A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma

Our plain-English summary of A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma, by P.A. Zucali, M. Perrino, F. De Vincenzo, et al (Lung Cancer, 2020).

The study

• Authors: P.A. Zucali, M. Perrino, F. De Vincenzo, L. Giordano, N. Cordua, F. D'Antonio, A. Santoro
• Journal: Lung Cancer
• Published: 2020;142:132-137
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC).

Patients And Methods: GEM (1000 mg/m2) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS).

Results: In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients.

Conclusions: The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This single-arm phase II trial at the Humanitas Clinical and Research Center near Milan, Italy, enrolled 23 patients with malignant pleural mesothelioma that had progressed after pemetrexed-based chemotherapy and whose tumors expressed PDGFR-beta and/or cKIT. Patients received intravenous gemcitabine plus oral imatinib in 21-day cycles. The main goal was a 3-month progression-free rate of 75%. Only 39.1% (9 of 23) were free of progression at 3 months, so the study did not reach its primary endpoint. Median progression-free survival was 2.8 months and median overall survival was 5.7 months. Four patients (17.4%) had a partial response. Drug-related side effects occurred in 17 patients (73.9%). Four (17%) had grade 3 effects, and none had grade 4 or 5. A table reported 6-month overall survival of 20% among the 10 patients with known professional or environmental asbestos exposure, compared with 61.5% among the 13 whose exposure was unknown. The authors did not discuss this in the text. The authors concluded the schedule was manageable and well tolerated but did not meet its primary endpoint. They named the single-arm design and small sample size as limitations.

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 (Simon optimal two-stage design)
• Who was studied: 23 patients with malignant pleural mesothelioma whose tumors expressed PDGFR-beta and/or cKIT on immunohistochemistry and whose disease had progressed after pemetrexed-based chemotherapy. They were treated at the Humanitas Clinical and Research Center, Rozzano, Milan, Italy, and enrolled from December 2014 to December 2015. 10 had known professional or environmental asbestos exposure and 13 had unknown exposure.
• Exposure: Treatment with gemcitabine 1000 mg/m2 on days 3 and 10 plus imatinib mesylate 400 mg orally on days 1 to 5 and 8 to 12 of a 21-day cycle. Asbestos exposure was recorded only as a patient characteristic (known professional/environmental vs unknown).
• Main results:
  • In all 23 patients, the 3-month progression-free survival rate was 39.1% (9/23), and the primary endpoint was not reached.
  • In all patients, median progression-free survival was 2.8 months.
  • In all patients, median overall survival was 5.7 months. Median follow-up was 34.5 months, and 21 patients had died.
  • Four patients had a partial response, an overall response rate of 17.4%. 11 (47.8%) had stable disease, and no complete remission was seen.
  • Any-grade drug-related adverse events occurred in 17 (73.9%) patients. Grade 3 events occurred in four (17%), three of them neutropenia.
  • No grade 4 or grade 5 treatment-related adverse events were observed.
  • Patients with ECOG performance status 0 had higher 6-month overall survival than those with status 1 to 2: 77.8% vs 15.4%, p = 0.012.
  • In Table 2, 6-month overall survival was 61.5% in patients with unknown asbestos exposure and 20% in those with known exposure (p = 0.034). 6-month progression-free survival was 30.8% vs 10% (p = 0.388).
• The authors' conclusion: The authors concluded that the gemcitabine-imatinib schedule was manageable and well tolerated. However, the study did not meet its primary endpoint, which in their view confirmed that imatinib is ineffective in the second-line setting even when combined with chemotherapy in selected patients.
• Limitations the authors state:
  • The trial was single-arm and had a small sample size.
  • Only 10 of the 23 patients received the combination as pure second-line therapy.
  • The statistical target was very ambitious compared with other studies in the same setting.
  • The distribution of biomarker expression did not allow the prognostic and predictive impact of cKIT and PDGFR-beta to be evaluated.
  • Quality of life was not evaluated.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Gemcitabine, Pemetrexed (Alimta), Pleural Mesothelioma, Chemotherapy, Cisplatin, Platinum-Pemetrexed, Immunohistochemistry, Progression-Free Survival.

Related studies

• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)
• Successful salvage chemotherapy with gemcitabine and vinorelbine in a malignant pleural mesothelioma patient previously treated with pemetrexed — T. Agatsuma, T. Koizumi, et al. (2010)
• Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors — B. Saraiya, R. Chugh, et al. (2012)
• Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma — P.A. Zucali, M. Perrino, et al. (2014)
• Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy — G. Toyokawa, M. Takenoyama, et al. (2014)
• Phase II study of gemcitabine plus docetaxel as second-line treatment in malignant pleural mesothelioma: a single institution study — I. Tourkantonis, N. Makrilia, et al. (2011)

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