Evan Alley, MD, PhD
Chemotherapy is the only approved first-line therapy for malignant pleural mesothelioma, which makes up 90% of malignant mesothelioma cases, and there is no approved second-line therapy. That may soon change, though, as findings from a subset of patients enrolled in the KEYNOTE-028 study suggest that the PD-L1 checkpoint inhibitor pembrolizumab (Keytruda) may be effective in treating this disease.
Researchers note that this is first study to present positive findings from a checkpoint inhibitor immunotherapy drug for the treatment of malignant pleural mesothelioma. The disease is primarily caused by the inhalation of asbestos, a fiber commonly found in some forms of insulation, vinyl floor tiles, and other material. Tumors form in the pleura, a thin membrane of cells that line the lungs and chest wall. Most patients survive less than 1 year. This poor prognosis is partially due to the fact that most patients are not diagnosed until they are already at a late stage of the disease.
KEYNOTE-028 is an ongoing phase 1b trial (NCT02054806) involving 13 different research sites in 6 different countries examining the effect of pembrolizumab on patients with advanced malignancies, including malignant pleural mesothelioma. This study evaluated a subset of 25 patients with this disease and an ECOG performance status of 0 or 1 who had either already been treated with chemotherapy or were unable to receive chemotherapy. None of the patients had been treated with a checkpoint inhibitor prior to the study. Investigators used immunohistochemistry to determine PD-L1 positivity, defined as expression on ≥1% of tumor cells
The first patients were enrolled 2 years ago and received a dose of pembrolizumab (10 mg/kg) every 2 weeks for up to 2 years until progression or intolerable toxicity. Median duration of therapy was 5.1 months. Fourteen patients experienced a reduction in tumor size. Median progression-free survival was 5.4 months (95% CI; range, 3.4-7.5) and median overall survival was 18 months (95% CI; range, 9.4-not reached). Fourteen patients died during the study, 9 due to disease progression. Median duration of response was 12 months (95% CI; 3.7-not reached).
At the time of data cutoff June 20, 2016, 21 patients had discontinued treatment, 2 remained on the drug, and 2 had completed the maximum 24 months of treatment set by the investigators.
“Most patients who receive a second-line therapy have a life expectancy of about 6 or 7 months, so to have 4 patients still ongoing at 2 years is very encouraging,” noted Evan Alley, MD, PhD, the study’s lead author and chief of hematology and medical oncology at Penn Presbyterian Hospital.
Sixteen of the 25 patients on this arm of the study experienced an adverse event (AE). The most common AEs in the mesothelioma cohort were grade 1/2 fatigue and nausea (reported in 6 patients each) and grade 1/2 arthralgia (n = 5).
Overall, however, “one great sign in this study is that none of the patients had to stop treatment because of side-effects,” Alley continued, although 3 patients had a dose interruption due to an immune-related AE: “Some had temporary stoppages, but they were able to continue. The drug appears to be well-tolerated.”
Study authors concluded that, “Pembrolizumab appears to elicit significant clinical activity with durable responses and a manageable safety and toxicity profile in patients with PD-L1-positive malignant pleural mesothelioma, with tolerable safety, an indication of clinical activity, and substantial duration of response.”
Currently multiple studies are under way to confirm these findings. There are already plans for future trials testing the combination of pembrolizumab with other treatments, 2 of which will be conducted at Penn. These studies are expected to launch later in 2017.
“This study provides evidence that some patients can have long-term disease control with this drug, which we haven’t seen before,” Alley said. “We need to better understand what we can do next to make immunotherapy more effective for more patients.”
Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomized, open-label, phase 1b trial [published online March 10, 2017]. Lancet Oncol
. doi: 10.1016/S1470-2045(17)30169-9.