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A Randomized Phase II Study Adding Axitinib To Pemetrexed‐Cisplatin In Patients With Malignant Pleural Mesothelioma: A Single‐Center Trial Combining Clinical And Translational Outcomes

W. Buikhuisen, M. Scharpfenecker, Arjan W. Griffioen, Catharina M. Korse, H. van Tinteren, P. Baas
Published 2016 · Medicine

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Introduction: Mesothelioma often presents with a high vessel count and increased vascular growth factors levels. Interference with angiogenesis may therefore improve outcome. This study reports on clinical and translational parameters in patients treated with the small molecule tyrosine kinase inhibitor axitinib and chemotherapy. Methods: Chemonaive patients with mesothelioma were eligible. Patients received pemetrexed (500 mg/m2 every 3 weeks) and cisplatin (75 mg/m2 every 3 weeks) and were randomized to receive axitinib daily (two 5‐mg tablets on days 2–19) or observation. Before treatment and after three cycles of chemotherapy, a thoracoscopy was performed to evaluate vascular changes. Results: Twenty‐five patients were randomized after a successful lead‐in with six patients who received axitinib. Median follow‐up was 45 months. In all but one patient, it was feasible to perform a second thoracoscopy. However, there was more grade 3 or 4 neutropenia leading to pneumonia in the axitinib group. The rates of partial response and stable disease in the axitinib arm were 36% and 43% compared with 18% and 73% in the chemotherapy‐only arm. Median progression‐free survival and overall survival (5.8 and 18.9 months versus 8.3 and 18.5 months) were not different between the two groups. Axitinib reduced vessel number and vessel immaturation. Yet, the mRNA levels of a number of vascular growth factors, their receptors, serum VEGF levels, and activation of tissue vascular endothelial growth factor receptor 2 were increased. Gene expression of platelet‐derived growth factor receptor beta, fms‐related tyrosine kinase 1, and fms‐related tyrosine kinase 4 even correlated with outcome. Conclusions: Axitinib was well tolerated in combination with cisplatin and pemetrexed. Despite the lack of a clinical benefit, axitinib reduced angiogenesis. Whether changes in differentially expressed growth factors in tissue and serum may serve as a biomarker needs further investigation.
This paper references
Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study.
H. Kindler (2011)
Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study.
W. Buikhuisen (2013)
Bevacizumab 15mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): Results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial.
G. Zalcman (2015)
Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality‐of‐life assessments
L. Locati (2014)
Phase II Study of Cediranib in Patients with Malignant Pleural Mesothelioma: SWOG S0509
L. Garland (2011)
A Phase II Study of Intermittent Sunitinib Malate as Second-Line Therapy in Progressive Malignant Pleural Mesothelioma
A. Nowak (2012)
A Disintegrin and Metalloprotease 10 Is a Novel Mediator of Vascular Endothelial Growth Factor–Induced Endothelial Cell Function in Angiogenesis and Is Associated With Atherosclerosis
M. Donners (2010)
Angiogenic cytokines in mesothelioma: a study of VEGF, FGF‐1 and ‐2, and TGF β expression
S. Kumar-Singh (1999)
Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth
Romulo J. C. Albuquerque (2009)
Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation.
A. Griffioen (2000)
Venous thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis of randomized clinical trials.
G. Sonpavde (2013)
Current data on predictive markers for anti-angiogenic therapy in thoracic tumours
N. Reinmuth (2010)
Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer
C. Belani (2013)
Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.
R. Motzer (2013)
S. Kumar-Singh (1997)
Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107).
T. Jahan (2012)
Independent expression of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with carcinoma and sarcoma.
C. Linder (1998)
Tumor angiogenesis: therapeutic implications.
J. Folkman (1971)
Diastolic Blood Pressure as a Biomarker of Axitinib Efficacy in Solid Tumors
B. Rini (2011)
A Phase II Study of Sorafenib in Malignant Mesothelioma: Results of Cancer and Leukemia Group B 30307
S. Dubey (2010)
Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma.
H. Kindler (2012)
Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy
J. Ebos (2007)
VEGF-A Stimulates ADAM17-Dependent Shedding of VEGFR2 and Crosstalk Between VEGFR2 and ERK Signaling
S. Swendeman (2008)
VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours
Y. Ohta (1999)
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
N. Vogelzang (2003)
Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours
M. Kozloff (2012)
Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada.
J. Van Meerbeeck (2005)
Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer.
H. Rugo (2011)
Thromboembolic events in patients treated with anti-angiogenic drugs.
P. Ferroni (2010)
Brief Report: A Phase II Study of Sunitinib in Malignant Pleural Mesothelioma. The NCIC Clinical Trials Group
S. Laurie (2011)

This paper is referenced by
ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma
A. Scherpereel (2020)
A review of bevacizumab in the treatment of malignant pleural mesothelioma.
S. Brosseau (2017)
Spotlight on bevacizumab and its potential in the treatment of malignant pleural mesothelioma: the evidence to date
Pavel A. Levin (2017)
ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.
I. Opitz (2020)
Novel systemic therapy against malignant pleural mesothelioma.
M. R. Mancuso (2017)
Analysis of survival of patients with metastatic malignant pleural mesothelioma.
A. Billè (2020)
Chemotherapy options versus "novel" therapies: how should we treat patients with malignant pleural mesothelioma.
M. Disselhorst (2020)
Scientific Advances and New Frontiers in Mesothelioma Therapeutics.
L. Mutti (2018)
Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future
Fabio Nicolini (2019)
Targeting the vasculature: anti-angiogenic agents for malignant mesothelioma
P. L. Chia (2016)
Malignant Mesothelioma: Has Anything Changed?
Roger Y Kim (2019)
Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma
M. Yin (2017)
Standard Chemotherapy Options and Clinical Trials of Novel Agents for Mesothelioma
M. Zauderer (2017)
Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?
L. Cantini (2020)
Novel therapies for malignant pleural mesothelioma.
A. Scherpereel (2018)
Targeting Angiogenesis in Malignant Pleural Mesothelioma
A. Scherpereel (2019)
The Role of Immunotherapy in Malignant Mesothelioma
Kastelik Ja (2018)
Targeting angiogenesis for patients with unresectable malignant pleural mesothelioma.
A. Tsao (2019)
Relationship between Progression-free Survival and Overall Survival in Randomized Clinical Trials of Targeted and Biologic Agents in Oncology
L. Hess (2019)
Current and prospective pharmacotherapies for the treatment of pleural mesothelioma
Emyr Bakker (2017)
Emerging Drug Therapies for Mesothelioma
D. B. Oien (2020)
A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group.
S. Laurie (2017)
A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma
M. O. Jamil (2017)
Chemotherapy for Malignant Pleural Mesothelioma: Past, Present and Future
A. Scherpereel (2017)
Biomarkers Progress and Therapeutic Implications in Malignant Mesothelioma
J. Feinstein (2020)
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