How novel melanoma treatments are improving outcomes for patients

Advances in the research and treatment of metastatic melanoma are helping patients live longer

Robert tow in south pole
Robert Tow as a US Navy flight engineer in Antarctica

Robert Tow did a three-year tour as a US Navy flight engineer in Antarctica, many times flying researchers up and back from the South Pole in massive C-130 transport planes. Now, at a base near Fort Worth, Texas, he teaches Navy and Marine flight engineers to fly those C-130s.

Robert Tow with his wife at their home in Fort Worth, Texas.Tall and fair-skinned, Tow had always been careful to protect his skin from harmful UV rays, especially in the blindingly white Antarctic conditions “where it’s daylight 24-7,” he said.

At a routine eye exam, his ophthalmologist recommended he get a small spot above his eye checked by his regular physician. “They did a punch biopsy, and it was melanoma. They cut it open to make sure they had gotten everything, and they had,” Tow said. “For 11 years, no problem – regular check-ups, nothing. No problems at all.”

Several years later, Tow started having bad pains in his gut after eating. He ignored them for a while.

“Back in the Navy, people knew we were flyers because our medical records were so thin,” he said. “We wouldn’t report anything. If we reported anything, we would be grounded and not allowed to do our job. So we’d suck it up, we’d deal with it.

“That was my mentality for years, until I spent a weekend rolling around and absolutely hurting. I went to my GP, and he said we’d have to do an ultrasound. My liver showed a bunch of nodules. So he referred me to Dr. Page, and that’s when all the fun started.”

Dr. Ray Page, President of The Center for Cancer and Blood Disorders in Fort Worth, Texas (Photo courtesy of CCBD) Dr. Ray Page, a community oncologist and hematologist, is President of The Center for Cancer and Blood Disorders in Fort Worth. Dr. Page also is on the melanoma medical committee for Elsevier’s Via Oncology, a decision support tool that uses clinical pathways (mapped-out treatment options) to help oncologists treat and track their patients. The committees meet regularly to determine which of the latest medical evidence should be included in Via’s pathways.

A melanoma expert, Dr. Page discovered that Tow had metastatic melanoma, the kind that can often be fatal. Typical melanomas, or skin cancers, can be surgically removed and often do not show up again. Metastatic melanoma is much more serious.

“I was thinking it was a bad stomach ulcer, something along those lines,” Tow said. “Dr. Page went in and got a biopsy my liver. The melanoma had not only metastasized into my liver, but it had gone into my bones, my lungs, my lymph nodes. It had just gone everywhere.

“When they got the biopsy and blood tests back from my liver, he basically looked at me and said, “Dude, we have to do something. You’ve got weeks.” It was 11 years since the melanoma on his eye had been removed.

Advancements in melanoma treatment

Dr. Page said advancements in the treatment of metastatic melanoma are saving lives. Two new classes of agents have emerged since 2011:

“Immunotherapy has changed the face of melanoma,” Dr. Page said. “The great thing about immunotherapy is that, even though it was developed seven or eight years ago for the very first time at places like Memorial Sloan-Kettering and UPMC (University of Pittsburgh Medical Center) and other places, those therapies have been well defined through clinical trials to where they can be safely and readily given at virtually any cancer center across the US.”

John M. Kirkwood, MDDr. John M. Kirkwood, Usher Professor of Medicine, Dermatology and Translational Science and co-leader of the Melanoma and Skin Cancer Program and co-director of the Pediatric Melanoma Program at the UPMC Hillman Cancer Center, has not used traditional chemotherapy with a melanoma patient since 2011. He is also a proponent of the recently developed immunotherapies and molecularly targeted therapies.

Dr. Kirkwood, a chair of the melanoma medical committee  of Elsevier’s Via Oncology, can trace his own interests and research into these melanoma therapies back to the late 1960s, when he started studies of melanoma in the laboratory, and the 1980s, when he co-founded the University of Pittsburgh Cancer Institute, now known as UPMC Hillman, and the melanoma program at UPMC. He has seen steady improvement in melanoma treatment since then.

The standard approach for management of melanoma, for a patient with a melanoma more than middling deep, was to offer a treatment that we actually developed here in Pittsburgh,” Dr. Kirkwood said. “We previously had done the Phase One and Phase Two trials with the agent called Interferon Alpha. Interferon Alpha was, for nearly 20 to 30 years, the first adjuvant therapy that benefitted patients with high risk of relapse and death after surgery from melanoma.”

From 1995 until 2015, Interferon Alpha was the only available treatment that could reduce relapses and the risk of death from metastatic melanoma, and it was used worldwide in most cancer centers to attempt to prevent relapse and death after operation for deep primary or lymph node-involving melanoma. “We treated thousands of patients with it, but it caused toxicity side effects that led to about a quarter of patients not being able to finish treatment for a year,” he said. “And it worked in about a third of patients to lower relapse rates, but that meant it didn’t work in about two thirds of patients, so that meant we needed to improve things.”

Other developments in cancer surgery, in particular the concept of sentinel lymph node evaluation developed by Dr. Donald L. Morton, have been key to helping patients overcome melanoma. Dr. Morton died in 2014.

“I was presenting our first results from adjuvant therapy with Interferon Alpha at the American College of Surgeons conference, and a fellow physician who was about a decade older than me and had been at UCLA and John Wayne Cancer Center named Donald Morton was presenting a new surgical technique: if you mapped any square millimeter of skin anywhere on our bodies it would drain preferentially to a single lymph node,” Dr. Kirkwood said. “This proved to be hugely helpful because it identified which lymph node would be the target of travel for any given melanoma in the skin, and would tell you which lymph node amongst the 30 or 40 in that basin that melanoma would drain to.

