Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma

Our plain-English summary of Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma, by A.S. Tsao, H. Lin, B.W. Carter, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: A.S. Tsao, H. Lin, B.W. Carter, J.J. Lee, D. Rice, A. Vaporcyan, S. Swisher, R. Mehran, J. Heymach, M. Nilsson, Y. Fan, M. Nunez, L. Diao, J. Wang, J. Fujimoto, I.I. Wistuba, W.K. Hong
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(2):246-257
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent.

Methods: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419.

Results: For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5-110), and the median posttreatment score was 41.9 (interquartile range 4.2-60) (p = 0.004). A decrease in p-SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p-SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels.

Conclusions: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This single-arm trial at M. D. Anderson Cancer Center in Texas (2008 to 2012) enrolled people with potentially operable malignant pleural mesothelioma. Patients took dasatinib by mouth, 70 mg twice a day, for 4 weeks before surgery. Of 28 enrolled, 24 could be evaluated for biomarker results. The main goal was to see whether dasatinib lowered tumor levels of activated Src (p-SrcTyr419). The median tissue score fell from 70 to 41.9 (p = 0.004). No significant tumor responses were seen. Median progression-free survival was 7.5 months (95% CI 2.1 to 15.5) and median overall survival 19.1 months (95% CI 11.5 to 24.1). Two patients died within 30 days of surgery. Measured from surgery, median progression-free survival was 6.9 months in patients whose p-SrcTyr419 fell versus 0.94 months in those whose level rose (p = 0.03). Higher baseline PDGFRB levels were associated with shorter progression-free survival. The authors concluded there was no significant efficacy signal and that dasatinib alone is unlikely to be studied further in this disease. They said the small number of patients limits interpretation. Asbestos exposure was not studied.

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-arm neoadjuvant (before-surgery) 'window of opportunity' drug trial with a tissue biomarker as its primary end point
• Who was studied: Patients with potentially resectable malignant pleural mesothelioma treated at The University of Texas M. D. Anderson Cancer Center, Houston, between 2008 and 2012. Of 56 screened, 28 had nonresectable tumors. Of 28 enrolled, 24 were evaluable for biomarker results; two missed several doses and two withdrew consent. Patient characteristics: median age 63 (range 46 to 79); 19 men and 5 women; 21 epithelioid and 3 biphasic tumors. Surgery: 8 had extrapleural pneumonectomy, 13 had pleurectomy/decortication, and 3 had incomplete (aborted) surgery.
• Exposure: Treatment with the drug dasatinib, 70 mg by mouth twice a day for 4 weeks before surgery, with or without radiotherapy after surgery, and optional maintenance dasatinib for up to 2 years. Asbestos exposure is not reported or studied.
• Main results:
  • All patients: median follow-up 19 months; median progression-free survival 7.5 months (95% CI 2.1 to 15.5); median overall survival 19.1 months (95% CI 11.5 to 24.1)
  • No significant responses were seen after 4 weeks of dasatinib
  • Two patients died within 30 days of surgery: one from a pulmonary embolus and one from pneumonia
  • The main side effects attributed to dasatinib before surgery were grade 1 to 2 fatigue, loss of appetite (anorexia), nausea and swelling (edema)
  • Tumor p-SrcTyr419 staining scores fell after 4 weeks of dasatinib: median 70 (interquartile range 37.5 to 110) before versus 41.9 (interquartile range 4.2 to 60) after, p = 0.004
  • Patients whose p-SrcTyr419 levels decreased after dasatinib had longer median progression-free survival than patients whose levels rose: 6.9 months versus 0.94 months, p = 0.03. In this biomarker-change analysis, survival was measured from the time of surgery.
  • Higher-than-median baseline PDGFRB staining was associated with worse progression-free survival: cytoplasm HR 2.54 (95% CI 1 to 6.41, p = 0.048), stroma HR 2.79 (95% CI 1.1 to 7.07, p = 0.03), nucleus HR 6.79 (95% CI 1.31 to 35.33, p = 0.023)
  • There were no significant correlations between overall survival and the PDGFR biomarkers
  • Patients negative for PDGFRB gene copy gain (FISH test) were more likely than FISH-positive patients to show a fall in PET/CT tumor uptake values: 60% versus 11.8%, p = 0.05. Nineteen patients were FISH-positive at baseline.
  • Only 4 of 17 eligible patients agreed to maintenance dasatinib; 2 of them withdrew after a few days
• The authors' conclusion: The authors concluded that dasatinib showed no significant efficacy signal and that dasatinib alone is unlikely to continue to be studied in malignant pleural mesothelioma. They suggested that the PDGFR pathway and its receptor subtypes may be important therapeutic targets.
• Limitations the authors state:
  • The number of patients was small, which limits interpretation of the results
  • Dasatinib was given for only 4 weeks so that surgery would not be delayed
  • PET/CT uptake values, used in place of standard radiologic response, are not validated for survival and can be falsely raised by prior talc pleurodesis or inflammation
  • Most eligible patients declined maintenance dasatinib because of treatment fatigue, which limits assessment of the drug's impact and of biomarker links to survival

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: Biomarker, Pleural Mesothelioma, Progression-Free Survival, Median Overall Survival, Immunohistochemistry, Platelet-Derived Growth Factor (PDGF), Hazard Ratio, Prognosis.

Related studies

• Prognostic significance of metabolic response by positron emission tomography after neoadjuvant chemotherapy for resectable malignant pleural mesothelioma — Y. Tsutani, T. Takuwa, et al. (2013)
• Dasatinib: an anti-tumour agent via Src inhibition — A. Gnoni, I. Marech, et al. (2011)
• Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report — A.Z. Dudek, H. Pang, et al. (2012)
• Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications — M.B. Suraokar, M.I. Nunez, et al. (2014)
• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)
• Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design — G.M. Stella, D. Lisini, et al. (2024)

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