First Immunotherapy Expected for the treatment of Malignant Pleural Mesothelioma

Accounting for approximately 80% ? 90% of all mesothelioma cases, malignant pleural mesothelioma or MPM is a rare but aggressive cancer. It is usually associated with occupational exposure to asbestos fibers and develops in the thin layer of tissue surrounding the lungs known as the pleura. Following exposure, these fibers accumulate in the body which causes chronic inflammation, leading to cellular and genetic damage that, in turn, may ultimately lead to serious asbestos-related diseases and cancer.

The peak of asbestos use was between the 1960s and the 1980s. In 1973 the demand of asbestos in the United States peaked at 804,000 tons. Worldwide demand for asbestos peaked in around 1977 when 25 countries produced nearly 4.8 million metric tons while industries in more than 85 countries produced thousands of products that included asbestos.

By the late 1970s, both demand and production of asbestos related products dramatically declined throughout the industrialized nations when the public began to understand the connection between exposure to asbestos and certain diseases such as malignant pleural mesothelioma. In the United States, this decline resulted in the closure of the last U.S. asbestos mine in 2002, ending more than a century of the country?s asbestos production, leading to a reduction of domestic consumption of asbestos to about 2,400 metric tons in 2005.

Early understanding
Medical understanding of the link between asbestos and disease did not exist when the modern development of asbestos industry started in the 1880s. Asbestos was generally thought to be a safe and useful.? Just as in other industries in the late 1900s, the mining and manufacturing of products that included asbestos included dust. And dust in an industrial setting, like the mining of coal, quartz, and asbestos and the use of cotton, was understood to be dangerous. But these dangers remained largely uncontrolled. As a result, in many industries fibroses, known as occupational dust diseases of the lungs, assumed epidemic proportions in a number of industries.

One of these fibroses was asbestosis – a form of pneumoconiosis or dust disease of the lung caused by asbestos. Asbestosis, a chronic and progressive condition, was first diagnosed among British factory workers in 1900. However, it was not named until 1924 when W.E. Cooke, a pathologist at Wigan Infirmary, gave it the name that clearly linked it to the inhalation of asbestos dust.[1][2]

Banning asbestos-containing products
Although clear medical evidence in the 1930s started to linked asbestos exposure to mesothelioma, and the United Kingdom took steps to protect workers in the 1930s by installing ventilation and exhaust systems, in the United States the federal government didn?t pass any legislation limiting exposure until the 1970s.

In that year, the United States Consumer Product Safety Commission (CPSC) banned the use of asbestos in wallboard patching compounds and gas fireplaces because the asbestos fibers in these products could be released into the environment during use.

Furthermore, government agencies such as the Occupational Safety and Health Administration (OSHA) and the United States Environmental Protection Agency (EPA) were created in the 1970s to increase limits exposing Americans to asbestos and other toxic pollutants.

But shocking as it may sound, the use of asbestos is still not banned in the United States. Under pressure from the asbestos industry a ruling issued by the Environmental Protection Agency (EPA) in 1989 banning most asbestos-containing products (banning all new uses but allowing uses developed before 1989) was overturned by the Fifth Circuit Court of Appeals in New Orleans in 1991.

Today, more than 50 countries, including the United Kingdom, Australia and all 28 countries of the European Union (EU), have banned the use of asbestos. The Canadian government has pledged to ban the use of asbestos by 2018. Unfortunately, the United States continues to import and use asbestos and the government has no clear plan for stricter regulations in place.

Unfortunately, asbestos is still being used and extracted in many developing countries.

?For these reasons, we expect to continue to see growing incidence of mesothelioma in the coming decades,? said Arnaud Scherpereel, MD, PhD, head of the Pulmonary and Thoracic Oncology Department at the University Hospital (CHU) of Lille in Lille, France and lead author of a study about malignant pleural mesothelioma presented at the 53rd annual meeting of the American Society of Clinical Oncology (ASCO) held in Chicago, Ill.

Sobering facts
Current there are no effective therapeutic options for the treatment of patients with malignant pleural mesothelioma – and the (limited) options are not yet well standardized. This is especially so regarding the best association between surgery and medical treatments.? [3]

Furthermore, it typically takes 30 to 40 years from asbestos exposure to development of MPM. Given the long time leading to diagnosis, the incidence of malignant pleural mesothelioma has, over the last decades been rising.

