Mesothelioma Clinical Trials Test Targeted Gene Therapy

For some patients, the future of mesothelioma cancer treatment may hinge on a pair of phase I clinical trials that opened earlier this year to study promising new drugs targeting specific genetic mutations.

Precision medicine may finally be taking hold with malignant mesothelioma, clearing the path for significant, long-overdue advancements.

The one-size-fits-all approach is fading.

“There is some realistic hope now for patients,” Dr. Anthony Tolcher, co-founder of NEXT Oncology in San Antonio, told The Mesothelioma Center at Asbestos.com. “I am very optimistic. New avenues for treatment are opening up.”

Pleural mesothelioma, which is caused by exposure to asbestos, is a rare cancer with no cure and a median survival of less than a year. It is typically treated with standard chemotherapy.

Although a multimodal regimen is optimal, less than a third of patients qualify for aggressive surgery and only a small percentage are helped significantly by the U.S. Food and Drug Administration-approved immunotherapy combination of Opdivo and Yervoy. There is plenty of room for mesothelioma treatment improvements.

Studies Focus on Genetic Mutations

“The mysteries behind mesothelioma are slowly revealing themselves and providing us with avenues for treatment,” Tolcher said. “There are a number of things coming along that look very promising.”

These latest clinical trials are part of that promise.

Tango Therapeutics is sponsoring a first-in-human clinical trial using the drug TNG908 for advanced solid tumors – including mesothelioma – for patients with a methylthioadenosine phosphorylase, or MTAP, genetic mutation.

Ikena Oncology is sponsoring a first in-human clinical trial studying IK-930, another small molecule agent, for advanced solid tumors – also including mesothelioma – for patients with neurofibromatosis type 2, or NF2, deficiency, another genetic mutation.

Each drug is designed specifically to target those mutations. Tolcher is involved with both trials.

The U.S. Food and Drug Administration recently granted IK-930 Fast Track Designation, which could expedite its review of the drug and lead to a speedier approval for mesothelioma cancer.

According to BioPortal, a highly regarded medical research tool for cancer genomics, the MTAP mutation is found in 33.3% of mesothelioma patients and the NF2 mutation is present in a different 32% of mesothelioma patients.

Both clinical trials are in the early stages and currently accepting new patients. The drugs have shown considerable promise in the laboratory, and the findings were presented at the American Society of Clinical Oncology annual meeting earlier this month.

“There are no guarantees when it comes to effectiveness this early in a study, but if you compare it to what I call blind chemotherapy, or immunotherapy, which has had a somewhat disappointing response rate with mesothelioma, these targeted therapies should be viewed as much more promising,” Tolcher said. “They are something a patient should think about and take hope in.”

Research Advances Mesothelioma Treatment

The lack of an effective treatment for mesothelioma in the past has been partially attributed to specific genetic mutations and an inability to identify biomarker targets.

Biomarker testing, however, has advanced considerably and become more accepted with mesothelioma, allowing new synthetic drugs to better target personalized, genetic profiles.

“Patients will go into these trials somewhat cautiously, but if standard therapy has failed, they should give it a try,” Tolcher said. “The thinking is often, ‘If it doesn’t benefit me, hopefully the research will benefit others with the same disease.’ The vast majority of patients who go into these early trials become part of the solution.”

Both phase I studies involve medication given orally and are designed to determine effective dosage levels and tolerability, along with preliminary anti-tumor activity.

Clinical Trials Ongoing at Multiple Centers

The multicenter study of TNG908 and the MTAP mutation will be hosted by NEXT Oncology – co-founded by Tolcher – in either San Antonio or Fairfax, Virginia. Patients also can enroll at MD Anderson Cancer Center in Houston or Tennessee Oncology in Nashville.

Ikena’s study of IK-930 and the NF2 deficiency is being done at sites in Grand Rapids, Michigan; Boston; Philadelphia; Nashville; Houston and San Antonio.

Earlier personalized therapy targeting a different mutation showed considerable promise with mesothelioma. In a phase II trial at multiple sites, patients identified with the BAP-1 genetic mutation received the novel protein inhibitor tazemetostat in a second-line setting and more than doubled the normal median disease control rate.

Genetic testing has changed the face of overall cancer care in recent years, although mesothelioma has been slow to benefit. Many still believe it represents the future of oncology and the future of mesothelioma treatment.

“We are in the golden age of drug development. People don’t realize how fast medical science is moving right now,” Tolcher said. “Never have there been so many new drugs being developed for cancer and in trials at the same time. This is something amazingly different than any other time in the history of cancer medicine.”

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