With immunotherapy gaining importance as a therapy for melanoma, and with excitement gathering about the potential added benefits that can come with combinations of these medications, there is a lot of interest in the kinds of side effects that will emerge with immunotherapy pairs. Encouraging recent data showed few differences in quality of life (QOL), global health and symptom burden between patients with melanoma who were treated with Opdivo (nivolumab) plus Yervoy (ipilimumab) or either agent alone. The results were from an analysis of patient-reported outcomes from the phase 3 CheckMate-067 trial.

After one year of follow-up, patients in the Opdivo plus Yervoy arm of the trial experienced no clinically meaningful change in health-related QOL — even though they showed significant improvements in survival. Additionally, patients treated with Opdivo alone or Yervoy alone showed no significant changes in QOL compared to baseline, said Dirk Schadendorf during a presentation at the 2015 Society for Melanoma Research Congress.

“The nivolumab plus ipilimumab treatment arm had the highest frequency of adverse events, but these adverse events did not seem to affect patient-reported QOL outcomes,” said Schadendorf, director of the Department of Dermatology at the West German Cancer Center at the University Hospital in Essen, Germany.

In the CheckMate-067 study, 945 patients with advanced melanoma were treated with Opdivo alone, Yervoy alone, or a combination of the two. Patients in the combination arm showed improved progression-free survival (PFS). The median PFS with the combination was 11.5 versus 6.9 months with Opdivo alone and 2.9 months with Yervoy alone.

Adverse events (AEs) were more frequent with the combination treatment, with 55 percent of patients in that arm experiencing having grade 3/4 (serious to severe) AEs versus 16.3 percent with Opdivo alone and 27.3 percent with Yervoy. Additionally, over 29 percent of patients in the combination arm experienced a treatment-related AE leading to treatment discontinuation.

Despite the higher incidence, AEs in the study were short-lived. The median time for resolution of grade 3/4 AEs was 1.7 to 4.2 weeks, Schadendorf said.

To assess patient-reported QOL, researchers used a questionnaire about health status, and another form in which patients rated their health status on a scale from 0 to 100 and also specifically rated five dimensions of their health: self-care, mobility, usual activities, pain/discomfort and anxiety/depression.

Schadendorf noted that patient characteristics were well balanced among the treatment arms at baseline, suggesting that it is unlikely that pre-existing patient health outcomes affected the results.

Reductions were seen in questionnaire scores across all arms; however, these findings were not deemed clinically meaningful because they did not represent a decrease in well-being of 10 ponts or more. At week five, there was reduction of 2.7, 4.3, and 3.1 points for Opdivo alone, the combination and Yervoy alone, respectively. Scores returned to baseline levels by week 25 in the Opdivo-alone arm and by week 31 in the combination and Yervoy-alone arms.

The ratings-scale scores improved at week 13 with Opdivo alone, which persisted throughout the trial. However, in the Yervoy-containing arms, these scores initially worsened before returning to baseline by week 13 for the combination and by week 19 for Yervoy alone. Scores on the five specific dimensions of health were stable for the Opdivo-containing arms and worsened with Yervoy until week 23.

“Even among patients who suffered severe toxicities such as colitis, treatment did not appear to have a significant effect on quality of life,” Schadendorf said. “Do the results in this study indicate that patients don’t care about toxicity when they receive a large survival benefit, or is it that QOL wasn’t affected because the toxicities were short-lived?”

One shortcoming of the analysis was that patients who discontinued treatment were not included in QOL assessment, Schadendorf said. To account for this, data are being analyzed that include patients who progressed or discontinued. Additionally, patients will continue to be followed in the study to assess whether the tumor control benefits observed in CheckMate-067 will affect long-term patient QOL outcomes, he said.

“One possible explanation for our findings in this study could be that the tools we have now — utilized in our analysis &mdash; are not very useful for assessing QoL in patients treated with newer immunotherapy agents,” Schadendorf said. “Yet these are the only instruments we have that are validated, and it could take years to obtain new and better validated tools.”

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Patients with melanoma who were treated with a combination of Opdivo and Yervoy showed no significant changes in their quality of life when compared to those who were treated with either agent alone. 

QOL Similar With Checkpoint Combo Versus Single-Agent Immunotherapy in Melanoma

Todd Greenlee first noticed a lump in his left armpit on Labor Day weekend in 2014. He didn’t think too much of it. Then, a couple of weeks later, he pressed on the lump and a bruise blossomed all the way down his left side. It hurt. Greenlee went to the doctor, and after several tests and appointments, he got the bad news: The lump was stage 4 melanoma that had spread through his lymph nodes and abdomen.

His oncologist, Joseph Clark of Loyola University Medical Center in Chicago, tried immunotherapy treatments: first a monoclonal antibody, then a clinical trial that multiplied Greenlee’s own immune T cells and trained them to fight his particular cancer. Each time, though, Greenlee’s disease would respond for a few months, then relapse. Finally, Clark tried a Hail Mary pass: very high doses of a 20-year-old treatment, one of the first immunotherapies, interleukin-2 (IL2).

Not long after beginning IL2, Greenlee started to notice white patches on his hands. Within a few months, Greenlee, a 43-year-old farm worker, had lost skin pigment over most of his body, a condition known as “vitiligo.”

That didn’t bother Greenlee too much, though, because soon after the vitiligo appeared, the spots of cancer that peppered his abdomen disappeared. More than a year later, his medical team still can find no evidence of disease.

“With regard to immune therapy, if people develop vitiligo while being treated for melanoma, that’s a good sign that treatment is working,” Clark explains.

Doctors had noticed a link between vitiligo and better melanoma outcomes as early as the 1940s, writing case studies about such patients. But no one had been able to determine whether vitiligo just happened to co-occur with good responses to treatment, or if the vitiligo actually contributed to those good responses.

