Pemetrexed (Alimta): improving outcomes in malignant pleural mesothelioma

During the past four decades, chemotherapy has failed to demonstrate a consistent clinical benefit for patients with unresectable or recurrent malignant pleural mesothelioma (MPM). Consequently, there has been no standard chemotherapy nor US Food and Drug Administration (FDA)-approved drug for patients with this disease. The introduction of pemetrexed (Alimta, Eli Lilly), a multitargeted antifolate agent, has improved the outlook for patients with mesothelioma by demonstrating a positive impact on quality of life and by prolonging survival. Pemetrexed is the first FDA-approved drug for the treatment of MPM. The combination of cisplatin plus pemetrexed is now the standard of care for the treatment of the disease. Furthermore, supplementation with vitamin B12 and folate has vastly improved the toxicity profile of pemetrexed. This article summarizes historical chemotherapy trials in MPM; discusses key features of clinical trial design for MPM; summarizes the results of a landmark Phase III trial of pemetrexed and cisplatin in MPM; discusses the relative contributions of pemetrexed and cisplatin to the regimen; explains the importance of vitamin supplementation of pemetrexed; and provides direction for future clinical trials in this disease.     

Pemetrexed (Alimta®): improving outcomes in malignant pleural mesothelioma

During the past four decades, chemotherapy has failed to demonstrate a consistent clinical benefit for patients with unresectable or recurrent malignant pleural mesothelioma (MPM). Consequently, there has been no standard chemotherapy nor US Food and Drug Administration (FDA)-approved drug for patients with this disease. The introduction of pemetrexed (Alimta^®, Eli Lilly), a multitargeted antifolate agent, has improved the outlook for patients with mesothelioma by demonstrating a positive impact on quality of life and by prolonging survival. Pemetrexed is the first FDA-approved drug for the treatment of MPM. The combination of cisplatin plus pemetrexed is now the standard of care for the treatment of the disease. Furthermore, supplementation with vitamin B12 and folate has vastly improved the toxicity profile of pemetrexed. This article summarizes historical chemotherapy trials in MPM; discusses key features of clinical trial design for MPM; summarizes the results of a landmark Phase III trial of pemetrexed and cisplatin in MPM; discusses the relative contributions of pemetrexed and cisplatin to the regimen; explains the importance of vitamin supplementation of pemetrexed; and provides direction for future clinical trials in this disease.     

A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin,Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol

Background

The purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM).

Carboplatin Plus Pemetrexed as First-line Treatment of Patients With Malignant Pleural Mesothelioma: A Phase II Study

IntroductionMalignant pleural mesothelioma (MPM) is a rapidly progressive tumor that is increasing in frequency worldwide. Treatment options are limited, and response to chemotherapy is poor. The aim of this phase II study was to evaluate the activity of the carboplatin/pemetrexed combination as first-line chemotherapy in patients with unresectable MPM.Patients and MethodsChemotherapy-naive patients with histologically confirmed MPM and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Treatment consisted of pemetrexed 500 mg/m² and carboplatin area under the concentration-time curve of 5 mg/mL/min, both administered on day 1 of a 21-day cycle. The treatment continued until 6 cycles were completed or until unacceptable toxicity or disease progression were observed.ResultsA total of 62 patients were enrolled. Of these patients, 18 (29%) had a confirmed partial response, whereas the disease remained stable in 34 patients (54.9%) and progressed in 10 patients (16.1%). The median overall survival (OS) was estimated at 14 months (95% CI, 11.8-16.2 months), and the median time to progression was 7 months (95% CI, 5.8-8.2 months). The difference in median OS between the epithelial histologic subtype (16 months) and the sarcomatoid subtype (11 months) was statistically significant.ConclusionThis study confirmed the activity of the carboplatin/pemetrexed combination in the first-line treatment of patients with MPM. It is a viable option, especially in cases in which side effects are generally anticipated.     

LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare but aggressive disease: median survival is 6 to 9 months if untreated. Standard first-line treatment for patients with unresectable MPM is cisplatin/pemetrexed, with a median overall survival (OS) of approximately 1 year. Improvements in first-line treatment options are needed. With the benefit of combining bevacizumab with standard therapy shown in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS), vascular endothelial growth factor (VEGF) pathway inhibition has gained renewed interest as a treatment approach. Nintedanib is an oral angiokinase inhibitor targeting multiple signaling pathways implicated in the pathogenesis of MPM, including the VEGF receptor. The phase III part of the international, phase II/III LUME-Meso study is evaluating the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with unresectable epithelioid MPM. Originally, this was a double-blind, randomized, phase II exploratory study and was amended to include a confirmatory phase III part following the recommendation of an internal Data Monitoring Committee and review of phase II data. The phase III part plans to enroll 450 chemotherapy-naive patients, who will be randomized to receive pemetrexed/cisplatin on day 1 and nintedanib or placebo on days 2 to 21, for a maximum of 6 cycles. Patients without disease progression who are eligible to continue study treatment will receive maintenance treatment with nintedanib or placebo until disease progression or undue toxicity. The primary end point is progression-free survival; OS is the key secondary end point. The study will use an adaptive design, including an interim analysis to reassess the number of OS events required to ensure sufficient power for OS analysis. The study is currently enrolling patients.     

Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901

BackgroundThe role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS).Patients and MethodsEligible patients with unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression, stratified by number of cycles (< 6 or 6), cis- or carboplatin containing regimen, and histology. Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months.ResultsA total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049).ConclusionMaintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.     

Treatment rationale and study design for a phase III,double-blind,placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer

Background  

To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed.     

Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) used to be a rare disease, but is recently increasing in incidence. Most MPMs were thought to have a causal relationship with asbestos exposure. However, a DNA sequence similar to simian virus 40 has been detected in MPM tumor cells, which suggests a role of viral infection in its etiology. MPM predominantly afflicts men over 60 years old, with a male to female ratio of 3 to 1. MPM is a challenging disease in all aspects, including diagnosis, staging and treatment. Its diagnosis requires a panel of immunohistochemical stains. Multimodal treatment including surgery has shown significant benefit in highly selected patients. Most cytotoxic drugs administered as a single agent have been evaluated, but none have consistently demonstrated response rates greater than 20%. The combination of gemcitabine plus cisplatin has become a standard regimen, although there has been significant variability in response rates between studies. The novel antifolates pemetrexed and raltitrexed are promising agents and undergoing 3 phase III studies. One of these studies is the largest trial ever conducted in MPM patients, which randomized 456 patients into cisplatin with or without pemetrexed groups. The median survival time was 12.1 months in the cisplatin with pemetrexed arm and 9.3 months in the cisplatin alone arm (p = 0.02). Another of these studies is currently being conducted to compare cisplatin with or without raltitrexed. The third study is comparing pemetrexed alone to supportive care. The results of these trials are expected to define the role of chemotherapy for patients with MPM.     

Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma

Introduction

The National Institute for Health and Clinical Excellence (NICE) has previously recommended pemetrexed plus cisplatin for the treatment of patients with advanced malignant pleural mesothelioma (MPM) and WHO performance status 0-1. Subsequent to this appraisal, randomised controlled trial (RCT) data for raltitrexed plus cisplatin and comparing chemotherapy to active symptom control (ASC) has become available, allowing a more complete analysis of the comparative efficacy and cost-effectiveness of first-line chemotherapy in MPM.

Methods

An adjusted indirect comparison is used to estimate the relative efficacy of raltitrexed plus cisplatin and pemetrexed plus cisplatin. A cost-effectiveness model is used to assess the lifetime costs and health outcomes associated with these comparators and ASC. Patient level data from the EORTC 08983 trial are used to estimate baseline progression and survival rates. Relative treatment effects are taken from RCTs; cost and utility data from the literature.

Results

Raltitrexed plus cisplatin and pemetrexed plus cisplatin were not found to be statistically significantly different with respect to overall response, progression free survival or overall survival. The cost-effectiveness analysis found raltitrexed plus cisplatin to be cost-effective at a cost per quality adjusted life year of £13,454 compared to cisplatin and £27,360 compared to ASC. Pemetrexed plus cisplatin is dominated by raltitrexed plus cisplatin as the raltitrexed combination offers marginally higher quality adjusted life years (QALYs) and life years (LYs) at a substantially lower total cost.

Conclusion

Raltitrexed plus cisplatin is a cost-effective first-line treatment for MPM. This conclusion was maintained across a number of sensitivity analyses.     

晚期骨肉瘤的二线化疗疗效观察

目的:观察培美曲塞联合顺铂治疗晚期复发转移性骨肉瘤的有效性和安全性。方法:收集 2009年 1 月至 2014年 12 月期间我们观察的30例一线化疗失败的出现转移的晚期骨肉瘤患者,行培美曲塞500 mg/m2,静脉滴注d1;顺铂75~100 mg/m2静脉滴注d1~d3,21天为1周期;化疗2个周期后按照RECIST标准评价客观疗效;如达到PR及SD的患者继续行原方案化疗2周期。结果:30例患者均完成化疗,可评价疗效。完全缓解0例(CR）,部分缓解(PR）5例,疾病稳定(SD)11例,疾病进展(PD)14例;有效率(RR)为16.7%,病控制率(DCR)为53.3%,中位无进展生存时间为8.0个月,中位生存时间为15.8个月,主要不良反应为限制性骨髓抑制,无患者出现肝肾功能不全和过敏反应,2例出现4级中性粒细胞及血小板减少。结论:培美曲塞联合顺铂方案二线治疗晚期复发转移性骨肉瘤疗效肯定,毒副反应可以接受。     

Phase II study of pemetrexed plus oxaliplatin for platinum-resistant advanced or metastatic non-small cell lung cancer patients

This study was designed to evaluate the efficacy of combination treatment of pemetrexed plus oxaliplatin as second-line treatment in advanced/metastatic non-small cell lung cancer (NSCLC) patients who have failed first-line platinum-based chemotherapy, assuming that oxaliplatin can overcome the resistance to a platinum agent and translate into better outcome. Patients having shown progressive disease on first-line platinum-based chemotherapy received pemetrexed (500 mg/m²) and oxaliplatin (120 mg/m²) every 21 days till disease progression, unacceptable toxicity, or patient’s refusal. As a result, 15 patients (10 squamous cell carcinoma, 15 men, and 12 ECOG of 1) participated in this study. Disappointedly, there was no response and 2 stable diseases, and therefore, as per protocol, we stopped the study early. Median survival time was 6.1 months. In conclusion, treatment with oxaliplatin and pemetrexed did not show activity in this population as second-line treatment. Further investigation could not be recommended or should be made in more selected population, such as, non-squamous NSCLC patients.     

