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

Our plain-English summary of 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, by M. Mark, S. Rusakiewicz, M. Früh, et al (ESMO Open, 2022).

The study

• Authors: M. Mark, S. Rusakiewicz, M. Früh, S. Hayoz, F. Grosso, M. Pless, P. Zucali, G.L. Ceresoli, A. Maconi, M. Schneider, P. Froesch, D. Tarussio, F. Benedetti, J. Dagher, L. Kandalaft, R. von Moos, S. Tissot-Renaud, S. Schmid, Y. Metaxas
• Journal: ESMO Open
• Published: 2022;7(3):100446
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

In plain English

This article was the final update of the SAKK 17/16 trial, a single-arm phase II study of lurbinectedin. The drug was given as second- or third-line palliative treatment to 42 patients with malignant pleural mesothelioma. The article did not study asbestos exposure. By the final data cut-off (22 March 2021), 36 patients (85%) had died. Median overall survival was 11.5 months (95% CI 8.8-13.8 months). An estimated 47% of patients (95% CI 32.1% to 61.6%) were alive at 12 months and 31% (95% CI 17.8% to 45.0%) at 18 months. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months), and no new safety signals were seen. In tumor samples taken at diagnosis from 29 patients, those who survived 3-6 months had more regulatory T cells and M2 macrophages than those surviving over 18 months. Seven patients had samples from both before and after treatment. In five of them, the M2 macrophage marker CD206 fell. The authors called all analyses exploratory and noted that very few post-treatment samples were available. They concluded that lurbinectedin continues to be active. Given the very small sample, they hypothesized that these immune cells are associated with survival.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Updated (final) analysis of a single-arm phase II drug trial (SAKK 17/16), with an exploratory laboratory (translational) analysis of tumor samples
• Who was studied: 42 patients with malignant pleural mesothelioma treated with lurbinectedin as second- or third-line therapy: 35 men and 7 women, median age 68 (range 52-84). Baseline tumor samples were available for 29 patients, and matched samples taken on day one of the second treatment cycle for 7 patients. The article does not state study locations or enrollment dates (it refers to an earlier publication).
• Exposure: Treatment with the drug lurbinectedin given alone (monotherapy). The dose is not given in this article. No asbestos exposure was studied.
• Main results:
  • Among all 42 patients, median overall survival was 11.5 months (95% CI 8.8-13.8 months). Median follow-up was 32.8 months.
  • 36 of the 42 patients (85%) had died; 31 of these deaths were caused by disease progression.
  • The estimated overall survival rate among the 42 patients was 47% (95% CI 32.1% to 61.6%) at 12 months and 31% (95% CI 17.8% to 45.0%) at 18 months.
  • Median progression-free survival among the 42 patients was 4.1 months (95% CI 2.6-5.5 months); one patient was free from progression at 12 months.
  • No new safety signals were observed with the longer follow-up.
  • In baseline samples from 29 patients, those who survived 3-6 months (n = 8) had higher regulatory T cells and M2 macrophages in stroma and tumor than those who survived more than 18 months (n = 4).
  • In Kaplan-Meier survival analysis of the 29 patients, those with lower regulatory T cells and lower M2 tumor-associated macrophages at baseline had better survival.
  • No significant differences were found for other immune markers, including PD-1, PD-L1, CD8 cells and M1 macrophages.
  • Among the 7 patients with samples before and after treatment, M2 macrophages decreased (lower CD206 expression) in 5. The macrophage marker CD163 was generally not affected.
  • CD8-positive T cells in the tumor increased in 2 of the 4 patients for whom this was available; these data were not shown.
• The authors' conclusion: The authors concluded that lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. Because of the very small sample size, they framed as a hypothesis that baseline tumor-associated macrophages and regulatory T cells are associated with survival.
• Limitations the authors state:
  • The authors called the low number of post-treatment tumor samples the major limitation.
  • Baseline samples were taken at diagnosis rather than just before lurbinectedin, so other factors may have influenced the observed changes.
  • No correction for multiple testing was applied, so all analyses are exploratory and hypothesis generating.
  • The small number of patients does not allow conclusions about CD8 T-cell infiltration and survival.
  • More data are needed before these immune cells can be used to guide treatment.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Palliative Care, Chemotherapy, Pleural Mesothelioma, Tumor Microenvironment, Statistical Significance, Median Overall Survival, confidence interval, Progression-Free Survival.

Related studies

• Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16) — Y. Metaxas, M. Früh, et al. (2020)
• Combination of cisplatin and lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma: Report of two cases — Y. Metaxas, R. Cathomas, et al. (2016)
• Long-term continuous erector spinae plane block for palliative pain control in a patient with pleural mesothelioma — J. Ramos, P. Peng, et al. (2018)
• Long-term benefit from immune modulation and anti-inflammatory treatment in metastatic mesothelioma — A.G. Dalgleish, E. McLean, et al. (2020)
• Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma — S. Canova, G.L. Ceresoli, et al. (2022)
• Who participates in LDCT screening for the early detection of lung cancer after long-term occupational exposure to asbestos dust? Results of the analysis of administrative and medical routine data from the German Social Accident Insurance — N. Oubaid, F. Greiner, et al. (2026)

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