In the last few years, however, a series of studies show that developing vitiligo during or after immunotherapy for melanoma, and sometimes for other skin cancers, does indeed mean that the immune system is in high gear, and is associated with a higher chance of remission or even cure.

While the exact mechanism of this phenomenon has yet to be well understood, experts say that figuring it out may lead to new immunotherapy treatments that can more effectively enlist a patient’s own immune system in fighting their cancer.

To understand how vitiligo might be related to better immune treatments, it’s good to review how the immune system works: All cells have proteins on their surfaces that act like biological bar codes, sort of like identity cards. Immune system cells — T cells, natural killer cells, white blood cells and so on &mdash; patrol the body, looking for cells that don’t have the right combination of proteins on their surface. When they find surface proteins, antigens, on cells that don’t pass the screen &mdash; that say “not-self” &mdash; the immune cells attack and kill the offenders.

An “auto-immune” disease or condition occurs when immune system cells start attacking cells that really aren’t invaders at all, but normal body cells. In the case of vitiligo, the immune cells attack “melanocytes,” the cells responsible for pigment in our eyes, hair and skin. An analysis of studies conducted over many years showed that this happens in only 3.4 percent of patients who receive immunotherapy for melanoma, but other researchers have found a much higher incidence; a 2016 study conducted in France found that 25 percent of 67 participating patients experienced vitiligo when taking the immunotherapy Keytruda (pembrolizumab) to treat their melanoma. This may be due to the fact that melanocytes and melanoma cells may share antigens that are targeted by the immune system when powerful immune-stimulating drugs are used.

When the immune system mistakenly attacks enough pigment cells, their destruction leaves behind white patches which may appear small and limited or may spread all over the body.

utside the context of cancer, vitiligo tends to appear in those between the ages of 10 and 30. And it appears to help prevent melanoma and other skin cancers in those who develop it spontaneously.

“There are a number of recent genome-wide association studies that reveal that the versions of genes that put you at risk for vitiligo are the same ones that protect you from melanoma,” explains John Harris, director of the Vitiligo Clinic and Research Center at the University of Massachusetts Medical School.

And if the vitiligo develops in response to immunotherapy for melanoma, “Studies have recently shown that those who get vitiligo have a 70 to 80 percent chance of a clinical response” to the treatment, says David Fisher, director of the Melanoma Center at Harvard’s Massachusetts General Hospital. “If they don’t get vitiligo, they have a lower chance of a major response, 20 to 30 percent.” Researchers say that stories of amazing outcomes in melanoma patients who have vitiligo, or develop it during treatment, circulate around clinics. For instance, Harris recently treated a patient who had a softball-sized melanoma in her armpit, but no metastases anywhere. “That’s incredibly unusual,” Harris says. “It’s probably the case that her vitiligo helped to protect her.”

Once it appears, whether spontaneously or because of immunotherapy, vitiligo usually does not go away. Doctors treat mild cases with topical creams such as systemic corticosteroids or topical immunomodulators, which can help with repigmentation. More widespread vitiligo may be treated with phototherapy, several sessions a week in a booth that emits ultraviolet B light, although this is considered a bad idea for people with melanoma, who are much better off avoiding any kind of tanning. If a patient stops these treatments, the vitiligo usually comes back.

Some patients, who are more bothered by the white patches, may choose to graft patches of their normal skin, or blister patches, onto small patches of vitiligo. More experimental treatments involve transplanting melanocytes from normal skin to the patches with vitiligo. These may not be options during treatment, though, because techniques such as micrografting only work on vitiligo that is inactive, points out Caroline Le Poole, who studies vitiligo and melanoma at Loyola University. In any case, she recommends not cosmetically treating vitiligo until there is absolutely no remaining evidence of melanoma tumor.

“Vitiligo is still kind of lumped into the ‘adverse events’ category,” says Mary Jo Turk, an associate professor of microbiology and immunology at Dartmouth College’s Geisel School of Medicine. “But now, people are starting to think, ‘Let’s look at vitiligo as a separate thing in this era of immunotherapy.’”

Generally, the strategies that have driven the field of immunotherapy over the last two decades have been to find therapeutic agents that target specific protein markers, antigens, on the surface of cancer cells. Or, scientists have tried to develop agents that somehow enhance the patient’s own immune system, enlisting it to help fight the cancer. For instance, if there’s normally a biological brake to regulate the immune response, an immunotherapy releases that brake so the immune system can move into motion.

For a long time, immunotherapy developers focused on “self-antigens,” protein markers that occurred on both the cancer cells and their normal counterparts, for instance cancerous melanoma cells and normal melanocytes. By appearing on cancer cells, these antigens make the aberrant cells appear normal, allowing them to hide from the immune system. More recently, the field has been exploring “tumor-specific” antigens, that is, protein markers that occur only in cancer cells.

The study that brought vitiligo into this discussion rose out of happenstance. Turk, the Dartmouth researcher, had a staffer come to her asking what to do about two cages of mice that had been on a shelf for about a year. The mice in one cage had vitiligo; the mice in the other did not. Turk decided to analyze the two populations and was shocked by what she found: The mice with vitiligo had enhanced immune T cells. The other mice did not.

Turk’s group published a 2011 paper using the data from the mice to show that, somehow, the destruction of melanocytes helped not only to keep T cells active, but to remind them to kill particular cells.

“Melanocyte destruction keeps the T cells alive for hundreds of days,” Turk says. “We were shocked to find this. This finding gave rise to other studies seeking to find out exactly what’s going on with melanoma patients who get vitiligo, and why they tend to have better outcomes. For instance, Le Poole has a grant to study autoimmune side effects of anti-tumor therapy and test measures to reverse them.

