New Therapies Are Changing the Outlook for Advanced Melanoma

On Target: Disrupting a Troublesome Pathway

All of the recently approved targeted therapies for melanoma disrupt an important communications route, or signaling pathway, in tumor cells. This pathway—known as the MAP kinase, or MAPK pathway—influences critical functions such as cell division and cell death.

Two key proteins in the MAPK pathway are BRAF and MEK. Mutations in the BRAF gene, which are present in more than half of advanced melanomas, can change the BRAF protein’s activity, allowing it to independently push the MAPK pathway into a state of constant activation, spurring tumors to grow and spread.

Two of the recent FDA-approved drugs, vemurafenib (Zelboraf) and dabrafenib (Tafinlar), target BRAF proteins. Both were approved based on findings from phase III trials that enrolled patients whose tumors had one of two specific mutations in the BRAF gene, which account for most BRAF mutations in patients with melanoma. [Patient tumor samples are tested for the mutations with a “companion diagnostic,” a test that is developed and travels through regulatory approval in tandem with a targeted agent.]

Recently updated results from the trial that led to vemurafenib’s approval showed that treatment with this BRAF inhibitor lengthened the time patients lived overall (overall survival) and without their disease worsening (progression-free survival) compared with treatment with the chemotherapy drug dacarbazine, which was a standard of care at the time the trial was launched. (See “A Snapshot of New Melanoma Therapies” below.)

* Overall survival results are expected in 2016
† Received accelerated approval from the FDA

Dabrafenib was approved on the basis of improved progression-free survival, again, compared with dacarbazine. The final analysis of overall survival will not be available until 2016, according to GlaxoSmithKline, which manufactures the drug and funded the trial on which the approval was based.

An enzyme called MEK cooperates with BRAF in the MAPK signaling pathway. BRAF proteins activate their MEK counterparts through a process called phosphorylation, and MEK inhibitors (which act on the normal form of the protein, not the result of a genetic mutation) disrupt the activation process. Thus, MEK inhibitors are used most effectively in patients with BRAF mutations, Dr. Streicher said.

Although several MEK-targeted drugs are in development, only one, trametinib (Mekinist), has been approved by the FDA to treat melanoma. The approval was based on improved progression-free survival in a large clinical trial that compared patients treated with the MEK inhibitor with those who received chemotherapy.

Not all patients treated with BRAF or MEK inhibitors experience tumor reductions. But in patients who do, the results can be rapid and dramatic, including complete eradication of tumors, explained Lynn Schuchter, M.D., a melanoma specialist at the University of Pennsylvania Abramson Cancer Center.

“You have very sick patients on oxygen and strong pain medications who can quickly come off of them,” she said.

But, Dr. Schuchter continued, tumors in nearly all patients eventually become resistant to all three drugs, typically within 6 to 7 months.

An Immunogenic Cancer

For reasons that researchers still don’t fully understand, melanoma is particularly immunogenic—that is, it is prone to inducing an immune response—making it an ideal disease in which to pursue a new generation of immune-based treatments.

An important breakthrough in cancer immunology was the discovery that tumors can co-opt a regulatory mechanism that acts to restrain the immune response and is controlled, in part, by specific proteins on the surface of immune cells called T cells. These “checkpoint” proteins allow T cells to eliminate threats (like certain bacteria or viruses), and then, at the appropriate time, dial back the immune response before it does lasting harm to the body.

Some tumor cells (and certain cells in the inflammation-ridden environment that surrounds many tumors) are able to manipulate this checkpoint program by improperly turning it on, masking them from attack by T cells and other immune cells.

Ipilimumab (Yervoy) was the first checkpoint inhibitor to be approved by the FDA (in 2011) to treat advanced melanoma. This drug, a monoclonal antibody, targets a checkpoint protein on T cells called CTLA-4, releasing them to attack tumors. The approval was based on improved overall survival in a large phase III trial that enrolled patients whose cancers were no longer responding to FDA-approved or other commonly used therapies.

At the European Cancer Congress in 2013, researchers presented an analysis of 12 clinical trials that included approximately 1,800 patients with advanced melanoma who were treated with different doses of ipilimumab. The median survival was 11.4 months, and more than 1 in 5 patients who received the drug lived for at least 3 years.

Pembrolizumab (Keytruda) targets a different checkpoint protein, called PD-1. The drug became the first PD-1 inhibitor to be approved by the FDA, which based its approval on positive results from an early-stage trial published in September 2014. In that trial, approximately one-fourth of patients with advanced melanoma who had previously received ipilimumab experienced tumor shrinkage.

And, based on early results from a phase III clinical trial, on December 22, 2014, the agency approved another PD-1 inhibitor, nivolumab (Opdivo), for advanced melanoma. Results from a different phase III clinical trial published in November 2014 showed that, among patients with advanced melanoma whose tumors did not have BRAF mutations, nivolumab improved overall and progression-free survival compared with dacarbazine. The rates of treatment-related side effects and serious side effects were similar in both groups.

Immunotherapy is showing the potential to be a transformative treatment, Dr. Schuchter said.