Patients diagnosed with the disease have a median life expectancy of only 13-15 months. All patients relapse despite initial chemotherapy, more than 50% of them within six months after stopping treatment.

These sobering facts represents a major unmet medical need.

Phase II study
But a potential treatment may be available. Early findings from an ongoing phase II clinical trial in France, called MAPS-2, show that immunotherapy may slow the growth of MPM after relapse.

In this trial, scientists investigated the hypothesis that inhibition of immune PD-1+/- CTLA-4 check-point(s) would delay tumor progression in patients with unresectable MPM, experiencing disease progression after one or two lines of chemotherapy including at least first-line with pemetrexed (Alimta?; Eli Lilly and Company) and platinum, without altering significantly the quality of life of patients.

Following 12 weeks of treatment, cancer had not worsened in 44% of patients who received nivolumab (Opdivo?; Bristol-Myers Squibb Company.) and in 50% of those who received nivolumab with ipilimumab (Yervoy?; Bristol-Myers Squibb Company).[5]

?Our findings suggest that immunotherapy may provide new hope to patients with relapsed mesothelioma,? Scherpereel noted.

?This randomized phase II trial may be enough to support the use of immune checkpoint inhibitors in this setting, but it is too early to conclude whether nivolumab alone or the combination of nivolumab and ipilimumab is better,? he added.

Study design
The MAPS-2 multi-center clinical trial, funded by Bristol-Myers Squibb, enrolled 125 patients with advanced MPM who had received up to two prior treatments, including standard platinum-based chemotherapy. The majority of patients (80%) were male, and the median age was 72 years. The patients were randomly assigned to treatment with nivolumab alone or nivolumab with ipilimumab until the cancer worsened; 70% of patients received at least 3 cycles of either treatment.

Major Findings
The authors report results from the first 108 patients treated on the study. The disease control rate or DCR, defined as the percentage of patients in which cancer either shrank or did not grow, was 44% among the patients who received nivolumab only and 50% among those who received nivolumab with ipilimumab (the 12-week DCR for all treatments previously tested in relapsed MPM was less than 30%). Tumors shrank in 17% of patients treated with nivolumab and 26% of those treated with nivolumab and ipilimumab.

After a mean follow-up of 10.4 months of the 125 patients, the median time until the cancer worsened (progression-free survival) was 4 months with nivolumab alone and 5.6 months with nivolumab and ipilimumab. The median overall survival was 10.4 months in the nivolumab group and not reached in the nivolumab with ipilimumab group (meaning that more than 50% were still alive at analysis). Mature quality-of-life data are not yet available.

The side effects were rather mild overall with the most common being thyroid problems, colon inflammation, and skin rash. Severe side effects were more common in the nivolumab plus ipilimumab group (18% vs. 10%), in which three treatment-related deaths occurred.

What’s Next
With 125 patients, MAPS-2 is the largest clinical trial of immune checkpoint inhibitors in mesothelioma to date, according to the authors. Many ongoing clinical trials are exploring nivolumab and other immune checkpoint inhibitors as second- or third-line treatments for MPM. In addition, several larger clinical trials investigating immune checkpoint inhibitors as initial therapy for MPM are already under way.

?Mesothelioma cells build a protective tumor microenvironment to shield themselves against the immune system?s attacks and even act against anti-tumor immune response,? Scherpereel explained. ?Therefore, therapies that shift the tumor microenvironment from a state of immune suppression to one of immune activation may hold promise in MPM.?

?We?re seeing a second wave of immunotherapy with expansion of its use in more cancer types. This study shows that immunotherapy may represent an effective new treatment approach for mesothelioma, a disease for which we?ve long had too little to offer,? observed Michael S. Sabel, MD, FACS, an ASCO Expert.

?These results will serve as a building block to improve the outlook for patients with this cancer,? he concluded.

Last editorial review: June 8, 2017

Featured Image: Small pieces of brocken asbestos plate as background. Courtesy: ? 2017 Fotolia. Used with permission. Photo 1.0: Arnaud Scherpereel, MD, PhD, University Hospital of Lille, France. Courtesy: ? 2017 ASCO/Scott Morgan.

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