Le Poole also has a T cell receptor cloned from vitiligo skin that she’s studying to see if these cells can be used to devise new immunotherapies.

But as with so many things in cancer research, it’s not simple. “It’s not a one-to-one relationship,” Le Poole explains. For instance, not all patients who have a good response to immunotherapy will get vitiligo. Likewise, not all those who get vitiligo will go into remission. The relationship is there, but it’s not absolute.

“If you generically stimulate immune responses, one person will be very different from the other,” Le Poole says. Even in animal models, you may think they’re genetically the same, but one will develop vitiligo and one will not. So there must be something environmental, as well.”

Fisher, of Harvard, thinks that, somehow, melanoma may be changing immune cells. “These immune drugs, the immune checkpoint inhibitors, are given to lots of cancer patients. But only the patients with melanoma sometimes develop vitiligo. It’s not like the drugs are injected into the melanoma; they’re systemic. So we suspect that somehow the melanoma is educating the immune systems. It’s not just neo-antigens [produced by the tumor], but also normal melanocyte proteins at work.”

Moving forward, researchers will try to detail the mechanisms that drive auto-immune and tumor cells in vitiligo. In cases where vitiligo signals a good response to immunotherapy, which cells are helping, how and how much? Also, do other immune biomarkers, such as the protein PD-L1, make cancer cells even more susceptible to treatment if the patient has vitiligo? How much does each kind of T cell contribute to the immune response against the cancer?

“If you find T cells in a patient, that doesn’t tell you which T cells are doing the job,” explains Turk. “You could find 20 kinds of T cells. Some recognize melanocytes; some don’t. Was it all 20 [that helped the patient respond to immunotherapy]? Or was it just three? Which ones? You can answer some of these questions in mice, but it’s much more difficult in humans.” In coming years, vitiligo and melanoma researchers say they will do their best to find those answers.

 

Why is the development of vitiligo a predictor of good response in patients taking immunotherapy for melanoma, and what can scientists learn from this? 


Connecting the Dots: Vitiligo Can Predict Immunotherapy Response in Melanoma

When it comes to the treatment of later-stage melanoma, there’s a lot of focus on the mutations that drive the disease.

BRAF, MEK, c-KIT — if one of these mutations is at the heart of your melanoma, you may be eligible to take a targeted drug specifically designed to squelch the effect of the mutation. It’s a strategy that has stirred excitement in recent years for its ability to prolong progression-free and/ or overall survival in some eligible patients.

But what if you don’t have any mutations that can be treated with approved targeted drugs? Will you find yourself taking chemotherapy, instead, which may be less effective and cause more serious side effects?

There may be other options, says Michael Postow, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. While chemotherapy may be right for some patients, there are also a number of newer treatment options, including immunotherapies and even some targeted therapies, available on the market or in clinical trials for patients regardless of whether their tumors harbor any of the most common driver mutations.

Most often, targeted treatments and immunotherapies are given if a melanoma progresses or recurs after surgery, or if the cancer was advanced or non-operable when diagnosed. Stage 3 and 4 melanomas are the cases most likely to be treated with these types of drugs.

Since BRAF mutations are common in melanoma and are treatable with targeted drugs, patients with advanced disease are typically tested for this biomarker, and the information is used to guide them and their physicians in creating treatment plans, Postow says. Patients who test negative for BRAF

mutations will likely not be helped by drugs that target BRAF, but rather than losing hope about treatment, that simply means they should consider other options, he says.

Since there are many methods for fighting melanoma these days, Postow concludes, “it doesn’t always matter what your mutation status is.”

Driver mutations like those in BRAF are changes in genes that may support the development of melanoma, and researchers have discovered a number of them.

Most driver mutations are in oncogenes. Before they mutate, oncogenes are known as proto-oncogenes, and they help cells grow. In its normal state, such a gene switches on and off as necessary so that cells don’t grow out of control. When they mutate, or when there are too many copies of them, proto-oncogenes become oncogenes. They get stuck in the “on” position, which can cause cells to grow out of control and lead to the development of cancerous cells. Mutations in the oncogenes BRAF (present in 37 to 50 percent of melanomas), NRAS (13 to 25 percent), MEK (6 to 7 percent), KIT (2 to 8 percent), CTTNB1 (2 to 4 percent), GNA11 (1 percent) and GNAQ (1 percent) may drive melanoma.

Mutations in the tumor suppressor gene NF1 may drive about 12 percent of melanomas. Tumor suppressor genes slow down cell production, correct DNA mistakes and tell cells when to die. All of these processes can prevent cancer. Mutations in these genes can cause them to get stuck in the “off” position, which can allow cancer to develop more freely.

Drugs that target mutations in BRAF, MEK and KIT have been approved by the U.S. Food and Drug Administration for the treatment of melanoma, and other common driver mutations, such as NRAS and NF1, are being studied and may have approved targeted treatments soon.

Of course, there are side effects associated with these drugs. For example, when Mekinist (trametinib), a MEK inhibitor, and Tafinlar (dabrafenib), a BRAF inhibitor, are given together, they can cause fever, fatigue, rash, nausea, diarrhea, swelling of the hands and feet, cough, headache and joint pain.

But what does all this mean for patients who don’t have any of these mutations?

When a patient doesn’t have mutations in three of the major known driver genes in melanoma, doctors might call that triple wild-type, triple-negative or pan-negative disease. A wild-type gene is one that doesn’t have mutations. There is some debate as to which three genes, when normal, constitute triple wild-type melanoma, but often this refers to melanomas without mutations in BRAF, KIT or NRAS. Alternatively, it can refer to wild-type BRAF, NRAS and NF1.

