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

Our plain-English summary of 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, by W.A. Buikhuisen, M. Scharpfenecker, A.W. Griffioen, et al (Journal of Thoracic Oncology, 2016).

The study

• Authors: W.A. Buikhuisen, M. Scharpfenecker, A.W. Griffioen, C.M. Korse, H. van Tinteren, P. Baas
• Journal: Journal of Thoracic Oncology
• Published: 2016;11(5):758-768
• Type of article: Randomized trial
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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/m(2) every 3 weeks) and cisplatin (75 mg/m(2) 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.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This single-center randomized phase II trial in Amsterdam studied people with malignant pleural mesothelioma who had not had chemotherapy before. It tested adding axitinib, a tablet drug that blocks blood-vessel growth signals, to pemetrexed-cisplatin chemotherapy. From July 2009 to October 2012, 32 patients enrolled. Six took axitinib in a lead-in phase, and 26 were randomized, one of whom withdrew. Among randomized patients, partial response was 36% with axitinib and 18% without, and stable disease was 43% and 73%. Median progression-free survival (5.8 versus 8.3 months) and overall survival (18.9 versus 18.5 months) did not differ significantly. Among all treated patients, severe (grade 3 or 4) neutropenia affected 45% of those given axitinib versus 9% of those given chemotherapy only. Biopsies were taken before treatment and at a second thoracoscopy after three cycles. Vessel density rose with chemotherapy alone but stayed the same with axitinib. The authors concluded that the combination was well tolerated but showed no signs of clinical activity. They cautioned that survival results in such a small group need careful interpretation.

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: Open-label, single-center, randomized phase II trial with a non-randomized lead-in cohort; combined clinical and laboratory (translational) outcomes
• Who was studied: 32 patients with malignant pleural mesothelioma who had not had chemotherapy, included July 2009 to October 2012 at the Netherlands Cancer Institute, Amsterdam. There were 6 lead-in patients and 26 randomized patients, of whom 1 withdrew. Overall, 20 received chemotherapy plus axitinib and 11 received chemotherapy only.
• Exposure: Treatment, not asbestos exposure: pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 every 3 weeks, with or without daily axitinib (5-mg tablets, days 2 to 19 of each cycle)
• Main results:
  • Among the 25 randomized patients, partial response was 36% and stable disease 43% in the axitinib arm, versus 18% and 73% in the chemotherapy-only arm. There was no difference in the number of responders, and no complete responses.
  • Median progression-free survival was 5.8 months (95% CI 4.6 to 24) in the axitinib group and 8.3 months (95% CI 6 to not available) in the chemotherapy-only group (p = 0.86). Median follow-up was 45 months.
  • Median overall survival was 18.9 months (95% CI 11.2 to not available) in the axitinib group and 18.5 months (95% CI 13.7 to not available) in the chemotherapy-only group (p = 0.78).
  • Grade 3 or 4 neutropenia occurred in 9 patients (45%) in the axitinib group versus 1 patient (9%) in the chemotherapy-only group.
  • Grade 2 hypertension occurred significantly more often with axitinib (p = 0.01). There were two thrombotic events (10%) in the axitinib arm, a pulmonary embolism and a stroke, both possibly related to axitinib.
  • A second thoracoscopy with partial pleurectomy was done in all 11 chemotherapy-only patients and in 16 of the 20 axitinib patients.
  • Microvessel density in tumor biopsies increased after chemotherapy alone (p less than 0.0001), while in the axitinib group microvessel density and the number of mature vessels stayed the same.
  • Across both groups, higher mRNA expression of PDGFRB, FLT1 and FLT4 in tumor tissue was significantly associated with worse outcome.
  • In serum, soluble VEGFR2 levels fell and VEGF levels rose during axitinib treatment.
• The authors' conclusion: The authors concluded that a second thoracoscopy was feasible and that the combination was well tolerated, with no signs of clinical activity. They also concluded that reducing microvessel density and increasing vessel maturity alone was not enough to improve progression-free or overall survival.
• Limitations the authors state:
  • All patients underwent cytoreductive surgery after three cycles, which may have confounded progression and survival.
  • The cohort was small, so progression-free and overall survival should be interpreted with care.
  • Because the study was small, the authors could not assign the biomarker-outcome correlations to treatment groups.
  • Fewer axitinib patients received additional pemetrexed-containing cycles after the second thoracoscopy (43% versus 73%), an imbalance that could have masked a benefit.

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: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Mesothelioma, Angiogenesis, Tyrosine Kinase Inhibitor, Chemotherapy, Thoracoscopy.

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• Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma — L.M. Krug, A.J. Wozniak, et al. (2014)
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• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)

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