Vienna, Austria—The relative lack of progress in the treatment of malignant pleural mesothelioma is in marked contrast to developments in the treatment of lung cancer overall, but several ongoing studies using different immune-based therapies have shown promise in the treatment of this type of cancer, according to Raffit Hassan, MD, Co-Chief, Thoracic and Gastrointestinal Oncology Branch, Senior Investigator, and Head, Thoracic and Solid Tumor Immunotherapy Section, National Cancer Institute Center for Cancer Research, Bethesda, MD.
The majority of patients with mesothelioma present with advanced disease and are not candidates for surgery. Currently, the only regimen approved by the FDA is pemetrexed plus cisplatin, which has shown a median overall survival of approximately 1 year. No drug has been approved for the treatment of mesothelioma since 2004, Dr Hassan reported at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer.
Several ongoing studies are evaluating immune checkpoint inhibition in mesothelioma, “but these are very small studies, and we need randomized clinical trials in order to define the role of these agents in mesothelioma,” said Dr Hassan.
But there are other, perhaps more promising, immune-based approaches, such as mesothelin immunotherapy. Dr Hassan has played a major role in validating the tumor differentiation antigen mesothelin as a target for cancer therapy and, in turn, the development of mesothelin-targeted immunotherapy. These therapies, developed particularly for patients with mesothelioma, also have a broad application for treating solid tumors.
Mesothelin is highly expressed in many solid tumors and in 100% of epithelial mesothelioma. In addition, approximately 80% of pancreatic adenocarcinomas express it, as well as 70% of ovarian cancers and approximately 50% of lung adenocarcinomas. The expression of mesothelin in normal human tissues is limited to mesothelial cells that line the pleura, pericardium, and peritoneum.
“The most important thing in terms of targeted therapy is the expression of mesothelin. It is really hard to find tumor antigens that can be targeted, but the fact that it is not expressed on an important organ makes it a good target for antibody-based therapies,” Dr Hassan explained.
SS1P is an immunotoxin with high affinity for mesothelin, and it is cytotoxic to mesothelin-expressing tumor cells of patients with mesothelioma and ovarian cancer. In a phase 1 clinical trial including 34 patients with mesothelin-expressing cancers who had not responded to standard therapies, minimal antitumor activity was observed, because SS1P was found to be immunogenic, with 30 (88%) of 34 patients developing neutralizing antibodies after cycle 1.
Ways to prevent antibodies to an immunotoxin include combining it with immunosuppressive drugs or modifying the toxin to make it less immunogenic. If patients are treated with pentostatin and cytoxan before SS1P, they develop fewer antibodies to SS1P, and some patients have shown a durable tumor response.
“However, it would be better to have a less immunogenic immunotoxin so that there is no need to use immunosuppressive drugs,” Dr Hassan noted.
According to Dr Hassan, LMB-100 is such a molecule, and it shows promise for patients who have not responded to standard therapy. It is an improved immunotoxin-targeting mesothelin that has shown reduced antigenicity, and much higher doses have been tolerated in mice than with SS1P.
“Also, when it is combined with a nab-paclitaxel, you get pretty dramatic tumor regression using a mesothelioma patient-derived xenograft model,” he added.
Where Do We Stand with Mesothelin-Targeted Therapies?
All eyes are on 2 antimesothelin agents currently in clinical trials for the treatment of pleural mesothelioma—amatuximab (first-line setting) and anetumab ravtansine (second-line setting).
In a single-arm phase 2 study of amatuximab plus pemetrexed and cisplatin as first-line treatment for malignant pleural mesothelioma, median overall survival was 14.8 months.
“Based on pharmacodynamics modeling, it appears you need to give the drug once a week,” Dr Hassan noted, which is currently being done in a randomized phase 2 trial of amatuximab as first-line therapy for pleural mesothelioma.
Anetumab ravtansine led to durable tumor regressions in a phase 1 study of patients with mesothelioma. Five (31%) of 16 patients treated with the maximum tolerated dose had a partial response, and 50% of patients who received it as second-line therapy responded. A randomized phase 2 trial of the drug as second-line therapy for pleural mesothelioma is open to enrollment.
Finally, CRS-207 has demonstrated safety in a phase 1 clinical trial, and is currently being analyzed in terms of progression-free survival and overall survival. CAR-T cell trials targeting mesothelin are also underway. Regression of large tumors and durable complete regression have been observed in mouse models, suggesting broad applicability to mesothelioma and other solid tumors.