Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16)

Our plain-English summary of Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16), by Y. Metaxas, M. Früh, E.I. Eboulet, et al (Annals of Oncology, 2020).

The study

• Authors: Y. Metaxas, M. Früh, E.I. Eboulet, F. Grosso, M. Pless, P.A. Zucali, G.L. Ceresoli, M. Mark, M. Schneider, A. Maconi, M. Perrino, C. Biaggi-Rudolf, P. Froesch, S. Schmid, C. Waibel, C. Appenzeller, D. Rauch, R. von Moos, Swiss Group for Clinical Cancer Research (SAKK)
• Journal: Annals of Oncology
• Published: 2020;31(4):495-500
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Systemic second- and third-line therapies for malignant pleural mesothelioma (MPM) result in a median progression-free survival (mPFS) of <2 months and median overall survival (mOS) of 6-9 months. Lurbinectedin binds to the DNA of the regulatory region while inhibiting tumour-associated macrophage transcription. In early trials, encouraging outcomes occurred in patients (pts) with MPM treated with lurbinectedin. We aimed to generate lurbinectedin efficacy and safety data among pts with progressive MPM.

Patients And Methods: Pts with progressing MPM treated with first-line platinum-pemetrexed chemotherapy with or without immunotherapy received lurbinectedin monotherapy. Treatment was given intravenously at 3.2 mg/m2 dose every 3 weeks until progression or unacceptable toxicity. Using Simon's two-stage design, the primary endpoint, progression-free survival (PFS) at 12 weeks (PFS12wks), was met if achieved by ≥21 pts (p0 ≤35% versus p1 ≥55%).

Results: Forty-two pts from nine centres across Switzerland and Italy were recruited. Histology was epithelioid in 33 cases, sarcomatoid in 5, and biphasic in 4. Overall 10/42 (23.8%) underwent prior immunotherapy and 14/42 (33.3%) had progressed ≤6 months after first-line chemotherapy. At data cut-off PFS12wks was met by 22/42 pts (52.4%; 90% confidence interval (CI): 38.7% to 63.5%; P = 0.015) with an mPFS of 4.1 months and mOS of 11.1 months. The best response was complete and partial remission observed in one patient each and stable disease in 20 pts. The duration of disease control was 6.6 months (95% CI: 5.2-7.4). No significant difference in PFS12wks, mPFS, and mOS was recorded in epithelioid versus non-epithelioid cases and pts with prior immunotherapy versus those without. Similar mPFS but shorter mOS were observed among pts who progressed within ≤6 months after first-line chemotherapy. Lurbinectedin-related grade 3-4 toxicity was seen in 21 pts, mostly being neutropenia (23.8%) and fatigue (16.7%).

Conclusions: The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity regardless of histology, prior immunotherapy, or outcome on prior treatment. CLINICALTRIALS.

Gov Identifier: NCT03213301.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

In plain English

This single-arm phase II trial had no comparison group. It tested lurbinectedin in 42 patients with malignant pleural mesothelioma that had progressed after first-line platinum-pemetrexed chemotherapy, sometimes also after immunotherapy. Patients enrolled from September 2017 to October 2018 at nine centres in Switzerland and Italy and received intravenous doses every 3 weeks. The study did not examine asbestos exposure. The main goal, being alive without progression at 12 weeks, was reached by 22 of 42 patients (52.4%; 90% confidence interval 38.7% to 63.5%). Median progression-free survival was 4.1 months (95% confidence interval 2.6 to 5.5) and median overall survival 11.1 months (95% confidence interval 8.8 to 13.3). Outcomes did not differ significantly by tumour type or prior immunotherapy. Patients who had progressed within 6 months of earlier chemotherapy had significantly shorter survival. Half the patients (21 of 42) had drug-related grade 3 to 4 side effects, mostly low neutrophil counts and fatigue; none died from treatment. The authors concluded the goal was met with acceptable toxicity and called for a larger randomised trial. They named the lack of a comparison group and central scan review as the major limitation.

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: international, multi-centre, single-arm phase II trial (Simon's two-stage design), no comparison arm
• Who was studied: 42 patients with malignant pleural mesothelioma that had progressed on or after one line of platinum-pemetrexed chemotherapy (10 also after one immunotherapy line), enrolled September 2017 to October 2018 at six centres in Switzerland and three in Italy; 33 epithelioid, 4 biphasic, 5 sarcomatoid; 35 men, 7 women; median age 68
• Exposure: Treatment with lurbinectedin at 3.2 mg/m2 as a 1-hour intravenous infusion every 3 weeks until progression, unacceptable toxicity or consent withdrawal. Asbestos exposure was not studied.
• Main results:
  • The primary endpoint, being free of progression at 12 weeks, was met by 22/42 patients (52.4%; 90% CI 38.7% to 63.5%; P = 0.015)
  • Best response: one complete remission (2.4%), one partial remission (2.4%) and 20 patients (47.6%) with stable disease for at least 12 weeks; objective response rate 4.8%, disease control rate 52.4%
  • Median progression-free survival for all 42 patients was 4.1 months (95% CI 2.6 to 5.5) after a median 15.8-month follow-up
  • Median overall survival for all 42 patients was 11.1 months (95% CI 8.8 to 13.3); 73.8% were alive at 6 months and 44.9% at 12 months; 29 patients had died at analysis, 25 from progression
  • Median duration of disease control among the 22 patients with disease control was 6.6 months (95% CI 5.2 to 7.4)
  • No significant differences between epithelioid and non-epithelioid (biphasic and sarcomatoid) cases: 12-week progression-free 63.6% versus 62.5% (P = 0.952), median PFS 4.1 versus 3.7 months, median OS 12.2 versus 10.0 months (P = 0.616)
  • No significant differences between patients with chemotherapy alone and those with prior immunotherapy: 12-week progression-free 61.4% versus 70%, median PFS 4.1 versus 3.2 months, median OS 11.9 versus 10.8 months (P = 0.244)
  • Patients who had progressed 6 months or more after prior chemotherapy (28) had significantly longer median overall survival than the 14 who progressed in under 6 months (13.3 versus 8.8 months, P = 0.007), with similar progression-free survival
  • Lurbinectedin-related side effects of any grade occurred in 38/42 patients (90.5%) and grade 3 to 4 in 21/42 (50%), mostly neutropenia (23.8%) and fatigue (16.7%); febrile neutropenia in 11.9%; no treatment-related deaths
  • No patient stopped because of grade 3 to 4 toxicity, but seven refused further treatment because of prolonged grade 1 to 2 toxicity
• The authors' conclusion: The authors concluded that the primary efficacy endpoint was reached with acceptable toxicity, that lurbinectedin is likely to be active in progressing malignant pleural mesothelioma with promising outcomes compared with historical data, and that further evaluation in a large randomised trial is warranted.
• Limitations the authors state:
  • No comparison arm and no central radiology review
  • Small trial size, with about two-thirds slowly progressing patients and mostly epithelioid histology, may call the overall survival result into question
  • Subgroup analyses were ad hoc and involved small numbers
  • No quality-of-life assessments were done

Topics

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

Medical terms in this study, explained in our Lexicon: Palliative Care, Pleural Mesothelioma, Progression-Free Survival, Median Overall Survival, Macrophage, Platinum-Pemetrexed, Chemotherapy, Immunotherapy.

Related studies

• A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma — W.S. Lam, J. Creaney, 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)
• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial — M. Maio, A. Scherpereel, et al. (2017)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• Phase II trial of ZD0473 as second-line therapy in mesothelioma — G. Giaccone, M.E. O'Brien, et al. (2002)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)

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