Mixed Melanoma Trial Results Point to Need for Tailored Studies

Effective melanoma therapies may be inching forward, with a number of the new class of potential therapeutics in the pipeline entering Phase III trials, and researchers presenting some of the first published data on other agents at this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

But with mixed results, some disappointing, some surprising, some researchers say clinicians and clinical trial designers must rethink development strategies, including patient selection, if some of the new class of biological therapeutics for melanoma are to make significant headway.

“The problem with melanoma is that, other than surgery, there really are no very good effective therapies. The chemotherapies that are out there are not curative but palliative treatments,” explains David Solit, MD, Elizabeth and Felix Rohatyn Chair and Assistant Attending Physician, Department of Medicine, Sloan-Kettering Cancer Center.

But medical science is progressing, says Dr. Solit, who spoke at the ASCO conference. “We actually know a lot of the genetic alterations that cause the cancer. In 2002 there was a mutation in a protein called BRAF that was identified, and the mutation is found in the tumor in 50% to 70% of patients with melanoma. Then there’s a protein called NRAS, which also gets mutated in 15% to 20% of melanoma patients. But when you have an NRAS mutation, you don’t have a BRAF mutation. In total, between 60% and 90% of patients have one of the two,” says Dr. Solit, who gave the presentation, “Genetic Predictors of RAF/MEK Dependence.”

But the news at ASCO was not all good for the new therapies.

Early Promise, Mixed Results

Some of the most important new strategies for treating advanced melanoma focus on the patient’s immune system.

“Two of the strategies use anti-CTLA 4 and anti-PD1 agents to take the brakes off the patient’s immune system. Both are receptors on a patient’s T-cells, which are part of the normal braking system, which is a good thing at most times, but not a good thing in regards to a cancer cell,” says Walter Urba, MD, PhD, Director of Cancer Research at the Earle A. Chiles Research Institute in Portland, Oregon.

“The other two strategies use antibodies 41BB or OX 40. At ASCO this year, we saw some late clinical trial results with the anti-CTLA 4 product, and the first published results with anti-41BB and anti-PD1,” says Dr. Urba, who also discussed very early results with his own institution’s investigational agent, OX 40.

A disappointing trial of a new potential therapeutic agent was a head-to-head trial of an agent called a MEK inhibitor, which was tested against temozolomide, a standard pre-existing chemotherapy for melanoma. There was no significant difference between the standard arm and the MEK inhibitor (AZD 6244 by Astra Zenaca), according to the trial results.

However, patient selection may be the problem. “Genetic differences are relevant, because the BRAF mutation found so often in melanoma patients, activates a protein called MEK. “If you have a RAF mutation, you may respond a lot better to a MEK inhibitor,” explains Dr. Solit, noting that in addition to the Astra Zenaca drug, another MEK inhibitor in research is a drug from Pfizer called PD 0325901. The Astra Zenaca drug, which encountered the disappointing result, is in Phase II trials, whereas the MEK inhibitor from Pfizer is only in Phase I.

“The problem with the Astra Zenaca trial is that they didn’t look for BRAF-mutated patients. It’s possible temozolomide is as good or better than AZD 6244 in unselected patients, but five of the six responders in the MEK inhibitor arm had BRAF mutations,” Dr. Solit says. “There is technology out there already to start looking for these mutations, and it has already become routine in lung cancer for other genes.”

There were some positive, surprising results presented as well, however. A Phase II trial of ipilimumab, an investigational immunomodulatory agent from Bristol Meyers Squibb, which is in late Phase III trials, was studied in a population of 115 patients in combination therapy with Budesonide, a currently existing therapy. “Our primary endpoint was to see whether in a randomized trial we could reduce the amount of diarrhea that occurs as a side effect of the Budesonide, and our primary endpoint was not successful, but ironically, the clinical results were outstanding. Our median survivals were over a year,” says Jeffrey Weber, MD, PhD, Director of the Donald A Adam Comprehensive Melanoma Research Center and Professor of Oncologic Sciences at the University of South Florida.

Updated survival data of three Phase 2 studies of ipilimumab in patients with metastatic melanoma (Stage III or IV) who had previously been treated were presented at the European Society for Medical Oncology in Stockholm. Study results show that approximately half of patients who received ipilimumab (10 mg/kg) remained alive beyond 1 year. The results are based on follow-up of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab (induction and maintenance) and show a consistent 1-year survival rate between 47% and 51%.

Combination Therapies of the Future, Today

Another promising strategy offering hope to advanced melanoma patients is to stimulate the patient’s immune system, by mimicking signal’s sent naturally by the body.

“We have learned from studying patients with melanoma just how powerful the immune system can be, but we need to supplement the response, and free it from some of its limitations,” says Robert H. Vonderheide, MD, Assistant Professor of Medicine at Abramson Cancer Center at the University of Pennsylvania.

