Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study

• Main Authors: Benedetti, F. (Author), Ceresoli, G.L (Author), Dagher, J. (Author), Froesch, P. (Author), Früh, M. (Author), Grosso, F. (Author), Hayoz, S. (Author), Kandalaft, L. (Author), Maconi, A. (Author), Mark, M. (Author), Metaxas, Y. (Author), Pless, M. (Author), Rusakiewicz, S. (Author), Schmid, S. (Author), Schneider, M. (Author), Tarussio, D. (Author), Tissot-Renaud, S. (Author), von Moos, R. (Author), Zucali, P. (Author)
• Format: Article
• Language: English
• Published: Elsevier B.V. 2022
• Subjects: lurbinectedin; M2 phenotype; malignant pleural mesothelioma; regulatory T cells; tumor-associated macrophages; tumor-infiltrating lymphocytes
• Online Access: View Fulltext in Publisher

 Background: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. Material and methods: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan–Meier method. Statistical significance was set at P value <0.05. Results: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. Discussion: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans. © 2022 The Author(s)