Back in 2005, when Philip Friedlander, MD, PhD, completed his fellowship, the first clinical trials of checkpoint inhibitor clinical trials were just beginning, and he was very interested in immunotherapy.
"A few of us were sitting together in a room, and I said that I wanted to focus on melanoma," Friedlander said.
"One of my friends said something to the effect of 'Oh, so you're going to focus on hospice care,' and at that time, that was a pretty accurate assessment," he commented.
Now director of the Melanoma Medical Oncology Program at The Tisch Cancer Institute at Mount Sinai in New York City, the last two decades have seen such an improvement in the prognosis of patients with advanced melanoma that the treatment of this cancer can be considered one of the great success stories in medicine.
Metastatic melanoma was once almost a death sentence, with a median survival of less than a year. Now, some patients are living for years, with a few out at more than 10 years.
Clinicians are now talking about a 'functional cure' in the patients who respond to therapy.
One obvious change is that "our clinics have become very crowded," says Paul B. Chapman, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City who has been treating melanoma patients since the 1980s.
"Our patients are living longer and we are now seeing them for years, something that was previously unheard of," he said.
The changes came about through a combination of several factors. "One was a better understanding of the immune system and the molecular biology of melanoma, and also its mutational profile," explained Friedlander. "The second was the ability of industry to develop drugs that target components in the immune system and mutated proteins."
This led to a slew of new therapies for melanoma, including immunotherapy with checkpoint inhibitors such as ipilimumab (Yervoy, Bristol-Myers Squibb), nivolumab (Opdivo, Bristol Myers Squibb), pembrolizumab (Keytruda, Merck) and others, as well as targeted therapies aimed at BRAF and MEK mutations, including vemurafenib (Zelboraf, Genentech/Roche), dabrafenib (Tafinlar, Novartis) and many others.
These new therapies have led to some "amazing" advances in the field of melanoma over the last 15 years, said Jeffrey M. Farma, MD, co-director of the Melanoma and Skin Cancer Program at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.
"Historically, we would never really consider patients with advanced melanoma to be cured. But now we are now seeing patients that have had exceptional responses with widespread metastatic disease who are now over 5 years out with no evidence of disease," he continued.
"In my practice this still amazes me," he noted. "We have to determine through research how to improve these deep responses that are durable."
To illustrate how profound these therapies can be in patients who respond to them, Farma explained that he shows the PET scan of one of his patients to every one of his new medical students, residents and fellows. The scan shows innumerable metastases in the soft tissue, lymph nodes, liver, abdomen, and lungs.
"Then patients then went on to receive program death (PD) inhibitors and within 6 months almost all the lesions melted away," Farma told Medscape Medical News. "I ended up removing some lymph nodes which had all dead melanoma and she thankfully is doing great, with no evidence of disease, living her life and off therapy. It's truly amazing!"
Reducing Premature Deaths
The American Cancer Society's most recent report to the nation on cancer highlights the spectacular progress in reducing premature deaths due to melanoma. From 2012 to 2016, which is the latest data available, the average decline in mortality was about 5%. Most notably, it was higher in in black Americans, at about 9%.
"That's a stunning change for a very serious disease for which we really had no effective treatments," said J. Leonard Lichtenfeld, MD, deputy chief medical officer for the national office of the American Cancer Society (ACS).
However, he emphasized that there are still many patients with advanced melanoma who don't respond to the treatments.
Not Long Ago, Little to Offer Chapman remembers a time, not so long ago, when medicine had little to offer these patients. He remembers hearing colleagues saying that "melanoma is what gives cancer a bad name!"
However, Chapman pointed out that melanoma wasn't really that much worse than other cancers during that time period — many other tumor types also had few therapeutic options.
"But still, prognosis was pretty poor," he said.
"In those days, we had a few treatments for melanoma, and sometimes they worked and mostly they didn't," he said. "Once in a while we had a patient who had a clear benefit, and occasional cures, but they were rare."
Until 2011, there were only two therapies that were approved for metastatic melanoma: chemotherapy with dacarbazine and immunotherapy with high-dose interleukin 2 (HD IL-2), and neither one was very effective at prolonging life, he noted.
