrey S. Weber, MD, PhD, director, Donald A. Adam Comprehensive Melanoma Research Center; senior member, Moffitt Cancer Center, Tampa, Florida. Key studies focused on PD-1 or PD-L1 antibodies.

Single-Agent PD-1 Inhibition

Antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway promote immune responses against cancer. In the forefront of new PD-1 agents are nivolumab and pembrolizumab. A phase 2 study of pembrolizumab presented at ASCO reported a response rate close to 40% and a lesser response rate (28%) in patients who previously progressed on ipilimumab.[6]

"In patients who were ipilimumab-naive, most of whom were previously untreated, we are getting close to a 40% response rate, with 1-year survivals in the range of 67%-69% and an 18-month survival of 62%," commented Dr Weber to Medscape. "Do the extrapolation; we are talking about at least a 24-month median survival, and that's pretty darn impressive data from pembrolizumab."

In September, the US Food and Drug Administration (FDA) approved pembrolizumab for use in patients with advanced or unresectable melanoma who are no longer responding to other drugs. Pembrolizumab is the first immunomodulator that acts as a programmed death (PD) inhibitor to be approved by the FDA. Pembrolizumab was granted priority review by the FDA and given breakthrough therapy and orphan drug designation, on the basis of results in a study of 173 patients with ipilimumab-refractory disease.[7] When the results with pembrolizumab were published in The Lancet, an accompanying editorial said they "add to the burgeoning literature on the potential of PD-1 blockade to improve outcomes in patients with metastatic melanoma."[8] The drug is also awaiting approval in Europe.

Nivolumab has proved to be another highly active PD-1 agent, and trials comparing single-agent nivolumab to chemotherapy have yielded strong response rates. One such study, presented at the 2014 European Society for Medical Oncology (ESMO), is a phase 3 randomized trial[9] of nivolumab vs investigator's choice of chemotherapy in 405 patients who had previously received and progressed on ipilimumab. The primary endpoint was objective response rate, which was 32% in patients on nivolumab and 11% in patients on chemotherapy. "Nivolumab effectively tripled the response rate of chemotherapy in patients who previously progressed on ipilimumab, commented Dr Ribas for Medscape. "These data will be of high relevance for patients with melanoma and their physicians, but these findings also go way beyond melanoma."

The CheckMate 066 trial, as presented at the Society for Melanoma Research (SMR) 2014 International Congress[10] and simultaneously published in the New England Journal of Medicine,[11] provided new data on nivolumab as first-line therapy in metastatic melanoma. The study reported the 1-year survival rate as 72.9% with nivolumab vs 42.1% with chemotherapy (dacarbazine), with a hazard ratio of 0.42 (P < .0001). Georgina Long, MD, PhD, from the Melanoma Institute Australia at the University of Sydney, who presented the results at the SMR meeting, commented, "Nivolumab first-line represents a potential new standard of care."[12] Nivolumab is so far approved only in Japan (as Opdivo), but approvals elsewhere are anticipated soon.

Combination Immunotherapy Sends Survival to a New Level

As strong as the results are for single-agent immunotherapies, combinations are resulting in even more dramatically high and durable response rates. On the basis of response rate and median survival reported in the COMBI-d trial, the FDA gave conditional approval for the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for the treatment of unresectable and metastatic melanoma expressing a V600E or V600K BRAF mutation. The accelerated approval is contingent on the results of the ongoing phase 3 COMBI-d trial, which was presented at ASCO.[13]

The issue of whether BRAF/MEK combination therapy is superior to single-agent therapy was resolved at ESMO. Two trials were presented,[14,15] both comparing the combination of a BRAF and a MEK inhibitor vs a BRAF inhibitor alone. The standard of care in Europe is to use a single-agent inhibitor, and the standard of care in the United States is a combination of a BRAF and a MEK. These trials provided definitive data regarding a new standard of practice.

One of the phase 3 trials, coBRIM,[14] combined vemurafenib and the MEK inhibitor cobimetinib. The other trial, COMBI-v, compared dabrafenib and trametinib with single-agent vemurafenib.

The coBRIM trial is a global multicenter study, conducted in more than 100 sites around the world and enrolling 495 patients. The primary endpoint was progression-free survival (PFS). The hazard ratio for PFS was 0.51, which tells us that there was a 49% improvement on the combination of vemurafenib and cobimetinib compared with vemurafenib alone. The median PFS of vemurafenib single agent was 6.2 months (which is what we expect from vemurafenib alone; we have always said that BRAF inhibitors have a median PFS of 6-7 months) and 9.9 months with the combination of dabrafenib and trametinib.

