Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma

doi:10.1016/j.lungcan.2014.03.006

Lung Cancer

Volume 84, Issue 3, June 2014, Pages 271-274

https://doi.org/10.1016/j.lungcan.2014.03.006 Get rights and content

Abstract

Objectives

Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.

Materials and methods

We reviewed charts of patients with MPM treated with vinorelbine and/or gemcitabine as second- or third-line therapy between 2003 and 2010. Toxicity was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. CT scans were reviewed with a reference radiologist according to modified RECIST criteria.

Results

Sixty patients were identified: 33 treated with vinorelbine, 15 gemcitabine, and 12 both agents. Eighty-three percent initially received pemetrexed-platinum. Toxicity was substantial: 46% experienced at least one episode of grade 3–4 toxicity. Of 56 patients evaluable radiologically, there was 1 partial response (gemcitabine) giving a response rate of 2% (95% CI: 0–10%). Forty-six percent had stable disease. Median progression free survival was 1.7 months for vinorelbine and 1.6 months for gemcitabine. Median overall survival was 5.4 and 4.9 months, respectively.

Conclusions

Response to second- or third-line vinorelbine or gemcitabine is rare. The high rate of stable disease warrants the continued use of these agents in this setting, though the impact on survival is questionable. These data justify the choice of placebo control arms in randomized trials of novel agents in previously treated patients.

Introduction

Most patients with malignant pleural mesothelioma (MPM) present with locally advanced disease, and treatment for these patients involves palliative chemotherapy. The combination of pemetrexed and cisplatin has become the standard first-line chemotherapy regimen based on the results of a randomized phase III trial showing that it improved median survival compared to treatment with cisplatin alone from 9.3 months to 12.1 months [1]. As the use of pemetrexed and cisplatin (or carboplatin) has become more routine, an increasing number of patients remain fit enough even after progression for consideration of second-line chemotherapy. However, the scarcity of data regarding the efficacy of further treatment leaves oncologists unsure how to proceed.

Many choose to treat their patients with either vinorelbine or gemcitabine based on subgroup analyses from first-line studies, small phase II trials, or retrospective analyses. Vinorelbine was studied in a phase II open-label trial in 63 MPM patients previously treated with chemotherapy, which did not include pemetrexed, yielding a response rate of 16% [2]. More than half of these patients also experienced severe toxicity. In an exploratory subgroup analysis of a first-line multicenter randomized trial comparing active symptom control to active symptom control plus chemotherapy with mitomycin, vinblastine, and cisplatin or weekly vinorelbine, there was a suggestion of a survival advantage with weekly vinorelbine [3]. A recent retrospective report described administration of vinorelbine to 59 MPM patients who previously received pemetrexed-platinum chemotherapy [4]. The response rate was 15.2% and median progression-free survival was 2.3 months.

Gemcitabine's efficacy was first-demonstrated as part of a phase II screening of drugs in which 27 chemotherapy naïve patients with MPM received weekly gemcitabine. The response rate was 7% and median survival was 8 months [5]. Analysis of the phase III trial that led to the approval of cisplatin and pemetrexed as first-line therapy for MPM demonstrated improved survival with the use of post-study chemotherapy, and gemcitabine was the most commonly used agent [6]. The CALGB conducted a phase II multicenter trial evaluating the activity of gemcitabine in chemotherapy naïve patients with MPM [7]. Among the 17 patients treated, there were no partial or complete responses and median survival was 4.7 months. Another phase II trial of gemcitabine in chemotherapy naïve patients with MPM demonstrated 2 objective responses among 27 patients (7%) and a median survival of 8 months [5]. Several additional studies have examined the efficacy of gemcitabine in combination with cisplatin in chemotherapy naïve patients with MPM [8], [9], [10] with response rates ranging from 16% to 47.6%. There is also a study of vinorelbine and gemcitabine given concurrently in MPM patients who previously received either single-agent pemetrexed or pemetrexed-platinum therapy showing a response rate of 10%, median time to progression of 2.8 months, and overall survival of 10.9 months [11].

These data certainly support the inclusion of vinorelbine and gemcitabine in the National Comprehensive Cancer Center Guidelines as preferred agents in the second-line setting, yet they are quite limited in scope. As such, we sought to augment the existing information by examining our institutional experience using vinorelbine and gemcitabine in patients with previously treated MPM.

Section snippets

Materials and methods

With the approval of the Memorial Sloan-Kettering Cancer Center Institutional Review Board, we reviewed the clinical records of all patients treated with vinorelbine and/or gemcitabine as second- or third-line therapy for MPM between 2003 and 2010. Clinical characteristics were extracted, including age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, prior therapy including surgery, chemotherapy, and radiation, as well as survival status. Although the patients included in

Patient characteristics

Sixty unique patients were identified. Thirty-three were treated with vinorelbine, 15 with gemcitabine, and 12 with both agents sequentially. Patient characteristics are displayed in Table 1. As is typical for MPM, the majority of patients were men and the predominant histology was epithelioid. Stage at diagnosis was divided as 32% stage II, 37% stage III, and 30% IV. The median age at diagnosis was 67 with a range of 41–85. Eight-three percent had received pemetrexed and platinum as their

