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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., Competing Interests: Disclosure MF declared unrestricted grants from Bristol Myers Squibb (BMS) and AstraZeneca paid to his institution, advisory board roles for AstraZeneca, Merck Sharp & Dohme (MSD); Roche, BMS; Boehringer Ingelheim, Pfizer, Takeda, payment for expert testimony from Takeda and Roche, meeting support from Merck, and participation on a Data Safety Monitoring Board for Roche. FG declared outside the submitted work personal fees for advisory role, speaker engagements and travel and accommodation expenses from MSD, Novocure, BMS, Boehringer Ingelheim, Pharmamar, Novartis, and Pierre Fabre, outside the submitted work personal fees for advisory role, speaker engagements, and travel, and accommodation expenses from MSD, Novocure, BMS, Boehringer Ingelheim, Pharmamar, Novartis, and Pierre Fabre, outside the submitted work personal fees for advisory role, speaker engagements and travel and accommodation expenses from MSD, Novocure, BMS, Boehringer Ingelheim, Pharmamar, Novartis, and Pierre Fabre. MP declared consulting fees from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Esei, MSD, Novartis, Pfizer, Roche, Takeda, Merck, speakers fee from Janssen, payment for expert testimony from Takeda and Novartis, support for attending meetings and/or travel from AstraZeneca, BMS, Boehringer Ingelheim, Roche, Vifor, and Takeda. PZ declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, BMS, Amgen, AstraZeneca, Roche, and Bayer, support for attending meetings and/or travel from MSD, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, BMS, Amgen, AstraZeneca, Roche, and Bayer, participation on a Data Safety Monitoring Board or Advisory Board for MSD, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, BMS, Amgen, AstraZeneca, Roche, and Bayer. GLC declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novocure, Zai Lab, MSD Oncology, AstraZeneca, BMS, and Bayer, participation on a Data Safety Monitoring Board or Advisory Board for Novocure. RvM declared advisory boards fees from AstraZeneca, MSD; Roche, Bristol-Myers Squibb; Pfizer, Pharmamar, Novartis, GlaxoSmithKline, Amgen, Gillead, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Vifor. SS declared grants from AstraZeneca, BMS paid to her institution, support for attending meetings and/or travel from Boehringer Ingelheim, Takeda, MSD, and participation on a Data Safety Monitoring Board or Advisory Board for MSD, AstraZeneca, Boehringer Ingelheim paid to her institution. YM declared consulting fees from Merck-Serono, BMS, Roche, Novartis, support for attending meetings and/or travel from PharmaMar, Merck, and participation on a Data Safety Monitoring Board or Advisory Board for Merck-Serono, BMS, Roche, Novartis, all paid to his institution. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)