By Mark Teich
With the recent FDA approval of the drug nivolumab (Opdivo®, previously approved for stage IV melanoma) as a treatment for stage III melanoma, we have reached the next important phase in the immunotherapy revolution. It is a revolution that most of the world’s top experts believe will one day, very possibly within a decade, turn advanced (stages III and IV) melanoma into a chronic, or even curable, disease rather than a deadly one.
In my 25 years at The Skin Cancer Foundation as a writer, editor and now scientific director, I’ve been privileged to see the prospects for treating advanced melanoma go from zero to limitless. When I began here in the early 1990s, not a single effective treatment existed for advanced disease. In the next several years, the FDA approved two immunotherapies (drugs that work by boosting the immune system’s ability to fight a disease), Interferon alfa-2b for high-risk, localized stage II patients and stage III patients, and Interleukin-2 for stage IV patients. Interferon kept melanoma from recurring for a while, but ended up not keeping patients alive longer. Interleukin did keep some patients alive longer, but not very many.
Finally, a Breakthrough
It wasn’t until 2011, after more than a dozen years with no more FDA approvals, that the revolution began in earnest. That year, two distinct types of treatment, targeted therapy and checkpoint blockade immunotherapy, fired their first salvos against stage IV melanoma. First, the FDA approved the drug vemurafenib (Zelboraf®), which targeted and turned off a defective cancer-causing gene called BRAF found in about half of all melanoma patients. Later in the year, the FDA approved ipilimumab (Yervoy®), a drug referred to as a checkpoint blockade immunotherapy because it blocks a key checkpoint called CTLA-4 that mistakenly sends messages to the immune system (specifically the T cells) to keep it from attacking melanoma. These drugs started keeping patients who formerly would have died in a few months alive for many more months, and often for two to three years or sometimes many more years.
In the six years since then, new targeted therapies and immunotherapies for stage IV melanoma have come fast and furiously, with close to a dozen FDA approvals. Especially notable have been the checkpoint blockade therapies nivolumab (Opdivo®) and pembrolizumab (Keytruda®), which block a different immune checkpoint, PD-1 (programmed death-1). They have proven even more effective than ipilimumab and produce fewer serious side effects. And seemingly the most effective of all has been a therapy combining ipilimumab and nivolumab (both produced by Bristol-Myers Squibb), though it can have harsher adverse effects for some patients than any of the other therapies used alone. Fortunately, physicians are learning how to detect and address these effects earlier. Most patients taking these newer drugs are now living at least two or three years longer than patients with advanced melanoma used to, and about 20 percent are living more than five years, apparently cured.
The Latest Developments
In 2015, ipilimumab was approved as a treatment for stage III melanoma. It was approved as an adjuvant therapy, meaning an additional treatment following surgery that is designed to help decrease the risk of the cancer coming back and spreading throughout the body. Ipilimumab quickly became the frontline therapy for stage III patients (meaning it’s considered the best treatment available and the first to be tried for most patients), because it not only delayed recurrence longer than interferon, but increased overall survival longer for more patients than any previous drug.
Now, just in the past couple of weeks, nivolumab has also been approved as an adjuvant therapy for stage III melanoma. The study that led to approval primarily showed that it delayed recurrence longer than ipilimumab, with far less serious adverse effects, which can derail a therapy and sometimes even lead to death. The ongoing study is now looking secondarily at overall survival.
“To date, only ipilimumab has demonstrated an overall survival (OS) benefit in this patient population,” says Awny Farajallah, MD, head of U.S. medical oncology for Bristol-Myers Squibb. “But that could change as OS results come in for nivolumab.”
Adjuvant therapy appears to be the next big thing in melanoma treatment, and more adjuvant therapies will probably be approved in the next couple of years. For example, study results on combination nivolumab-ipilimumab as an adjuvant therapy are expected by the end of 2020. Why are these treatments so important? Simply, the earlier you detect and treat melanoma, the greater your chances of long-term survival and avoiding recurrence. Patients with early melanoma have an estimated 98 percent five-year survival, stage III patients 63 percent five-year survival and stage IV patients, even with the new drugs, only 20 percent five-year survival. Your chances of stopping melanoma cold are far better if you can attack it effectively at stage III rather than stage IV.
“We’re very excited about the approval of adjuvant nivolumab,” Dr. Farajallah says. “To date, 71 to 85 percent of stage III patients will have a recurrence, and this gives us an important additional option to bring those numbers down.” In 18 months of testing, he notes, patients went 66 percent longer without a recurrence on nivolumab versus 52 percent on ipilimumab, with far fewer dangerous adverse reactions.
“Adjuvant therapy is an important part of our efforts to advance cancer treatment through immuno-oncology, with the ultimate goal of providing a potential cure,” says Dr. Farajallah.
Mark Teich is the scientific director at The Skin Cancer Foundation. He has served as the executive editor of the Foundation’s Melanoma Letter for more than two decades.