The Role of Immunotherapy in Treating Mesothelioma

Health care providers are in desperate need of better agents to treat patients with mesothelioma, according to Dr. Sanjay Popat, a consultant thoracic medical oncologist at the National Heart and Lung Institute, Imperial College London.

Once patients fail front-line chemotherapy treatment, there are no approved agents, Popat explained. Therefore, he chaired a clinical trial to examine the use of the immunotherapy medication Keytruda (pembrolizumab) in patients with advanced malignant pleural mesothelioma. Researchers then compared those results to patients being treated with chemotherapy alone.

In an interview with CURE® during the European Society for Medical Oncology Congress 2019, he discussed the phase 3 study’s findings and what they mean for patients.

CURE®: In the PROMISE-meso trial, immunotherapy, specifically, checkpoint inhibitors were used. Why was this approach taken?

Popat: The reason for using checkpoint inhibitors is that we have seen some very encouraging data in mesothelioma in a number of separate cohort studies. One of the most important cohort studies is the Keynote-028 mesothelioma cohort, which demonstrated response rates of about 20%. This is very encouraging given the response rate that we normally see with chemotherapy in that setting is about 5%. Since then, there have been a number of small cohorts which have also reported using checkpoint inhibitors and that started to slip into standard practice. We wanted to do a randomized study to formally evaluate the role of checkpoint inhibitors in this setting.

Can you discuss the design of the trial and key inclusion criteria?

The study was a randomized phase 3 (trial). The patients included had malignant pleural mesothelioma with a good performance state of zero or 1, adequate organ function, measurable or evaluable disease and they had to have a tissue block available for research. Patients were randomized in a one-to-one manner stratified to histology to either pembrolizumab every three weeks for up to two years stopping at progression or allowed to continue beyond progression but still deriving clinical benefit, or they were randomized to institutional choice of chemotherapy, which is single agent chemotherapy. Patients who were randomized to chemotherapy were allowed to cross over to receive pembrolizumab on progression.

The primary endpoint of the study was progression-free survival. Unfortunately, the primary endpoint was not met. Pembrolizumab was not superior to standard chemotherapy. We looked at key secondary endpoints including response rate, overall survival and duration of response. When we look at overall response rate, we see there is an improved response rate with pembrolizumab — almost four times that seen with chemotherapy — with a response rate of 26% compared with 4% seen with chemotherapy. However, the duration of response was similar with the two groups. We can clearly see there are more responses with pembrolizumab that are deeper responses. One of the key secondary endpoints was overall survival. Unfortunately, there was no overall survival advantage for pembrolizumab, but bear in mind that 63% of patients crossed over from chemotherapy to pembrolizumab making overall survival interpretation quite difficult.

What does this mean for patients?

Clearly, pembrolizumab is an active drug in mesothelioma. We know that the response rate is high, but the duration of response isn’t as long on average as we would like to see in this population. Most patients crossed over, therefore receiving pembrolizumab prior to chemotherapy is a very reasonable option for patients because the absolute survival that we saw was actually very good for a second-line indication.

We need to do more work. We need to do better and deeper analyses to find out who are those patients that really benefit from pembrolizumab and who are those patients for who this (treatment) is irrelevant. We probably need to move checkpoint inhibitors into the front-line setting, combine them with standard platinum pemetrexed chemotherapy as we have done for lung cancer and see if there is a meaningful survival advantage.