Working at the Speed of Light in Melanoma Advancements

The measures available for treating advanced melanoma were sparse in March 2011, when Yervoy (ipilimumab) became the first drug in 13 years to earn approval from the U.S. Food and Drug Administration (FDA) for treatment of the disease. Since then, the toolbox of drugs has rapidly expanded.

“In the last five years, there have been FDA approvals for 12 new agents and combination therapies for patients with advanced melanoma,” said Keith T. Flaherty, M.D., who moderated a Peer Exchange panel titled “Treatment of Advanced Melanoma and Basal Cell Carcinoma.” The panel was hosted over the summer by the website OncLive®, a sister publication to CURE®.

Novel melanoma treatments fall broadly into two categories. One encompasses agents that target cell signaling in the MAP kinase (MAPK) pathway, which is a chain of proteins inside a cell that transmits messages. The other category includes agents that target immune system proteins.

Several more melanoma treatments are poised to emerge from the pipeline. But even without additional advances, data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals. On the panel, experts in the field offered guidance based on their experience with the latest drugs.

AN UNUSUAL MALIGNANCY

What sets melanoma apart from other malignancies is its high mutational burden and immunogenicity, meaning its ability to react to certain substances by waging a strong immune response. Jeffrey S. Weber, M.D., Ph.D., explained how the interplay between these two factors makes melanoma highly susceptible to targeted therapies. “If you look at average mutational load, melanoma is No. 1 of all tumors, with a median of about 600 to 700 individual non-synonymous mutations,” he said.

Non-synonymous means the mutation is found only in tumor-cell DNA, where it encodes peptides and protein fragments not expressed by normal cells. This is important because melanoma grows from melanocytes, or pigmented skin cells, that have undergone dangerous changes, and one function of melanocytes is to present antigens, or foreign substances found in the body, to immune cells. When the melanoma melanocytes present the “alien” mutationencoded antigens to T cells, it triggers an immune response. “A lot of mutations means the cells grow out of control and make cancers, (but the cell) contains within it the potential seed of its own destruction…by the immune system,” Weber said.

Georgina Long, Ph.D., M.B.B.S., identified the three most common genetic drivers of melanoma as BRAF V600 mutations, NRAS mutations and NF1 alterations. Approximately 40 percent of patients with cutaneous melanoma (disease that occurs on the skin) have a BRAF mutation, up to 25 percent have an NRAS mutation and about 12 percent have an NF1 mutation. Other driver mutations include MEK1, KIT, CTNNB1 and GNAQ.

Long said BRAF V600 mutations are the most critical aberrations to test for when evaluating patients for treatment, since they are common and drugs exist that can target them. Long’s institution also routinely tests for RAS, NF1 and KIT aberrations, in case patients are eligible for clinical trials testing drugs that target those mutations. The frequency of driver mutations varies according to melanoma site and sun damage. As Jason J. Luke, M.D., explained, “There are melanocytic melanomas that can arise in other parts of the body, including acral lentiginous melanomas (which can occur on the palms or soles or under fingernails) or mucosal melanomas, as well as uveal melanomas (which occur in the eye), and we see a different mutational spectrum in those types of tumors.”

For example, while 40 percent of patients with cutaneous melanoma have a BRAF mutation, just 5 percent of patients with mucosal melanoma do. Conversely, 20 percent of patients with mucosal melanoma have a KIT mutation, compared with only 2 percent of patients with cutaneous melanoma. Clinical trials are evaluating therapies in melanoma patients that target mutations other than BRAF. “We haven’t cured melanoma, and there’s a lot of work still to be done,” Luke said.

Circling back to the interplay between mutational burden and immunogenicity, Luke said he and his colleagues are investigating whether certain genetic aberrations compromise the immune system’s ability to attack melanoma cells through pathway disruption. The findings could lead to novel targeted therapies that hone in on signaling pathways instead of driver mutations.

APPROACHING ADVANCED DISEASE

“The toughest issue right now in melanoma medical oncology (is) what to do with stage 3 patients,” Luke said. These are patients whose melanoma has spread to lymph nodes or lymphatic vessels in a region of the body close to the original cancer site. The first approach is excision of the primary tumor with wide margins and removal of regional lymph nodes.

Jonathan S. Zager, M.D., the lone surgeon on the panel, discussed how he weighs whether a patient with stage 3 or stage 4 (distant metastatic) melanoma is eligible for resection (surgery): Does the patient have bulky nodal disease or a tumor encroaching on an important vein or artery? “I can resect anything, but…you have to think about the functional and cosmetic consequences of the resection,” he said.

For patients with unresectable disease, clinicians must decide whether to use therapeutics to try to shrink the tumor until it becomes resectable; and for patients with resectable disease, clinicians must decide whether using an adjuvant, or post-therapy, regimen to reduce the chances of recurrence outweighs its toxicities. Outside of a clinical trial, the choice between targeted mutation therapy versus immunotherapy hinges on whether the tumor has a BRAF mutation.

UNRESECTABLE ADVANCED MELANOMA

According to Zager, BRAF inhibitors shrink unresectable melanoma faster than immunotherapy in patients with a BRAF mutation. “The tumor doesn’t have to go away — it just has to make surgery easier for the surgeon and for the patient,” he said. In the adjuvant setting, acquired resistance is a concern with targeted mutation therapies, but it’s less of a worry in the neoadjuvant, or pre-treatment, setting. Long said, “In the neoadjuvant setting, where you’ve got a patient and you need a quick reduction, you don’t worry so much about acquired resistance.”

