Keytruda Survival Benefits Similar to Chemo for Relapsed Mesothelioma, Phase 3 Trial Finds

Treatment with the immunotherapy Keytruda (pembrolizumab) appears to be as effective as conventional chemotherapy for treating malignant pleural mesothelioma patients who relapse after one course of platinum-based chemotherapy, data from a Phase 3 trial show.

Although more of these advanced cancer patients responded to Keytruda than to chemotherapy, notable differences in survival were not seen. More study is needed to determine cancer patients most likely to benefit from immunotherapies, its researchers said.

These findings were in the poster, “A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM): Results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial,” presented at the recent European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona.

Keytruda is an immune checkpoint inhibitor (developed by Merck; known as MSD outside the U.S. and Canada) that has been approved by the U.S. Food and Drug Administration and by the European Medicines Agency (EMA) to treat several types of cancer.

It is a monoclonal antibody that targets and blocks the activity of the PD-1 receptor (a protein found on the surface of immune cells), which cancer cells use to avoid being targeted and killed by immune cells.

PROMISE-meso (NCT02991482) is a Phase 3 trial comparing the efficacy of Keytruda to standard chemotherapy in people with advanced malignant pleural mesothelioma — a lethal form of cancer in the pleura, the protective lining around the lungs — who failed to respond to a previous course of platinum-based chemotherapy.

The trial enrolled 144 advanced mesothelioma patients who were randomly assigned to treatment with Keytruda at a dose of 200 mg every three weeks, or to conventional chemotherapy with a single agent of choice (gemcitabine or vinorelbine).

All patients assigned to chemo had the option of switching to Keytruda if their disease progressed while receiving treatment.

The study’s primary endpoint was progression-free survival, or the time patients go until disease progression or death. Secondary endpoints included overall survival, response to treatment, and safety assessments.

New data from PROMISE-meso presented at the ESMO Congress showed that 22% of Keytruda-group patients responded to treatment, while only 6% of those receiving chemo did so.

Although Keytruda was associated with better treatment responses compared to conventional chemotherapy, it failed to prolong patients’ median overall survival (10.7 months vs. 11.7 months in the chemo group), as well as the median time these people lived without showing signs of disease progression (2.5 months vs. 3.4 months).

These findings were similar even after investigators adjusted data to account for the 45 patients who switched from chemo to Keytruda during the trial.

“In PROMISE-meso, nearly four times more patients responded to immunotherapy than standard chemotherapy, but unfortunately these responses did not delay progression or improve survival. These findings are disappointing but, as in previous studies, some patients benefited from immunotherapy for long periods,” Sanjay Popat, consultant Thoracic Medical Oncologist at the Royal Marsden Hospital, said in a news release. Popat presented the findings of PROMISE-meso at ESMO.

“If we can find out how this happens, we will have a better idea of which patients should preferentially receive this treatment over chemotherapy,” he said. “Nevertheless, whilst pembrolizumab was not superior to chemotherapy, survival was similar, and so pembrolizumab may represent an alternative.”

The most common adverse events experienced by patients receiving chemotherapy were fatigue (19%) and nausea (27%). For those on Keytruda, it was fatigue (19%).

The incidence of severe (grade 3), life-threatening (grade 4) or fatal (grade 5) treatment-related adverse events was slightly higher among patients treated with chemo (24% versus 19%). Deaths in two study participants, one from each treatment group, were attributed to side effects of treatment.

Popat said that future studies should investigate the effects of immune checkpoint inhibitors like Keytruda alone and in combination with other anti-cancer drugs in patients who are at earlier stages of the disease.

“In studies of lung cancer, we have already learned that we can improve results with immunotherapy by combining it with chemotherapy and the same may be true with mesothelioma. I would advise clinicians to enroll their patients into one of the large ongoing trials of first-line combination treatment so we can get answers as soon as possible about how to improve mesothelioma treatment,” Popat said.

“Meanwhile, we need to better understand which patients benefit most from immunotherapy,” he added.