The immune response in melanoma patients can be so pronounced that in rare cases, tumors even shrink in the face of it, says Dr. Vonderheide.

Dr. Urba agreed. “The immune response in melanoma is different from other cancers,” he explains. “One of the thoughts is that melanoma tumors are more immunogenic. Sometimes the response occurs after disease progression. In a couple percent of every patient population, the patient comes in and looks for all the world like they’re having tumor progression, and they end up having the tumor go away in response. The rationale is, that maybe it takes time for an immune response to build up and eliminate tumor cells following these investigational therapies,” he says, noting that these delayed responses can occur 8 or 12 weeks following therapy.

To attempt to take advantage of melanoma’s unique immunogenicity, Pfizer has developed an investigational agent that acts on an immune receptor called CD40, according to Dr. Vonderheide. “This is an antibody that binds to CD40 and mimics the signal sent to activate the immune system.”

The CD40 agonist has been tested by itself and in conjunction with standard chemotherapy drugs carboplatin and paclitaxel. The first clinical trial with the agent started about 4 years ago, and was reported 2 years ago at ASCO. Though the drug is only in Phase I trials, “taking it to Phase II is definitely warranted,” notes Dr. Vonderheide. “In the second study, we saw clinical activity: one patient has regressed, and remained in remission for years.”

In another study, the CD40 agonist will be given, along with chemotherapy, every 3 weeks, and the trial is enrolling as many as 30 patients, according to Dr. Vonderheide.

With some of the therapies, lack of experience in testing them may lead to unpredictable future results; in others, the sheer longevity of their period in trials can lead to skepticism.

“Anti-CTLA 4, an anti-inhibitory drug, has probably been in clinical trials for about 7 years, whereas anti-PD1, which is also an anti-inhibitory drug, has probably not been in trials for much more than a year,” says Dr. Urba, noting that the 41BB has also been in trials for 2 years.

For some drugs, clinical trials have enrolled hundreds of patients over the years, while other novel agents have only been tested in a few dozen humans. “The delayed response phenomenon, for example, has not been seen with other agents besides ipilimumab and tremilimumab, but with the other agents, the number of patients who have been treated is so small I’m not sure if we would have seen it,” he adds.

Still, the novel agents, whether young or old, often offer the only hope for advanced melanoma patients to hold onto.

“Nonetheless, it’s probably going to be a long series of trials to figure out which are the patients who are going to benefit. It’s a targeted therapy, and it doesn’t work for everybody. But we have insight into who it would work in, and we need to incorporate that information into our clinical trial design,” Dr. Solit says.

Vitiligo, Sometimes a Warning Sign, May Someday Provide a Cure for Melanoma

Vitiligo, a skin condition that affects individuals of every age and ethnic group, often brings patients in to see a dermatologist. While this condition is not entirely benign, ongoing research is indicating that it may hold clues to potential future therapies for a far more deadly disease: melanoma.

The research is investigating whether vitiligo is actually an auto-immune disease that may be related to other immunological conditions. Vitiligo, which causes white patches on the skin in about 1 million Americans, may hold the secret to using the same immunological activity to fight cancer.

“In one of our projects, we are working to isolate T-cells from the skin of patients who have active vitiligo,” says Caroline Le Poole, PhD, Associate Professor of Pathology, Microbiology and Immunology at the Oncology Institute of Loyola University Chicago Stritch School of Medicine.

“The T-cells are there to recognize the pigment cells, and they do so quite efficiently,” says Dr. Le Poole, who recently received a $1.7 million grant to study the disease. In vitiligo, the body’s immune system usually acts abnormally, attacking and destroying healthy melanocytes or skin pigment cells, she explains. “But those same T-cells, which act abnormally in vitiligo patients, are exactly the ones we would love to have if you had melanoma. The T-cells of melanoma patients may be less efficient compared to those of vitiligo patients at targeting the tumor.”

“If you have vitiligo, you most likely have a lesser chance of developing melanoma, because a vitiligo patient would be somewhat protected from developing melanoma. However, if you have melanoma you have a likelier chance of developing vitiligo. In fact, the appearance of vitiligo in a melanoma patient is a positive prognostic indicator, because if you have vitiligo, you will have a better immune response to melanoma,” she says.

Vitiligo: The Nature of a Common Skin Condition

While vitiligo affects every variety of people, the condition is more noticeable in dark-skinned people. It is thought that some form of stress initiates the condition, which can be progressive.

“There are different forms of vitiligo, generally recognized based on the distribution pattern of the white lesions. The forms include focal vitiligo and generalized vitiligo, which is characterized by the strikingly symmetrical distribution of the vitiligo lesions,” she says. In generalized vitiligo, the patient’s T-cells would choose to activate on both sides of the patient’s body, because of similar conditions there.

