A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group

Our plain-English summary of A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group, by S.A. Laurie, D. Hao, N.B. Leighl, et al (Lung Cancer, 2017).

The study

• Authors: S.A. Laurie, D. Hao, N.B. Leighl, J. Goffin, A. Khomani, A. Gupta, C.L. Addison, A. Bane, J. Seely, M.L. Filion, G.R. Pond, M.N. Levine
• Journal: Lung Cancer
• Published: 2017;104:65-69
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM.

Methods: This open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500mg/day for 5days on, 2days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design.

Results: 12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1.

Conclusions: Dovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This open-label phase II trial tested dovitinib, an oral drug that blocks several growth-signal receptors (VEGFR and FGFR), in adults with advanced malignant pleural mesothelioma that had already been treated with platinum-antifolate chemotherapy. Twelve patients were enrolled at 5 Canadian centres between February 2013 and August 2014. They took 500 mg daily for five days, then rested for 2 days. At 3 months, 50% were alive and free of progression (95% CI 28.4–88.0%). Median progression-free survival was 2.6 months (95% confidence interval 1.2 months to not reached), and median overall survival was 4.0 months. Of 8 patients whose response could be assessed, one had an unconfirmed partial response, five had stable disease and two had progressive disease. Five patients needed dose reductions for toxicity, and no deaths were attributed to treatment. The result was enough to move to the trial's second stage, but the trial committee did not expand the trial. One of 12 tumour samples showed low FGFR-1 amplification. The authors concluded that dovitinib alone had limited activity. They also said the small numbers gave insufficient data for firm conclusions from the biomarker studies.

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, multicentre, single-arm phase II drug trial with a two-stage design (trial NCT01769547)
• Who was studied: 12 adults (10 male, median age 67) with advanced malignant pleural mesothelioma previously treated with platinum-antifolate chemotherapy, enrolled at 5 centres in Canada between February 2013 and August 2014
• Exposure: Treatment with dovitinib, 500 mg orally daily for 5 days followed by 2 days off, in 28-day cycles. Dose reductions to 400 mg and then 300 mg were allowed. Asbestos exposure is not studied or discussed.
• Main results:
  • Among the 12 patients, the 3-month progression-free rate was 50% (95% CI 28.4–88.0%)
  • Median progression-free survival was 2.6 months (95% confidence interval 1.2 to not reached; maximum 7.3 months)
  • Median overall survival was 4.0 months (maximum 8.9 months)
  • Of 8 response-evaluable patients, one had an unconfirmed partial response and two had progressive disease at the first assessment
  • Of the 8 evaluable patients, five had stable disease as best response, with a median duration of 56 days
  • Although 6 of 12 patients were progression-free at 3 months, the trial committee did not proceed to stage 2, citing efficacy not substantially better than other VEGFR inhibitors and poor tolerance
  • Among the 12 patients, dose reductions to 400 mg for toxicity were needed in 5. Grade 3 toxicities possibly related to dovitinib occurred in 3. No deaths were attributed to study therapy.
  • Of 12 archival tumour specimens tested by FISH, one showed low FGFR-1 amplification
  • No change from baseline in plasma biomarkers was prognostic for outcomes
• The authors' conclusion: The authors concluded that single-agent dovitinib, like other VEGFR tyrosine kinase inhibitors, had limited activity in advanced previously-treated malignant pleural mesothelioma. They also concluded that the role of the FGFR pathway needs further characterization.
• Limitations the authors state:
  • The authors said the small sample size, the lack of objective responses and early withdrawal of several patients meant there were insufficient data to draw substantial conclusions from the biomarker studies
  • The authors questioned whether consistent FGFR1 inhibition was achieved at the doses delivered

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: Pleural Mesothelioma, Antifolate, Fibroblast, Chemotherapy, Systemic Therapy, Angiogenesis, confidence interval.

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