There was an early readout of overall survival (OS). It's premature and was triggered not by the OS events but by the PFS events. The hazard ratio is very encouraging at 0.65, but the median was not reached in either arm. Obviously we will have to follow up with this study to know the impact on OS.

The COMBI-v study[15] looks at a combination of dabrafenib and trametinib compared with single-agent vemurafenib. This study was run in multiple sites around the globe and enrolled 704 patients. The primary endpoint was OS, and that was met with a hazard ratio of 0.60, showing a 40% improvement in being on dabrafenib and trametinib compared with vemurafenib. This is the first study that had improved OS data for the combination of a BRAF and a MEK inhibitor compared with a BRAF inhibitor alone. The median OS in patients on single-agent vemurafenib was 17.2 months, and the median of the combination has not been reached. The PFS also is consistent with the OS data. The hazard ratio was 0.56, with 7.3 months of PFS with vemurafenib alone and 11.4 months with the combination of dabrafenib and trametinib.

BRAF/MEK Combo: Likely New Standard of Care

Dr Ribas said, "With these studies, we are reaching a very clear conclusion: It's better to give the combination of BRAF and MEK inhibitors than to give BRAF inhibitors alone to patients who have a BRAF-mutant advanced melanoma. For patients with advanced melanoma that is BRAF-mutation positive, the combination of a BRAF and MEK inhibitor works better than a BRAF inhibitor alone. Experts reporting at the plenary session of ESMO say that such combinations should be the new standard of care in this patient population, which accounts for about 40% of all melanoma."

The combination of ipilimumab with nivolumab first made headlines last year at ASCO 2013, when the activity shown by the combination was, in a phase 1 trial,[16] described as "truly remarkable." This year, long-term results from this same study received similar accolades.[17] The combination of ipilimumab and nivolumab produced an unprecedented median survival of 40 months for patients with advanced melanoma, which is nearly double the OS previously reported with either agent alone.

"Just a few years ago, the median survival for patients diagnosed with advanced melanoma was as little as a year or less. It's truly remarkable that we're seeing a median survival of over 3 years in this trial," commented lead author Mario Sznol, MD, professor of medical oncology at Yale School of Medicine in New Haven, Connecticut, at a press briefing at ASCO.[18] "Even in the latest era of targeted and immunotherapy agents, the median survival is, on average, only about 16 to 18 months with any new treatment alone."

The complete response rate was 17% among the patients who received the ipilimumab/nivolumab concurrent therapy at maximum doses. However, among all of the patients in the trial, including those who received sequential therapy, the complete response rate was about 10%, he said.

In comments to Medscape Oncology, Dr Weber referred to the concurrent ipilimumab/nivolumab study as a highlight of the melanoma data presented at ASCO. "Now we are getting into another dimension, although admittedly another dimension of survival, response, and side effects. The response rate is about 45% in an updated expanded cohort of those with concurrent nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg (the standard dose). This regimen could be continued for as long as 96 weeks. The response rate was in the mid-40% range, but of greater importance, the 2-year survival was 79%. That is very impressive. It is perhaps the best 2-year survival that I have ever seen, an important landmark in melanoma."

However, the survival data are balanced against a 62% rate of grade 3/4 immune-related adverse events (IRAEs), many of which were easily reversible. Whenever the rate of side effects at grade 3/4 exceeds the response rate, commented Dr Weber, "you have to sit up and take notice. Nonetheless, a 70%-plus survival rate at 2 years is outstanding in melanoma.

'Long Duration of Survival in Reach for Any Patient'

Asked what he considered the single most significant advance for clinical practice in 2014, Dr Weber responded, "With the recognition that high response rates and long duration of survival were achieved with PD-1 antibodies, and with the recent FDA approval of pembrolizumab, they are within the reach of any patient with melanoma, and soon will be for patients with head and neck, lung, renal, and other solid tumors." In the next 5 years he foresees the detection of resistance to targeted and immune drugs through the use of single-cell genomics, which will result in even more personalized and improved therapy.

At the SMR International Congress held in Zurich, Switzerland, in November, a presenter looked back on the year in melanoma. 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, in summing up the meeting, said that he was feeling "upbeat." 2014 has been a "fantastic" year for melanoma. "I think that we have cure in our sights for this disease, which has long been considered incurable," Dr McArthur 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."


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