For tumors that do not have BRAF mutations, Zager said he often uses the vaccine T-VEC. In a phase 3 trial that included patients with unresected stage 3b to 4 melanoma, T-VEC produced a significantly better durable response rate than a different immune-stimulating drug, granulocyte macrophage colony-stimulating factor (16.3 percent versus 2.1 percent, respectively). “It’s extremely well-tolerated,” he said, describing adverse effects as similar to mild or moderate flu symptoms that last for one or two days after injection.

Zager said T-VEC is a great option for patients who cannot or will not use systemic therapy. Weber described T-VEC as something of a “niche drug” that can help prime an immune response before administering a PD-1 checkpoint inhibitor alone, or added to other immunotherapies.

Immunotherapy combinations have shown good efficacy in trials, and the FDA has approved Yervoy plus Opdivo for patients with BRAF-positive disease. Long reviewed results from the phase 2 CheckMate-069 trial, which assessed a Yervoy/Opdivo combination in patients with stage 3 unresectable or stage 4 metastatic melanoma.

At the 2016 Annual Meeting of the American Association for Cancer Research, investigators reported that the two-year overall survival (OS) rate was 64 percent overall and 69 percent in patients whose melanoma did not include a BRAF mutation. “This is pretty incredible stuff,” Long said.

Ongoing trials are attempting to combine a BRAF inhibitor with immunotherapy. Luke said early data from phase 1 trials of such combinations have indicated lackluster response rates.

ADJUVANT IMMUNOTHERAPY

The panel had a spirited discussion about the risks and benefits of adjuvant high-dose Yervoy. In October 2015, the FDA expanded Yervoy’s indications to include a 10 mg/kg adjuvant regimen for completely resected melanoma in patients with cancer that had spread to lymph nodes near the original site, and was larger than 1 mm in those nodes. Approval was based on findings from a phase 3 trial that randomly assigned adults with stage 3 melanoma to highdose Yervoy (n = 475) or placebo (n = 476). Participants were required to have undergone complete resection and to have never received prior systemic therapy. Median recurrence-free survival was significantly longer in the Yervoy arm than in the placebo arm (26 months versus 17 months, respectively).

“That’s a 25 percent reduction in the risk of recurrence,” said Long, whose home country of Australia has not approved the adjuvant regimen. She also noted that OS data were not yet mature; but since then, updated findings from the trial demonstrated that, at a median of 5.3 years’ followup, the five-year overall survival rate was 65.4 percent with Yervoy compared with 54.4 percent in the control arm. Long pointed out that the high dose used in the trial was very toxic. Five treatment-related deaths occurred during the trial, but Weber noted that there were fewer deaths over time with Yervoy than in the placebo arm.

Although the two experts disagreed over the meaningfulness of the on-study deaths, they agreed that clinicians must weigh the study’s findings cautiously when making treatment decisions. Long said she doubted Australian oncologists would find that the benefits of using highdose Yervoy outweighed the serious risks.

Luke said that, even if the trial found an OS benefit with high-dose Yervoy, he was not sure the toxicities, some of which could make patients ineligible for subsequent therapies, would be worth it. “There are ongoing trials investigating agents in this space, so I would really prioritize the idea that patients should participate in those,” he said.

SYSTEMIC THERAPY FOR METASTATIC DISEASE

The paradigm for patients who have unresectable metastases is still evolving. Luke said the thinking used to be that mutation-targeting therapy was more suitable for high-volume BRAF-positive melanoma, which might be symptomatic, and that immunotherapy was better for low-volume disease. “I think our recent data are starting to say that at least there’s equipoise, or perhaps it’s the reverse,” he said. Luke explained that newer data show patients with less than three sites of disease, normal lactate dehydrogenase (LDH) levels (which indicate the health of the body's tissues) and good performance status have better longterm outcomes with mutation-targeting therapy than those with bulky disease. Recent studies have also found that patients with bulky disease and higher LDH levels fare better with immunotherapy combinations than many other patient groups.

On the mutation therapy front, Long discussed longterm data from the phase 3 COMBI-d trial that included 423 people, randomly assigning patients with BRAFpositive metastatic melanoma to Tafinlar plus Mekinist or to Tafinlar monotherapy. “The three-year survival in a normal LDH patient on dabrafenib and trametinib is 70 percent,” Long said. The panel concurred that trials of new immunotherapy regimens should perform posthoc analyses of OS data by LDH level and that, going forward, trials should include LDH breakdowns in their protocols.

TARGETED THERAPY FOR OTHER MUTATIONS

“We need targeted therapy options for other patients,” Flaherty said. He brought up binimetinib, a MEK inhibitor being studied in patients with NRAS mutations. Long said a phase 3 study that compared binimetinib with the chemotherapy dacarbazine showed benefits in progression-free survival and response, but not in OS. “But it is a wonderful foundation, because there’s definitely a signal there,” she said. MEK inhibition also disrupts signaling along the MAPK pathway, which Long noted is “constitutively active in the majority of melanomas, even if they’re not BRAF-mutated.” Other molecular targets being explored are CDK4/6 and CDKN2A.

“Melanoma is an exciting cancer that’s really forging the way of treating cancer in a novel way. I’m really keen to continue to pursue that with clinical trials of novel combinations, because I would like to see the melanoma cure rate increase,” Long said, adding that she believes about one-third of patients are being cured.

Luke predicted that the best is yet to come, but said that progress depends on patients participating in clinical trials. Weber urged trial sponsors to let investigators mine their clinical trial data, which could lead to new discoveries.