Many scientists may have lost their initial high hopes for checkpoint immunities in treating malignant pleural mesothelioma (MPM), but Aaron S. Mansfield, MD, at the Mayo Clinic remains convinced immunotherapy will replace current second-line treatment and challenge standard therapy.
In an editorial, “Immune checkpoint inhibition in malignant mesothelioma: Does it have a future?” Mansfield said investigators should continue to encourage patients to participate in clinical trials of checkpoint inhibitors for mesothelioma, which he believes could improve the treatment landscape. The editorial was published in the journal Lung Cancer.
According to Mansfield, three events contributed to the loss of interest in checkpoint therapy. Two clinical trials — one of the anti-PD-L1 drug avelumab, and one of tremelimumab, a checkpoint blocker targeting CTLA-4 — failed to effectively combat mesothelioma. In addition, a study showed that mesothelioma is a cancer with a low accumulation of mutations, leading researchers to conclude that it is unsuitable for checkpoint therapy.
But the reality may be more complex than the trials would indicate.
In treating other cancers, it is standard to test for PD-L1 expression to determine whether the patient would benefit from checkpoint therapy targeting it or PD-1. Studies indicate that about 40% of MPM patients express PD-L1, and that its presence is linked to a poor prognosis, but analyses show its production can vary between the main tumor and metastases, as well as between primary tumors on opposing sides of the chest.
Those insights spurred further checkpoint inhibitor trials in malignant pleural mesothelioma.
One Phase 1 study (NCT02054806), which included mesothelioma patients who had at least 1% PD-L1 detected in their tumor, showed that the PD-1 inhibitor Keytruda (pembrolizumab) controlled disease in 76% of the patients. Among them, 24% improved and 52% had stable disease. There were three moderate to severe adverse events during the study.
Updated information from the trial showed that 40% of patients had a complete or partial response, or stable disease for six months or more. The median overall survival was 18 months. All patients had received previous treatment.
Keytruda was also tested in a larger, Phase 2 trial (NCT02399371) that included patients without detectable PD-L1 production. Those patients made up about half of the study group.
Patients lived without progressing for a median of 6.2 months, and the median overall survival had not been reached when the study was presented. In total, 21% of the 35 patients had a partial response, and 56% stabilized.
Mansfield emphasized that the results were attained regardless of patients’ lack of PD-L1.
A Phase 2 study of Opdivo (nivolumab) resulted in progression-free survival of 3.7 months among 34 treated patients. At 12 weeks, 15% had a partial response and 35% had stable disease — again, irrespective of their PD-L1 status.
The investigational PD-L1 blocker avelumab was also tested in mesothelioma (NCT01772004), and showed an overall response rate of 9.4% and a disease control rate of 56.6%, regardless of the presence or absence of PD-L1 expression.
Early data suggest checkpoint blockade results in disease control rates of 50% or more, Mansfield said, with survival times that are better than or equal to standard care approaches. But several factors could influence the overall picture of the treatment approach, he said.
Trials have used different tools to assess patients’ responses, and that could contribute to results varying, Mansfield said. Also, studies show that patients with inherited mutations in the BAP-1 gene may fare better than those without such variants. Not classifying patients based on that information could skew the results of a trial, he noted.
In addition, Mansfield pointed out that there is likely a difference between therapies that target PD-1 and those that target PD-L1. PD-1 can bind to two factors — PD-L1 and PD-L2 — to suppress immune reactions. Blocking PD-L1, however, does not prevent PD-1 and PD-L2 from interacting. So far, no data have been compiled to show whether this is clinically significant for treating mesothelioma.