UK Study Matches Mesothelioma Treatments to Genetic Profile

University of Leicester researchers soon will open the first molecularly stratified clinical trial for malignant mesothelioma with the hope of moving the future of treatment toward more personalization.

The phase II trial in the United Kingdom is designed to match therapy with a patient’s specific genetic profile.

“We’re trying to bring the right drug to the right patient at the right time,” Professor Dean Fennell, chair of thoracic medical oncology at Leicester and chief trial investigator, told Asbestos.com. “We need to find different treatments that work for different people. This is a step in that direction.”

The British Lung Foundation funded the clinical trial, which is expected to start early in 2019 and conclude by 2022.

“The problem with mesothelioma has been the one-size-fits-all approach to drug development, and it hasn’t worked,” Fennell said. “We are now entering the era of personalized treatment for many cancers, including this one.”

Mesothelioma Treatment Advances Overdue

A combination of chemotherapy with cisplatin and pemetrexed is still the only FDA-approved treatment for unresectable mesothelioma. The treatment hasn’t changed in 14 years, contributing to the typically dismal prognosis.

Various experimental drugs — particularly immunotherapy drugs — have shown great effectiveness in select individuals but little effectiveness for the majority of patients.

The lack of consistency, in part, has been attributed to specific genetic mutations and an inability to identify biomarker targets.

Mesothelioma tumors in some patients are drug sensitive but not in others with the same histology.

This trial is designed to help researchers better understand the genomic basis of drug response. It involves coupling predictive biomarkers with targeted therapy.

“The simple fact is that not all patients with mesothelioma are the same. Some will have a gene that allows a response to a particular drug, while others do not have that,” Fennell said. “But there may be another drug for which they may respond.”

Study Involves Three Steps, Four Different Therapies

The mesothelioma clinical study will involve three steps:

• Stage 1: Biomarker testing and molecular profile analysis based on tissue sample. The result will be used to classify each patient into one of several different treatments.

• Stage 2: Treatment type and its frequency will be delivered based on the specific molecular profile of each patient.

• Stage 3: Genomic analysis of why a patient responded or didn’t respond to treatment. And what factors led to eventual drug resistance.

The clinical trial will begin with four separate treatments, and patients could receive all four treatments sequentially, depending upon their genetic profile.

The four treatments include:

• Rucaparib: FDA approved the drug in 2018 for certain types of ovarian cancer. Rucaparib targets a DNA repair enzyme that enables continued cell replication.

• Abemaciclib: Used for certain types of breast cancer. Abemaciclib targets the tumor suppressor protein known as p16INK4a.

• Pembrolizumab and Bemcentinib: This immunotherapy combination is already used for breast cancer and certain lung cancers.

• Atezolizumab and Bevacizumab: Another immunotherapy combination that targets a mutation of PD-L1, a cell-surface protein that regulates the immune system.

More Treatments Will Be Added to Trial

Although the study will begin with only four treatment options, Fennell believes it will expand to several more throughout the trial, depending on the genetic mutations found.

“We’re seen some really exciting developments in biology in recent years. The knowledge of genetics today puts us in a much better position than just a few years ago,” he said. “This is just the beginning.”

To qualify for the trial, patient must have an expected survival time of at least 12 weeks and received at least one prior round of chemotherapy.

The trial will start at the University of Leicester, but it is expected to expand into multiple cancer centers across the U.K.

“I think this eventually will change the way mesothelioma is treated,” Fennell said. “We have to answer, not just who responds to treatment, but why they respond. There are different drugs out there that will help different patients. We have to put it together.”

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