To date, clinical data on ICIs in PeM remain quite sparse. While some trials have demonstrated efficacy of anti-PD-1 and anti-PD-L1 therapy in mesothelioma, which target programmed cell death protein 1 and programmed cell death 1 ligand 1, respectively, the representation of PeM cases in these studies has been very limited owing to their relative rarity. In the large negative randomized DETERMINE trial of tremelimumab [antibody against cytotoxic T-lymphocyte associated protein 4 (CTLA-4)] versus placebo [4], PeM was included, but only 18 patients with peritoneal disease were enrolled (out of 571 total mesothelioma patients), thereby preventing subgroup analysis for efficacy specifically in PeM. The lack of efficacy observed in the DETERMINE trial might have been due to the single-agent use of anti-CTLA-4 as well as the specific anti-CTLA-4 agent selected. More recent mesothelioma immunotherapy trials such as KEYNOTE-028 (anti-PD-1) and IFCT-1501 MAPS2 (anti-PD-1 monotherapy or combined with anti-CTLA-4) have excluded patients with a peritoneal primary site. Notably, in these trials, the agents used—pembrolizumab and nivolumab with and without ipilimumab, respectively—have demonstrated response rates ranging from 20 to 31%. Furthermore, PlM immunotherapy trials have not simultaneously developed or reported on predictive biomarkers that might facilitate improved patient selection.
PD-L1 expression levels as well as high tumor mutational burden (TMB) have been intensely investigated and shown some utility as predictors of ICI responses in different cancers [5]. In PlM, a trend associating high PD-L1 expression and a higher response rate has been reported, warranting further investigation. Given the modest activity in PlM of the currently available checkpoint inhibitors, predictive markers beyond PD-L1 and TMB are necessary to identify patients most likely to derive benefit from checkpoint inhibition, a need made even more pressing by the fact that TMB is notably low in PlM [6], as is also the case for PeM, as shown in the present study.
In other tumors, such as non-small cell lung cancer, immunotherapy given in combination with cytotoxic chemotherapy is emerging as the preferred treatment approach for tumors that are TMB low and PD-L1 low or negative. Evaluation of this combination approach in mesothelioma is ongoing in the PreCOG trial (NCT0289919). Based on the data from Shrestha and colleagues [3], examination of BAP1 status in relation to immunotherapy response in mesothelioma is warranted. Interestingly, in uveal melanoma, another disease with frequent BAP1 loss, the loss of BAP1 expression is associated with an increased infiltration of CD3+ and CD8+ T cells [7], a finding paralleled in PeM tissues by the investigations of Shrestha and colleagues [3]. Whether BAP1 loss might be more broadly applicable across different cancer types as a biomarker for an immune-inflamed tumor microenvironment will require further studies. Shrestha and colleagues also report higher expression of several immune checkpoint molecules, including PD-L1 (CD274) in BAP1-altered PeM. In light of this, we re-analyzed the TCGA PlM data according to BAP1 status and found a similar but sub-significant trend for PD-L1 (CD274) to be higher in BAP1-altered samples, but the most significant association was for the mRNA signature of activated dendritic cells to be more prominent in the BAP1-altered group (Fig. 1).