The Meso Foundation is happy to present this special guest blogpost from Lee M. Krug, MD, Associate Attending Physician in the Division of Thoracic Oncology, Department of Medicine at Memorial Sloan-Kettering Cancer Center in New York, New York and Director of the Mesothelioma Program at Memorial Sloan-Kettering Cancer Center. Dr. Krug has investigated multimodality approaches for patients with early stage malignant pleural mesothelioma, has led a multicenter U.S. trial of induction chemotherapy before extrapleural pneumonectomy, and has a current study testing the feasibility of chemotherapy followed by pleural radiation. Dr. Krug also has a strong interest in novel therapeutics for patients with more advanced disease, and is the principal investigator of an international, phase III trial of a histone deacetylase inhibitor, vorinostat. Dr. Krug led the committee for the National Comprehensive Cancer Network (NCCN) that established treatment guidelines for mesothelioma, and is currently the chairman of the Scientific Advisory Board and serves on the Board of Directors at the Meso Foundation.
The Annual Meeting of the American Society for Clinical Oncology (ASCO) was held in Chicago, IL from June 1-5, 2012. This is the largest meeting in oncology each year with over 25,000 attendees from all over the world. Several abstracts of interest to mesothelioma were presented, so I thought I would summarize the results of a few of the most interesting:
Randomized Phase II Trial of Pemetrexed/Cisplatin with or without CBP501 in Patients with Advanced Malignant Pleural Mesothelioma: CBP501 is a novel compound that enhances the ability of cisplatin to damage cancer cells. In this international trial, patients received treatment with standard chemotherapy (pemetrexed and cisplatin), or they received it in combination with CBP501. 63 patients participated in total; 40 were in the group with CBP501. The only additional side effect of CBP501 seemed to be a rash that occurred during the infusion. Forty percent of the patients who received chemotherapy plus CBP501 had tumor shrinkage as compared to 17% of the patients who received chemotherapy alone. The average time before the cancer grew back was 5.9 months in the CBP501 arm, and 4.7 months in the other arm. Although the patients who received chemotherapy alone fared less well than expected, the results seemed encouraging. Another similar trial with CBP501 has also been conducted in lung cancer and until those results become available later this year, plans for future trials are unclear.
Amatuximab, a Chimeric Monoclonal Antibody to Mesothelin in Combination with Pemetrexed and Cisplatin in Patients with Unresectable Pleural Mesothelioma: Results of a Multi-Center Phase II Clinical Trial: Mesothelin is a protein that is present at high levels on the surface of mesothelioma tumor cells. Amatuximab (previously known as MORAb-009) is an antibody that binds to mesothelin, tagging the cell for destruction by the immune system. In this trial, eighty-nine patients received treatment with the combination of pemetrexed, cisplatin, and amatuximab. After completing six rounds of chemotherapy plus the antibody, patients continued on treatment with the antibody alone. Twenty percent of patients experienced an allergic reaction or some other reaction during the infusion. Thirty-nine percent of patients had tumor shrinkage, and the average time before the cancer started to grow again was about 6 months. These results are typical for chemotherapy alone, and the benefit of amatuximab was difficult to tease out since this was not a randomized trial. However, a subgroup of patients stayed on amatuximab for a much longer time than expected, and the overall survival for all patients was also somewhat better than expected. Efforts are underway to find a biomarker that would help predict which patients are most likely to benefit from amatuximab, and future trials are being planned.
NGR-hTNF as Second-Line Treatment in Malignant Pleural Mesothelioma: Tumor necrosis factor (TNF) has long been known to have the ability to kill cancer cells by targeting the blood vessel cells in the tumor, but it is too toxic to administer in its native form. NGR-hTNF is a drug made by fusing TNF to a protein segment that lessens the toxicity and enhances its anti-cancer effects. In this trial, NGR-hTNF was given by itself either weekly or every three weeks to patients with mesothelioma who had previously received treatment with chemotherapy. Fifty-seven patients participated. Side effects were negligible. One patient had tumor shrinkage, though 25 had stabilization. The average time for tumor growth was 3 months. A large, international, phase III trial is ongoing in which patients who previously received treatment with chemotherapy are randomized to receive treatment with weekly NGR-hTNF or a standard chemotherapy treatment of the physician’s choice. Dr. Brahmer will be discussing this trial further as part of the Mesothelioma Podcast series on June 13, 2012 at 9pm EST.
A Phase II study of mTOR Inhibitor Everolimus (RAD001) in Malignant Pleural Mesothelioma: mTOR is a molecule that sends growth signals within a cell, and it is overstimulated in many different cancers including mesothelioma. Everolimus is a pill that blocks mTOR, and it is approved for the treatment of kidney cancer. In this study run by the Southwest Oncology Group, 61 patients previously treated with chemotherapy were enrolled and given everolimus. No patients experienced tumor shrinkage; forty percent had stabilization. However, treatment with everolimus did not significantly improve the progression time. Thus, everolimus was not effective for the treatment of mesothelioma, perhaps because other signaling molecules exist that may bypass mTOR. Newer agents that inhibit mTOR plus other molecules, like PI3 kinase, are in development and show some promise as a potential treatment in mesothelioma.