Regardless of how you define triple wild-type melanoma, patients who fit into the category may still eventually find themselves on a road toward targeted therapy.

“Most patients who are triple wild-type may have other drivers that we’re just not testing for routinely,” Postow says. Identifying them and developing medications that effectively target them could give these patients more options, and researchers are pursuing that avenue now.

A handful of clinical trials are exploring Akt-inhibiting drugs for Akt-mutated but BRAF and NRAS wild-type melanomas. ALK mutation may also be a driver of melanoma, and clinical trials are exploring inhibition of the Akt protein in BRAF and NRAS wild-type melanomas.

Another experimental therapy may target melanomas driven by fusion proteins. Most genes tell cells which proteins to make. When two or more genes join and produce a protein, it’s called a fusion protein. Some fusion proteins, which occur in 4 to 8 percent of melanomas that lack BRAF, NRAS and KIT mutations, could drive melanoma growth. According to early studies, melanomas driven by these proteins might respond to experimental treatment with Nexavar (sorafenib), a targeted drug known as a kinase inhibitor which is approved to treat certain kidney and liver cancers. Fusion protein-driven melanomas may also respond to the MEK inhibitor Mekinist. The MEK gene is closely related to the BRAF gene, and MEK inhibitors are often used in combination with BRAF inhibitors to bolster their effects against melanoma.

“We have lots of potential targets,” says Ryan Sullivan, an oncologist at Massachusetts General Hospital. “It’s probably a good idea to have your tumor genotyped more completely than just looking at BRAF, NRAS and KIT. If you have an actionable mutation, it can be a transformative therapy.”

Cancer cells, by their nature, can escape the immune system’s typical disease-fighting mechanisms. Immunotherapy drugs trigger the immune system to recognize and better fight these stealthy cancer cells. Whether someone benefits from this type of drug is not necessarily related to mutational status.

BRAF mutations and who go on immunotherapy tend to have the same response rate of progression-free survival, and probably overall survival, as patients who don’t have a BRAF mutation,” Sullivan says. “That’s true for ipilimumab (Yervoy), high-dose interleukin-2, combination ipilimumab and nivolumab (Opdivo), and it’s probably true for single-agent anti-PD-1 antibodies.”

PD-1 inhibitors, which include Keytruda (pembrolizumab) and Opdivo, block a protein on the surface of immune cells, called PD-1, that acts as a checkpoint that prevents the immune system from attacking cancer cells that express a molecule called PD-L1. PD-L1 latches onto PD-1 proteins on the surface of immune cells, and this allows the cancer to slip through the gates of the immune system. When PD-1 is blocked, the immune cells are able to recognize cancer cells as a threat and attack them. “Certainly, PD-L1 expression can happen in the triple wild-type, no matter how you define it,” Sullivan says.

Desmoplastic melanoma, for example, doesn’t typically have any of the major driver mutations, such as BRAF, NRAS or KIT. “It tends to arise from sun-damaged skin, so it has an enormous amount of mutations and responds pretty well to PD-1 therapy,” Sullivan says.

Even people whose tumors don’t appear to express PD-L1 could benefit from PD-1 inhibitors, Sullivan adds. A tumor might express such low levels of PD-L1 that it tests negative, but the cancer could still respond to PD-1 blockers. “And PD-L1 is inducible, so a negative isn’t necessarily still a negative and a positive isn’t necessarily still a positive several months later.”

Yervoy blocks another protein on the surface of T-cells, CTLA-4, and outcomes with the drug are not affected by whether a patient’s cancer expresses a BRAF mutation, Postow points out.

Data are mixed as to whether someone with an NRAS mutation might have a better response to immunotherapy. Data that Sullivan and his colleagues collected on 229 patients showed that those with NRAS mutations were more likely to benefit from immunotherapy. But more recent studies, he says, have contradicted that finding.

Side effects of PD-1 inhibitors can include cough, fatigue, nausea, skin rash, itching, diarrhea and joint pain. CTLA-4 inhibitors can cause side effects including diarrhea, fatigue, itching and rash.

Experimental cell therapies serve as an immune system redesign.

This approach first causes lymphodepletion with the chemotherapies cyclophosphamide and fludarabine, and then infuses the immune system with T cells that are custom-made to recognize and fight melanoma. Melanoma tumors already contain these types of T cells, known as tumor-infiltrating lymphocytes (TIL), but typically in numbers too small to fight the cancer. When a tumor is removed, TILs can be extracted from the tumor tissue and grown in a lab, then injected back into the body of the patient. When the new, larger number of T cells are injected, it is as if the patient is getting a new immune system. Some studies show that 40 to 70 percent of people treated with lyphodepletion followed by adoptive cell transfer respond to it. About 40 percent have a long-lasting, potentially curative response.

Side effects can be expected with this approach because it involves chemotherapy, and because the immunotherapy IL-2 is injected into patients along with the laboratory-bred T cells. Side effects common to both regimens can include nausea and vomiting, diarrhea, drops in blood counts that can lead to infection or bruising, and fatigue.

Chemotherapy can also spark mouth sores and hair loss, and IL-2 can bring fever or flu-like symptoms, rash and swelling of the extremities.

Researchers are currently recruiting patients, regardless of mutational status, for clinical trials of adoptive cell transfer in combination with other drugs.

The bottom line is that, while people with BRAF and KIT mutations are candidates for certain medications that others are not, immunotherapy outcomes are generally not drawn along the lines of gene mutations.

“At the end of the day,” Sullivan says, “you’re going to recommend some sort of immunotherapy and, if the patient is healthy, combination therapy or maybe treatment as part of a PD-1 based clinical trial.”

“It’s not about BRAF-mutant or BRAF wild-type,” Postow adds. “It’s all just about patients.”