Other forms include segmental vitiligo, the development of which is quicker and shorter. “The lesions in segmental vitiligo are much harder to treat,” she says. “One could also distinguish a form of the condition we call occupational vitiligo, encountered in patients who have been exposed in the workplace to certain chemicals, which can put you over the hurdle, and bring in the first spots.”

Vitiligo patients sometimes present to Loyola University Medical Center, according to Dr. Anthony Peterson, MD, Interim Division Director of Dermatology at the institution. He sometimes refers patients with vitiligo to participate in Dr. Le Poole’s study.

“Ninety percent of patients who come in are concerned about their cosmetic appearance,” says Dr. Peterson. Other patients express misplaced concerns that they may have cancer, or that the disease may be contagious, he adds. And, vitiligo does bear a certain relationship to melanoma, Dr. Peterson says. “The patient may come in because they develop a halo effect where the skin around a mole has turned white. The body was developing an immune response to an atypical mole.”

While the physician should screen the patient for melanoma, not all such patients have skin cancer, Dr. Peterson notes, explaining that 20% of patients with halo nevi have an association with melanoma or atypical moles.

In addition, melanoma patients who experience the rare spontaneous remission sometimes have vitiligo symptoms. Alternatively, vitiligo can occur in patients who have received experimental melanoma vaccines.

Health Concerns

Though most patients initially present with vitiligo for cosmetic concerns, the immunological condition, which is sometimes thought to be associated with vitiligo, may have other, more serious effects.

“In many cases, if a patient has vitiligo, the patient may have other autoimmune diseases as well. For autoimmune thyroiditis, the prevalence among vitiligo patients is between 20% and 25%,” Dr. Le Poole says. “The antibody attacks one’s thyroid cells, and you can have goiter, or a hyperactive or hypoactive thyroid. You can have a slower or faster metabolism, and either gain or lose weight,” says Dr. Le Poole, who adds that other autoimmune conditions associated with vitiligo include diabetes, alopecia, Addison’s disease and sarcoidosis.

“The biggest risk from vitiligo is related to sun exposure,” says Dr. Peterson. “The patches do not tan, and are more susceptible to burns, as well as to skin cancer over time, because they have no photo-protection; they have no pigment that would normally turn brown.”

On the other hand, cosmetic treatments for vitiligo sometimes also carry their own risk for melanoma. “Vitiligo is a progressive condition, and if they have 50% depigmentation, they might choose to take out the rest by chemical treatment. This gives them an even skin tone,” explains Dr. Le Poole, adding that she is also studying whether monobenzone (Benoquin), the FDA-approved drug for depigmentation, could also be useful in treating melanoma.

“Most commonly we start off with the least invasive treatment, such as topical steroids or immuno-modulators,” says Dr. Peterson. “However, if we are treating a large area, using a topical cream is not always feasible, and we may expose the skin to controlled doses of narrow-band ultra-violet light,” he says. “Ultra violet light can sometimes cause secondary cancers over time.”

Treating Melanoma

Developing a new treatment for melanoma is of great importance, because of the current lack of effective chemotherapies for metastatic melanoma.

“Most melanomas we have to excise surgically. Beyond that, there is interferon, which you can use for up to 1 year, but it is poorly tolerated,” says Dr. Peterson. “The best chance of a cure is getting it early, before it gets to the lymph nodes. But if the melanoma is 1 millimeter in depth, 20% of the time you already have it in a lymph node. And with lymph node involvement, there is a 30% survival rate at 15 years,” he adds.

Accordingly, Dr. Le Poole and her colleagues are studying whether a better understanding of vitiligo can result in new treatments for melanoma.

In one study, which has been ongoing for 3 years, Dr. Le Poole is collaborating with Michael Nishimura, PhD, a Professor in the Department of Surgery at the Medical University of South Carolina. In that study, the scientists are comparing cell samples from 12 melanoma patients to samples from 12 vitiligo patients.

In another study, Dr. Le Poole is investigating only patients with vitiligo, in collaboration with Dr. Jose Guevara-Patino at the University of Chicago. That is the study that recently received the grant funding for 5 years, according to Dr. Le Poole. The idea is to stop stress from igniting an immune response to pigment cells, and halt the depigmentation process.

While the treatments have not yet been tested in human melanoma patients, Dr. Nishimura, who is collaborating with Dr. Le Poole, says that he has had success in a mouse model. “We have taken a transgenic mouse with a human gene that spontaneously develops vitiligo. We can put human melanoma cells in an immune-incompetent mouse, and let them grow until you can feel a tumor. We then transfer the transgenic T-cells into them, and we find that they then can clear the tumor,” says Dr. Nishimura.

