Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial

Our plain-English summary of Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial, by C.J. de Gooijer, V. van der Noort, J.A. Stigt, et al (The Lancet. Respiratory Medicine, 2021).

The study

• Authors: C.J. de Gooijer, V. van der Noort, J.A. Stigt, P. Baas, B. Biesma, R. Cornelissen, N. van Walree, R.C. van Heemst, M.Y. Soud, H.J.M. Groen, A.J.S. den Brekel, W.A. Buikhuisen, G.P. Bootsma, F. Dammeijer, H. van Tinteren, F. Lalezari, J.G. Aerts, J.A. Burgers, NVALT19 study group
• Journal: The Lancet. Respiratory Medicine
• Published: 2021;9(6):585-592
• Type of article: Randomized trial
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.

Methods: We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847.

Findings: Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection.

Interpretation: Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.

Funding: Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This randomised, open-label, phase 2 trial in 18 Dutch hospitals enrolled 130 patients between March 2014 and February 2019. Patients were enrolled with unresectable malignant mesothelioma without progression after at least four cycles of first-line platinum and pemetrexed; one was later rediagnosed with another cancer. Patients were assigned to gemcitabine plus supportive care (65) or supportive care alone (65). The article does not report asbestos exposure. Progression-free survival, the time until disease worsened or death, was longer with gemcitabine: median 6.2 versus 3.2 months (hazard ratio 0.48, 95% CI 0.33 to 0.71). A masked central review confirmed this. Overall survival did not differ significantly: median 16.4 versus 13.4 months (HR 0.90, 95% CI 0.60 to 1.34; p=0.60). Grade 3 to 4 adverse events occurred in 33 of 64 gemcitabine patients and 10 of 62 supportive-care patients. One gemcitabine patient died of a treatment-related infection. The authors concluded that gemcitabine prolonged progression-free survival. They noted the trial was not placebo controlled and did not measure quality of life, and said the benefit needs confirmation in a phase 3 trial.

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: Prospective, investigator-initiated, randomised, open-label, phase 2 trial in 18 hospitals
• Who was studied: 130 patients were enrolled in the Netherlands between March 20, 2014, and Feb 27, 2019. They were eligible if they were aged 18 or older and had unresectable malignant mesothelioma with no disease progression after at least four cycles of first-line platinum and pemetrexed. 65 were assigned to gemcitabine plus supportive care and 65 to supportive care alone. Disease was pleural in all 65 gemcitabine patients and in 64 supportive-care patients; 1 supportive-care patient had peritoneal and pleural disease.
• Exposure: Not an asbestos exposure study. The studied intervention was maintenance intravenous gemcitabine, 1250 mg/m² on days 1 and 8 of 21-day cycles, plus supportive care, compared with best supportive care alone. The article reports no data on asbestos exposure or fiber type.
• Main results:
  • Progression-free survival as assessed by local investigators was a median of 6.2 months (95% CI 4.6 to 8.7) in the gemcitabine group and 3.2 months (2.8 to 4.1) in the supportive care group (HR 0.48, 95% CI 0.33 to 0.71; p=0.0002).
  • On masked independent central review, median progression-free survival was 5.3 months (95% CI 4.2 to 7.1) in the gemcitabine group and 2.8 months (2.5 to 3.2) in the supportive care group (HR 0.49, 95% CI 0.33 to 0.72).
  • Median overall survival was 13.4 months (95% CI 12.4 to 17.8) with supportive care alone and 16.4 months (95% CI 11.6 to 20.2) in the gemcitabine group. The difference was not statistically significant (HR 0.90, 0.60 to 1.34; p=0.60).
  • An objective radiological response was recorded in 8 (17%) of 48 gemcitabine patients with measurable disease and in 2 (4%) of 50 supportive-care patients (p=0.048).
  • Grade 3 to 4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in 10 (16%) of 62 patients in the supportive care group.
  • One patient (2%) in the gemcitabine group died from a treatment-related grade 5 infection.
  • One patient in the supportive care group had their diagnosis changed to a malignancy other than malignant mesothelioma during the study and was censored at that point.
• The authors' conclusion: The authors concluded that switch-maintenance gemcitabine plus supportive care after first-line platinum and pemetrexed gave significantly longer progression-free survival than supportive care alone.
• Limitations the authors state:
  • The trial was not placebo controlled.
  • Quality of life was not measured.
  • Overall survival may have been confounded by treatments given after the study, including gemcitabine given to 20 patients in the supportive care group.
  • Recruitment into the study was slow.
  • The trial was exploratory, and the potential benefit needs to be confirmed in a phase 3 trial.

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, Chemotherapy, Malignant Mesothelioma, Disease Progression, First-line Therapy, Unresectable, Pemetrexed (Alimta), Performance Status.

Related studies

• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response — F. Dammeijer, C.J. De Gooijer, et al. (2021)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)
• Second-line gemcitabine-based chemotherapy regimens improve overall 3-year survival rate in patients with malignant pleural mesothelioma: a multicenter retrospective study — H. Mutlu, S. Gündüz, et al. (2014)
• Epirubicin and gemcitabine as first-line treatment in malignant pleural mesothelioma — L. Portalone, A. Antilli, et al. (2005)
• 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)

Browse more research in The Lancet. Respiratory Medicine, or return to medical research.