 

Triple wild-type melanoma may not respond to approved targeted drugs, but immunotherapy can be an excellent option. 


Wild Card: Treating Triple Wild-Type Melanoma

In less than two months last year, the FDA approved five new or expanded indications for drugs. As it stands now, the National Comprehensive Cancer Network (NCCN) has identified seven single or combination therapies for first-line treatment of metastatic or unresectable disease, including three checkpoint immunotherapy agents and four targeted therapies.

Notably, single-agent Yervoy (ipilimumab), the CTLA-4—targeting antibody that launched the checkpoint therapy era, is now considered a second-line choice for metastatic or unresectable disease in the NCCN recommendations. (High-dose, single-agent Yervoy is recommended in the adjuvant setting.) Another novel therapy, Imlygic (TVEC, or talimogene laherparepvec), is recommended as primary treatment for stage 3 in-transit disease and in certain unresectable disease settings.

Until recently, the choice of first-line therapy in the metastatic setting would have turned on whether the patient had a 

 gene mutation, a population that includes 37 percent to 50 percent of malignant melanomas, according to My Cancer Genome. Patients whose tumors harbor 

V600E or V600K mutation would most likely be recommended for therapy with a regimen including a targeted treatment known as a BRAF inhibitor.

Now, however, Opdivo (nivolumab) and Keytruda (pembrolizumab), both PD-1—targeting immunotherapies, are approved as first-line treatment for patients with metastatic disease even for those with 

Although this bounty of choices is good news for patients with melanoma, several key questions have emerged: Should immunotherapy or targeted agents be the first-line choice for metastatic melanoma? And, does it make a difference how these agents are sequenced?

Those questions were discussed in detail recently at the 12th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® that Physicians’ Education Resource (PER®) hosted in Miami Beach, Florida, on February 20, 2016.

Indeed, the issue was the focus of a Medical Crossfire session in which two of the world’s leading experts on melanoma therapy, Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center, and Jeffrey S. Weber, deputy director of NYU Langone’s Laura and Isaac Perlmutter Cancer Center, tackled the question in a debate-style format.

Despite making strong arguments for each viewpoint, both presenters and other leading researchers at the conference noted that questions about first-line systemic therapy for metastatic melanoma have not yet been fully resolved in clinical studies or by oncology experts.

The NCCN is in the process of updating its guidelines — even though they were last revised in November 2015 &mdash; and the Society for Immunotherapy of Cancer, which published the first consensus statement on the use of the emerging therapies in 2013, also is working on a new version.

Atkins, who helped pioneer the development of the immunotherapies interleukin and interferon in melanoma treatment starting more than 20 years ago, argued that immunotherapy is the better choice for first-line treatment because of several factors.

He said immunotherapy produces durable, treatment-free responses while patients must continue to take BRAF inhibitors, and that clinical trials have demonstrated the checkpoint-targeting agents work as well against 

-mutant tumors as they do against disease not driven by 

“I think immunotherapy accomplishes what the patients want, which is that it produces complete responses where you can stop the treatment and the response is maintained — so treatment-free survival,” Atkins said in an interview. “You don’t see that with the targeted therapies except in a rare patient population.”

As far as sequencing is concerned, Atkins said the use of immunotherapy followed by targeted therapy if needed offers the potential for “two shots on goal.” He cited a retrospective study that found that prior treatment with Yervoy did not negatively influence response to BRAF inhibition (which included single-agent and combination BRAF/ MEK regimens) but that outcomes with Yervoy following targeted therapy were poor.

Of 193 patients who had discontinued anti-BRAF therapy in that study, only 34 were able to go on to Yervoy treatment. Among these patients, the median progression-free survival (PFS) was 2.7 months and the median overall survival (OS) was five months. Those patients alive after one year went back on BRAF inhibitor therapy.

Moreover, Atkins said he believes “immunotherapy is now the better treatment.” He pointed to waterfall plots showing similar tumor shrinkage with combination BRAF/ MEK inhibition and Opdivo and more durable responses with immunotherapy agents. Updated data from a phase 1 study of Yervoy plus Opdivo combination therapy demonstrate that 68 percent of patients were alive after a median follow-up of 32.7 months.

“We know from immunotherapy that the majority if not all of the patients who are alive at three years are likely cured, and you just can’t say that with BRAF inhibitors,” said Atkins.

Further studies are needed to answer the sequencing question in patients with 

 mutations, Atkins indicated. He is serving as the principal investigator on a National Cancer Institute (NCI)—sponsored phase 3 trial that will evaluate upfront therapy with Tafinlar (dabrafenib)/Mekinist (trametinib) followed by Yervoy/Opdivo, compared with the immunotherapy combination followed by the targeted therapy tandem.

Recruitment for the trial, which aims to enroll approximately 300 people, had been temporarily suspended because of a pending shortage of Tafinlar/Mekinist research drug supply at the NCI, according to Atkins. At press time, the trial (NCT02224781) was listed as recruiting.

Although he argued in favor of first-line immuntherapy treatment during the Medical Crossfire, in an interview Atkins discussed some of the nuances in making frontline recommendations.

He said starting with immunotherapy might not be as critical in the setting of combination checkpoint agents as opposed to single-agent immunotherapy, particularly for patients who are symptomatic from their disease. In such instances, he said, starting the patient with targeted therapy to cytoreduce the tumor and then administering immunotherapy might be a better option.

Making the case for upfront targeted therapy for patients with 

 mutations was Weber, who has helped develop checkpoint agents and targeted therapy strategies in melanoma and who served as program co-chair for the PER meeting.

The FDA has now approved two combinations that employ a dual pathway inhibition strategy: the BRAF inhibitor dabrafenib plus the MEK inhibitor Mekinist, and Zelboraf (vemurafenib) and Cotellic (cobimetinib), which inhibit the same pathways, respectively. The agents are approved in the metastatic setting for patients with BRAF V600E or V600K mutations.

