This is the first retrospective study to investigate the efficacy of second-line chemotherapy for patients with MPeM, including monotherapy with various chemotherapy agents and immune checkpoint inhibitors. While there are a few reports on the efficacy of cisplatin plus pemetrexed as first-line chemotherapy for MPeM, the efficacy of second-line chemotherapy remains unknown.
As the first-line chemotherapy for MPeM, the expanded access programme in the United States showed an ORR of 29.8% and a median OS of 13.1 months [6], and another expanded access programme in Europe reported an ORR of 20% [7]. Several retrospective studies, including this updated analysis, have shown similar efficacy.
As for second-line chemotherapy, there are a few reports on MPlM, and some benefits of vinorelbine have been suggested for refractory MPlM. In a phase II trial, the median OS was 9.6 months in patients with previous exposure to chemotherapy [11]. Rechallenge with a pemetrexed-based therapy has reported a median second-line OS of 13.6 months for patients who obtained disease control during first-line chemotherapy for MPlM [12]. Moreover, a longer survival was shown for patients with MPlM who received second-line chemotherapy than those who did not. The median OS was 15.3 vs. 9.8 months, respectively [13]. In contrast, the efficacy of second-line chemotherapy for MPeM remains unknown. Gemcitabine and docetaxel have also shown efficacy with a median OS of 8 and 12.2 months, respectively, for chemo-naïve patients with MPlM [14],[15]. In this study, gemcitabine was the most commonly used regimen. Patients who received second-line chemotherapy showed similar efficacy compared to previous reports of MPlM; however, the efficacy of each regimen cannot be compared due to the small sample size.
Three patients were treated with nivolumab, and two of them showed a long OS and second-line OS of more than 20 and 12.5 months, respectively. Recently, immunotherapy has shown promising results in patients with MPlM who progressed after at least one treatment line. In several phase II trials of MPlM, nivolumab, an anti-programmed death-1 antibody, showed a median PFS of 2.6–6.1 months, and 6-month survival rates of 29–74% [16],[17]. Moreover, combination therapy with nivolumab and ipilimumab, an anti-cytotoxic T lymphocyte antigen 4 inhibitor, has shown an ORR of 28% and a median PFS of 5.6 months in a phase II trial of MPlM [18]. Although the efficacy of second-line chemotherapy with immune checkpoint inhibitors is not clear for MPeM, it is expected to improve survival considering the benefits for MPlM. A phase II trial of tremelimumab plus durvalumab for mesothelioma has shown an immune-related ORR of 28%; however, the clinical outcomes of MPeM are unknown [19]. A phase III trial of nivolumab in mesothelioma, including MPeM, is ongoing [20].
However, in this study, there was no remarkable difference in OS (time from first-line chemotherapy to death) between patients with and without subsequent chemotherapy after first-line failure. Furthermore, it is necessary to select patients with MPeM suitable for second-line chemotherapy. In the univariate analysis to investigate the prognostic impact of age, sex, ECOG PS, histology, asbestos exposure, ascites, and distant organ metastasis, none of them were significantly associated with second-line OS. The number of cycles of first-line platinum doublet chemotherapy showed significant association with second-line OS and PFS. These findings suggest that second-line chemotherapy may be a good option and should be considered for patients with a favourable general condition who have completed 6 cycles of first-line chemotherapy.
There are some limitations to this study. First, this study was performed at a single institution, and the sample size was too small to accurately evaluate the efficacy of each regimen. Second, since this was a retrospective study and the patients’ background was not well balanced, we could not compare the efficacy of each regimen. Third, the adverse event data collected retrospectively were insufficient. Finally, because of the property of MPeM with few target lesions, we were unable to adequately assess the response.