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.
"It was a year of therapy which was initially an infusion in the hospital for the first month and then injections three times a week for 11 months," he explained. "Most patients did not finish therapy due to the toxicities. It made you feel like you had the flu, muscle aches, fatigue, and dehydration."
Targets and Immunotherapy
Two advances, taking place independently of each other, essentially hijacked the course of treatment for advanced melanoma.
The first was the Human Genome Project, which mapped out and enhanced the understanding of human genes and laid out the foundation for deciphering the pathogenesis of cancer. The discovery of genetic and epigenetic alterations in tumors enabled the development of targeted therapies as well as diagnostic tests that identify patients who are most likely to benefit.
Mutations in BRAF were initially described in 2002, with V600E being the most common mutation. "We learned that the BRAF mutations are recurrent in many cancer types, but it really stood out in melanoma," said Chapman. "We see it in about half of all patients."
Researchers began looking at small molecules that inhibited BRAF, paving the way for new targeted treatments. The result was vemurafenib, which was approved by the FDA in 2011 for patients with melanoma that was unresectable or metastatic with the BRAF-V600E mutation. Two years later, dabrafenib also received a regulatory thumbs-up for the same indication.
Other approvals for targeted agents followed, including MEK inhibitors and combinations of different drugs in these two groups.
The other advance was in immunotherapy.
This was, in fact, what drew Chapman into the field. "There was really a robust interest in it and that's why I was directed to melanoma, as it was the only area where immunotherapy was really being investigated," he said. "Melanoma doctors were the only ones really studying it and there was a sense that melanoma might be more responsive to immunotherapy."
He pointed out in the "early days," very few responses were seen. "There was a hint that interferon works sometimes, and some data that interleukin 2 worked in other patients."
The emergence of immune checkpoint inhibitor drugs was a very important development in cancer immunotherapy, but Chapman recalled that the very early experimental work wasn't all that provocative. "Truth be told, when these drugs were tested in mice, the results weren't particularly astounding, and it was kind of the effect with other drugs that didn't work in the clinic," he said. "But it showed enough of a signal with the CTLA-4 antibody that it was worth testing in human trials. That later led to the anti-PD-1 antibody which was even more active."
A turning point came in 2010, when results reported at the annual meeting of the American Society of Clinical Oncology (ASCO) demonstrated for the first time an improvement in overall survival in a phase 3 randomized controlled trial in this setting.
These first results were from a trial in which patients with metastatic melanoma who received ipilimumab plus a peptide vaccine had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone. Ipilimumab also showed, compared with the peptide vaccine, a near doubling of the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%).
Ipilimumab, which targets CTLA-4, became the first checkpoint inhibitor to receive approval for the treatment of melanoma.
"Ten years out from that study, there's a subset of patients who are alive and doing well from those initial four doses given a decade earlier," Friedlander pointed out.
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."
The 'C' Word
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).
Although talk of a cure may be premature, these results, along with others, show that "some patients can live for years and we can think of that as a functional cure at least," she she commented in a Medscape Medical News story in August.
The concept of a "functional cure" has been used in HIV to describe a patient who has undetectable viremia, no disease progression, no CD4 loss, and a lack of HIV transmission, even though the virus itself has not been completely eradicated from the body.
In cancer, this same concept was suggested more than two decades ago (Journal of Clinical Oncology. 1995;13:801-807) that in the wake of new treatment and insights into the disease, pharmacologically controlling cancer may result in an equally acceptable outcome for patients.
Hesitancy to Discuss Cure
However, oncologists have traditionally had a hesitancy to discuss cure, Lichtenfeld told Medscape Medical News.
"Along with many other physicians of my generation, I have grown up with the concept that cure is a goal that everyone aspires to, but we also know that many cancers can remain dormant for years or even decades before they show up again," he added.
"This is true, for example, with breast cancer, where patients can have recurrences 10 to 15 years after it was first diagnosed," he said. "Thus, there is a reluctance among many oncologists to say that patients can be cured."
As another example, he mentioned Hodgkin's disease, which is now treated with chemotherapy and radiation, and many patients achieve long-term survival. However, an analysis he was involved with found that "even though we were seeing long-term survival — and even though patients had survived 10-15 years with newer treatments — they still had traces of disease in their body," he explained. "We found that if they had died accidentally, there were still traces of Hodgkin lymphoma in their body, even though there was nothing that could be detected clinically, at least with the technology we had then."
Another issue is quality of life, and this needs to be achieved along with a cure, Lichtenfeld commented.
Successes have been seen with childhood leukemias and other cancers, where survival rates are now very high, but these children grow with the consequences of the adverse effects of therapy. "Just because someone can survive doesn't mean that they can thrive, and that is something we need to understand and address," Lichtenfeld said.
The potential to cure patients is here today, but to achieve that, "we need to pay attention to the quality of care, access to care, and support of that care," he added.
"I would like to see everyone cured, but until we get to that point, I would like to see everyone get the best possible care — and not have barriers in place," he concluded.
Farma has disclosed no relevant financial relationships. Chapman reports relationships with Rgenix, Bristol-Myers Squibb, Genentech, Takeda, Cell Medica, Merck, Immunocore, and Pfizer. Lichtenfeld is co-chair of the National Council on Skin Cancer Prevention, for which he receives no compensation. Friedlander reports relationships with Regeneron, Array, Aspyrian, Incyte, Clovis, Allergan, and Marrimack. Topalian has numerous financial disclosures.
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Cite this: 'Truly Amazing': Huge Change in Melanoma Prognosis - Medscape - Oct 24, 2019.