Taking Melanoma by Storm

Jen Sotham was living in South Korea in 2010 when she found a “funky-looking” mole on her inner knee. She had the mole removed, and was given a diagnosis of melanoma. Thinking her brush with cancer was behind her, she didn’t think too much more about it until 2013. That’s when she noticed a lump in her groin, on the same side as her mole.

“The lump turned out to be a malignant lymph node,” Sotham, 41, recalls. “This time, I had six weeks of targeted radiation.”

But it wasn’t enough. A year later, scans revealed that her melanoma had metastasized to her lungs and breast. Sotham had stage 4 melanoma. At that point, she very abruptly left her “rich and rewarding life and job as a university professor” and went home to New York to be treated.

As it turned out, research was on her side. In addition to having the BRAF gene mutation in her tumor, which increased her treatment options, Sotham did not have any brain metastases. The latter made her eligible for the expanded clinical access study of the immunotherapy combination of Opdivo (nivolumab) and Yervoy (ipilimumab).

Three months after starting treatment, Sotham found out she’d had a complete response. And the day before the combination received accelerated approval from the U.S. Food and Drug Administration (FDA) on Oct. 1, Sotham received more good news. After her third set of scans, she continued to show few signs of cancer. Her lung tumors had shrunk considerably, and her other tumors were gone.

Sotham was able to benefit from the first immunotherapy combination for cancer patients to reach this point in the approval process. An application for full FDA approval is pending, with a decision expected in January.

Immunotherapy Taking Melanoma by Storm

The advance represents yet another chapter in a story of scientific progress that has exploded in the past few years. Since 2011, eight new drugs have been approved for the treatment of melanoma, and more advances have come in the form of several approved combinations of newer drugs.The approval of the combination that helped Sotham is based on findings from the phase 2 CheckMate-069 trial, which showed that combining Opdivo with Yervoy as a front-line treatment for melanoma was much more effective than giving Yervoy alone. The combination resulted in a 60 percent response rate compared with 11 percent for Yervoy alone.

The two drugs work through complementary mechanisms. Yervoy energizes T cells, specialized white blood cells with the ability to recognize and destroy cancer cells, by turning off a switch (CTLA-4) in the T cell that would otherwise inhibit this power. Similarly, Opdivo focuses on T cells, but it turns off a different molecular switch (PD-1) to release their power to seek and destroy cancer cells. These switches are known as “checkpoints” as they reign in the immune system to avoid hyperactivity; inhibiting them allows the immune system to recognize cancer cells more easily.

In addition to working as a combination, both Yervoy and Opdivo are effective alone. To date, clinical trials suggest that Yervoy works in 10 to 20 percent of patients with unresectable or metastatic melanoma. The FDA also recently approved it for use after surgery in patients with stage 3 melanoma who face a high risk of recurrence. That approval was based on results from the phase 3 EORTC 18071 trial, in which, at a median follow-up of 2.74 years, the median recurrence-free survival of participants was 26.1 months with Yervoy versus 17.1 months with placebo.

As for Opdivo, early studies suggest that PD-1 inhibitors like this one may be twice as effective as Yervoy. In December 2014, the FDA approved Opdivo for use in patients with melanoma who had previously been treated with Yervoy. A few months later, the FDA awarded Opdivo priority, or expedited, review as frontline therapy for patients with advanced melanoma who have not yet been treated. The FDA expected to make a decision by Nov. 27, after seeing new data that may support a frontline approval regardless of whether patients have a BRAF mutation.

Other PD-1 inhibitors are also moving rapidly through the pipeline. In September 2014, through the FDA’s expedited approval process, Keytruda (pembrolizumab) was approved for patients with advanced or unresectable melanoma following progression on prior therapies; in a trial, it improved progression-free survival in comparison with chemotherapy. In August, the FDA granted a priority review of the drug as a frontline treatment for those with advanced melanoma, based on findings from the phase 3 KEYNOTE-006 study, which showed that Keytruda bested Yervoy in that setting. A decision is expected on Dec. 19, 2015.

As these drugs stimulate the immune system, they can cause autoimmunity — typically manifest as inflammation in different parts of the body. The most common side effect of Yervoy and PD-1 inhibitors is rash. Less common but more dangerous is colitis, an inflammation of the colon’s lining that can cause abdominal cramps and diarrhea. Hormonal problems, hepatitis and liver or lung inflammation may also occur. Significant side effects occur less frequently with PD-1 inhibitors than with Yervoy.

It’s long been hoped that a vaccine might be the ultimate immunotherapy and provide a cure for melanoma, but numerous efforts have tried and failed. Yet that trend may be changing. On Oct. 27, the FDA approved Imlygic (T-VEC), the first vaccine for patients with advanced melanoma, which is injected directly into lesions. Engineered from a herpes virus, the vaccine is for patients who have undergone surgery for melanoma and then develop recurrences that cannot be surgically removed.

