New approaches transform the treatment of a dangerous cancer.
Robert Parker first noticed the black spot on his scalp in the summer of 2013. A biopsy determined it was melanoma, and he quickly had surgery to remove the tumor.
All seemed OK until about a year later, when an X-ray revealed that the cancer had recurred and metastasized, spreading into his organs and lungs. That’s when Parker sought the expertise of Steven O’Day, MD, professor of medical oncology, director of immuno-oncology and director of clinical research at the John Wayne Cancer Institute at Providence Saint John’s Health Center.
“It was so bad, I thought I would just get painkillers for the short time I had left,” Parker says. “I’m not supposed to be alive.”
But today, Parker, an entrepreneur and chairman emeritus of a microfinance company, is alive and thriving at his Malibu home, thanks to a new crop of innovative melanoma treatments that have revolutionized the way oncologists fight the disease. Melanoma has historically been one of the hardest cancers to treat because it’s so unpredictable and resistant to conventional treatments, like chemotherapy.
“It accounts for only 4% of all skin cancers but 80% of deaths from skin cancer,” Dr. O’Day says. “It’s important that people get regular skin exams by the doctor or dermatologist once they’re in their 30s or 40s, especially if they had lots of sun exposure as a child or they have a lot of moles or a family history of melanoma.” That’s because melanoma usually starts as a tumor on the skin caused by exposure to UV rays, either from the sun or from tanning beds. But unlike other types of skin cancer, melanoma is highly aggressive, with the ability to move rapidly into the bloodstream.
It also mutates easily, so it can quickly become resistant to treatments like chemotherapy.
Once it has metastasized, the cancer can fan out along the highways of the circulatory system, setting up camp wherever and whenever it likes, from the lymph nodes to the internal organs. And that means traditional treatments like surgery, chemotherapy and radiation have little to no effect once it’s in the bloodstream.
“Melanoma has been a prime candidate for immune therapy investigation because these traditional therapies could never be established as standard treatments,” says Mark Faries, MD, the Institute’s director of therapeutic immunology and director of the Donald L. Morton, MD, Melanoma Research Program. “It’s amazing what has happened with melanoma. There were just a handful of drugs approved over the last few decades, but in the last five years there’s been a whole series of new drugs approved. The two most promising categories of advancement in melanoma treatment today are immune therapies and targeted therapies.”
“After I started the meds to attack the tumors, I felt better the next day. Within just eight days the tumors had shrunk, and I felt like a new man. What they do is a miracle.”
Current immune therapies include drugs like ipilimumab (Yervoy), which strengthens the body’s immune system by boosting the number and effectiveness of the body’s T-cells, and two new drugs that bind to a pathway on the cancer cells called PD-1 receptors. The two new PD-1 drugs are pembrolizumab (Keytruda) and nivolumab (Opdivo). To understand how they work, imagine a patient’s body as a battleground. Ipilimumab recruits and builds an army of T-cell soldiers against the enemy melanoma, while pembrolizumab strips the enemy’s camouflage and hits them with a floodlight so the soldiers know whom to attack.
In addition to these immune therapies, the nascent and growing field of targeted therapies uses melanoma’s own mutations against it, preventing the cells from growing and eventually killing them.
A study by the Cancer Genome Atlas Research Network, which includes Institute researchers Dave S.B. Hoon, PhD, director of molecular oncology, and Sharon Huang, PhD, has helped uncover melanoma’s most common genome, methylome and transcriptome changes (changes in cells that can lead to disease). The results, recently published in the June issue of the journal Cell, describe four melanoma subtypes—BRAF, RAS, NF1 and triple-wild-type—suggesting that it may be more effective for doctors to treat each subtype individually, rather than considering melanoma as a single disease with one standardized treatment.
The study confirms a recent previous publication in the journal Cell in which Dr. Hoon’s group was involved in a comprehensive assessment of melanoma mutations. Some medications are already available that “target” specific genetic mutations, such as the BRAF mutation.
Robert Parker (left) with the former Chinese Minister of Culture, Cai Wu. Parker, who is the current Chinese business ambassador to the president of China, thought he wouldn’t survive advanced melanoma. But an immunotherapy beat back the cancer.