“I’ve had patients who’ve had complete responses and are now 4 years out with no evidence of disease,” she said. PD-1 inhibitors may have the greatest potential of the currently available therapies, Dr. Schuchter added. With these agents, “we’re seeing more complete responses and fewer side effects.”

Moving toward Combinations

Although these drugs all show some level of efficacy when used alone, “the real question is how to combine them to find the most effective way to create long-term control of tumors,” Dr. Streicher said.

Some progress has been made on that front.

The only FDA-approved combination, thus far, is trametinib plus dabrafenib for patients with metastatic melanoma whose tumors have BRAF mutations.

The combination was initially approved based on early results from a late-stage trial that showed a substantially higher rate of tumor responses and longer duration of tumor responses with the combination than with dabrafenib alone. Updated results showed a modest but statistically significant improvement in progression-free survival with the combination treatment. In another phase III trial that compared the trametinib-dabrafenib combination with vemurafenib alone, patients who received the combination had better overall and progression-free survival, according to results published in November 2014.

In addition to improvements in progression-free survival, Dr. Schuchter said, the combination treatment also dramatically reduces the risk of skin-related side effects often seen when BRAF or MEK inhibitors are used alone.

In the trial that compared trametinib plus dabrafenib with vemurafenib alone, for example, 18 percent of patients treated with the BRAF inhibitor alone developed non-melanoma forms of skin cancer, squamous cell carcinoma or keratoacanthoma, compared with only 1 percent of patients treated with the BRAF-MEK inhibitor combination.

Findings from several recent clinical trials suggest that other combinations could receive regulatory approval in the near future. For example, results from a large clinical trial of patient with melanoma whose tumors had BRAF mutations showed the combination of vemurafenib plus the investigational MEK inhibitor cobimetinib improved median progression-free survival compared with vemurafenib alone (9.9 months versus 6.2 months) as well as tumor response rates (68 percent versus 45 percent).

And, as was the case with the dabrafenib-trametinib combination, patients treated with both drugs were less likely to experience serious skin-related side effects, although there was an increased risk of some other side effects, including diarrhea and visual impairment.

Targeted therapies are not the only drugs being tested in combination. In an early-phase clinical trial presented at the 2014 American Society of Clinical Oncology annual meeting, for example, patients with advanced disease who received ipilimumab plus nivolumab had a median overall survival of 40 months, nearly twice that seen in clinical trials that have tested either agent alone.

“Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20 to 25 percent survived 2 years,” said the trial’s lead investigator Mario Sznol, M.D., of Yale School of Medicine, in a news release. “So it’s truly remarkable that we’re seeing a median survival over 3 years in this trial.”

Dr. Sznol cautioned, however, that the trial was small and the results need to be validated in a larger study.

Which Treatments for Which Patients?

With multiple effective options available to patients with advanced melanoma, a pressing issue facing clinicians and patients is which treatments to use and when. For many patients “we just don’t know yet what the best initial treatment will be,” Dr. Streicher said.

Regardless of whether patients’ tumors have BRAF mutations, treatment decisions should also be driven by clinical factors, Dr. Schuchter said. For patients with BRAF mutations who have more extensive disease and are experiencing symptoms (patients with advanced melanoma can be asymptomatic for extended periods), starting with a BRAF inhibitor rather than a checkpoint inhibitor may be the preferred option, she explained, because these drugs can produce more immediate tumor responses and, consequently, symptom relief.

“For patients not on a clinical trial, I try to start with the combination” of dabrafenib plus trametinib, Dr. Schuchter said. “It looks like it might be more effective [than either drug alone], and has fewer skin toxicities.”

Findings from clinical trials may soon be able to help guide these decisions.

NCI, for example, is planning a trial in patients whose tumors have BRAF mutations that will compare initial treatment with a targeted therapy combination against an immunotherapy combination. According to Dr. Streicher, the trial is currently under review and should launch in 2015.

New Therapies, Different Side Effects

Several researchers noted that the common side effects of this new generation of cancer therapies are not any worse than those seen with chemotherapy or radiation. But they are different from the side effects that clinicians and their staffs are used to seeing.

Managing the side effects of these new drugs, Dr. Sondak noted, “can require special expertise and training.”

In general, patients tolerate BRAF and MEK inhibitors fairly well and experience mostly minor side effects. But in addition to their skin-related side effects, patients treated with these agents can experience high fevers, diarrhea, and joint pain—which have led some clinical trial participants to halt treatment. Some patients treated with these drugs have also developed melanoma that was distinct from their original cancer.

Similarly, many patients treated with checkpoint inhibitors experience only minor side effects. But these therapies can also cause severe skin rashes, diarrhea, and an inflammation of the colon called colitis. The drugs can also cause serious immune-related reactions. In an early-stage trial of nivolumab, for example, several patients died as a result of lung inflammation.

And although dual checkpoint blockade with PD-1 and CTLA-4 inhibitors has “shown promising results,” Dr. Sondak noted, “the side effects have been higher for patients who receive the two types of antibodies together.”

With all of the new therapies, patient education is critical, Dr. Schuchter stressed. “We need to educate our patients about these side effects and their early signs, so they can report them to their doctors,” she said. “If we catch many of these issues early, often they can be more easily managed and we can avoid some of the more serious problems these drugs can cause.”