Mesothelioma remains an invariably fatal cancer, but advances in treatment are improving overall response, progression free survival, overall survival, and quality of life. Further improvements in outcomes will depend on continuing advances in diagnosis and treatment and eradication of exposure to asbestos.
“Mesothelioma affects about 30,000 patients worldwide,” said Wanda Cui, MBBS, Peter MacCallum Cancer Centre, Melbourne, Australia. “Asbestos continues to be used in many regions of the world, which has implications on cancer care into the future.”
The approval of ipilimumab-nivolumab as first line treatment in 2021 dramatically improved patient outcomes, Dr. Cui said during a Sunday symposium on mesothelioma, but the primary therapeutic approaches—chemotherapy, chemotherapy plus antiangiogenics, immune checkpoint inhibition, and chemo-immunotherapy—all have different advantages.
Chemo-immunotherapy offers the best overall response rates, up to 56%, and the best overall survival, up to 20.5 months, in clinical trials, but has yet to be proven superior to chemotherapy or immunotherapy alone.
Chemotherapy plus bevacizumab shows the longest progression free survival, 9.2 months, with overall survival of 18.8 months.
Immune checkpoint inhibition, specifically the combination of nivolumab and ipilimumab, offers the greatest improvements in quality of life and overall survival of 18.1 months, compared to chemotherapy alone.
Data on PD-L1 expression as a prognostic factor are mixed and tumor mutation burden has limited utility as a biomarker. Early trials suggest that a high four-gene inflammatory score including CD8A, STAT1, LAG3, and CD274 genes, is associated with better results from checkpoint inhibition, but prospective, confirmatory studies are needed.
Pathological assessment of mesothelioma is also improving. The 5th edition of World Health Organization Classification of Tumours: Thoracic Tumours, published in 2021, introduces new insights into benign and preinvasive mesothelial proliferations and a new definition of mesothelioma in situ (MIS). According to the new edition, MIS diagnosis should be based on biopsy of 100–200 mm2 from multiple sites rather than small biopsies or cytology alone.
“Immunohistochemical or molecular analysis for BAP1 and CDKN2A are essential,” said Francoise Galateau Salle, MD, professor of pathology, MESOPATH College, Unité de Pathologie Moléculaire et de Researche sur le Cancer de Lyon, Lyon, France. “You can see invasion on cytology, but you can see a 50% increase in MIS if those markers are queried.”
The term “malignant mesothelioma” is no longer acceptable, Dr. Salle added, and should be replaced by “mesothelioma” for all uses.
Other changes include the use of four histologic types: epithelioid, biphasic, sarcomatoid, and desmoplastic. Grading—high or low grade—should be reserved for epithelioid mesothelioma and not used with the other three types. Pleomorphic cytological features indicate worse prognosis and can be seen in both epithelioid and sarcomatoid subtypes. Molecular characteristics are emerging as potential indicators for therapeutic strategies, but they are not yet ready for clinical use.
Randomized trials for recurrent mesothelioma have resulted in poor results historically, but more recent data in chemotherapy, immunotherapy, and targeted therapy show promise.
For example, combination gemcitabine and ramucirumab has yielded improved progression free and overall survival compared to gemcitabine alone, said Dean Fennell, PhD, professor and director of the Mesothelioma Research Programme, University of Leicester, Leicester, UK. And vinorelbine shows good disease control but requires an intact spindle assembly checkpoint, he said. During mitosis and meiosis, the spindle assembly checkpoint maintains genome stability.
“There are some patients who benefit, but who are they?” Dr. Fennell asked. “Cells that are selected for resistance to vinorelbine have an accelerated cellular proliferation, implying that they have a dysfunctional spindle assembly checkpoint. We are trying to understand the mechanisms of resistance in these patients, and thereby identify the ones you want to avoid giving vinorelbine to.”
Immune checkpoint inhibition is the standard first-line approach to mesothelioma, but PD-L1 levels do not predict overall survival for patients treated with nivolumab.
“The future has to be about trying to reactivate host immunity,” Dr. Fennell said. “AXL (anexolekto) and VEGF (vascular endothelia growth factor) as immunosuppressive modulators and targets and PARP (poly ADP ribose polymerase) inhibitors may have a role to play in second line therapy.”
Targeted therapy approaches have been less successful in mesothelioma compared to lung cancers in part because of its discrete genetic landscape. Most lung cancers feature gain-of-function mutations, Dr. Fennell said, while mesothelioma more often features loss-of-function mutations. Loss-of-function mutations can be more difficult to target but are not invulnerable.
“We have hit that mark in the past, and we can do it again in the future,” he said.
CAR (chimeric receptor antigen)-T cell and TruC (T cell receptor fusion constructs) are the newest frontiers in mesothelioma and other solid tumors. CAR-T cell approaches have been challenging in solid tumors, but new binding targets may make a difference in adoptive T cell therapy.
The cell surface glycoprotein mesothelin is highly expressed in multiple solid tumors, including mesothelioma, said Raffit Hassan, MD, senior investigator at the National Cancer Institute. In normal tissue, mesothelin is expressed only in the mesothelial cells of the pleura, peritoneum, and pericardium, making it an attractive target. Patients in early trials have largely shown stable disease, but 12.5% of patients had partial response following off-protocol use of pembrolizumab with median overall survival of 23.9 months. A phase II study of CART followed by pembrolizumab is under way.
TruC is the latest approach in adoptive T cell therapy, with strong preliminary results in a Phase I study of Gavo-cel with 81% disease control rate and 31% overall response rate by investigator assessment. A phase II study is still enrolling. “Mesothelin is an excellent target for T cell therapies, not just in mesothelioma but in other solid tumors as well,” Dr. Hassan said. “Better patient selection may have an effect on outcomes.”