Discussion

Since the trial that led to the FDA approval of pemetrexed-platinum chemotherapy as first-line therapy for MPM 10 years ago [1], there have been no therapeutic advances for this disease. Yet, at the time of progression after therapy with pemetrexed-platinum, many patients are candidates for further therapy. Patients are often treated with vinorelbine or gemcitabine in this setting, yet the data supporting these choices were not necessarily obtained in similar patients. As summarized above, most

Conclusion

Ultimately, the lack of impact on survival of second-line therapy is discouraging. Perhaps biomarkers, such as BRCA1 expression which may predict benefit from vinorelbine, could be used to better select patients [14]. Ideally, though, novel therapeutics need to be discovered. Given the orphan nature of this disease and the associated limitations on drug development resources, future studies must be thoughtfully planned with strong preclinical rationale, in the appropriate clinical context, and

Funding

No specific funding source was identified for this work.

Conflict of interest statement

The authors have no conflicts of interest to declare.

References (14)

J. Stebbing et al.
The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma
Lung Cancer
(2009)
M.F. Muers et al.
Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial
Lancet
(2008)
C. Manegold et al.
Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma
Ann Oncol
(2005)
H.L. Kindler et al.
Gemcitabine for malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B
Lung Cancer
(2001)
M.J. Byrne et al.
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma
Ann Oncol
(2004)
L.M. Krug et al.
VANTAGE 014: vorinostat (V) in patients with advanced malignant pleural mesothelioma (MPM) who have failed prior pemetrexed and either cisplatin or carboplatin therapy: a phase III, randomized, double-blind, placebo-controlled trial
Eur J Cancer
(2011)
N.J. Vogelzang et al.
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma
J Clin Oncol
(2003)

There are more references available in the full text version of this article.

Cited by (92)

Established and new treatment roadmaps for pleural mesothelioma: opinions of the Turkish Collaborative Group
2023, Current Problems in Cancer
Pleural mesothelioma (PM) is a cancer of the pleural surface, which is aggressive and may be rapidly fatal. PM is a rare cancer worldwide, but is a relatively common disease in Turkey. Asbestos exposure is the main risk factor and the most common underlying cause of the disease. There have been significant improvements in diagnoses and treatments of many malignancies; however, there are still therapeutic challenges in PM. In this review, we aimed to increase the awareness of health care professionals, oncologists, and pulmonologists by underlining the unmet needs of patients with PM and by emphasizing the need for a multidisciplinary treatment and management of PM. After reviewing the general information about PM, we further discuss the treatment options for patients with PM using immunotherapy and offer evidence for improvements in the clinical outcomes of these patients because of these newer treatment modalities.
EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study
2022, The Lancet Oncology
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.
Epizyme.
Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors
2022, Journal of Thoracic Oncology
The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.
Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.
Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The “regulation of antigen processing and presentation of peptide antigen” gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.
Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors.
Treatment Patterns and Outcomes of Patients With Advanced Pleural Mesothelioma at an Academic Referral Centre
2022, Clinical Lung Cancer
Overall survival (OS) for malignant pleural mesothelioma (MPM) in vulnerable subgroups remains poorly understood with scarce data available to guide treatment decisions. The study describes real-world detailed treatment patterns and outcomes of patients with advanced MPM overall and specifically in elderly and poor performance status (PS) patients.
Retrospective chart review was performed for all patients with histologically confirmed MPM seen at University Health Network/Princess Margaret Cancer Centre (UHN-PM).
A total of 667 patients with MPM were identified and 304 advanced-disease MPM (aMPM) patients had continuing care at UHN-PM (UP-cohort). In the UP-cohort, 77% of patients received ≥ one line of systemic treatment. Systemic therapy trial participation was 39%. Patients not treated with systemic therapy (29%) were more likely to be ≥ 75 years and PS ≥ 2. Median OS was 15.3 months (95%CI 13.6-18.3), with longer survival in treated vs. untreated patients (17.4 vs. 10.6 months; P = .01). Longer survival with systemic treatment was seen in patients ≥75 years (12.7 vs. 6.6 months) and patients with poor PS (9.1 vs. 5.9 months). Median progression-free-survival (PFS) and OS for patients treated with second-line therapy was poor (3.0 and 8.9 months, respectively).
In our real-world analysis of patients with aMPM treated at an academic referral centre, systemic treatment was given to the majority of patients and benefit was seen even in the elderly and poor PS patients frequently underrepresented in clinical trials. Trial participation was potentially facilitated by the formation of a dedicated multidisciplinary MPM clinic.
Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial
2021, The Lancet Oncology
There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma.
RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0–2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m² on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36.
Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7–28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59–0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7–14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9–8·9) in the gemcitabine plus placebo group. Grade 3–4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3–4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths.
Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting.
Eli Lilly Italy.
For the Italian translation of the abstract see Supplementary Materials section.
Mesothelioma: Pleural, Version 1.2024 Featured Updates to the NCCN Guidelines
2024, JNCCN Journal of the National Comprehensive Cancer Network

View all citing articles on Scopus

View full text

Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma

Abstract

Objectives

Materials and methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Patient characteristics

Discussion

Conclusion

Funding

Conflict of interest statement

Lung Cancer

Lancet

Ann Oncol

Lung Cancer

Ann Oncol

Eur J Cancer

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

J Clin Oncol