A Phase II Study of Pazopanib in Patients with Malignant Pleural Mesothelioma: NCCTG N0623 (Alliance)

Our plain-English summary of A Phase II Study of Pazopanib in Patients with Malignant Pleural Mesothelioma: NCCTG N0623 (Alliance), by K. Parikh, S.J. Mandrekar, K. Allen-Ziegler, et al (The Oncologist, 2020).

The study

• Authors: K. Parikh, S.J. Mandrekar, K. Allen-Ziegler, B. Esplin, A.D. Tan, B. Marchello, A.A. Adjei, J.R. Molina
• Journal: The Oncologist
• Published: 2020;25(6):523-531
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Preclinical and clinical data have shown promise in using antiangiogenic agents to treat malignant pleural mesothelioma (MPM). We conducted this phase II study to evaluate the efficacy and toxicity of single-agent pazopanib in patients with MPM.

Materials And Methods: Patients with MPM who had received 0-1 prior chemotherapy regimens were eligible to receive pazopanib at a dose of 800 mg daily. The primary endpoint was progression-free survival rate at 6 months (PFS6), with a preplanned interim analysis for futility. Secondary endpoints included overall survival (OS), PFS, adverse events assessment and clinical benefit (complete response, partial response [PR], and stable disease [SD]).

Results: Thirty-four evaluable patients were enrolled, with a median age of 73 years (49-84). The trial was closed early because of lack of efficacy at the preplanned interim analysis. Only 8 patients (28.6%; 95% confidence interval [CI], 13.2-48.7%) in the first 28 evaluable were progression-free at 6 months. PFS6 was 32.4% (95% CI, 17.4-50.5). There were 2 PR (5.9%) and 16 SD (47.1%). The overall median PFS and OS were 4.2 months (95% CI, 2.0-6.0) and 11.5 months (95% CI: 5.3-18.2), respectively. The median PFS and OS for the previously untreated patients was 5.4 months (95% CI, 2.7-8.5) and 16.6 months (95% CI, 6.6-30.6), respectively; and 2.0 months (95% CI, 1.3-4.2) and 5.0 months (95% CI: 3.0-11.9), respectively, for the previously treated patients. Grade 3 or higher adverse events were observed in 23 patients (67.6%).

Conclusion: Single-agent pazopanib was poorly tolerated in patients with MPM. The primary endpoint of PFS6 was not achieved in the current study. ClinicalTrials.gov identification number. NCT00459862.

Implications For Practice: Single-agent pazopanib did not meet its endpoint in this phase II trial in malignant mesothelioma. Pazopanib is well tolerated in mesothelioma patients with a manageable toxicity profile. There is a need to better identify signals of angiogenesis that can be targeted in mesothelioma. Encouraging findings in frontline treatment warrant further investigations in combination with chemotherapy or immunotherapy.

© AlphaMed Press 2019.

In plain English

This single-arm phase II trial tested oral pazopanib, 800 mg daily, in people whose malignant pleural mesothelioma could not be removed by surgery. Asbestos exposure was not studied. Of 34 patients enrolled from March 2007 to December 2008, 19 had no earlier chemotherapy and 15 had received a pemetrexed-containing regimen. The main goal was the share alive and progression-free at 6 months without having stopped treatment for adverse reactions, refusal or other therapy. At a planned interim check, only 8 of the first 28 evaluable patients succeeded, and the trial closed early for lack of efficacy. In all, 32.4% (11/34; 95% CI, 17.4% to 50.5%) succeeded. Median overall survival was 11.5 months (95% CI, 5.3 to 18.2) overall, 16.6 (6.6 to 30.6) in untreated and 5.0 (3.0 to 11.9) in previously treated patients. Grade 3 or higher adverse events, whatever their cause, occurred in 23 patients (67.6%). The article calls the drug both poorly and well tolerated. The authors concluded the main goal was not met and further development of pazopanib for this use is unlikely to be fruitful.

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 phase II clinical trial (no control group) with a preplanned interim analysis for futility. A primary-endpoint success was a patient alive and progression free at 6 months who had not gone off treatment because of adverse reactions, refusal, or alternate therapy.
• Who was studied: 34 patients with unresectable malignant pleural mesothelioma, enrolled March 23, 2007 through December 28, 2008 through NCCTG/Alliance sites in the USA. 19 were treatment-naive and 15 had received one prior pemetrexed-containing regimen. Median age was 73 (range 49 to 84), and 82.3% were men.
• Exposure: Pazopanib (an antiangiogenic multikinase inhibitor), given orally at 800 mg daily for up to 2 years or until progression or unacceptable toxicity. Asbestos exposure was not studied.
• Main results:
  • At the preplanned interim analysis, 8 of the first 28 evaluable patients (28.6%; 95% CI, 13.2% to 48.7%) were progression free at 6 months. The study therefore did not meet its success criteria and was closed.
  • The 6-month progression-free survival rate was 32.4% (11/34; 95% CI, 17.4% to 50.5%) in all patients, 42.1% (8/19; 95% CI, 20.3% to 66.5%) in those with no prior treatment, and 20% (3/15; 95% CI, 4.3% to 48.1%) in those with prior treatment.
  • Median progression-free survival was 4.2 months (95% CI, 2.0 to 6.0) overall, 5.4 months (95% CI, 2.7 to 8.5) in treatment-naive patients, and 2.0 months (95% CI, 1.3 to 4.2) in previously treated patients.
  • Median overall survival was 11.5 months (95% CI, 5.3 to 18.2) overall, 16.6 months (95% CI, 6.6 to 30.6) in treatment-naive patients, and 5.0 months (95% CI, 3.0 to 11.9) in previously treated patients.
  • There were no complete responses. Two partial responses occurred, both in the group with no prior treatment (10.5% of that group). The overall clinical benefit rate was 52.9%.
  • Adverse events were counted regardless of whether they were attributed to treatment. Grade 3 or higher adverse events occurred in 23 of 34 patients (67.6%), and grade 4 or higher in 5 (14.7%). Three patients had grade 5 (fatal) events, none judged treatment related.
  • Eight patients (23.5%) stopped treatment because of adverse events.
• The authors' conclusion: The authors concluded that the trial did not meet its primary endpoint of 6-month progression-free survival. Given poor results with similar drugs in mesothelioma, they judged further development of pazopanib for this use unlikely to be fruitful. The article is inconsistent about tolerability: its final conclusion calls the drug well tolerated, while the abstract and discussion say it was poorly or not well tolerated.
• Limitations the authors state:
  • The study had no control group and compared its efficacy with historical values.
  • Comparisons with other trials should be interpreted with great caution because of differences in design, sample size and patients.
  • Progression was judged from tumor size on imaging, which the authors say may not capture how this type of drug works and may explain differences between the survival endpoints.

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, Progression-Free Survival, Overall Survival, confidence interval, Malignant Mesothelioma, Mesothelioma, Angiogenesis.

Related studies

• Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials — X. Wang, X. Wang, et al. (2017)
• 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.A. Buikhuisen, M. Scharpfenecker, et al. (2016)
• 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)
• Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors — B. Saraiya, R. Chugh, et al. (2012)
• A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design — F. Passiglia, P. Bironzo, et al. (2021)
• Research priorities in mesothelioma: A James Lind Alliance Priority Setting Partnership — R.J. Stephens, C. Whiting, et al. (2015)

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