Mixing and Matching: Multiple Treatments in Sequence or Combination are Key in Fighting Melanoma


Following surgery with medication, combining immunotherapies or targeted drugs and adding radiation to immunotherapy can improve effectiveness in treating various stages of melanoma.

From the earliest phase of cancer through its spread to other parts of the body, doctors have a growing array of effective tools to use against melanoma.

At the 17th Annual Focus on Melanoma, experts from Penn Medicine’s Abramson Cancer Center explained what treatment for each stage of disease can entail — and how using different kinds of therapies in sequence or combination can often bring extra benefit.

Later stages of melanoma bring the need for medical treatments aside from surgery — the primary treatment for the early stages of melanoma. “The good news is that, yes, we have active treatments that can be effective even when melanoma has spread and become stage 4, or metastatic,” said medical oncologist Tara C. Mitchell.

To treat stages 3 and 4 disease, she mentioned a variety of options.

Checkpoint inhibitors block the activity of the proteins PD-1 or CTLA4, which some cancers generate as a way of evading detection by the immune system. The drugs can be used by themselves, in sequence or in combination.

“We have a serious conversation about (combination immunotherapy) with patients whose tumor has spread to many places in the body, filling up their liver, lung or brain,” she said. “We want to do everything at once to get the best possible chance of working — even accept more toxicity. This is a very effective option with advanced metastatic melanoma, especially when it’s gone to the brain. It can be very long-lasting.”

PD-1 inhibitors such as Keytruda (pembrolizumab) and Opdivo (nivolumab) can also be used after surgery in stage 3 disease to help decrease the chances of recurrence, Mitchell said. That concept is being tested in clinical trials for patients with high-risk stage 2 disease.

Even earlier in the course of treatment, there can be a role for immunotherapy, as well as targeted drugs and radiation, before surgery, added surgical oncologist Giorgos C. Karakousis.

“In some cases, it can shrink tumors and make surgery easier, less extensive and less morbid,” he said. In other instances, giving medicine first “may tell us whether a tumor responds to that treatment. When we take the tumor out, we see if it’s alive or dead and has responded to the therapy.” Finally, he said, giving immunotherapy while an early-stage tumor is present may help the body learn to recognize the cancer so it can later fight any lingering cells or recurrences.

Another option is TVEC (talimogene laherparepvec), an anticancer vaccine that is injected into tumors. “If melanoma comes back and just spreads on the skin where surgery was, and now there are spots all over the scar that are too much for surgery, we can inject this viral therapy,” Mitchell said. “The drug is an engineered virus that can’t infect the patient but uses the machinery of the virus to replicate in tumor cells and cause them to die.”

There are also a variety of drugs that target the proteins BRAF and MEK in the tumor’s DNA, used in combination — such as Braftovi (encorafenib) plus Mektovi (binimetinib), or Zelboraf (vemurafenib) plus Cotellic (cobimetinib). “Half of melanomas have the BRAF gene mutated or abnormally turned on, so instead of normal cells dividing and dying, these cells continue to grow, causing melanoma to grow and spread,” she said. “Now, we have three BRAF inhibitors and three MEK inhibitors. By blocking both, we can get better control in more patients for a longer time.”

To help prevent cancers from developing resistance to these combinations, researchers at the University of Pennsylvania are exploring the addition of a third agent, hydroxychloroquine, to the regimen. “They work early and effectively for patients who are treated,” she said.

Lastly, clinical trials are key. Around the world, trials are testing combination therapies for melanoma, including immunotherapy plus a BRAF inhibitor; immunotherapy plus radiation; immunotherapy plus TVEC; and novel immunotherapies.

Another important emerging option in later-stage melanoma is chimeric antigen receptor (CAR)-T cell therapy, noted oncologist Saar I. Gill.

In this type of immunotherapy, a patient’s disease-fighting white blood cells are removed in a blood draw. They are then multiplied in a lab for several weeks and genetically engineered to home in on melanoma cells. “We expose them to a virus, which pastes itself into the cells and delivers a new message — a blueprint. It makes them recognize cancer,” he said. Then, the cells are infused back into the patient.

University of Pennsylvania research led to the Food and Drug Administration’s approval of two such drugs for use in certain blood cancers, Yescarta (axicabtagene ciloleucel) and Kymriah (tisagenlecleucel), and this type of therapy is being tested in patients with melanoma. But because CAR-T cell therapy doesn’t work for all eligible patients, Gill said, more work must be done.

“The power of the immune system is such that we can cure this disease, conceivably,” he said. “We’d like, at first diagnosis, to be able to make the chance of relapse go away — which is cure, essentially.”

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