Taking Aim at Malignant Pleural Mesothelioma

An Expert Interview With Lee M. Krug, MD

Shira Berman; Lee M. Krug, MD


December 07, 2011

Editor's Note: Malignant pleural mesothelioma is a rare, difficult-to-treat cancer that is seen primarily in older men who were exposed to asbestos many decades earlier. In 2003, the addition of pemetrexed to cisplatin as a first-line treatment for patients with nonresectable mesothelioma was shown to improve overall survival,[1] but the median survival is still only about 1 year and there is no standard of care for patients whose disease continues to progress.[2]

In an attempt to improve outcomes, researchers have conducted a number of clinical trials evaluating angiogenesis inhibitors, tyrosine kinase inhibitors, histone deactylase (HDAC) inhibitors, and other targeted therapies, but positive results remain elusive. Most recently, the HDAC inhibitor vorinostat, which showed good results in a phase 1 trial,[3] demonstrated no clinical benefit in a large phase 3 trial.[4]

At the same time, however, investigators are beginning to better understand the biology of the disease and have identified mutations in the gene encoding BRCA1-associated protein-1 (BAP1) that might predispose patients to mesothelioma developing.[5,6]

In an interview with Medscape, Lee M. Krug, MD, associate attending physician in the Division of Thoracic Oncology at the Memorial Sloan-Kettering Cancer Center in New York, discussed what has been learned from recent clinical trials, how new research findings might influence strategies moving forward, and how practicing clinicians should optimally approach patients with this disease.

Medscape: In the past few years, a number of small, early-phase clinical trials of targeted therapies for patients with mesothelioma have failed,[7,8,9] and you reported negative results from a large phase 3 trial of vorinostat at the recent European Multidisciplinary Cancer Congress.[4] Why has it been so difficult to identify new therapies for patients with mesothelioma?

Lee M. Krug, MD: Mesothelioma is a rare cancer, so it is difficult to make advancements in treatment. Few large trials can be conducted because there are a limited number of patients to enroll, and industry support for drug development and research grants to study disease mechanisms are tough to come by. Because of all these factors, research into how to improve therapy for this disease has lagged, and so outcomes for patients with mesothelioma remain poor.

There have been a number of targeted therapies studied, mostly in phase 2 trials. There was good rationale for studying these drugs in this disease, even though the trial results did not turn out to be positive. A few trials are still underway, including a phase 3 trial of pemetrexed/cisplatin ± bevacizumab being conducted in France,[10] although final data from a randomized phase 2 trial combining bevacizumab with gemcitabine/cisplatin did not show a survival benefit with the combination.[11]

With vorinostat, data from preclinical studies suggested a scientific rationale for studying HDAC inhibitors in mesothelioma,[12] and we had hints of activity in a small phase 1 trial,[3] but the benefit was not borne out in the large phase 3 trial.[4]

I think we have learned that it is not sufficient to use therapies that are effective in other cancers, even if there seems to be a good rationale for using them. We need to look more closely at the biology of the disease and try to develop treatment strategies that are directed more specifically at mesothelioma.

Medscape: Two papers published in Nature Genetics described genetic mutations in BAP1 and the potential role that they may play in the development of mesothelioma.[5,6] Is that a direction that research should move into -- Identifying genetic mutations and developing drugs that target those mutations?

Dr. Krug: Those 2 papers were extraordinarily important, probably the biggest news in mesothelioma this year. They actually identified BAP1 in 2 different settings. One group, led by Mark Ladanayi, a pathologist here at Memorial Sloan-Kettering Cancer Center, showed that about 20%-25% of asbestos-associated tumors harbored BAP1 mutations, and the second group found that germline BAP1 mutations are also seen in families where there was a family history of mesothelioma but no clear-cut asbestos exposure.

Interestingly, there was an overlap with ocular melanoma -- the same mutation was seen in patients with ocular melanoma and in families that have both mesothelioma and ocular melanoma in their family trees.

It is still too early to know the clinical implications of this. We do not know exactly how BAP1 functions or how best to target it, but certainly it is a major research focus that we are actively pursuing here and that others are pursuing as well.

Medscape: The next step would be to develop drugs that target BAP1 or other molecular changes specific to mesothelioma.

Dr. Krug: Absolutely. The greatest successes in other malignancies were seen when we identified mutations and then figured out how best to target them. There are examples in every solid tumor, most recently of course, in melanoma with vemurafenib and BRAF mutations.[13]

It would be great if we could identify similar types of targeted therapies in mesothelioma for select groups of patients. BAP1 is certainly one potential target because it has a very high rate of mutations. We also know that mesothelioma harbors NF2 mutations at a high rate,[14] which may indicate usefulness for some drugs, such as mTOR inhibitors, that signal through that pathway. In fact, there is a line of interest in mTOR inhibitors in mesothelioma -- activity has been seen in a phase 1 trial of GDC-0980, a combination mTOR/PI3K inhibitor,[15] and a phase 2 trial of the mTOR inhibitor everolimus is underway.[16] Results of these and other studies may give us some insight into future directions for therapy.

Medscape: At a number of different points, the National Comprehensive Cancer Network (NCCN) guidelines emphasize the importance of patients being treated by a multidisciplinary team of physicians who have experience in treating patients with mesothelioma. Why is this so important?

Dr. Krug: It is crucial for patients with mesothelioma. The management approach might seem straightforward for patients who have obviously advanced disease or for those who are too frail to undergo any kind of multimodality therapy. Oftentimes, however, the approach is not so clear, and being able to evaluate patients in a multidisciplinary setting by a whole team of people who are focused on this disease offers a more well-rounded treatment approach.

Medscape: For oncologists practicing in the community, which is where the vast majority of patients are seen -- should they refer the patient or consult with a larger center that has such a team in place?

Dr. Krug: If it is at all possible, I would encourage referral or consultation. There is a fair bit of nihilism among oncologists with regard to available treatments for patients with mesothelioma. But, in fact, sometimes we can do more than you might think.


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