Plural Immunotherapy

TODAY, PEOPLE WHO HAVE pleural malignant mesothelioma have just one Food and Drug Administration (FDA)- approved regimen: chemotherapy. But that might change soon, thanks to impressive improvements in survival rates among patients treated with combination immunotherapy in clinical trials.

Mesothelioma is a relatively rare, aggressive cancer that affects the mesothelium, a thin layer of tissue that covers most internal organs; pleural mesothelioma, the most common type, occurs in the area around the lungs. Risk factors include asbestos exposure, smoking and family history. The five-year survival rate is fairly low, and more effective treatments are needed — and they may be on the way.

The trial that showed immunotherapy’s promise tested drugs known as checkpoint inhibitors in patients with pleural mesothelioma. These drugs hamper the activity of proteins such as PD-1 and CTLA-4, which ordinarily keep the immune system under control; the treatment frees up T cells, the body’s army of disease fighters, to recognize and attack cancer cells.

The PD-1 inhibitor Opdivo (nivolumab), alone and combined with the CTLA-4 inhibitor Yervoy (ipilimumab), was tested in patients whose disease had relapsed on prior treatment with Alimta (pemetrexed) and platinum chemotherapy, the current standard that has some, but limited, temporary effectiveness. The results showed a one-year overall survival rate of 51 percent with Opdivo alone and 58 percent with the combination, higher than would be expected with standard therapy.

Known as MAPS2, the noncomparative, randomized, phase 2 trial was sponsored by the French thoracic cancer clinical trials consortium Intergroupe Francophone de Cancérologie Thoracique. Lead study author Gérard Zalcman, M.D., presented its results during the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid in September.

In an interview with CURE®, Zalcman, head of the thoracic oncology department at Hôpital Bichat-Claude Bernard at Université Paris Diderot, reviewed the MAPS2 trial and discussed the promise of immunotherapy in patients with mesothelioma.

CURE®: Can you comment on the MAPS2 results?

Zalcman: This was a trial assessing Opdivo or Opdivo plus Yervoy in patients with mesothelioma in the second- or third-line setting. It was a noncomparative randomized trial, so we are not allowed to compare the two arms directly. The median follow-up was 15 months.

The most remarkable data of this presentation are the overall survival data. With Opdivo, the median overall survival was 13.6 months, which is amazing in this setting and these patients. The median overall survival of the Opdivo plus Yervoy arm had not yet been reached after 15 months of follow-up, suggesting that it could be over 15 months. This trial ran very fast because we accrued 125 patients within five months, with the last patient accrued in September 2016. There were no specific signals to worry about in this toxicity profile. There were slightly more immunological side effects (such as thyroid problems, rash and inflammation of the colon) in the combination arm, but nothing that was statistically significant. There were three toxic deaths in the combination arm, which occurred very early in the study course, and with no more (such deaths) after. This suggests that the investigators have learned how to manage such immunologic toxicities, but careful monitoring remains imperative.

We also presented data about PD-L1 protein expression as measured by immunohistochemistry (IHC) tests. We showed that the expression of PD-L1 in more than 1 percent of a tumor’s cells was associated with overall response. When we selected the stronger expressers — meaning PD-L1 in more than 25 percent of tumor cells — this was associated with overall response and disease control rates.

For overall survival, it is more complex. In the Opdivo arm, PD-L1-positive patients did better than the PD-L1- negative group. However, in the combination arm, the outcomes of IHC testing for PD-L1 had no influence on OS. Therefore, PD-L1 could be a good biomarker for (estimating) the likelihood of Opdivo’s effectiveness in patients with pleural mesothelioma but is not a good biomarker for the combination.

What is the first-line standard of care for patients with mesothelioma?

Currently, first-line mesothelioma treatment is based on the backbone of pemetrexed/cisplatin chemotherapy plus or minus Avastin (bevacizumab), a drug that cuts off a tumor’s blood supply. The median overall survival ranges from 15 to 19 months, and there is currently no recognized second-line treatment for this disease. Therefore, the positivity of this MAPS2 trial supports the use of immunotherapy as second- and third-line therapy. This has actually been suggested as an option by the National Comprehensive Care Network panel, which creates guidelines for clinical practice. The company developing these drugs is going to seek breakthrough designation for the combination from the FDA, which would prompt the agency to streamline its review of the regimen for the treatment of pleural mesothelioma.

There is a large phase 3 trial running in the first-line setting comparing the combination of immunotherapy with standard chemotherapy. If this trial meets its endpoints, it could mean that, in the near future, we will use chemotherapy in the second- and third-line settings, instead of as an initial treatment after diagnosis, and that combination immunotherapy of Opdivo plus Yervoy would move into the first-line setting.

What are potential biomarkers in mesothelioma that could make it susceptible to targeted drugs or specific immunotherapies?

Currently, we don’t know of a good biomarker for mesothelioma. Some cancers carry a very large number of genetic mutations, and this makes them particularly susceptible to treatment with checkpoint inhibitors. But mesothelioma is a tumor where the mutational tumor burden is very low. Therefore, something like mutational burden will not be a good biomarker. We will try to test this, but I don’t think we are expecting it to be a good biomarker.

We see that PD-L1, at least with the antibodies we tested, might be difficult to go to clinical practice with, since it is of no use (in predicting the effectiveness of the) combination therapy.

One possible biomarker has to do with how densely lymphocytes, or white blood cells, infiltrate a tumor, and we will have to study this quantitatively and qualitatively. We have such data — we have done the study — but it is not statistically analyzed yet. We will have to see if the density of lymphocytic infiltration could add something as a biomarker to predict response.

The good biomarker will ultimately be the one that predicts survival, not just response, because it is not always correlated.

It has been a long time since a therapy has been approved for mesothelioma. Can you put into context what these recent advances mean for this disease landscape?

These trials are clearly an advance for the treatment of patients, provided that these drugs are accepted by regulatory agencies. This is a rare disease, and the development of drugs in rare diseases is different. The dose that will be submitted to the FDA will rely on data from this study to support its registration. I believe that authorities are ready to accept such a registration with such data, and I am pretty sure these drugs will soon be available, at least in the United States. The situation could be more difficult in Europe, where we may be more reluctant to register these drugs. The patients and advocacy groups will have an important role to play to support this registration.