“Previously, surgeons would take out the melanoma and all the lymph nodes that seemed to be anatomically closest, but that left many patients with lymph nodes missing from their arm pit, their neck or their groin, and accordingly a fraction of 10, 15 or sometimes a higher percent with swelling of that limb and no longer able to be the golfer or the swimmer or whatever the sports person they wanted to be because of edema.”

Defining the sentinel lymph node as the first tumor-draining node led to the development of the sentinel lymph node biopsy, now a standard procedure for patients with melanoma deeper than 0.8 mm in thickness, as well as for breast cancer. Many believe that the sentinel lymph node idea has saved US  healthcare system close to $4 billion a year in unnecessary procedures and subsequent harms.

“What we learned in that sentinel lymph node mapping experience is that oftentimes the lymph node that was the anatomically closest to the melanoma was not the lymph node in the correct lymph node group,” Dr. Kirkwood said.

Novel drug therapies developed

Even back to 2010, oncologists did not have any drug or other therapy that could improve their metastatic melanoma patients survival reliably and predictably. Many drugs, however, were in the midst of Phase Three clinical trials since then, and more than a dozen agents are now available that improve survival.

“Amazingly we have six agents that improve outcomes in an adjuvant setting – operable disease that has high risk of relapse where we think you can prevent the recurrance so you don’t ever have to worry about the fatal, distant disseminated disease,” Dr. Kirkwood said.

“We have a huge way to go for inoperable disease,” he added. “Forty percent of patients will respond (to the immunotherapy treatments), and many of those will be durable, but that of course means the flipside number is that 60 percent will need something else. There are combinations of therapies that will do better, maybe even 50 or 60 percent response, but those combinations have toxiticites in 60 or 70 percent of patients, as well.”

Dr. Kirkwood outlined some of those newer therapies, many approved by the US Food and Drug Administration (FDA) within the last three years (not an exhaustive list):

  • BRAF inhibitors: Zelboraf (vemurafenib) from Genetech (Roche), Tafinlar (dabrafenib) from Novartis, and Braftovi (encorafenib) from Array BioPharma
  • MEK inhibitors: Cotellic (cobimetinib) from Exelixis and Genentech (Roche), Mekinist (trametinib) from Novartis, and Mektovi (binimetinib) from Array BioPharma are targeted anti-tumor therapies, which target the drivetrain of the tumor – improves the durability and quality of the response and reduces some of the problematic skin toxicities
  • Checkpoint blockade immunotherapy (CBI) – Yervoy (ipilimumab) from Bristol-Myers Squibb, and tremelimumab (formerly ticilimumab) first from Pfizer and now MedImmune (AstraZeneca); and Keytruda (pembrolizumab) from Merck and Optivo (nivolumab) from Bristol-Myers Squibb.

“What all patients need to know, because they can help to push surgeons who don’t always think about this when they’re operating, is that BRAF testing is now relevant for anyone who has a lymph node involved by melanoma, or anyone who has any distant metastatic disease and may need therapy,” Dr. Kirkwood said. “We cannot decide what to do for a patient intelligently without having the BRAF mutational status. So when they have a tumor biopsy done, if that’s not done, we’re out of luck.”

Treating Tow’s metastatic melanoma

For Tow, the discovery of his metastatic melanoma was the beginning of a long road to recovery.

Dr. Page had the latest research at his fingertips, with clinical decision support from Elsevier’s Via Oncology.

“Via Pathways is a great resource,” said Dr. Page. “I’ve served on the Via melanoma pathways committee for the past 12 years as a community oncology representative. That committee meets every three months, and we review all the scientific data that’s significant in melanoma diagnosis, management and treatment.

“The committee involves truly world-class melanoma experts who are academic, but it also gives you the flavor from community oncologists like myself who can give you a more real-world perspective of what’s going on with cancer patients in the community and in rural areas that don’t have resources,” he said. “The Via committee is a great resource for me, just to be able to have the opportunity to interact with brilliant people and great minds who live and breathe melanoma every day.”

Dr. Page started Tow with Opdivo (nivolumab) and Yervoy (ipilimumab): four treatments three weeks apart.

“The first treatment was fine, but the last three I had reactions that Dr. Page said were textbook – it was just tearing me up,” Tow said. “They actually had to hit me with a heavy downer to get me to sit through the infusion. I’d get freezing cold, violently shivering, coughing, couldn’t breathe, while sitting in the infusion chair – it was no fun.”

The journey to recovery

Tow underwent almost three years of treatment. Today, he’s free of the melanoma.

“My blood work is great, my liver is working great,” Tow said. “It’s just me physically getting myself up and having to do things. I’m tired all the time, and I have to force myself to get up and do things. I was a runner, but I can’t run because of what the melanoma did to my spine, but that’s something I can live with. I ride bikes now because I still have to be outside.”

For Dr. Page, it’s also been a journey – one of discovery, as he and his patients participate in some of the latest therapies science had developed.

“The reason you can do (these therapy combinations) is because of the work that people did evaluating those drugs in a systematic manner through clinical trials and research,” Dr. Page said, “and the willingness of patients with advanced melanoma to participate in clinical trials and try new drugs and therapies, to advance the science.”

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Written by

Christopher Capot

Written by

Christopher Capot

Christopher Capot heads up external and internal communications for Elsevier's health, education and corporate R&D businesses. He has been a public relations and media relations professional at agencies and corporations for more than 20 years. Prior to that, he was an award-winning newspaper journalist, last working as a business reporter at the New Haven Register in Connecticut. He works in Elsevier's New York office.

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