Elsevier

The Lancet

Volume 387, Issue 10026, 2–8 April 2016, Pages 1405-1414
The Lancet

Articles
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial

https://doi.org/10.1016/S0140-6736(15)01238-6Get rights and content

Summary

Background

Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma.

Methods

In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18–75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0–2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0–1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m2 pemetrexed plus 75 mg/m2 cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456.

Findings

From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9–22·6]) than with PC (16·1 months [14·0–17·9]; hazard ratio 0·77 [0·62–0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3–4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC.

Interpretation

Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease.

Funding

Intergroupe Francophone de Cancérologie Thoracique (IFCT).

Introduction

Malignant pleural mesothelioma is a rare but aggressive cancer, mainly caused by exposure to asbestos.1 The disease has a poor prognosis, with sarcomatoid or mixed (sarcomatoid and epithelioid) histologies, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and male sex usually reported as poor prognostic factors.2 It is generally refractory to local treatment when diagnosed and usually progresses, resulting in a median overall survival (OS) of 12–36 months for localised disease and 8–14 months for advanced disease.3

The present standard of care for first-line systemic treatment is cisplatin plus pemetrexed, based on a median OS of 12·1 months (13·3 months in patients receiving vitamins B12 and B9) compared with 9·3 months for cisplatin alone and a median progression-free survival (PFS) of 5·7 months compared with 3·9 months.4 Findings from a phase 2 study also showed a median OS of 12·7 months and a median PFS of 6·5 months with pemetrexed plus carboplatin for advanced malignant pleural mesothelioma.5

Vascular endothelial growth factor (VEGF) signalling plays a crucial part in mesothelioma cell physiopathology.6, 7 Antiangiogenic treatments targeting VEGF were therefore a rational approach to be tested in malignant pleural mesothelioma. Several antiangiogenic drugs have already been assessed as single drugs, with modest activity.8, 9, 10, 11 Addition of bevacizumab to gemcitabine plus cisplatin for treatment of malignant pleural mesothelioma was assessed in a randomised, placebo-controlled, phase 2 study by Kindler and colleagues,12 who reported a median PFS of 6·9 months with bevacizumab versus 6·0 months in the placebo group. However, median OS was 15·6 months for the triplet combination versus 14·7 months for gemcitabine plus cisplatin, which was not significantly different, possibly related to a large proportion of patients receiving second-line pemetrexed-based treatment in both groups.12 An alternative explanation could be an underpowered design due to the long survival in the control group as compared with the 4 month PFS, which was used to calculate sample size and power. Whether VEGF plasma concentrations could serve as prognostic biomarkers or predict bevacizumab efficacy in malignant pleural mesothelioma remains controversial owing to the absence of data from phase 3 trials.

Research in context

Evidence before this study

We searched MEDLINE for full-text articles published from Jan 1, 2000, to Dec 31, 2014, in English or French, reporting phase 3, randomised, clinical trials and phase 2 studies relevant to our study. We used the terms “mesothelioma”, “bevacizumab”, “angiogenic inhibitors”, and “chemotherapy”. We found that the standard of care for medical treatment of mesothelioma is pemetrexed plus cisplatin on the basis of a phase 3 study done in 2003 reporting a 12·1 month overall survival (OS) that exceeds 13 months in patients receiving vitamins B9 and B12. Angiogenic inhibitors as monotherapies were reported with modest efficacy because of the role of vascular endothelial growth factor in mesothelioma biology. Investigators of three phase 2 studies reported interesting results with the triple association of the angiogenic drug bevacizumab and a platinum-based doublet with either gemcitabine or pemetrexed. However, no phase 3 data had been reported for addition of bevacizumab to the present standard of care (pemetrexed and cisplatin).

Added value of this study

A pemetrexed-based chemotherapy doublet was recommended as a treatment option for malignant pleural mesothelioma by the 2007 National Institute for Health and Care Excellence guidance that was in place at the beginning of our study for patients with WHO performance statuses of 0 or 1 deemed to have advanced disease and for whom surgical intervention was deemed inappropriate. Findings from our study of bevacizumab plus pemetrexed and cisplatin compared with pemetrexed and cisplatin alone showed a significantly improved median OS and progression-free survival with addition of bevacizumab. Mesothelioma traditionally has a poor prognosis; however, in our study, patient subgroups that have previously shown poor prognosis benefited as much as other subgroups from addition of bevacizumab, including those with an ECOG performance status of 2, a haemoglobin concentration of ≤140 g/L, thrombocytosis, a leucocyte count of 8·3 × 109/L or higher, or sarcomatoid or mixed histology. Therefore, these data show an alternative to present options that have not been improved on since the pivotal study by Vogelzang and colleagues of pemetrexed plus cisplatin more than 10 years ago.

Implications of all the available evidence

Addition of bevacizumab to the present standard of care cisplatin and pemetrexed significantly increased OS and progression-free survival in mesothelioma, with manageable toxic effects. We believe that this result has important implications for future first-line treatment of mesothelioma because the pemetrexed plus cisplatin plus bevacizumab regimen should be considered as a new treatment option for patients with newly diagnosed mesothelioma who are eligible to receive bevacizumab and who are not candidates for curative-intent surgery.

The phase 2/3 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) was initiated to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. The primary phase 2 outcome was disease control rate at 6 months in the PCB group, established by an expert panel masked to the randomisation arm using modified Response Evaluation Criteria in Solid Tumors,13, 14 with safety as a secondary outcome. This phase 2 part met its statistical outcome, reporting 27 patients with 6 month disease control of the first 47 patients included (57%) in the experimental group, without any unexpected toxicity signals.15 The phase 3 part of the study was then initiated in 2010. Here, we report the results of the phase 3 part of MAPS as the continuation of the positive results of the phase 2 part.

Section snippets

Study design and participants

In this multicentre, randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18–75 years from 73 hospitals in France. We recruited patients with histologically proven malignant pleural mesothelioma with pleural biopsies (thoracoscopy was recommended) who had not received previous chemotherapy, had an ECOG performance status of 0–2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery (according to a multidisciplinary tumour board, including

Results

Between Feb 13, 2008, and Jan 5, 2014, we randomly assigned 448 patients to PCB (223 [50%]) or PC (225 [50%]), with 222 (>99%) receiving PCB and 224 (>99%) receiving PC (figure 1). Baseline characteristics were balanced between groups (table 1). The dose actually delivered compared with the theoretical dose for cisplatin was 91·8% for the PCB group versus 93·2% for the PC group, 95·6% versus 97·0% for pemetrexed, and 98·6% versus not applicable for bevacizumab. The proportion of patients who

Discussion

The present standard of care for first-line treatment of malignant pleural mesothelioma is cisplatin plus pemetrexed.4 In this large, multicentre, randomised, controlled trial, addition of bevacizumab to cisplatin and pemetrexed significantly improved OS, the primary outcome of this study. As only pleural mesothelioma were included in this trial, these results do not apply to peritoneal mesothelioma. Patient subgroups that have previously shown poor prognosis had similar OS increases to other

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