Chemotherapy was once the standard of care but now it is typically used as third-line therapy, Chapman explained. "It's just not used that often anymore, and the more junior doctors don't even know the doses."
Dacarbazine was the first systemic drug approved for metastatic melanoma in 1975 but was also the last chemotherapeutic agent to receive approval for this indication.
"Dacarbazine had a 5%-20% response rate and no overall survival benefit," said Friedlander. "Subsequent studies of combinations of chemotherapy also didn't show any survival benefit and that was very disappointing."
HD IL-2 was approved in 1998 for metastatic melanoma, and had a response rate of about 16%, and a durable response rate of about 5%, explained Friedlander. "But this was for a very select group of patients who could withstand the cardiopulmonary side effects and other toxicities, although it highlighted the role of the immune system in fighting melanoma."
There was also immunotherapy with interferon alfa-2b, which received FDA approval in 1995 for adjuvant treatment after excision in patients who were disease-free but remained at high risk for recurrence.
"We used to offer adjuvant interferon in hopes of decreasing the chance of recurrence," commented Farma. But it did not extend overall survival, and significant toxicity limited its use.
Data showing that some patients with metastatic melanoma treated with ipilimumab were still alive 10 years later came to light in 2013, from a large pooled analysis of almost 5000 patients. This showed that 21%-22% of patients were alive at 3 years, and also showed a plateauing of the overall survival curve. Additionally, 17% were still alive after 7 years, with no deaths after that, and the longest follow-up in the database was 9.9 years.
Following quickly on the heels of ipilimumab were new drugs that acted at another point on the same immune pathway — these were drugs that blocked the programmed cell death (PD), such as pembrolizumab and nivolumab. They showed higher response rates and lower rates of serious adverse events as compared to ipilimumab, as well as better rates for progression-free and overall survival.
Another development was combining the two different mechanisms of action of immunotherapy, and the combination ipilimumab and nivolumab has shown better results than either drug alone.
Recently reported results from the CheckMate 067 trial show the superiority of combination vs monotherapy. The 5-year overall survival rates were 52% for the combination of nivolumab and ipilimumab, as compared with 44% for nivolumab, and 26% for ipilimumab when given alone.
Progression-free survival at 5 years mirrored the overall survival data, as it also showed a clear benefit for the combination (36%) vs 29% for nivolumab alone, and 8% for ipilimumab alone.
"Because ipilimumab and the PD-1 inhibitors work on different parts of the immune system, there was the idea to combine the two," said Friedlander. "We are now seeing responses of 60% with combination ipilimumab and nivolumab — but as expected, there is also more immune mediated toxicity."
None of the combination therapies has been compared head to head, so it is yet unknown which one may be the most optimal. "Similarly, BRAF/MEK inhibitor combinations have not been compared head to head in a randomized fashion with upfront immunotherapy to see which is the better starter therapy," Friedlander added. "There are still a lot of unknowns."
With each new drug approval, the survival rates are getting pushed ever higher. But does this mean the patients are cured?
Chapman believes that patients can be cured. "From our own large series, which is one of the oldest and largest, about 75% of the complete responders have remained in complete remission 3 years after being off treatment," he said. "I like to think that we have cured some of them."
The patients will continue to be followed for "as long as they want to be followed," he added.
In a Medscape video commentary from last year, Jeffrey Weber, MD, a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at New York University Langone Health in New York City, also mentioned the c-word when in discussing the results of original KEYNOTE-001 trial of pembrolizumab for stage IV metastatic melanoma patients. He pointed out that 16% of patients (of a total of 655 patients) had a complete response at 2 years.
"My personal prediction is that many of those in complete response at 2 years who stay there will probably be cured of their melanoma," Weber commented.
"In the immunotherapy era, we can now begin to talk of cures for patients with melanoma," he concluded.
Another expert in the field has also used the 'c' word. Suzanne L. Topalian, MD, associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore, Maryland, recently published long-term survival data from some of the initial clinical trials with nivolumab. The results show a "long tail" of overall survival, with a flattening off after 3 years. The 5-year overall survival reached 34% in patients with melanoma, 28% in those with renal cell carcinoma (RCC), and 16% in patients with non-small cell lung cancer (NSCLC).