Elsevier

The Lancet Oncology

Volume 20, Issue 2, February 2019, Pages 239-253
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(18)30765-4Get rights and content

Summary

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.

Introduction

Malignant pleural mesothelioma is a rare but aggressive malignancy of the pleural surface, commonly associated with occupational asbestos exposure, and its incidence is increasing worldwide.1 Patients with malignant pleural mesothelioma usually have a very poor prognosis, with a median overall survival of approximately 12 months, despite some patients having surprisingly long tumour doubling time, indicative of a slow-growing tumour, specifically in the second-line or third-line setting. Moreover, patients often exhibit strong resistance to chemotherapy, and few patients are suitable candidates for multimodal treatment, including radical surgery.2 In 2015, we initiated a phase 3 open-label randomised controlled trial, the IFCT-GFPC-0701 Mesothelioma Avastin plus Pemetrexed-cisplatin Study (MAPS), which showed an overall survival benefit when adding bevacizumab to standard cisplatin plus pemetrexed chemotherapy (median overall survival 18·8 months [95% CI 15·9–22·6] with bevacizumab vs 16·1 months [14·0–17·9] without bevacizumab; hazard ratio [HR] 0·77 [95% CI 0·62–0·95]; p=0·017).3 However, an optimal second-line treatment for malignant pleural mesothelioma has not yet been defined by the most recent guidelines.2, 4, 5, 6, 7

Research in context

Evidence before this study

On Nov 15, 2015, we searched PubMed for studies assessing immunotherapeutic antibody use of anti-programmed cell death 1 (PD-1) or anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibodies in patients with mesothelioma using the following search terms: “mesothelioma” and “nivolumab” OR “pembrolizumab” OR “atezolizumab” OR “avelumab” OR “durvalumab” OR “ipilimumab” OR “tremelimumab” OR “PD-1” OR “PD-L1”, OR “CTLA-4”. Additionally, we examined abstracts from the 2015, 2016, and 2017 editions of the American Society of Clinical Oncology annual meeting. Although several studies confirmed that mesothelioma tumour cells do express immune checkpoint proteins, including programmed cell death ligand 1 (PD-L1), and that mesothelioma specimens at times show high stromal infiltration by immune cells such as lymphocytes or monomacrophage and dendritic cells, we found no published clinical studies investigating the safety or efficacy of the anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab combination or anti-PD-1 nivolumab monotherapy in patients with malignant pleural mesothelioma. One large randomised phase 2b trial (DETERMINE; NCT01843374) assessed tremelimumab, an anti-CTLA-4 antibody, administered alone versus placebo as second-line or third-line treatment in 564 patients with malignant pleural mesothelioma, but no survival gain was recorded compared with placebo. Also, a phase 1b trial in 25 patients with PD-L1-expressing malignant pleural mesothelioma (>1% positive tumour cells) treated with the anti-PD-1 antibody pembrolizumab, mostly as second-line treatment, reported five (20%) patients with an overall response and 13 (52%) patients with stable disease, along with a median duration of response of 12 months (95% CI 3·7–not reached), without any safety concerns. Last, a single-arm phase 2 trial (NIBIT-MESO-1; NCT02588131) assessed the combination of 1 mg/kg anti-CTLA-4 tremelimumab and 20 mg/kg anti-PDL-1 durvalumab intravenously injected every 4 weeks in four doses and followed by maintenance durvalumab, as first-line or second-line treatment in patients with unresectable malignant mesothelioma. The authors reported evidence of clinical activity, with 11 (28%) of 40 patients having an immune-related partial response (median duration of response 16·1 months) and another 26 (65%) with immune-related disease control, resulting in a median immune-related progression-free survival of 8 months and median overall survival of 16·6 months.

Added value of this study

On Nov 15, 2015, no second-line or third-line treatment had as yet shown efficacy in patients with malignant pleural mesothelioma who had received first-line pemetrexed and platinum-based chemotherapy with or without bevacizumab (ie, the standard first-line treatment strategy in patients with unresectable malignant pleural mesothelioma). Furthermore, no PD-1-directed or PD-L1-directed antibodies, non-PD-1-directed targeted immunotherapies, or dual immunotherapies had been approved for malignant pleural mesothelioma indications. There is thus a substantial unmet need for new therapeutic strategies assessing immunotherapies in patients with relapsed malignant pleural mesothelioma. Our study achieved its statistical endpoint and is, to the best of our knowledge, the first to assess the safety and efficacy of anti-PD-1 nivolumab monotherapy or anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab combination therapy in patients with malignant pleural mesothelioma as second-line or third-line treatment following first-line pemetrexed and platinum-based chemotherapy. These findings provide supporting evidence that both monotherapy with nivolumab and combination therapy with both nivolumab and ipilimumab are effective in this setting.

Implications of all the available evidence

Our findings, in 125 randomly assigned patients, clearly show that immune checkpoint inhibitors achieve notable clinical activity in relapsed malignant pleural mesothelioma, either as monotherapy or combination therapy, at standard doses. The data showed that immune checkpoint inhibitors are capable of inducing antitumour objective responses according to Response Evaluation Criteria in Solid Tumours criteria for mesothelioma, as well as significant median progression-free and overall survival, with a tolerable safety profile, in this orphan-disease population. Although these results require further confirmation in larger trials, they could now justify the use of immune checkpoint inhibitors in patients with relapsed malignant pleural mesothelioma who have no other efficient therapeutic options available.

