Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial

Our plain-English summary of Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial, by A. Scherpereel, J. Mazieres, L. Greillier, et al (The Lancet. Oncology, 2019).

The study

• Authors: A. Scherpereel, J. Mazieres, L. Greillier, S. Lantuejoul, P. Dô, O. Bylicki, I. Monnet, R. Corre, C. Audigier-Valette, M. Locatelli-Sanchez, O. Molinier, F. Guisier, T. Urban, C. Ligeza-Poisson, D. Planchard, E. Amour, F. Morin, D. Moro-Sibilot, G. Zalcman, French Cooperative Thoracic Intergroup
• Journal: The Lancet. Oncology
• Published: 2019;20(2):239-253
• Type of article: Randomized trial
• Cited by: 367 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma.

Methods: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272.

Findings: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure).

Interpretation: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials.

Funding: French Cooperative Thoracic Intergroup.

Copyright © 2019 Elsevier Ltd. All rights reserved.

In plain English

This randomised phase 2 trial at 21 French hospitals tested two immunotherapy regimens in malignant pleural mesothelioma that had progressed after one or two treatment lines including pemetrexed and platinum chemotherapy. It did not study asbestos exposure. In 2016, 125 eligible patients were assigned to nivolumab alone (63) or with ipilimumab (62). The trial was not designed to compare the two groups. The main measure was 12-week disease control, judged by masked central review. Of the first 108 eligible patients, 24 of 54 on nivolumab (44%; 95% CI 31 to 58) and 27 of 54 on the combination (50%; 37 to 63) achieved it. Median overall survival was 11.9 months (95% CI 6.7 to 17.7) with nivolumab and 15.9 months (10.7 to not reached) with the combination. Severe (grade 3 to 4) drug-related side effects affected 9 of 63 nivolumab and 16 of 61 combination patients. Three combination patients died from treatment toxicity. The authors concluded that both regimens showed promising activity without unexpected toxicity and need confirmation in larger trials. The authors noted that patients selected for good performance status may have had a good prognosis.

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: Multicentre, randomised, non-comparative, open-label phase 2 clinical trial of drug treatment
• Who was studied: 125 eligible adults with relapsed malignant pleural mesothelioma (63 in the nivolumab group, 62 in the nivolumab plus ipilimumab group), recruited March 24 to August 25, 2016, at 21 hospitals in France, after one or two prior lines of treatment including pemetrexed and platinum
• Exposure: No asbestos exposure was assessed. The treatments studied were intravenous nivolumab 3 mg/kg every 2 weeks, or the same nivolumab dose plus ipilimumab 1 mg/kg every 6 weeks
• Main results:
  • Primary endpoint (12-week disease control, first 108 eligible patients). Nivolumab group: 24 (44%; 95% CI 31 to 58) of 54. Nivolumab plus ipilimumab group: 27 (50%; 37 to 63) of 54. The authors stated the endpoint was met in both groups
  • 12-week disease control in the intention-to-treat population. Nivolumab group: 25 (40%; 28 to 52) of 63. Combination group: 32 (52%; 39 to 64) of 62
  • Objective responses (first 108 patients). Nivolumab group: 10 (19%; 8 to 29) of 54. Combination group: 15 (28%; 16 to 40) of 54
  • Median progression-free survival. Nivolumab group: 4.0 months (95% CI 2.8 to 5.7). Combination group: 5.6 months (3.1 to 8.3)
  • Median overall survival. Nivolumab group: 11.9 months (95% CI 6.7 to 17.7). Combination group: 15.9 months (10.7 to not reached). The trial was not powered to compare the groups
  • Grade 3 to 4 drug-related adverse events. Nivolumab group: 9 (14%) of 63. Combination group: 16 (26%) of 61
  • Three (5%) treatment-related deaths in the combination group (fulminant hepatitis, encephalitis, acute kidney failure). None in the nivolumab group
  • Exploratory analysis with both groups combined: PD-L1 expression in at least 1% of tumour cells (28-8 assay) was associated with objective response. 16 (39%) of 41 PD-L1-positive patients responded, compared with 7 (12%) of 58 PD-L1-negative patients (p=0.002)
• The authors' conclusion: The authors concluded that nivolumab alone and nivolumab plus ipilimumab both showed promising activity in relapsed malignant pleural mesothelioma without unexpected toxicity, and that both regimens require confirmation in larger clinical trials
• Limitations the authors state:
  • Patients were selected for good performance status and may have had a better prognosis than typical patients
  • The design was non-comparative, so it cannot show whether one regimen is better than the other
  • The 25% PD-L1 cutoff was chosen post hoc from the data
  • Biomarker analysis was possible in only about 80% of patients
  • The open-label design could have influenced the quality-of-life analysis
  • Subgroup analyses were exploratory and only hypothesis-generating

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: Nivolumab (Opdivo), Ipilimumab (Yervoy), Pleural Mesothelioma, Pemetrexed (Alimta), Chemotherapy, Monoclonal Antibody, CTLA-4, Performance Status.

Related studies

• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)
• NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma — V.D. Haakensen, A.K. Nowak, et al. (2021)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• Ipilimumab/Nivolumab-related Opsoclonus-Myoclonus-Ataxia Syndrome Variant in a Patient with Malignant Pleural Mesothelioma — B. Maller, E. Peguero, et al. (2018)
• Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial — H.L. Kindler, S. Novello, et al. (2022)
• Outcome prediction based on [18F]FDG PET/CT in patients with pleural mesothelioma treated with ipilimumab and nivolumab +/- UV1 telomerase vaccine — S. Thunold, E. Hernes, et al. (2025)

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