Learning from the past to design better trials in second-line treatment for mesothelioma patients

Our plain-English summary of Learning from the past to design better trials in second-line treatment for mesothelioma patients, by A. Addeo, G.L. Banna, P.Y. Dietrich (Ecancermedicalscience, 2018).

The study

• Authors: A. Addeo, G.L. Banna, P.Y. Dietrich
• Journal: Ecancermedicalscience
• Published: 2018;12:881
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer characterised by modest sensitivity to systemic chemotherapy. The standard treatment remains platinum-based chemotherapy with pemetrexed. Recently, the addition of an antiangiogenic drug, bevacizumab, to first-line chemotherapy has been shown to improve overall survival. All the patients, unfortunately, will progress, and currently, there is no standard treatment approved in second-line. Recently, the results of the NGR015 phase III randomised with NGR-hTNF plus chemotherapy versus placebo in addition to physician's choice second-line chemotherapy for MPM have been published. Despite encouraging data achieved in previous phase I and phase II studies, the NGR-hTNF drug failed to meet the primary endpoint of the study, although a signal of activity was observed in the group of patients who had a shorter treatment failure interval from the first-line treatment. Hereby, we start from this recent trial to highlight once more the importance of thoroughly investigating possible predictive factors during the early drug development phase to allow more efficient phase III trial design, thus avoiding the possibility of potentially effective molecules like NGR-hTNF, continuing to be wasted.

In plain English

This article was a short communication, an opinion piece on how clinical trials are designed. It reported no new patient data and did not discuss asbestos exposure. The authors used a separate, previously published phase III trial, NGR015, as their example. That trial compared the drug NGR-hTNF with placebo, each added to second-line chemotherapy chosen by the physician, in people with malignant pleural mesothelioma. As the authors described it, NGR015 did not meet its main goal of improving overall survival. It did suggest a possible benefit in patients with a short treatment-free interval after their first treatment, but this came from an exploratory analysis done after the fact. The authors argued that factors such as tumour histology, BAP1 mutation and treatment-free interval should have been used to balance the trial groups. They noted that, as far as they knew, ongoing second-line mesothelioma trials did not properly address treatment-free interval. The authors concluded that predictive factors and proper stratification are the way to design successful trials, and that ignoring them might lead to further failures.

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: Short communication (commentary on trial design); no original data
• Who was studied: No patients were studied by the authors. The article discusses the separately published NGR015 phase III trial in previously treated malignant pleural mesothelioma patients receiving second-line chemotherapy.
• Exposure: Not an asbestos exposure study. The treatment discussed was NGR-hTNF, a drug described as increasing chemotherapy penetration into the tumour, given with second-line chemotherapy.
• Main results:
  • As described by the authors, the separate NGR015 trial did not meet its primary endpoint of overall survival.
  • As described by the authors, NGR015 suggested a possible clinically meaningful interaction in patients with a short treatment-free interval (TFI) from first-line therapy. The cutoff was the median time from a post-hoc exploratory sensitivity analysis.
  • The authors argued that NGR015 should have stratified patients by histology, BAP1 mutation and TFI, in addition to performance status and chemotherapy.
  • The authors noted that histology was not used as a stratification factor in NGR015, despite being an independent prognostic factor in the earlier phase II study.
  • The authors noted that the earlier phase II trial studied TFI only as a continuous variable, not as a two-group variable that could identify a cutoff.
  • The authors stated that, as far as they knew, ongoing second-line malignant pleural mesothelioma trials did not properly address TFI in their design.
• The authors' conclusion: The authors concluded that predictive factors and proper stratification are the way to design successful trials. They added that failing to account for them, especially TFI, might lead to further trial failures even when a drug may be effective.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Chemotherapy, Pemetrexed (Alimta), Bevacizumab, Overall Survival.

Related studies

• 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 clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma — D.A. Fennell, C. McDowell, et al. (2012)
• A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma — A.K. Nowak, C. Brown, et al. (2013)
• Phase II trial of ZD0473 as second-line therapy in mesothelioma — G. Giaccone, M.E. O'Brien, et al. (2002)
• 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)

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