Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma

Our plain-English summary of Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma, by A.S. Tsao, N. Harun, J.J. Lee, et al (Clinical Lung Cancer, 2014).

The study

• Authors: A.S. Tsao, N. Harun, J.J. Lee, J. Heymach, K. Pisters, W.K. Hong, J. Fujimoto, I. Wistuba
• Journal: Clinical Lung Cancer
• Published: 2014;15(3):197-201
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM).

Methods: A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels.

Results: Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done.

Conclusion: The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.

Copyright © 2014 Elsevier Inc. All rights reserved.

In plain English

This was a phase I trial, a small early study mainly meant to find the highest tolerable dose. It tested the drug imatinib mesylate added to the chemotherapy drugs cisplatin and pemetrexed. Seventeen patients with unresectable malignant pleural mesothelioma who had never had chemotherapy were enrolled between September 2006 and April 2009. The article does not discuss asbestos exposure. The maximum tolerated dose was dose level 3 (imatinib 600 mg), where nausea and vomiting limited dosing. There were no treatment-related deaths. Across all 17 patients, median progression-free survival was 7.9 months and median overall survival was 8.8 months. Patients with the sarcomatoid type did worse. The 6 patients who finished all 6 cycles had a median overall survival of 22.4 months. The authors cautioned that this group was more likely to do well anyway, so it was hard to claim the regimen was effective. In tumor tissue from 14 patients, higher p-PDGFRa levels were linked to longer survival. The authors concluded that the combination helped some patients but was not well tolerated.

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: Phase I dose-escalation clinical trial (standard 3 + 3 design) of a three-drug treatment
• Who was studied: 17 patients with unresectable malignant pleural mesothelioma of any histologic type who had not received chemotherapy, enrolled September 2006 to April 2009. There were 14 men and 3 women, median age 61 (range 48-79). Tumor types were 7 epithelioid, 5 biphasic and 5 sarcomatoid.
• Exposure: No asbestos or fiber exposure is reported. What was studied was a treatment: daily oral imatinib mesylate (300 to 600 mg depending on dose level) plus intravenous cisplatin and pemetrexed every 28 days, for up to 6 cycles.
• Main results:
  • The maximum tolerated dose was dose level 3 (cisplatin 75 mg/m2, pemetrexed 500 mg/m2, imatinib mesylate 600 mg). Nausea and vomiting were the dose-limiting toxicity.
  • The most common side effects at any grade were nausea, fatigue, hypomagnesemia and anemia. There was 1 grade 4 anemia event and no treatment-related deaths.
  • Best response: 1 partial response, 3 minor responses, 7 stable disease and 3 progressive disease. Three patients were not evaluable.
  • Among all 17 patients, median progression-free survival was 7.9 months and median overall survival was 8.8 months.
  • Compared with patients with epithelioid or biphasic types, patients with the sarcomatoid type had worse progression-free survival (P = .01) and worse overall survival (P = .009). An ECOG performance status of 0 or 1 predicted improved overall survival (P = .001) and progression-free survival (P = .013).
  • Six patients completed all 6 cycles; 7 completed 2 or fewer. In the 6 who completed all 6 cycles, median progression-free survival was 9.6 months and overall survival was 22.4 months. Their overall survival was better than that of patients who did not complete treatment (P = .006).
  • Of 14 patients with adequate tumor tissue, those with higher than median p-PDGFRa expression in tumor cells had better overall survival (P = .013).
  • Of 12 patients with successful PDGFRB FISH results, none had increased gene copies or gene amplification, so no correlation with outcomes could be made.
• The authors' conclusion: The authors concluded that the regimen had clinical benefit in some patients but was not well tolerated. They considered it unlikely to be developed further and called for study of other anti-angiogenic agents.
• Limitations the authors state:
  • Because of the small sample size, results were not adjusted for other factors.
  • Patients who completed 6 cycles had better performance status and none had sarcomatoid tumors, so their longer survival may not reflect the regimen.
  • The tissue studies were small, and tissue samples were not collected prospectively.
  • The trial had no maintenance therapy arm.

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: Cisplatin, Pemetrexed (Alimta), Unresectable, Pleural Mesothelioma, Platelet-Derived Growth Factor (PDGF), Progression-Free Survival, Median Overall Survival, Sarcomatoid.

Related studies

• 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)
• A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma — P.A. Zucali, M. Perrino, et al. (2020)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol — N. Fujimoto, K. Aoe, et al. (2018)
• Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors — B. Saraiya, R. Chugh, et al. (2012)
• LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma — G.V. Scagliotti, R. Gaafar, et al. (2017)

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