Identifying the specific cancer subtype “gives you the option: If you have this melanoma mutation(s), you can get drug ‘X,’” Dr. Hoon explains. “It will also allow us to identify, in the future, why patients with specific patterns of genomic or transcriptome changes progress more than others and are more responsive to treatment.”
Today targeted therapies on the market include drugs like dabrafenib (Tafinlar) and trametinib (Mekinist), designed specifically for melanoma with the BRAF mutation, which accounts for about half of melanoma patients.
“We can easily test for it, and if you have it, these targeted drugs block the mutation and kill cancer cells,” Dr. O’Day explains. “Someone with widespread melanoma can see their tumors melt away within a week.” Current and future research is focused on targeted therapies for other genetic subtypes.
Fortunately for Parker, testing showed his melanoma had the BRAF mutation, and Dr. O’Day started him on the targeted therapies right away.
“I’m usually 240 pounds with a 38-inch waist, but the tumors had swelled my abdomen to a 55-inch waist,” says Parker, who is the current Chinese Business Ambassador to the president of China, Xi Jinping. “After I started the meds to attack the tumors, I felt better the next day. Within just eight days the tumors had shrunk, and I felt like a new man. What they do is a miracle.”
The downside is that, currently, targeted therapies on their own may only work for a limited time before the cancer becomes resistant to them as well. So these medications are primarily used for patients with advanced cancer, like Parker—who need a fast response and temporary remission that gives doctors time to find a long-term plan using other treatments.
Another patient of Dr. O’Day’s, Shawn Quirk, didn’t have the BRAF mutation, and it took longer for him to find the right combination of treatments. The 54-year-old Ventura resident is a two time Ironman triathlete and long-distance trail runner who, despite having a basal cell skin cancer removed from his back, never found a mole on his skin to indicate he had melanoma.
Instead, Quirk found a lump in his right armpit that turned out to be melanoma in his lymph nodes. By the time a biopsy determined it was cancer, one of the nodes had burst and the melanoma had already started to spread along his arteries. He spent six months on an older treatment called interferon, but the cancer eventually spread to his lungs and liver.
“Surgery couldn’t cure me because I had stage III cancer. The disease was doing its thing and growing fast,” Quirk says. “I went on Yervoy for 12 weeks, and while the side effects where minimal, Yervoy did not help. But then I went on Keytruda, and two weeks after my first infusion, I woke up, rolled over and didn’t feel any pain. It was just gone.”
While there is nothing fortunate about cancer, both Quirk and Parker overcame substantial odds because their melanoma diagnoses came at a time of incredible innovation—though these new treatments are not yet a silver bullet for all cases of melanoma.
“Survival is definitely going up,” Dr. Faries says. “We’re already seeing people living longer and potentially being cured of their cancer even at advanced stages. We just need to keep our momentum and make those responses happen for more people. The drugs we have right now don’t work for everyone— maybe not even the majority.”
Dr. Faries points to even newer treatments on the horizon that may offer promising result on their own or in combination with current drugs. One, called TVEC, uses a modified herpes virus that is injected directly into melanoma, stimulating a localized immune reaction directly at the site of the tumor rather than jump-starting the entire body’s immune system like ipilimumab, which can have serious side effects if supercharged T-cells start attacking healthy parts of the body.
“The side effects to TVEC are limited to reactions at the local injection site,” Dr. Faries says, “while the treatment can work on the injected tumors and non-injected ones around it.”
Another promising field of treatment for which Dr. Faries conducts research is called tumor infiltrating lymphocytes (TILs). “In TILs therapy, a metastatic tumor is taken out, brought to a lab and put into a culture to assist growth of immune cells,” he explains. “Part of the problem with melanoma is the immune system is not strong enough, but we can expand those cells into very large numbers, creating an army of immune cells to be given back to the patient fully formed.”
A diagnosis of melanoma is still frightening, but the advances have ushered in a new era of hope for people who receive that bad news. “With melanoma I’ll be looking over my shoulder the rest of my life,” Quirk says. “But these drugs have given me my life back, and with a disease where nothing is for sure, that seems like a miracle.”