Clinical outcomes and prognostic factors of patients with advanced mesothelioma treated in a phase I clinical trials unit

Our plain-English summary of Clinical outcomes and prognostic factors of patients with advanced mesothelioma treated in a phase I clinical trials unit, by D. Papadatos-Pastos, D. Roda, M.J. De Miguel Luken, et al (European Journal of Cancer, 2017).

The study

• Authors: D. Papadatos-Pastos, D. Roda, M.J. De Miguel Luken, A. Petruckevitch, A. Jalil, M. Capelan, V. Michalarea, J. Lima, N. Diamantis, J. Bhosle, L.R. Molife, U. Banerji, J.S. de Bono, S. Popat, M.E.R. O'Brien, T.A. Yap
• Journal: European Journal of Cancer
• Published: 2017;75:56-62
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: We have previously reported a prognostic score for patients in phase I trials in the Drug Development Unit, treated at the Royal Marsden Hospital (RPS). The RPS is an objective tool used in patient selection for phase I trials based on albumin, number of disease sites and LDH. Patients with mesothelioma are often selected for phase I trials as the disease remains localised for long periods of time. We have now reviewed the clinical outcomes of patients with relapsed malignant mesothelioma (MM) and propose a specific mesothelioma prognostic score (m-RPS) that can help identify patients who are most likely to benefit from early referral.

Methods: Patients who participated in 38 phase I trials between September 2003 and November 2015 were included in the analysis. Efficacy was assessed by response rate, median overall survival (OS) and progression-free survival (PFS). Univariate (UVA) and multivariate analyses (MVA) were carried out to develop the m-RPS.

Results: A total of 65 patients with advanced MM were included in this retrospective study. The PFS was 2.5 months (95% confidence interval [CI] 2.0-3.1 months) and OS was 8 months (95% CI 5.6-9.8 months). A total of four (6%) patients had RECIST partial responses, whereas 26 (40%) patients had RECIST stable disease >3 months. The m-RPS was developed comprising of three different prognostic factors: a neutrophil: lymphocyte ratio greater than 3, the presence of more than two disease sites (including lymph nodes as a single site of disease) and albumin levels less than 35 from the MVA. Patients each received a score of 1 for the presence of each factor. Patients in group A (m-RPS 0-1; n = 35) had a median OS of 13.4 months (95% CI 8.5-21.6), whereas those in group B (m-RPS 2-3; n = 30) had a median OS of 4.0 months (95% CI 2.9-7.1, P < 0.0001). A total of 56 (86%) patients experienced G1-2 toxicities, whereas reversible G3-4 toxicities were observed in 18 (28%) patients. Only 10 (15%) patients discontinued phase I trials due to toxicity.

Conclusions: Phase I clinical trial therapies were well tolerated with early signals of antitumour activity in advanced MM patients. The m-RPS is a useful tool to assess MM patient suitability for phase I trials and should now be prospectively validated.

Copyright © 2017 Elsevier Ltd. All rights reserved.

In plain English

This retrospective review covered 65 patients with advanced malignant mesothelioma (61 pleural, 4 peritoneal) treated in 38 phase I trials at the Royal Marsden Hospital, UK, between September 2003 and October 2015. The article does not discuss asbestos. Median overall survival was 8.0 months (95% CI 5.6 to 9.8) and median progression-free survival 2.5 months (95% CI 2.0 to 3.1). Four (6%) had partial responses and 26 (40%) stable disease beyond 3 months. Mild to moderate side effects affected 56 patients (86%), severe ones 18 (28%). Ten (15%) stopped because of side effects; no deaths were attributed to the trial drugs. The authors built a mesothelioma-specific prognostic score from a neutrophil-to-lymphocyte ratio above 3, more than two disease sites, and albumin below 35 g/L. Patients scoring 0 to 1 (35) had a median survival of 13.4 months (95% CI 8.5 to 21.6), versus 4.0 months (95% CI 2.9 to 7.1) for the 30 scoring 2 to 3. The authors concluded the treatments were well tolerated with early signs of activity, and that the score needs prospective validation.

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: Retrospective analysis of patients treated in phase I clinical trials at a single unit
• Who was studied: 65 patients with advanced malignant mesothelioma (61 pleural, 4 peritoneal; 43 male, 22 female; median age 64) treated in 38 phase I trials at the Royal Marsden Hospital Drug Development Unit, Sutton, UK, September 2003 to October 2015
• Exposure: Not asbestos. The exposure was experimental phase I trial treatments: 28 patients (43%) received PI3K pathway agents, 12 (18%) received histone deacetylase inhibitors, and 9 (14%) received chemotherapy combined with a trial agent. Other drug classes were also used.
• Main results:
  • Whole study population: median overall survival 8.0 months (95% CI 5.6 to 9.8) and median progression-free survival 2.5 months (95% CI 2.0 to 3.1)
  • 4 of 65 patients (6%) had confirmed partial responses: 2 to PI3K pathway inhibitors, 1 to an aurora kinase A inhibitor and 1 to an immune checkpoint inhibitor. 26 (40%) had stable disease longer than 3 months.
  • Patients given a PI3K pathway inhibitor showed a trend toward longer overall survival than other patients (median 12.2 vs 7.1 months), but P = 0.29, which is not statistically significant
  • Side effects: 56 patients (86%) had grade 1 to 2 toxicities and 18 (28%) had grade 3 to 4 toxicities. 10 (15%) discontinued because of drug-associated toxicities. No deaths were attributed to the investigational agent.
  • In multivariate analysis, three factors were associated with poorer overall survival: a neutrophil-to-lymphocyte ratio above 3 (HR 2.1, 95% CI 1.0 to 4.2), enlarged lymph nodes (HR 2.3, 95% CI 1.1 to 4.6) and more than two disease sites (HR 4.0, 95% CI 1.7 to 9.2)
  • Prognostic score groups: group A (score 0 to 1, n = 35) had a median overall survival of 13.4 months (95% CI 8.5 to 21.6). Group B (score 2 to 3, n = 30) had 4.0 months (95% CI 2.9 to 7.1). P less than 0.0001.
  • No group A patients died within 90 days of starting the trial. The 90-day mortality in group B was 33% (10 of 30), and 5 of 6 patients with a score of 3 died within 90 days.
• The authors' conclusion: The authors concluded that phase I trial therapies were well tolerated, with early signals of antitumour activity in advanced malignant mesothelioma. They considered the mesothelioma prognostic score a useful tool for judging suitability for phase I trials and said it should now be prospectively validated.
• Limitations the authors state:
  • Stable disease lasting more than 3 months in 26 patients may have been confounded by slowly progressing mesothelioma
  • Patients were not molecularly matched to targeted therapies, and only a modest number gained clinical benefit
  • The prognostic score has not yet been prospectively validated

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Clinical Trial, Malignant Mesothelioma, Median Overall Survival, Progression-Free Survival, confidence interval.

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