Weber said that OS data for the combination of Tafinlar and Mekinist are more mature than findings from the Opdivo/Yervoy studies. An analysis of pooled data from three combination Tafinlar/Mekinist clinical trials demonstrated a median OS of 25 months to 26 months, with 36 percent of the patients remaining alive after four years.

“The urban legend of no tail on the curve is not true,” said Weber. “It is not true that as soon as you stop you will progress and not true that all will progress. There will be a significant tail on that curve.”

Weber elaborated on these thoughts in an interview. “The ‘urban legend’ was that the BRAF and MEK inhibitors had a high response rate, but almost all of the patients would progress quickly, progression-free survival would be less than one year, and most patients would have to go on another therapy or would die of their disease,” he said.

“That’s not exactly true. There does appear to be a plateau in the curve at about 30 percent for the patients who receive dabrafenib and trametinib,” said Weber. “I am sure

it will be virtually identical for vemurafenib and cobimetinib, which have a very similar median survival and one-year survival track record as dabrafenib and trametinib.”

Weber said a further argument for first-line combination targeted therapy is that clinical trial findings indicate that patients with normal lactate dehydrogenase (LDH) levels and less than three disease sites achieved better OS outcomes than those with a heavier disease burden. He said the one-year and three-year OS rates for patients in this category were 90 percent and 70 percent, respectively, “which is outstanding by any criteria.”

By contrast, he said, an analysis of overall response rates among participants who received the combination of Opdivo and Yervoy in the CheckMate-067 trial indicated that LDH and sites of disease are “weak prognostic factors for checkpoint inhibition.”

“These findings suggest that oncologists probably want to intervene with BRAF and MEK drugs earlier rather than later,” Weber said in the interview. “The targeted therapy will not work as well if patients are receiving immunotherapy first, then they progress, have high LDH and high disease burden. The association of patients doing well with targeted therapy with low disease burden bodes well for starting with targeted therapy and using immunotherapy in the second-line setting.”

Additionally, preclinical work suggests BRAF/MEK induction therapy administered over several weeks to a month “alters the tumor microenvironment, making a ‘cold’ tumor ‘hot,’” thus supporting a targeted therapy approach in the first line. “This is actually quite important,” he said. “It doesn’t work the other way.”

Interviews with several of the other experts on the faculty at the PER conference illustrated other nuances associated with first-line therapy for patients with stage 4 disease that cannot be treated with curative intent through surgery.

Michael A. Postow, an assistant attending physician at Memorial Sloan Kettering Cancer Center who is among the most prominent researchers into checkpoint blockade strategies in melanoma treatment, said in an interview during the conference that he bases his recommendation on clinical factors.

 mutation has a lot of brain metastases or very symptomatic disease, I give that patient targeted therapy with BRAF and MEK inhibitors because we have more proven efficacy at this point about BRAF and MEK inhibitors in the brain than we do for immune therapy in the brain,” said Postow.

“Immune therapy can work in the brain, but we don’t have as much robust data for that as we do for the BRAF and MEK inhibitors. Also, the BRAF and MEK inhibitors have a very rapid onset of disease response,” he added. “But most patients, I try to give immune therapy to, if I can, as their first treatment, just because it has remarkable outcomes, and our hope is that long-term, those great outcomes will persist,” Postow said.

Tara C. Gangadhar, an assistant professor of medicine at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, said immunotherapy is often the first choice for frontline therapy at her center but not necessarily the combination of Opdivo plus Yervoy. Toxicities with the combine checkpoint agents are a concern, she indicated.

In the three-arm CheckMate-067 study, grade 3/4 adverse events (AEs) were reported in 55 percent of patients in the Opdivo/Yervoy group compared with 27.3 percent for Yervoy alone and 16.3 percent for Opdivo monotherapy. Diarrhea, colitis, increased lipase and increased ALT and AST levels (indicators of potential kidney and liver problems) were the most frequently reported grade 3/4 AEs.

“Patients with melanoma are so unique that the treatment plan has to be individualized,” said Gangadhar. “In some patients, we would choose this dual checkpoint blockade option. In all patients, we would consider whether there is a clinical trial option available in the first line that includes PD-1 blockade in combination with another agent that seems promising.” “Our preference is to use single-agent [immunotherapy] in the front line in the absence of randomized data showing an improved outcome with the combination compared with single- agent PD-1,” she added.

Although many questions regarding which approach is optimal remain unsettled, the cumulative upswing in outcomes for patients with melanoma is certain. “There are arguments for both sides,” Weber said in an interview. “But I do think all of these combinations are not only going to delay progression, but we are going to cure some of these patients.”

In the fast-moving world of melanoma treatment, new therapeutic options for patients with metastatic disease are emerging faster than oncology researchers can establish guidelines for their optimal clinical use. That is raising questions about which should be the firstline choice in metastatic melanoma &mdash; targeted drugs or immunotherapy &mdash; and how these drugs should be sequenced. 


The New Front Line in Melanoma: Immunotherapy OR Targeted Agents?

LAURA KENT took a combination of two immunotherapies in a clinical trial, and now has no evidence of her recurrent melanoma. - PHOTO BY MICHAEL CRABB

After Laura Kent learned that a mole on the back of her left arm was cancerous in May 2014, she endured three surgeries to remove it, along with several nearby lymph nodes. Through all of that, the cancer kept coming back. Kent’s tumor tested positive for one of the BRAF mutations that is now treatable with targeted anti-cancer drugs, but her doctors at Fox Chase Cancer Center in Philadelphia thought she might do even better on a treatment that would prompt her own immune system to eliminate the cancer.