Understanding of malignant pleural mesothelioma pathogenesis has substantially improved during the past few years, leading to innovative drugs and strategies,8, 9 with targeted therapies and immunotherapies sparking new hope for patients with this disease.3, 9, 10, 11 By instigating chronic inflammation and localised tumour immunosuppression, the immune system plays a crucial part in malignant pleural mesothelioma pathogenesis, with improved outcomes correlated with higher intra-tumour infiltration by CD8+ cytotoxic T cells.12 Conversely, high tumour expression of programmed cell death ligand 1 (PD-L1), which inhibits T-cell function via binding programmed cell death 1 (PD-1), has been associated with poor prognosis in mesothelioma (median overall survival 5·0 months (IQR 2·0–9·5) in PD-L1-positive patients vs 14·5 months (9·0–19·0) in PD-L1-negative patients).9, 13, 14

Among the different immunotherapies evaluated so far to restore antitumour immune response in malignant pleural mesothelioma, immune checkpoint inhibitors (ICIs) have garnered the most attention on the basis of their efficacy, particularly in melanoma and non-small-cell lung cancer (NSCLC).9, 10 Cytotoxic T-lymphocyte protein 4 (CTLA-4) is an immune checkpoint that blocks interactions between antigen-presenting cells, such as dendritic and naive T cells, occurring early in the antitumour cycle. After encouraging phase 2 trial results, tremelimumab, an anti-CTLA-4 antibody, was tested alone versus placebo in second-line or third-line treatment of patients with malignant pleural mesothelioma in a large randomised phase 2b trial (DETERMINE),15 but survival was not improved compared with placebo. By contrast, several studies assessing ICIs targeting the PD-1 or PD-L1 pathway have generated promising results.9, 16 In a phase 1b trial, five (20%) of 25 patients with PD-L1-expressing malignant pleural mesothelioma (≥1% positive tumour cells) treated with the anti-PD-1 monoclonal antibody pembrolizumab, mostly as a second-line treatment, had an overall response, and 13 (52%) achieved stable disease. The median duration of response was 12 months (95% CI 3·7–not reached), with no safety concerns.16 Other trials assessing anti-PD-1 or anti-PD-L1 antibodies in malignant pleural mesothelioma have reported similar proportions of patients with responses.9, 10 Another anti-PD-1 monoclonal antibody, nivolumab, is being assessed as third-line monotherapy versus placebo in the UK in a randomised phase 3 trial (CONFIRM; Cancer Research UK trial number CRUK/16/022).

Checkpoint antibody combination trials are another area of great interest in malignant pleural mesothelioma research. Combined 1 mg/kg tremelimumab and 20 mg/kg durvalumab given in four intravenous doses every 4 weeks, followed by maintenance durvalumab at the same dose and schedule for nine doses, was tested in a single-arm phase 2 trial (NIBIT-MESO-1) as first-line or second-line treatment in patients with unresectable malignant mesothelioma.17 The trial met its primary endpoint with 11 (28%) of 40 patients exhibiting immune-related partial responses (median duration of response 16·1 months [IQR 11·5–20·5]); 26 (65%) of 40 had immune-related disease control, leading to a median immune-related progression-free survival of 8·0 months (95% CI 6·7–9·3) and a median overall survival of 16·6 months (13·1–20·1).17 Baseline tumour PD-L1 expression had no predictive or prognostic value.

Based on this rationale, we aimed to assess, in patients with malignant pleural mesothelioma, the value of nivolumab as a single drug or in combination with the anti-CTLA-4 monoclonal antibody ipilimumab in a second-line or third-line setting by means of a randomised, non-comparative phase 2 trial.

Section snippets

Study design and participants

This multicentre, randomised, controlled non-comparative, open-label phase 2 trial was done at 21 hospitals in France. We recruited patients aged at least 18 years with malignant pleural mesothelioma that was histologically proven by pleural biopsy (thoracoscopy recommended), irrespective of PD-L1 tumour status. Eligible patients had disease progression according to modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria for mesothelioma, version 1.018 (centrally assessed with

Results

Between March 24 and August 25, 2016, we recruited 132 patients and randomly assigned 68 patients to nivolumab and 64 patients to nivolumab plus ipilimumab. After group assignment, five patients in the nivolumab group and two in the combination group were found to be ineligible and excluded from the intention-to-treat population. The intention-to-treat population therefore included 125 patients (63 in the nivolumab group and 62 in the nivolumab plus ipilimumab group) Because accrual was faster

Discussion

Our findings show that nivolumab monotherapy and nivolumab plus ipilimumab combination therapy provide clinically meaningful response and survival benefits for patients with pretreated malignant pleural mesothelioma who progressed after one or two lines of treatment, including pemetrexed–platinum doublet chemotherapy. The combination group had a slightly greater proportion of all-grade drug-related adverse events (93% with combination vs 89% with monotherapy) and three toxicity-related deaths (

Data sharing

The data sharing statement is in the appendix (p 9).

References (37)

  • PJ Hollen et al.

    Quality of life assessment in individuals with lung cancer: testing the Lung Cancer Symptom Scale (LCSS)

    Eur J Cancer

    (1993)
  • J Adam et al.

    Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer

    Ann Oncol

    (2018)
  • S Lantuejoul et al.

    PD-L1 testing for immune checkpoint inhibitors in mesothelioma: for want of anything better?

    J Thorac Oncol

    (2017)
  • MD Hellmann et al.

    Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study

    Lancet Oncol

    (2017)
  • AK Nowak et al.

    DREAM: a phase II trial of durvalumab with first line chemotherapy in mesothelioma—final result

    J Thorac Oncol

    (2018)
  • B Thapa et al.

    The immune microenvironment, genome-wide copy number aberrations, and survival in mesothelioma

    J Thorac Oncol

    (2017)
  • A Scherpereel et al.

    Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma

    Eur Respir J

    (2010)
  • I Woolhouse et al.

    British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma

    Thorax

    (2018)
  • Cited by (0)

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