Tazemetostat for Pleural Mesothelioma Shows Encouraging Results

Mesothelioma is a rare, aggressive cancer affecting the lining that surrounds organs. The most common form of the disease, pleural mesothelioma, develops in the tissue lining the lungs. The disease is very difficult to treat because it does not grow as a solid tumor and is usually not possible to remove with surgery. It can be controlled with drugs and radiation therapy but not cured. More than 50% of pleural mesotheliomas have a mutation called BAP1.

Now results of a clinical trial suggest that a drug called tazemetostat (Tazverik®) could be effective in a significant portion of people with pleural mesothelioma. The phase 2 trial, led by Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Marjorie Zauderer, showed that tazemetostat could control the disease in people whose pleural mesothelioma cells contain a BAP1 mutation.

“This is the first targeted therapy we’ve seen to have a real effect on slowing or stopping pleural mesothelioma,” Dr. Zauderer says. “Although targeted therapies have been successful with many other cancers, one problem with mesothelioma has been that there aren’t many alterations we can target. Now that is changing.”

The drug was given to 74 people whose cancer contained a BAP1 mutation and whose disease had progressed after they had received chemotherapy. The results were better than expected. Dr. Zauderer said that based on earlier trials of similar patients, doctors had expected tazemetostat to control the disease — keep it from getting worse — in 35% of people after 12 weeks. But in this new study, the drug controlled disease in 51% of patients.

Tazemetostat has already been approved by the FDA for certain types of lymphoma and sarcoma. It can be taken as a pill, and people in the trial reported very minimal side effects. Results of the study were published May 16, 2022, in the journal Lancet Oncology.

“Mesothelioma usually moves rapidly, with an average survival of around 12 to 14 months,” says Dr. Zauderer. “A big proportion of people in the trial had stable disease or even shrinkage of their cancer for more than six months — and this is after they have already exhausted the standard treatments.”

Tumor Testing Yields a Target

The clinical trial grew out of earlier research at MSK by physician-scientists Marc Ladanyi and Ross Levine. In 2011, Dr. Ladanyi, an experimental pathologist, found that 50% to 60% of pleural mesothelioma tumors carry a BAP1 mutation. Four years later, Dr. Levine’s team found that when BAP1 is inactivated in mice, the levels of a protein called EZH2 go up and cause mesothelioma cells to grow out of control. Dr. Levine’s lab also showed that blocking EZH2 could inhibit the growth of these tumors.

“After making their findings, Dr. Levine and Dr. Ladanyi were able to connect with thoracic surgeon [and mesothelioma specialist] Prasad Adusumilli and me, and we worked to quickly translate these findings into a clinical trial,” Dr. Zauderer says.

She explains that tazemetostat will likely be used in combination with other drugs. Studies are in progress testing the medication in combination with immunotherapy drugs called checkpoint inhibitors.

But for some people in the trial, tazemetostat provided a benefit by itself — especially for such a lethal disease. “For a fair amount of people, the effect lasted quite some time,” Dr. Zauderer says.

Dr. Zauderer says MSK’s comprehensive approach to profiling tumors makes it possible to unearth new targets and begin testing drugs in a short time.

“After we found out how common BAP1 was in mesothelioma, I took action to make sure every mesothelioma case at MSK was tested for the mutation,” she says. “That way, when a drug like tazemetostat becomes available for testing, we have already identified who may benefit. All this testing — genetic, molecular, and other types of profiling — yields information that can prove useful if a new treatment pops up.”