So, under the care of medical oncologist Anthony Olszanski, in January 2015, Kent was entered into a trial of two immunotherapy treatments: Imlygic (talimogene laherparepvec), a genetically modified form of the herpes virus, and Keytruda (pembrolizumab), which targets the immune-suppressing protein PD-1. The Imlygic was injected directly into her melanoma lesion, and then, a few hours later, she received an infusion of Keytruda.

After three doses of the combination treatment, which Kent received every other week, her melanoma disappeared. “That was when I knew I would not die from this cancer,” says Kent, 39, who lives in Harrisburg, Pennsylvania.

Kent expected to keep taking Keytruda for a full year, but the drug caused her to develop joint pain, a possible consequence of this and other treatments that alter the immune system. But her oncologists couldn’t find any sign of her cancer anyway, so they took her off all treatments. Six months later, she is still cancer-free — and grateful she was able to get there without chemotherapy.

“If I had chemo, my quality of life would have been really bad,” she says. “And the cancer more than likely would have come back. The fact that [the combination] got rid of the cancer so quickly was just a godsend.”

Melanoma remains a fertile territory for the development of new, highly effective therapies — particularly drugs that stimulate the immune system to fight off the cancer. Imlygic, for instance, was approved by the U.S. Food and Drug Administration in October of 2015, and Keytruda was approved in September 2014 as a second-line drug and then in December 2015 for first-line use.

At the same time, researchers are discovering new mutations in melanoma and developing drugs to target them. Targeted treatments that have already been approved have improved the prognosis for patients who test positive for the BRAF mutations known as V600E and V600K, so now research teams all over the country have launched hundreds of clinical trials, testing not only new targeted treatments but cocktails of these drugs in combination with immunotherapies that might someday reverse the poor outcome for patients who would have run out of options just a few years ago.

Although responses to newer treatments still tend not to be permanent, there’s good cause for enthusiasm in this cancer type. “It’s very exciting times for melanoma,” says Anthony Olszanski, associate professor in the department of hematology/oncology at Fox Chase Cancer Center. “There’s good reason for patients to be in trials and good reason to have more hope for our patients.”

The Imlygic/Keytruda combination trial is generating excitement among oncologists because of the potential of these drugs, each approved as a single agent, to work together to capitalize on two different methods for activating the immune system. Imlygic is what’s known as an oncolytic virus: It has a natural ability to kill cancer cells, but it is also specially engineered to include a protein called granulocyte macrophage colony-stimulating factor (GM-CSF), which attracts immuneboosting cells to the tumor. Keytruda works differently, because it inhibits the PD-1 “checkpoint” that can be activated in some cancers, preventing the immune system from recognizing and attacking cancer cells.

With Imlygic, “the immune system may recognize the melanoma better, and then when [Keytruda] is given, it enhances the immune system’s effect,” Olszanski says. In an early trial including 16 patients with advanced, previously untreated melanoma, which released data in November 2015, 56 percent of participants responded, including two who experienced complete remissions. That bested the performance seen with either agent alone. And based on those results, the trial moved into phase 3 at more than 20 cancer centers, and continues to recruit patients.

Scientists continue to uncover new immune checkpoints that govern the development and growth of melanoma. One emerging target is indoleamine 2,3-dioxygenase (IDO1), an enzyme that allows tumors to stay under the radar of the immune system. Several drugs are being developed to inhibit IDO — an approach that may be even more promising in combination with other immunotherapies. For example, an IDO1 inhibitor from Incyte called epacadostat is set to enter a phase 3 trial in combination with Keytruda in 2016; the trial (NCT02752074) is not yet recruiting.

Among the first 19 patients with melanoma treated in a phase 1 trial of Keytruda plus epacadostat, 10 responded to the treatment, including three who saw their tumors completely disappear. The side effects were mild and similar to what’s commonly seen with Keytruda alone, most often a rash. The benefit was similar to what’s generally seen with an already approved combination treatment in melanoma — Yervoy (ipilimumab), which inhibits an immune checkpoint called CTLA-4, plus the PD-1 inhibitor Opdivo (nivolumab) &mdash; says Jason Luke, assistant professor of medicine at the University of Chicago and an investigator for the epacadostat/Keytruda trials. With Keytruda and epacadostat “there was no increase in side effects relative to [Keytruda] alone, so that’s exciting,” he says. “That could potentially become the new standard of care.”

no longer has evidence of metastases after

participating in a trial of an experimental

Susan Giorango had a melanoma on her cheek that had spread to her lungs and adrenal glands when she was accepted into an early trial of the epacadostat/Keytruda combination in 2014. An initial regimen of Yervoy had helped to shrink the tumors, but it wasn’t until she started the experimental combination that Giorango’s doctors told her they believed all of her metastases were gone.

During the trial, Giorango took two pills twice a day for a year. She remains on the regimen and returns to the University of Chicago every three months for blood tests and imaging scans. She doesn’t recall ever feeling sick from taking any of the treatments, she says, aside from developing a minor rash that could be easily controlled with a cream.

“I’m living the good life,” says Giorango, 63, a widow with three children and five grandchildren. Without the new treatment choices, she says, “I was told I had 12 to 18 months to live. This opportunity was wonderful.”

Another experimental therapy is derived from patients’ own tumor cells. Called LN-144, it is now entering a phase 2 trial that is still recruiting (NCT02360579). LN-144 is based on a technology called “adoptive cell therapy,” which was developed at the National Cancer Institute. The therapy combines tumor infiltrating lymphocytes — white blood cells that occur naturally inside tumors and work to kill cancer &mdash; with interleukin-2 (IL-2), an immuneboosting drug.

