The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma

doi:10.1016/j.lungcan.2008.04.001

Lung Cancer

Volume 63, Issue 1, January 2009, Pages 94-97

https://doi.org/10.1016/j.lungcan.2008.04.001 Get rights and content

Summary

Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30 mg/m² for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3–11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM.

Introduction

Malignant pleural mesothelioma (MPM) is a rapidly lethal malignancy causally associated with exposure to asbestos with a prevalence that is set to increase significantly in Europe over the next decade [1], [2], [3], [4]. MPM is often refractory to cytotoxic treatment, which may be due to intrinsic apoptosis resistance [5]; a variety of single agents achieve low response rates of around 20% [6], [7], [8], [9].

No reported randomised trial has yet confirmed a benefit of chemotherapy over best supportive care although one trial, MS-O1 (active symptom control versus vinorelbine versus mitomycin/cisplatin/vinblastine) is due to report full data [10]. Two phase 3 randomised trials comparing either the ‘gold standard’ doublet pemetrexed (Alimta^®) and cisplatin [8], [11], [12], or ralitrexed (Tomudex^®) and cisplatin [13], [14] versus cisplatin alone, confirmed a survival advantage for both doublets [15].

The efficacy of radical surgery is not yet proven due to a lack of randomised evidence [16], and radical radiotherapy although providing palliative benefit, does not appear to improve overall survival (OS) [17].

There exists only a paucity of reports of second-line therapy for individuals with relapsed MPM. Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. We have recently published the use of the triplet irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in the front line and second-line settings. In relapsed disease, progression-free survival (PFS) measured 7.3 months (95% CI: 3.4–11.2) and overall survival was also 7.3 months (95% CI: 4.8–9.8) [18].

Vinca alkaloids have known activity in MPM and vinflunine monotherapy has reasonable response rates in untreated individuals [19]. Vinorelbine has been used as part of a first-line triplet regimen in combination with cisplatin and gemcitabine in 12 patients [20] and we have studied its use in combination with oxaliplatin, a doublet that was found to be associated with significant toxicities with 18% of patients developing grade III or IV neutropenia [21]. A recent study evaluated gemcitabine–vinorelbine on days 1 and 8 of a 3 weekly cycle in 30 individuals pretreated with pemetrexed: a partial response (PR) was observed in 10% and stable disease (SD) occurred in 33.3% with grade III or IV neutropenia occurring in 10% of patients [22]. Overall, the gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM.

We have also previously studied weekly single-agent vinorelbine, in the first-line setting (n = 29), which was found to induce a partial response rate of 24%, a stable disease rate of 55% with 21% having disease progression during chemotherapy [23]. Although grade III or IV neutropenia occurred at least once in 62% of patients, only one patient experienced neutropenic sepsis requiring hospital admission and intravenous antibiotics. To investigate use of this regimen further, we wished to establish the efficacy and toxicity of weekly vinorelbine in 63 individuals with relapsed previously treated MPM.

Section snippets

Patients and methods

A total of 63 patients with MPM, previously treated with one chemotherapy regimen were enrolled onto a single-center trial of weekly vinorelbine. The study had appropriate institutional ethical review board approval, and all patients provided written, informed consent. All recruited individuals were required to have measurable, histologically confirmed, inoperable, MPM and to be >18 years old, with Eastern Cooperative Oncology Group (ECOG) performance statuses (PSs) of 0–2 and no uncontrolled

Results

Table 1 demonstrates the patient characteristics for the 63 individuals with relapsed MPM. The median age was 59 years (range 29–77), the majority (94%) were male and all patients had pleural ‘only’ MPM (no patients with peritoneal disease were included). Histology was available on all patients and the majority (62%) had epithelial histology, with more advanced IMIG staging (III or IV in 64%) although only 22% had an ECOG performance status of 2, the remainder having an ECOG performance status

Discussion

Weekly vinorelbine demonstrates useful clinical activity in the second-line treatment of MPM and appears well tolerated in the second-line setting; its use requires validation in prospective randomised studies.

It is surprising that the median overall survival on a salvage study was 9.6 months and the stable disease rate at 6 months was 68% though this may reflect the aggressive nature of MPM when progression does occur, often following cessation of cytotoxic chemotherapy. In our previous study

Conflict of interest

None.

Acknowledgment

We are grateful to the study participants and Linda Clarke for help with patient notes.

