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New Malignant Melanoma Treatments Show Promise for Other Cancers

A Clinical Trial Led by The Angeles Clinic and Research Institute and Cedars-Sinai Cancer Identified a Combination of Immune-Harnessing Therapies That Improves Survival

Investigators from The Angeles Clinic and Research Institute, an affiliate of Cedars-Sinai Cancer, have determined that a combination of drugs that act on the immune system in distinct ways improves survival for patients with the deadliest form of skin cancer. The results of their multicenter Phase Ib clinical trial were published in the peer-reviewed journal, Journal for ImmunoTherapy of Cancer.

In this study, the investigators explored combining standard immune checkpoint inhibitors with a new class of immunotherapies called ImmTACs (immune-mobilizing monoclonal T-cell receptors against cancer).

While immune checkpoint inhibitors prevent tumors from deactivating cancer-killing immune cells called T-cells, ImmTACs draw T-cells directly to tumor cells via receptors for T-cells on one side and tumor cells on the other.Omid Hamid, MD

“The results of this study point toward new combination treatments that can help patients whose melanoma has progressed despite first-line therapy,” said Omid Hamid, MD, chief of Translational Research and Immuno-Oncology at Cedars-Sinai Cancer at The Angeles Clinic and Research Institute, medical director of the Cutaneous Malignancies Disease Research Group at Cedars-Sinai Cancer, and lead author of the study. “Once these treatments receive regulatory approval, they represent the next set of options for these skin cancer patients.”

The study enrolled 85 patients whose malignant melanomas had progressed despite previous treatment with standard immune checkpoint inhibitor therapy. All were treated with a combination of an ImmTAC and immune checkpoint inhibitors. The combination produced one-year overall survival rates above 76%, with no unexpected side effects.

The ImmTAC used in the study, tebentafusp, is the first drug to be approved by the U.S Food and Drug Administration (FDA) for treating ocular melanoma, the most common type of eye cancer.

While cutaneous melanoma—cancer that forms in the skin’s pigment-producing cells—isn’t the most common form of skin cancer, it is the most lethal, Hamid said. It causes about 10,000 deaths in the U.S. each year by spreading deeper into the skin or to other parts of the body.

Immune checkpoint inhibitors have dramatically improved survival rates for patients whose skin cancer has spread. Many of these drugs—including pembrolizumab, nivolumab, avelumab, ipilimumab, durvalumab and atezolizumab—have been studied by Hamid and his team in first-in-human clinical trials to treat melanoma. Later, the therapies also were approved by the FDA to treat basal and squamous skin cancers, as well as lung, gastroesophageal, endometrial and breast cancers.

“A decade or so ago, median survival for metastatic melanoma was six months,” Hamid said. “But thanks to our ability to harness the power of the immune system, the median survival is now six years and greater. Unfortunately, these immune checkpoint inhibitors don’t work for everyone.”

Previous studies have shown that immune checkpoint inhibitors like nivolumab and pembrolizumab benefit only 30%-40% of patients.

“Adding an ImmTAC to these immune checkpoint inhibitors produced an amazing one-year survival rate,” Hamid said. “This was also the first trial to show that we can safely combine ImmTACs and immune checkpoint inhibitors in patients whose cancer progressed despite treatment with standard immune checkpoint inhibitor therapy.”

This data has now been translated to other clinical trials with ImmTACs that offer options for patients with a wide variety of tumors, including melanomas, sarcomas, and endometrial, ovarian, and non-small cell lung cancers, Hamid said.

Investigators are moving forward with a Phase III trial of the tebentafusp and immune checkpoint inhibitor combination for patients with newly diagnosed cutaneous melanoma.

“The incidence of cutaneous melanoma is increasing dramatically,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “Metastatic disease is difficult to treat, but through innovations and trials, we have made major strides in extending survival for these patients. We are continually exploring cutting-edge therapies to provide new opportunities for these patients.”

Funding: The study was funded by pharmaceutical developer Immunocore Ltd.

Read More on the Cedars-Sinai Blog: Don’t delay getting a skin exam. Here’s what to expect