Targeted Therapy Making Progress with Pleural Mesothelioma

Future treatment of pleural mesothelioma cancer continued its move toward a more personalized, targeted approach with the latest results from a multi-center clinical trial involving tazemetostat, a novel protein inhibitor.

Tazemetostat, also known as the brand name Tazverik, showed impressive effectiveness in a second line setting for patients with the BAP1 genetic mutation.

The disease control rate for patients was 54.1% at 12 weeks and 32.8% at 24 weeks, numbers that exceeded expectations. There currently is no FDA-approved second-line treatment for pleural mesothelioma, an aggressive cancer with no cure caused primarily by an exposure to asbestos.

Lancet Oncology published a study on May 16 detailing the phase II clinical trial results.

“I think this is an incredible development, actually,” co-author Dr. Dean Fennell, chair of thoracic and medical oncology at University of Leicester and University Hospitals in the United Kingdom, told The Mesothelioma Center at Asbestos.com. “It’s taking the whole field (of therapy) in a different direction.”

Blocking the Enzyme EZH2

Tazemetostat works by blocking the enzyme EZH2, which inhibits the genes that normally would suppress cancer tumor growth. The clinical trial was designed to target patients with a mutated BAP1 gene, which typically leads to a higher expression of EZH2 and an accelerated growth of the cancer.

It was not designed as a one-size-fits-all therapy, such as standard-of-care chemotherapy most often used with mesothelioma, but as precision medicine. The BAP1 gene mutation is found in just over half of patients with mesothelioma.

“Targeted therapy, that idea, is very underdeveloped with mesothelioma,” Fennell said. “This is one of the few examples of a single gene, BAP1, and we’ve tried to target it with a drug. In future treatment, what we may begin to see is more of a stratification, or a splitting of the disease, into different groups that respond well to particular treatments.”

Tazemetostat FDA Approved

Tazemetostat already has been approved by the U.S. Food and Drug Administration for treating synovial sarcoma, non-Hodgkin lymphoma and certain genetically defined solid tumors.

This latest clinical trial was conducted at seven different centers throughout the United States and several others in the United Kingdom and France. The U.S. locations were City of Hope Cancer Treatment & Research Center in Duarte, California; Mayo Clinic in Rochester, Minnesota; UCLA Comprehensive Cancer Center in Los Angeles; University of California-San Francisco Medical Center; Dana Farber Cancer Institute in Boston; Memorial Sloan Kettering Cancer Center in New York City; and Massachusetts General Hospital in Boston.

The trial included 70 patients with the BAP1 gene mutation, all of whom were previously treated, but either the cancer had returned or it had stopped responding to treatment.

After the start of treatment with tazemetostat — given orally in 21-day cycles — the median progression free survival was 18 weeks and the median overall survival was 41 weeks. Less than 5% of the patients experienced serious side effects related to the drug.

“We saw good response, tumors shrinking and the drug clearly had activity,” Fennell said. “Some of the patients definitely benefited from the treatment. Yes, there is  real potential here.”

BAP1 Genetic Mutation Is Key

The 54.1% disease control rate at 12 weeks was defined as either complete response, partial response or stable disease. The stable disease rate by itself was 62%.

Epizyme is the pharmaceutical company producing the drug and promoting it as a potential second-line therapy for several cancers already treated with chemotherapy.

The BAP1 genetic mutation is also being targeted with other drugs on mesothelioma patients. The University of Florida, for example, is conducting a phase II trial to determine the effectiveness of niraparib, another protein inhibitor, on several cancers, including mesothelioma.

There is an ongoing clinical trial in France, at Hospices Civils de Lyon, studying the use of talazoparib, a similar drug, for mesothelioma patients with the BAP1 mutation. Several locations in the United Kingdom are studying the effectiveness of rucaparib with BAP1 mutations and mesothelioma.

The National Cancer Institute is studying the BAP1 germline mutation and its predisposal to mesothelioma, looking for ways to effectively identify the cancer earlier than normal and making it more treatable.

The most effective proven treatment today is still a multidisciplinary approach that would include surgery, chemotherapy and radiation, but only a third of those diagnosed even qualify for aggressive surgery.

Second line treatments, such as tazemetostat, are still being watched closely, particularly after this latest clinical trial.

“This is the first targeted therapy we’ve seen to have a real effect on slowing or stopping pleural mesothelioma,” Dr. Marjorie Zauderer, study co-author from Memorial Sloan Kettering, said in a press release. “Although targeted therapies have been successful with many other cancers, with mesothelioma, there aren’t many alterations we can target. Now that is changing.”

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