Using Molecular Profiling to Study the Possibility of Targeted Therapies in Mesothelioma

Dean A. Fennell, MD, PhD

Dean A. Fennell, MD, PhD

Investigators at 3 medical centers in the United Kingdom are conducting an umbrella trial (MIST; NCT03654833) in which they are assessing multiple targets for treating patients with mesothelioma. The goal is to eventually develop new strategies for treating the disease.

The MIST study will occur in 3 stages. First, in the molecular screening stage, tumors are tested for predictive biomarkers. During stage 2, treatment is given to each patient based on the biomarkers uncovered in the first stage of the trial. In the final stage, the investigators will perform a genomic analysis using the DNA and RNA biopsies from tissue and blood. From these biopsies, there will be a development of molecular profiles used to identify biomarkers for response to treatment.

Various arms of the treatment stage of the trial are open, including an arm looking at PARP inhibition with rucaparib (Rubraca) in patients withBRCA1/BAP1-negative mesothelioma. This arm has already been completed and findings from this study are expected to be released next year.

The study is active with approximately 120 patients enrolled. Patients with mesothelioma who had prior chemotherapy are still being recruited. The primary outcome is disease control rate, which the investigators will assess using CT scans.

In an interview withTargeted Oncology, Dean A. Fennell, MD, PhD, professor and chair of thoracic medical oncology, University of Leicester and University Hospitals of Leicester NHS Trust, explained the need for the MIST trial and personalized treatment for patients with mesothelioma.

TARGETED ONCOLOGY: What options currently exist for treating patients with mesothelioma? Why is this such an unmet need?

Fennell: There is only one universal treatment that we use for mesothelioma and that's chemotherapy with pemetrexed and platinum, with either cisplatin or carboplatin. That comes from a licensed study from 2003. We have not seen any new studies leading to registration of licensed agents outside of Japan, where they have access to nivolumab (Opdivo) in the second line. Other than that, there are no second-line or beyond standards of care in the rest of the world.

TARGETED ONCOLOGY: What alterations are commonly seen in patients with mesothelioma?

Fennell: The most common mutation is in theBAP1gene, a deubiquitinase. In terms of copy numbers and loss of DNA material,CDKN2Ais the most common copy number alteration.

TARGETED ONCOLOGY: What targeted therapies have been considered to treat these alterations? Has there been any success with these agents?

Fennell: We're seeing some glimmers of success, certainly from the point of view of genetically-targeted therapeutics. A trial was run and completed last year by my colleague Majorie Zauderer, MD, of a BAP1-directed targeted therapy called EZH2 inhibition. This trial met its primary endpoint as a phase II trial. This trial suggests that a targeted therapy may work, at least against BAP1.

TARGETED ONCOLOGY: Can you discuss the MIST trial?

Fennell: We started a trial called the MIST trial, which is an umbrella study, whereby we'll be able to look at multiple targets concurrently, in the hope that we may be able to develop new targeted strategies.

This is one of the first trials that is taking patients prospectively and profiling them from a molecular point of view and then applying personalized treatments to these patients. We've now completed one of these [arms], which is a PARP inhibitor study and we plan to present those data next year in one of the major congresses.

We have other trials this month looking at CDKN2A as a target and, beyond that, immunotherapy combinations will feature within the group of trials that we're studying.

TARGETED ONCOLOGY: On the subject of personalized treatment of mesothelioma, is there any research you can highlight?

Fennell: One of the most important [new] strategies is the targeting of arginine metabolism. We have a global study at the moment called the ATOMIC study, which is led by Peter Szlosarek, MD, PhD [NCT02709512]. This is using an approach to essentially deprive the tumor of arginine, in the context of a genetic mutation ASS1 loss. We are waiting to see what the results of that study show.

TARGETED ONCOLOGY: What are the key points to take away from your presentation at WCLC?

Fennell: We know thatCDKN2Ais a very bad mutation to have. Patients do much worse with mesothelioma if they harbor this mutation. The preclinical evidence so far suggests that if you can restore the tumor suppressor, which has been lost by the mutation, that the tumor does not like that. [By restoring the tumor suppressor] we can slow down or in fact induce apoptosis or cell death within these tumors.

My hope is that with arm 2 of the MIST trial, in which we are looking at targeting CDKN2A in mesothelioma, we may be able to help these patients with poor prognoses live longer and have a better quality of life.

Reference:

Mesothelioma Stratified Therapy (MiST): A Multi-drug Phase II Trial in Malignant Mesothelioma (MiST). U.S. National Library of Medicine Clinical Trials website. clinicaltrials.gov/ct2/show/NCT03654833. Accessed September 18, 2019.