With several more melanoma treatments poised to emerge from the pipeline, data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals.
Keith T. Flaherty, MD
The armamentarium for advanced melanoma was sparse in March 2011, when ipilimumab (Yervoy) became the first drug in 13 years to earn approval FDA approval for the disease. Since then, the armamentarium has rapidly expanded.
“In the last 5 years, there have been FDA approvals for 12 new agents and combination therapies for patients with advanced melanoma,” said Keith T. Flaherty, MD, who moderated an OncLive Peer Exchange panel titled “Treatment of Advanced Melanoma and Basal Cell Carcinoma.”
An Unusual Malignancy
Novel melanoma treatments fall broadly into 2 categories: agents that target MAPK pathway signaling or agents that target immune system proteins. Several more melanoma treatments are poised to emerge from the pipeline. Data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals.What sets melanoma apart from other malignancies is its high mutational burden and immunogenicity. Jeffrey S. Weber, MD, PhD, explained how the interplay between these 2 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 derives from transformed melanocytes, and one function of melanocytes is to present antigens to immune cells. When the melanoma melanocytes present the “alien” mutation-encoded 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, PhD, MBBS, identified the 3 most common genetic drivers of melanoma as BRAF V600 mutations, NRAS mutations, and NF1 alterations. Approximately 40% of patients with cutaneous melanoma have a BRAF mutation, up to 25% have an NRAS mutation, and about 12% have an NF1 mutation.1
Jeffrey S. Weber, MD, PhD
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. Long’s institution also routinely tests for RAS, NF1, and KIT aberrations in case patients are eligible for a clinical trial.
The frequency of driver mutations varies according to melanoma site and sun damage. As Jason J. Luke, MD, explained, “There are melanocytic melanomas that can rise in other parts of the body, including acral lentiginous melanomas or mucosal melanomas, as well as uveal melanomas, and we see a different mutational spectrum in those types of tumors.”
For example, 40% of patients with cutaneous melanoma have a BRAF mutation compared with 5% of patients with mucosal melanoma. Conversely, 20% of patients with mucosal melanoma have a KIT mutation compared with only 2% of patients with cutaneous melanoma.1 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.
Approaching Advanced Disease
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.“The toughest issue right now in melanoma medical oncology [is] what to do with stage III patients,” Luke said. These are patients whose melanoma has spread to regional lymph nodes or lymphatic vessels. The first approach is excision of the primary tumor with wide margins and removal of regional lymph nodes.
Jonathan S. Zager, MD, the lone surgeon on the panel, discussed how he weighs whether a patient with stage III or stage IV (distant metastatic) melanoma is eligible for resection. 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 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
Agents and regimens approved for US patients whose tumors have a BRAF mutation include vemurafenib, dabrafenib, trametinib, a combination of dabrafenib and trametinib, and a combination of cobimetinib and vemurafenib. Novel FDA-approved immunotherapy treatments include ipilimumab, a CTLA-4 inhibitor; the PD-1 inhibitors pembrolizumab and nivolumab; and talimogene laherparepvec (TVEC), an oncolytic virus therapy.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. 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.”
Georgina Long, PhD, MBBS
For BRAF-wild tumors, Zager said he often uses T-VEC. In a phase III trial that included patients with unresected stage IIIB to IV melanoma, T-VEC produced a significantly better durable response rate than granulocyte macrophage colony-stimulating factor (16.3% vs 2.1%, respectively; P <.001).2 “It’s extremely well tolerated,” he said, describing adverse effects as similar to mild or moderate flu symptoms that last for 1 or 2 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 ipilimumab plus nivolumab for patients with BRAF-positive disease. Long reviewed results from the phase II CheckMate-069 trial, which assessed an ipilimumab/nivolumab combination in patients with stage III unresectable or stage IV metastatic melanoma.
At the 2016 American Association for Cancer Research meeting, investigators reported that the 2-year OS rate was 64% overall and 69% in patients with BRAF wild-type melanoma.3 “This is pretty incredible stuff,” Long said. Ongoing trials are attempting to combine a BRAF inhibitor with immunotherapy. Luke said early data from phase I trials with such combinations have indicated lackluster response rates.The panel had a spirited discussion about the risks and benefits of adjuvant high-dose ipilimumab. In October 2015, the FDA expanded ipilimumab’s indications to include a 10 mg/kg adjuvant regimen for completely resected melanoma in patients with pathologic involvement of regional lymph nodes >1 mm.
Jonathan S. Zager, MD
Approval was based on findings from a phase III trial that randomly assigned adults with stage III melanoma to high-dose ipilimumab (n = 475) or placebo (n = 476).4 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 ipilimumab arm than in the placebo arm (26 vs 17 mo, respectively; HR, 0.75, 95% CI 0.64- 0.90; P = .0013).
“That’s a 25% reduction in the risk of recurrence,” said Long, whose home country of Australia has not approved the adjuvant regimen. She also noted that overall survival (OS) data were not yet mature and that the high dose was very toxic. Five treatment-related deaths occurred during the trial, but Weber noted that there were fewer deaths over time with ipilimumab than in the placebo arm.
Although the 2 experts disagreed over the meaningfulness of the on-study deaths, they agreed that without OS data, clinicians must weigh the study’s findings cautiously when making treatment decisions. Long said she doubted Australian oncologists would find the benefits of using high-dose ipilimumab outweighed the serious risks.
Systemic Therapy for Metastatic Disease
Luke said even if the trial finds an OS benefit with high-dose ipilimumab, he is not sure the toxicities, some of which could make patients ineligible for subsequent therapies, are 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.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 lowvolume disease. “I think our recent data are starting to say that at least there’s equipoise or perhaps it’s the reverse,” he said.
Jason J. Luke, MD
Luke explained that newer data show patients with <3 sites of disease, normal lactate dehydrogenase (LDH) levels, and good performance status have better long-term 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.
Targeted Therapy for Other Mutations
On the mutation therapy front, Long discussed long-term data from the phase III COMBI-d trial (N = 423), which randomly assigned patients with BRAF-positive metastatic melanoma to dabrafenib plus trametinib or to dabrafenib monotherapy. “The 3-year survival in a normal LDH patient on dabrafenib and trametinib is 70%,” 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 protocol.“We need targeted therapy options for other patients,” Flaherty said. He brought up binimetinib, an MEK inhibitor being studied in patients with NRAS mutations. Long said a phase III study that compared binimetinib with dacarbazine showed a benefit 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 the way of treating cancer in a novel way,” said Long. “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,” she 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.