A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma

Our plain-English summary of A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma, by W.S. Lam, J. Creaney, F.K. Chen, et al (Lung Cancer, 2020).

The study

• Authors: W.S. Lam, J. Creaney, F.K. Chen, W.L. Chin, S. Muruganandan, S. Arunachalam, M.S. Attia, C. Read, K. Murray, M. Millward, J. Spiro, A. Chakera, Y.C. Gary Lee, A.K. Nowak
• Journal: Lung Cancer
• Published: 2020;140:87-92
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment.

Materials And Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients.

Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes.

Conclusions: The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This was a single-centre, open-label phase II trial of AZD4547, an oral drug that blocks fibroblast growth factor receptors 1 to 3. It enrolled people with malignant pleural mesothelioma whose disease had worsened after one or two earlier treatments, the first being platinum (cisplatin or carboplatin) with pemetrexed. Between April 2016 and December 2018, 24 patients (21 male) took 80 mg twice daily. The main goal was freedom from progression at 6 months. Three of 24 patients (12 %) reached it, which met the trial's stopping rule. Median progression-free survival was 91 days (95 % CI 69 to 180) and median overall survival was 220 days (95 % CI 180 to 363). One patient had brief, unconfirmed tumour shrinkage; 19 had stable disease and 5 progressive disease as their best response. No side effect went above grade 2, but dry mouth, high blood phosphate and fluid under the retina were common; three patients withdrew because of side effects. Loss of BAP1 protein in tumours was not linked to outcome. The authors concluded the study does not support AZD4547 as a single agent in pre-treated mesothelioma.

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: Single-centre, open-label, single-arm phase II drug trial using a Simon's two-stage design
• Who was studied: 24 adults with malignant pleural mesothelioma that had progressed after one or two lines of systemic therapy (first line platinum plus pemetrexed), recruited April 2016 to December 2018; 21 were male; median age 69.5 years
• Exposure: Treatment with the oral drug AZD4547, 80 mg twice daily continuously on 3-weekly cycles. The article reports no data on asbestos exposure.
• Main results:
  • 3 of 24 patients (12 %) were progression-free at 6 months, meeting the stopping criteria
  • Across all 24 patients, median progression-free survival was 91 days (95 % CI 69 to 180) and median overall survival was 220 days (95 % CI 180 to 363)
  • One patient had a 32 % tumour reduction at 6 weeks but progressed by 12 weeks, an unconfirmed partial response
  • 19 patients (79 %) had stable disease for at least 6 weeks and 5 patients (21 %) had progressive disease as their best response
  • Among the 24 patients, the most common toxicities were xerostomia (62.5 %), hyperphosphatemia (54 %), retinopathy (50 %), mucositis (41 %), dysgeusia (38 %) and onycholysis (38 %). No toxicity exceeded grade 2.
  • Three patients (12.5 %) withdrew because of toxicities
  • 12 of 24 patients developed subretinal fluid; all 12 remained asymptomatic
  • 19 of 24 patients (79 %) had tumours negative for BAP1 protein. Median progression-free survival was 87 days in those who retained BAP1 (n = 5) and 84 days in those who lost it (n = 19), with no difference between the groups.
• The authors' conclusion: The authors concluded that the study does not support AZD4547 as a single agent in pre-treated mesothelioma, or BAP1 loss as a marker of potential efficacy
• Limitations the authors state:
  • Quality of life was not formally measured
  • Because the drug lacked efficacy, the median duration of treatment was short
  • For 9 of the patients with subretinal fluid, long-term follow-up imaging was not available to show whether the fluid resolved

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Fibroblast, Malignant Mesothelioma, CT Scan, Modified RECIST (mRECIST), Mesothelioma, BAP1.

Related studies

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• 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)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma — A.K. Nowak, M.J. Millward, et al. (2012)
• Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma — M.G. Zauderer, S.L. Kass, et al. (2014)
• Pemetrexed for malignant pleural mesothelioma: Is it a standard second-line therapy? — K. Tamura, Y. Fujiwara (2010)

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