Targeted Therapy Remains Important

In a phase 3 OPTiM trial, patients took either Imlygic or the immunotherapy Sargramostim (granulocyte macrophage colony-stimulating factor). With Imlygic, patients experienced a significant improvement in durable response rates, and also a 4.4-month boost in overall survival, although this was not considered statistically significant. The most frequently occurring allgrade side effects for patients receiving Imlygic included fatigue, chills, fever, nausea, flu-like illness and injection-site pain. There were more serious side effects in the Imlygic arm.Another treatment approach is to identify weak spots in cancer cells, complicated but flawed biochemical engines, and target those areas with drugs. Targeted therapy takes advantage of years of intensive research into how different cancers operate.

Even as gains have been made, research is continuing. For instance, one mutation that occurs in melanoma affects the c-KIT gene. Gleevec (imatinib) and Tasigna (nilotinib) block c-KIT’s activity and have been approved for use in other cancers; trials are now underway in melanoma.

Further along is targeted therapy for patients with the most common melanoma target, the BRAF gene. First identified as an oncogene in 2002, BRAF helps direct cell growth in healthy cells. But in about half of melanomas, a mutation sets BRAF on high, amplifying and ultimately distorting growth signals. Since then, researchers have been developing drugs to hit that target.

In August of 2011, just five months after Yervoy cleared the FDA, Zelboraf (vemurafenib) was approved, along with a genetic test to identify the most common BRAF mutation. Another BRAF inhibitor, Tafinlar (dabrafenib), debuted in 2013, along with Mekinist (trametinib), which takes aim at a different driver of melanoma, the MEK gene, which encodes a protein that is “downstream” of BRAF, and itself can be mutated as well.

There are similarities between the side effects caused by targeted drugs for melanoma. Common are rash, sunburn or sun sensitivity, and nausea. Possible serious side effects include problems with the heart, liver, kidney, lungs, skin or eyes. A potential serious side effect is a higher risk for the development of skin cancers, but this risk decreases when BRAF and MEK inhibitors are combined. Using the drugs in combination also decreases the debilitating rash that can be the most difficult side effect.

In fact, experts say, combinations of these types of drugs are the next frontier.

For instance, researchers have found that Tafinlar and Mekinist work better together than either does alone. The FDA gave an accelerated approval of their use together for advanced melanoma in early 2014, and, after a priority review, granted the combination full approval in late November 2015.

Also just recently, on Nov. 10, 2015, the FDA approved the MEK inhibitor Cotellic (cobimetinib), in combination with Zelboraf, for the treatment of people with BRAF V600E or V600K mutation-positive advanced melanoma, based on advantages in both progression-free survival and overall survival with the combination compared with Zelboraf alone.

Over the next few years, researchers will be mixing and matching more therapies to unlock the ideal combinations.

Part of the puzzle is drug resistance. Targeted therapy typically works for only six to 12 months, after which the cancer often adapts. Will different combinations of drugs slow down resistance?

Ravi Amaravadi, co-leader of the Cancer Therapeutics Program at the Abramson Cancer Center at the University of Pennsylvania, is developing drugs that fight resistance by dampening a cellular recycling process called autophagy. “Autophagy is the way cells get rid of damaged parts,” explains Amaravadi. So if a treatment is damaging the cancer, it may be able to mend itself through autophagy. “We’re trying to block that healing capacity.” An already approved malaria medication, hydroxychloroquine, has shown promise in early trials, and new trials with a BRAF and MEK inhibitors are already under way. Melissa A. Wilson, assistant professor of medicine at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, has recently received a grant to test whether adding an antibody targeting the ERBB3 mutation to BRAF and MEK inhibitors will help combat resistance. Another important arm of research is focused on predicting which drugs will work on which patients. As of now, researchers have no idea why some patients experience dramatic successful outcomes using immunotherapy, while others see no benefit. Finding biomarkers, either in the genetic code or the immune system, will help make sure patients get the right treatment. “These are expensive drugs with fairly substantial toxicities,” explains Lynn Schuchter, chief of hematology/oncology at the Abramson Cancer Center at the University of Pennsylvania. “We want to be able to identify the proper patients.”

For all of these improvements, Schuchter is still not satisfied, and worries that the field needs to restock its cupboard of big ideas. The blockbuster ideas have been realized, she says, and developments over the next few years “will be more nuanced.”

On the Horizon

“These new therapies are effective, but they are not helping most patients,” she says. “We still need new approaches.”One new immunotherapy approach that’s still in the clinic is Cavatak, another vaccine-based treatment. Cavatak is derived from a cold strain and has shown some promise. It is being tested alone and in combination with other approaches.