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EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study
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Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma.
We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (C_max), time to C_max (T_max), area under the concentration-time curve (AUC) to day 15 (AUC_0–t), area under the curve from time 0 extrapolated to infinity (AUC_0–∞), and the half-life (t_1/2) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286.
Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean C_max was 829 ng/mL (coefficient of variation 56·3%), median T_max was 2 h (range 1–4), mean AUC_0–twas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC_0–∞ was 3180 h·ng/mL (46·6%), and the geometric mean t_1/2 was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6–85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42–67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3–4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred.
Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy.
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Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial
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Currently, there is no US Food and Drug Administration approved therapy for patients with pleural mesothelioma who have relapsed following platinum-doublet based chemotherapy. Vinorelbine has demonstrated useful clinical activity in mesothelioma, however its efficacy has not been formally evaluated in a randomised setting. BRCA1 expression is required for vinorelbine induced apoptosis in preclinical models. Loss of expression may therefore correlate with vinorelbine resistance.
In this randomised, phase 2 trial, patients were eligible if they met the following criteria: age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, histologically confirmed pleural mesothelioma, post platinum-based chemotherapy, and radiological evidence of disease progression. Consented patients were randomised 2:1 to either active symptom control with oral vinorelbine versus active symptom control (ASC) every 3 weeks until disease progression, unacceptable toxicity or withdrawal at an initial dose of 60 mg/m² increasing to 80 mg/m² post-cycle 1. Randomisation was stratified by histological subtype, white cell count, gender, ECOG performance status and best response during first-line therapy. The study was open label. The primary endpoint was progression-free survival (PFS), measured from randomisation to time of event (or censoring). Analyses were carried out according to intention-to-treat (ITT) principles. Recruitment and trial follow-up are complete. This trial is registered with ClinicalTrials.gov, number NCT02139904.
Between June 1, 2016 and Oct 31, 2018, we performed a randomised phase 2 trial in 14 hospitals in the United Kingdom. 225 patients were screened for eligibility, of whom 154 were randomly assigned to receive either ASC + vinorelbine (n = 98) or ASC (n = 56). PFS was significantly longer for ASC+vinorelbine compared with ASC alone; 4.2 months (interquartile range (IQR) 2.2–8.0) versus 2.8 months (IQR 1.4–4.1) for ASC, giving an unadjusted hazard ratio (HR) of 0·60 (80% CI upper limit 0.7, one-sided unadjusted log rank test p = 0.002); adjusted HR 0.6 (80% CI upper limit 0.7, one-sided adjusted log rank test p < 0.001). BRCA1 did not predict resistance to ASC+vinorelbine. Neutropenia was the most common grades 3, 4 adverse events in the ASC +vinorelbine arm.
Vinorelbine plus ASC confers clinical benefit to patients with relapsed pleural mesothelioma who have progressed following platinum-based doublet chemotherapy.
This study was funded by Cancer Research UK (grant CRUK A15569).
Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial
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Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody–drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab.
In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0–1, and who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m² once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.
Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4–5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4–5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1–5·2] vs 4·5 months [4·1–5·8]; hazard ratio 1·22 [0·85–1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).
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The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma

Summary

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest

Acknowledgment

The European mesothelioma epidemic

Br J Cancer

Survival from rare cancer in adults: a population-based study

Lancet Oncol

Advances in the systemic therapy of malignant pleural mesothelioma

Nat Clin Pract Oncol

Malignant mesothelioma resistance to apoptosis: recent discoveries and their implication for effective therapeutic strategies

Curr Med Chem

Defective core-apoptosis signalling in diffuse malignant pleural mesothelioma: opportunities for effective drug development

Lancet Oncol

Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials

J Clin Oncol

The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guidelines

J Thorac Oncol

BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112

Thorax

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma

J Clin Oncol

Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program

Clin Lung Cancer

Randomized phase III study of cisplatin with or without ralitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada

J Clin Oncol

Short-term treatment-related symptoms and quality of life: results from an international randomized phase III study of cisplatin with or without ralitrexed in patients with malignant pleural mesothelioma: an EORTC Lung-Cancer Group and National Cancer Institute, Canada, Intergroup Study

J Clin Oncol

Systemic chemotherapy in the management of malignant peritoneal mesothelioma

Eur J Surg Oncol

Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary

Lung Cancer