In data presented last September from a trial of 101 patients with advanced metastatic melanoma, 54 percent of participants responded positively to the treatment, including 24 who had complete remissions. Of those, all but one remained disease-free for between 30 and 47 months. “That’s promising, and I think we’ll see a lot of activity on this front in the next two or three years,” says Jeffrey Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University and co-director of its melanoma program. Weber serves on the scientific advisory board for Lion Biotechnologies, which is developing the treatment.

The first immune checkpoints that were discovered and targeted, PD-1 and CTLA-4, remain of interest to researchers, particularly in what’s called the “adjuvant” setting, where patients have been successfully treated with surgery and the main goal is to prevent a recurrence. One such trial is comparing Yervoy to Keytruda in patients who had advanced melanoma lesions that were removed.

Yervoy has already been shown to help prevent recurrence. A study published last year in patients who had undergone surgery reported that median survival without recurrence was 26 months in patients on Yervoy, versus 17 months for those taking a placebo. Overall, the drug reduced the risk of recurrence by 25 percent. Based on those results, in October 2015, the U.S. Food & Drug Administration approved the use of Yervoy at a dose of 10 mg/kg for patients with stage 3 melanoma who have undergone surgery to remove the cancer and nearby lymph nodes and have been rendered free of disease.

Fatigue, nausea, itching, diarrhea and rash are some of the most common side effects of both Yervoy and Keytruda. Also common with Keytruda are cough, decreased appetite, constipation and joint pain.

Some immune checkpoints don’t interfere with the immune response but rather promote it by boosting the activity of cancer-killing T cells in the immune system. Three of the most promising of those stimulatory checkpoints are glucocorticoid-induced tumor necrosis factor receptor (GITR), CD137 and OX40 (also known as CD134). Researchers have developed “agonists,” or drugs that boost the activity of those checkpoints, and they are now in early-stage trials. “This might work well with checkpoint inhibition,” Weber explains. Inhibitors “take the brakes off, whereas OX40 and these other molecules promote the activity. If you cut the brakes and hit the gas, the car might go a little faster than if you just cut the brakes.”

Even though immunotherapy has moved to the forefront of melanoma care, researchers are still discovering mutations and coming up with new ways to shrink tumors by exploiting them. For example, several drugs are being investigated that target mutations in a gene called NRAS. These include drugs that inhibit MEK (mitogen-activated protein kinase), an enzyme that becomes overactive and that promotes cell growth and survival.

One such treatment, binimetinib, has been turning in impressive results in a phase 3 trial. In December 2015, researchers reported that the drug nearly doubled progression-free survival to 2.8 months in patients with advanced NRAS-mutated melanoma when compared to the chemotherapy drug dacarbazine. Inhibiting MEK might also be effective in patients with a mutation called NF1. Side effects could include rash, swelling and, in rare cases, injury or stress to muscle or the heart or brain; an elevated level of myelocytes in the blood; or eye changes.

The standard of care for patients with BRAF-positive melanoma is to combine a BRAF inhibitor with a MEK inhibitor, such as the already approved Mekinist (trametinib), which is given with Tafinlar (dabrafenib), Luke says. But other subgroups of patients might benefit from different combinations, including patients with NRAS mutations. For example, CDK4 is another target in NRAS-mutant melanomas that may be important. Early trials combining MEK inhibitors with CDK4 inhibitors have been promising. “It improved the response rate from about 20 percent to between 35 percent and 50 percent,” Luke says. That said, the side effects can be severe, ranging from abdominal pain to fatigue, raising questions about whether using such combinations will be practical in the clinic.

Another subset of the disease called uveal melanoma, which occurs in the eyes, may benefit from inhibition of MEK. A mid-stage trial is underway investigating Mekinist in patients with this type of melanoma that is metastatic, both as a solo therapy and in combination with an experimental compound that inhibits a protein called Akt. Inhibiting c-MET, another enzyme that promotes cell growth and metastasis, may also prove useful in this patient population. A phase 2 trial of Xalkori (crizotinib), a c-MET inhibitor, in patients with uveal melanoma who face a high risk of recurrence (NCT02223819) is now recruiting. And early data suggests that yet another mutation, called c-KIT, may be important in melanoma, including the uveal form. Several drugs are already approved to target this mutation, including Gleevec (imatinib) and Sutent (sunitinib), and several trials are underway in uveal melanoma.

The most common side effects of Xalkori include upper respiratory infection, nausea, dizziness, diarrhea, fatigue and rash. Sutent can also cause fatigue, diarrhea and nausea, as well as heartburn, changes to taste and hypertension. Many oncologists who treat melanoma believe the future is pointing to combinations of three different drugs. While mutation-targeted therapies can work quickly and in a higher percentage of patients, immune therapies tend to give longer responses. So combining the two types of therapies, along with developing better tests to match the right tumor to the right drug or combinations, remains a high priority.

For example, one ongoing phase 1 study combines the BRAF inhibitor Zelboraf (vemurafenib), the MEK inhibitor Cotellic (cobimetinib) and the experimental immunotherapy atezolizumab, which is in the class of drugs called PD-L1 inhibitors; the trial, NCT01656642, is recruiting. A combination of Zelboraf and Cotellic was approved by the FDA based on a phase 3 trial that produced an overall response rate of 69.6 percent versus 50 percent for Zelboraf alone. Investigators involved in the triple-therapy study hope the addition of atezolizumab will boost the response rate even more without adding to the toxicities.

Another triple combination generating excitement in the melanoma community is a study of Keytruda with the BRAF inhibitor Taflinar (dabrafenib) and the MEK inhibitor Mekinist.

“There are many triple combinations that are being looked at,” Weber says. “They have the potential to be terrific.”

In clinical trials, melanoma remains a ripe discovery ground for the application and combination of immunotherapies and targeted drugs.


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