But perhaps the most technologically alluring experimental immunotherapy is adoptive cell therapy: the idea that we can grow, train and transplant parts of the human immune system. In 2009, Jamie Goldfarb had a tumor the size of a quarter removed with a wide excision from her leg. Goldfarb had a lymph node biopsy as well. The surgeon then declared her cancer-free. Over the next year, several infections developed near the surgical site. The surgeon went back in and found a mass of melanoma in the deep tissue. After a PET scan and another wide excision, she was again declared cancer-free. Goldfarb got pregnant, had a baby, and then, just as she was preparing to return to work in January 2011, her oncologist suggested a precautionary scan. Everyone was surprised to discover metastatic disease in her pancreas and liver. She had no symptoms.

Goldfarb lives in the D.C. area, and even before the biopsy, her doctor advised her to see a melanoma specialist at the nearby National Cancer Institute. Just three days after the biopsy confirmed cancer, she was learning about an adoptive cell therapy called TIL — for tumor infiltrating lymphocytes.

Lymphocytes are white blood cells, and, in TIL therapy, a tumor is harvested from a cancer patient, and then the white blood cells inhabiting the tumor, which hold the power to fight the disease, are harvested and multiplied in the lab over several weeks. Goldfarb met the scientists who grew her cells, and viewed them under the microscope. “They built me a new immune system in the lab,” says Goldfarb. “It was awesome.”

While she was waiting for the TIL cells to grow, Goldfarb underwent two rounds of IL-2, which knocked the tumors in her pancreas and liver back for a few months. But by August, a new scan found more than 35 new tumors, making it clear that it was time to move on to the TIL therapy. With a dose of strategic chemotherapy, Goldfarb’s immune system was wiped out, and billions of new immune cells were introduced with a simple intravenous infusion.

Nonetheless, monthly scans showed continued tumor growth, and by December her doctors suggested that Goldfarb think about next steps. She said she needed a little more time, and then she caught an ordinary winter cold. While she was sick, she felt her immune system jump to life, and her tumors began to shrink. By the time she had the January scan, they were significantly decreased, and kept on shrinking. As of about two years ago, there was no evidence of disease.

TIL, whose side effects can include fever, chills and anemia — plus symptoms caused by the chemotherapy, including gastrointestinal disturbances and fatigue — is still only available via clinical trial at about a dozen institutions worldwide, and it’s expensive. But it can be very effective. “I have seen firsthand the power of this therapy in producing a durable response in patients,” says Roda Amaria, a melanoma specialist at MD Anderson Cancer Center in Houston who is working with TIL. “It is an aggressive approach not possible for all melanoma patients due to the intensiveness of the therapy. And its widespread application has been limited by the labor-intensiveness of growing the cells.”

Finding the Best Available Therapy

Still, there are good reasons why institutions continue to try to perfect the procedure. “We invest so much time and money on these trials because we’re trying to provide a long-lasting impact, even though we know the majority of these drugs are not going to save people, only treat them for a period of time,” says Amaria. “These immune therapies have a chance to give someone a second life, and have the ability to produce long-term favorable responses in a cancer that is known to be very aggressive and often fatal.”This is an important time for melanoma patients, their doctors and researchers. “After many years of no progress in treating melanoma, we have seen an amazing leap forward, with more than a half-dozen new drugs now available,” says Tim Turnham, executive director of the Melanoma Research Foundation. “Most experts agree that when we understand how to use these drugs, half of the patients with metastatic melanoma will either be cured or left with chronic disease.”

At this juncture, it’s essential that patients are confident that their treatment teams are current with the rapidly changing landscape. “I think there is still a lot of art in treating melanoma,” Turnham says, “and the key is experience. Doctors who treat a lot of melanoma know the drugs, have a better sense of how to manage the possible side effects and are more likely to have access to clinical trials.”

Even with these new options, many people will be left with no effective treatment. Turnham notes that major gaps remain — dealing with brain metastases, understanding melanoma that starts in the eye or in the mucosal membrane and understanding why these new drugs work for some patients and not for others. “We cannot rest on our accomplishments. We need more clinical trials of promising drugs and combinations, more innovation in developing new treatment approaches,” says Turnham. “Only by continuing the push for research will we finally be at the place where every patient has access to safe, effective drugs to treat their melanoma.”

For the past 10 years, it was a given among melanoma specialists that the best options were only available in trials. That may change very soon as new treatments permeate the system and evidence accumulates from ongoing clinical trials.

But for now, Schuchter still thinks it’s “the best choice to enroll someone in a clinical study.” Some of the best reported treatment outcomes, she says, are for drug combinations that are still available only in clinical trial.

That makes sorting through treatment options all the more challenging for patients thrown into the whirlwind of a cancer diagnosis.

It would be hard to find someone more prepared for this than Jamie Goldfarb — her husband’s job is managing clinical oncology trials. Still, they were totally overwhelmed.

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“It is essential for oncology patients to be their own advocates,” she says, “but there are so many things to think about.”