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Combination treatments target advanced melanoma


Treatments that combine newer targeted therapies have begun to lift the “death sentence” that advanced melanoma formerly carried, an expert says.


Denver - Treatments that combine newer targeted therapies have begun to lift the “death sentence” that advanced melanoma formerly carried, an expert says.

Dermatologists are very adept at detecting melanoma, says Delphine J. Lee, M.D., Ph.D.

“Then once we diagnose it, we know, if the melanoma is less than 1 mm in diameter, the risk of death from melanoma is pretty low. But when it gets beyond 1 mm, we are less involved, and care is managed by our medical and surgical oncology colleagues,” Dr. Lee says. She is director of translational immunology at the John Wayne Cancer Institute’s Dirks/Dougherty Laboratory for Cancer Research, Santa Monica, Calif.

“Our patients still look to us to be a source of information,” she notes.

For patients whose only serious health concern is melanoma, Dr. Lee says, “It’s probably more important to maintain a relationship with their dermatologist than their family practitioner. So it’s our job to be aware of melanoma beyond the primary lesion” in terms of treatment options and outcomes data.

In the latter area, “Melanoma used to be sort of a death sentence, especially when it reached more advanced stages. But now, even if a patient has a brain metastasis, there is hope. And our ability to convey that - not false expectations, but the objective data we have - allows us to give better care to our patients,” she says.

New day dawning

Regarding treatments, patients with metastatic melanoma have a growing list of options.

“Metastatic melanoma is having a new day in terms of options for patients. Before 2011, no therapy showed an overall survival advantage,” Dr. Lee says. Oncologists typically prescribed chemotherapy such as dacarbazine, she says, “But it was really no better than placebo.”

Ipilimumab, the first oncology drug to show a survival advantage in metastatic melanoma, earned Food and Drug Administration (FDA) approval in 2011. A typical course of ipilimumab involves infusion every three weeks for 12 weeks, Dr. Lee says. In its pivotal trial in advanced melanoma, ipilimumab provided a median overall survival advantage of more than three months versus a control vaccine (Hodi FS, O’Day SJ, McDermott DF, et al. N Engl J Med. 2010;363(8):711-723).

Pegylated interferon alpha and vemurafenib, the first targeted BRAF inhibitor, also gained approval in 2011.

“It was determined that if patients have a specific mutation in the BRAF pathway, giving them vemurafenib to specifically target that mutation in that protein can provide amazing, rapid results, almost shrinking the tumor away,” Dr. Lee says.

Unfortunately, she adds, long-term recurrences are common with vemurafenib. Over time, “The tumor figures out a way around it.”

Additionally, dabrafenib, an oral drug that also targets a BRAF mutation, earned FDA approval in 2013. Although this drug provided improved short-term disease control in pivotal trials, Dr. Lee says that, as with vemurafenib, “The problem was that patients’ cancers recurred.”

But combining dabrafenib with trametinib - an oral agent that targets mitogen-activated protein kinase (MAPK) kinase (MEK) - appears to provide very good outcomes, she says. In a phase 2 study, patients who got the combination fared better across the board than patients who got dabrafenib alone (Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367(18):1694-1703).

Additionally, Dr. Lee says, “The combination that got everybody’s attention was nivolumab and ipilimumab.”

In this regard, a study showed that 22 of 46 treated patients experienced lesion reductions of at least 80 percent (Wolchok JD, Kluger H, Callahan MK, et al. N Engl J Med. 2013;369(2):122-133). Accordingly, she says, “Combination therapy or sequential therapies will probably be the way to go. My colleagues in medical oncology seem to favor this approach. For example, if you block BRAF, the cancer develops resistance. But if you block BRAF and MEK, maybe you can hold back that resistance a little longer.”



On the horizon

Other drugs on the near-term horizon include lambrolizumab (whose maker, Merck, expects to complete a special rolling New Drug Application in the first half of 2014) and nivolumab. They target programmed death 1 (PD-1), a receptor expressed on T cells which helps to shut down the immune system after threats such as a cold virus have been vanquished.

“The problem is, in cancer we don’t want it to turn off,” Dr. Lee says.

Blocking PD-1 directly - as these two drugs do - lifts the regulatory mechanism, she says, allowing the immune system to target the cancer continuously. As such, she says, both drugs have produced very good clinical responses.

In a phase 1 nivolumab trial, the majority of lesions either shrunk or remained stable in size (http://www.ncbi.nlm.nih.gov/pubmed/22658127. Topalian SL, Hodi FS, Brahmer JR, et al. N Engl J Med. 2012;366(26):2443-2454).

However, Dr. Lee says, among the mechanisms that melanoma uses to “hide” from the immune system is PD-1 ligand (PD-L1), which is believed to be expressed on cancer cells and binds to PD-1. In a study of a PD-L1 antibody, 45 percent of patients with advanced melanoma remained progression-free at 24 weeks (Brahmer JR, Tykodi SS, Chow LQ, et al. N Engl J Med. 2012;366(26):2455-2465).

Regarding high-dose IL-2, Dr. Lee says patients who respond within the first 18 months tend to do well. However, “The infusion must be performed at a center by an expert because there are risks, including death, on IL-2 therapy. Oncologists who treat with IL-2 are aware of these problems and monitor patients very closely.”



Additional options

For patients with metastases limited to the skin (and negative lymph nodes or no sentinel lymph node biopsy/ SLNB), standard therapy is surgical excision, according to Dr. Lee. But for patients who may have too many superficial lesions to remove surgically, she says, National Comprehensive Cancer Network guidelines suggest local injectable treatments to stimulate the immune system. These include Bacillus Calmette-Guerin (BCG), interferon and IL-2.

For BCG, a seminal study shows that approximately 90 percent of injected lesions regressed at seven years (Morton DL, Eilber FR, Holmes EC, et al. Ann Surg. 1974;180(4):635-643). “Intriguingly,” Dr. Lee says, “this study also showed regression in 17 percent of uninjected lesions.”

Additionally, adoptive cell therapies, also called tumor infiltrating leukocytes or adoptive cell transfer therapy, have allowed some patients to achieve very durable responses, sometimes lasting several years. Dr. Lee says, however, that this therapy may be difficult to provide on a broad scale, particularly in the setting of limited healthcare resources.

“It’s extremely labor-intensive. The tumor is removed, and then the immune cells found in the tumor are cultured in a petri dish under highly controlled, sterile conditions,” Dr. Lee says.

Once the sample expands to billions of cells, she says, oncologists inject them into the patient.

Regarding thin melanomas (measuring less than 1 mm), sentinel lymph node biopsy (SLNB) remains controversial.

“The general idea is that the technique follows the drainage pattern of the primary lesion, to determine whether any tumor cells have spread in the most likely path,” she says.

Ultimately, patients must decide regarding SLNB for themselves.

“But it’s our job to give them some statistics to help them make those decisions,” Dr. Lee says.

Disclosures: Dr. Lee is a principal investigator on an Allergan trial and owns Biogen Idec stock. She reports no relevant financial interests.

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