In the experiment, results of which have not yet been published, Dr. Nishimura has been able to cure 90% of about a dozen mice with both human and mouse melanoma. The transgenic mouse, with a human T-cell receptor, was created by his colleague, Shikhar Mehrotra, PhD, Assistant Professor in the Department of Aurgery at the Medical University of South Carolina.

Vaccine Trials Advance Melanoma Knowledge and Techniques

Two other 2008 trials in metastatic melanoma made contributions to medical science in this field.

Peptide Vaccine Shows Efficacy

One trial delivered somewhat promising results concerning an experimental melanoma therapy, and may have offered insights into treatment for experienced melanoma oncologists.

In a 5-year trial involving 131 metastatic melanoma patients, scientists administered Interleuken-II with an experimental vaccine in three different arms.

Between 1998 and 2003, all patients received the same two treatments, IL-II and GP 100-2009 M, albeit in different combinations. The first cohort received the vaccine, an experimental therapy available from the National Institute of Health, for 6 weeks prior to the IL-II; the second arm received the vaccine and the IL-II simultaneously, and the third arm received the two treatments simultaneously, but received more IL-II than the other cohorts.

“The third group received more intensive IL-II; they got IL-2 every 3 weeks throughout the treatment, whereas it is normally given on weeks 1 and 3 and then no further for another 8 to 9 weeks,” explains Jeffrey A. Sosman, MD, Professor of Medicine and Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center. Dr. Sosman coauthored the paper, which appeared in the May 2008 issue of the Journal of Clinical Oncology.

The study, which did not have a control arm offering IL-II alone, was a follow-up of a 1998 study by Rosenberg in Nature Medicine. While the Rosenberg study was promising, and found a 42% response rate in patients who received both treatments, the more recent study delivered somewhat disappointing results, Dr. Sosman says.

“The standard response rate with IL-II is about 15%,” he says. “We did not find results as good as were found in the prior study, but our first arm was not bad.” Forty-two patients, or about 23.8%, responded to the treatment. In arm two, 12.5% responded, and in arm three, 12.8% responded, according to the study results.

“This was a very small vaccine we studied, which has been around for over 10 years,” says Dr. Sosman, noting that the vaccine is made from nine amino acids, which induce an immune response. “GP-100 uses a small peptide that binds to the cells in your body and thereby triggers your own T-lymphocytes to kill your tumor, which also expresses that peptide,” he adds.

While Interleuken-II is a standard treatment for metastatic melanoma, with somewhere between 5% and 10% of patients responding, it is not certain what therapeutic advantage the experimental vaccine adds.

Healthy Patients May Qualify for more Doses of Interleuken

Another unique aspect of the GP-100 study was the third patient arm, in which patients received more IL-II. “The median amount in the third arm was about 50 doses of IL-II per patient. The patients got 2 weeks in between treatments, but most could not get all four treatments,” according to Dr. Sosman.

“IL-II is associated with significant toxicity, and it is not a treatment for everybody, nor is it a treatment that should be used by physicians who don’t use it a lot,” he says, noting that Interleuken causes a number of side effects, such as vascular leak syndrome, in which patients drop their blood pressure, decrease their urine output, and the kidney function worsens. “It can also cause blood or fluid to pool outside of the blood vessels, and it causes fluid in the lungs, belly and legs, which is part of why their blood pressure drops,” he explains.

“I don’t think people could tolerate much more frequent dosing. For one thing, in the third arm, there were 2 weeks in-between treatments instead of one, which made it a little more tolerable. But we had trouble in that some patients did not come in for all their treatments, because they just couldn’t take it. So you need to pick patients very carefully, to make sure their heart and lungs and kidney function work well,” Dr. Sosman says.

Designer Melanoma Vaccine Murine Trial Success

A molecule using a double-strategy against melanoma metastases to the lung in mice showed promise, according to a recent paper published in the November issue of Nature Medicine.

The first strategy used by the team that developed the molecule is to attach a segment of short interfering RNA, which resembles melanoma, to the molecule, thereby alerting the body’s immune system to the presence of melanoma. The RNA targets the immuno-receptor RIG/I, a ligand described in Science in 2006. The second strategy is to silence the BCL-2 gene.

“There are a lot of different genes involved in melanoma, but one gene that is over-expressed is BCL-2, which protects cells against apoptosis. We down-regulate this gene so the cell can die, and at the same time, with the other prong, which creates a TH-response, we enhance the immune response, which makes the cell die,” says Professor Gunther Hartmann , MD, Director of the Institute of Clinical Chemistry and Pharmacology at University Hospital in Bonn, who co-authored the paper.

The paper reported the trial of the experimental vaccine in mice. “The mice develop lung metastases, and we are able to reduce the development of the metastases. Some mice are cured, while in others we reduce the tumor load,” Hartmann said. “For the first time, this therapy combines RNA interference with immune recognition of specific types of viruses,” Dr. Hartmann says.