According to a related commentary, malignant pleural mesothelioma has a poor prognosis and treatment options are scarce. Pemetrexed and platinum doublet chemotherapy has been the standard first-line therapy for non-resectable disease since 2003, when an RCT showed a survival benefit of 2·8 months vs. cisplatin alone. Treatment remained unchanged for more than a decade, until 2016, when the MAPS trial showed that adding bevacizumab, to first-line chemotherapy extended survival to 18.8 months compared with 16.1 months with chemotherapy alone. It notes no second-line or third-line treatment has been established for relapsed or progressive disease, despite substantial academic endeavour. Thus the publication of this phase II study and also one (INITIATE) in the Lancet Respiratory Diseases of immune checkpoint inhibitors (ICIs) alone or in combination, represents important progress.
The MAPS2 study (n=125) reported 12-week disease control was achieved by 25 (40%) of 63 patients on nivolumab and 32 (52%) of 62 patients on nivolumab plus ipilimumab. Grade 3–4 toxicities developed in 9 (14%) and 16 (26%), respectively. Regimens require evaluation in larger trials.
The commentary cautions that ICIs are not without side-effects, especially when used in combination, noting that more than 93% of patients who received nivolumab and ipilimumab in these two studies had an adverse event. It adds however that perspective is required as chemotherapy is associated with much higher complication rates; 44% of patients treated with pemetrexed and cisplatin have grade 3 or 4 neutropenia, and more than 75% have some degree of nausea and vomiting. Thus the deciding factor will be whether clinicians and patients consider the risk of side-effects to be outweighed by potential benefit.
It calls for well-designed phase 3 trials to assess the clinical efficacy of ICIs in the second-line and third-line setting. It notes several studies are underway. It adds that these phase 3 trials will also enable clarification of ongoing areas of uncertainty. Of particular interest is the role of tumour PD-L1 expression in predicting treatment response, as well as the most sensitive assay with which to measure it and the optimal threshold to define high or low expression.
An editorial notes that some hotly debated areas remain, such as the use of surgery before or after chemotherapy. A recent report of retrospective data indicated that both approaches had similar survival. However, this debate really needs to be answered by a randomised trial and an EORTC-funded trial is underway. It notes that the treatment armamentarium and research efforts for mesothelioma continue to grow. Investigators are experimenting in mice with the use of inhaled therapies, and the National Cancer Institute has awarded a grant of $10.7 million to the University of Pennsylvania to study CAR T-cell therapy.