Mesothelioma is a cancer that most commonly starts in the pleura, layers of tissue that cover each lung. More rarely it starts in the peritoneum, the layer of tissue in the abdomen that surrounds the digestive system organs. Yet no matter where it presents patients typically receive a poor prognosis of 12-21 months upon diagnosis. In this interview you can discover the current treatment options for mesothelioma, advancements that have been made in immunotherapy for this disease and what is being done to advance patient selection for this treatment modality.
Could you tell us about the current treatment options for mesothelioma?
There are several trials now incorporating anti-angiogenic agents and immunotherapies into the standard treatment paradigms for mesothelioma. However standard therapy is still platinum/pemetrexed with the addition of bevacizumab if available.
Following this, immunotherapy is becoming a more realistic option. There are currently no approved immunotherapies, however some patients have been able to access drugs such as pembrolizumab (Keytruda) through co-payment schemes.
More novel trials are investigating antibody drug conjugates where chemotherapy is bound to a targeting antibody. This way the chemotherapy is only delivered to cancer cells, potentially sparing the side effects which occur from normal cell death.
Could you tell us about some of the anti-angiogenic agents for malignant mesothelioma?
Currently the only available therapy is an antibody to VEGF termed bevacizumab. It was shown to be effective in a large French study although has not changed treatment paradigms in many countries. Many other anti-angiogeneic agents have been trialed including thalidomide, sorafeninb, sunitinib and others (reviewed here Chia et al Targeting the vasculature: antiangiogeneic agents for malignant mesothelioma 2016).
The large Phase II LUME Meso study was positive and has launched a Phase III trial. In LUME Meso, patients either received placebo or the pan VEGF/FGF/PDGF/c-kit inhibitor nintedanib in combination with cisplatin/pemetrexed chemotherapy. The study met its primary endpoint with a significant prolongation of progression free survival. The Phase III results are now eagerly awaited. Nintedanib is an oral drug and much better tolerated than bevacizumab. If the Phase III is positive, it will likely change practice.
What advancements have been made in immunotherapy for mesothelioma?
The excitement surrounding immunotherapy in mesothelioma is really based around some small studies where some patients achieved remarkable results. These results in a small group are exciting as there have been no real changes to management in mesothelioma since 2003. The initial excitement comes from a small initial study called Keynote-028 in which 25 selected patients received the PD-1 inhibitor pembrolizumab. Five achieved a partial response (20%) and 13 (52%) had disease stabilisation. More recently the MAPS-2 study was presented at Annual Society of Clinical Oncology Annual meeting (2-6 June 2017, IL, USA) and demonstrated that immunotherapy combinations may have greater role than single agent immunotherapy. This trial randomized patients after chemotherapy to receive either single agent nivolumab or the combination of nivolumab+ipilimumab.
The MAPS2 study was a large study and very inclusive allowing the more aggressive subtypes (sarcomatoid, biphasic) to be included. The data are still very immature, but the signal suggests that combining Nivo+Ipi may have a more favorable response rate and disease control rate than nivolumab alone (25.9% vs 18.5% and 50% vs 44.4% respectively). That said, the combination therapy arm was not statistically powered to be compared to the single agent arm and there were three treatment related deaths.
Although there is a lot excitement about immunotherapy, you have previously cautioned that we should still keep in mind that not all patients respond well to this therapeutic modality. Could you tell us what research is being done to advance patient selection for immunotherapy in mesothelioma?
The next steps are to combine agents. Immunotherapy+chemotherapy has been shown to be effective in lung cancer, immunotherapy + anti-angiogenics or indeed combinatinos of all these agents. Certainly it seems that a multipronged approach may be necessary for some mesotheliomas, although we must not forget that the more the number of combinations the higher the risk of side effects.
What advancements do you hope will be made treatment options for mesothelioma patients over the next decade?
I am very optimistic that we are closing in on therapies that will enable mesothelioma to become more of a chronic disease than a rapid killer. I have witnessed some amazing responses to immunotherapy and unlocking factors that enhance or enable immune activation promises to control and perhaps even cure some patients.
Any closing comments?
More research is needed. I would caution clinicians from changing practice based on immature data. It will be important to see the updates of these and other studies being undertaken. I am hopeful that our treatment paradigms are close to changing, however.
Associate Professor Thomas John is a medical oncologist specializing in lung cancer, mesothelioma and genetics. He received his medical degree from Monash University in 1996 and PhD from University of Melbourne in 2008. He underwent post-doctoral research using PDX models of NSCLC under the guidance of Prof Ming Tsao and Frances Shepherd in Toronto. He has received awards from the American Society of Clinical Oncology as well as the American Association for Cancer Research for his research into lung cancer and melanoma. He leads a laboratory group researching both lung cancer and mesothelioma with an interest in immunology, methylation and novel targets. He is funded by the National Health and Medical Research Council and the Cancer Council of Australia.
Financial disclosures: Advisory boards and Honoraria Pfizer, Merck, BMS, AstraZeneca, Novartis. No conflicts of interest.