培美曲塞治疗19例复发性晚期非小细胞肺癌

背景与目的：晚期复发的非小细胞肺癌治疗效果差,可选择的药物不多。本研究探讨培美曲塞单药或联合顺铂/卡铂治疗晚期复发性非小细胞肺癌（NSCLC）的疗效以及不良反应。方法：经病理学或细胞学确诊的复发性晚期NSCLC患者19例,其中男性9例,女性10例,中位年龄48岁,KPS评分≥70。单药治疗：培美曲塞500mg/m^2,第1天静脉滴注每3周重复;联合治疗：培美曲塞500 mg/m^2第1天＋顺铂60 mg/m^2第2天静脉滴注每3周重复;或培美曲塞500 mg/m^2第1天＋卡铂300 mg/m^2第2天静脉滴注每3周重复。至少2周期以上可评价疗效及不良反应。结果：19例中16例可评价疗效,全组无CR/PR病例,MR 2例,SD 10例,PD 4例,疾病控制率75%（12/16）。中位生存时间9个月,1年生存率为31%（5/16）。主要不良反应为粒细胞下降、贫血和胃肠道反应。结论：培美曲塞单药或联合铂类治疗晚期复发NSCLC疗效确切,不良反应发生率低,耐受性较好。     

A case report of malignant pleural mesothelioma with long-term disease control after chemotherapy

Long duration of responses to chemotherapy in patients with malignant pleural mesothelioma (MPM) is rare. The authors report a patient with inoperable MPM who achieved complete remission with combination chemotherapy of cyclophosphamide, doxorubicin, and cisplatin. 5-fluorouracil and mitomycin C (FM) induced another remission after recurrence of the tumor. Retreatment with FM after chemotherapy had been stopped for 20 months yielded another continuing response. The overall tumor-control time is more than 4 years. Literature reviews and the authors' results suggest that MPM may be a chemosensitive tumor in some patients. Additional evaluations of CAP, FM, and methotrexate combination regimens in this disease should be considered.     

Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience

Background

The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients.

Methods

Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS = 0-2, adequate organ function, measurable disease.Chemotherapy was gemcitabine 1000 mg/m² days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m² or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan.

Results

Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1-2 (15:2).The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75).Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%).

Conclusion

Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.     

Standard therapy for the treatment of malignant pleural mesothelioma

Almost all of the established cytotoxic agents have now been examined both as single-agents and in combination chemotherapy regimens as treatment approaches for malignant pleural mesothelioma (MPM). Until recently, only few agents have consistently produced objective response rates greater than 20%, and no agent has improved median survival beyond 10 months. The recent development of several new cytotoxic agents, such as the novel antimetabolite pemetrexed, has yielded encouraging results. In particular, pemetrexed produces response rates of up to 45%, and increases median survival to over 12 months when used in combination with cisplatin. This doublet-based chemotherapy regimen is now the standard therapy for the first-line treatment of MPM.     

High response of second-line chemotherapy with pemetrexed or gemcitabine combined with carboplatin in patients with non-small-cell lung cancer experiencing progression following 6 months after concluding platinum-based chemotherapy

Because of improved therapeutic results after first-line platinum-based chemotherapy in patients with stage IV non-small-cell lung cancer (NSCLC), second-line chemotherapy may be considered for a growing number of patients. Approximately, 10% of patients have an interval time after concluding first-line platinum-based chemotherapy greater than 6 months. These patients may achieve high tumor responses when platinum is again used in second-line treatment. Twenty-three patients experiencing progression following 6 months after concluding platinum-based chemotherapy were managed with second-line treatment with carboplatin combined with gemcitabine or pemetrexed. Overall response, progression-free survival (PFS), and overall survival (OS) after initiation of second-line treatment were calculated for all patients. Median PFS after first-line treatment was 12.6 months (95% confidence interval [95% CI], 10.4–14.7 months). Partial response was achieved in 7 of 23 patients, resulting in an overall response of 30.4% (95% CI, 11.6–49.0). Following initiation of second-line chemotherapy, median PFS was 5.9 months (95% CI, 1–10.9 months) and median OS was 12.5 months (95% CI, 3.5–21.5 months). The 1-year survival rate for all patients was 61.0% (95% CI, 29.5–82.0). Adding these results to those of the 10 previously published trials, 75 of 326 patients, 23%, (95% CI, 18.7–27.3) presented an overall response with the use of second-line platinum-based chemotherapy. The use of platinum combinations as second-line chemotherapy seems to have a place in the management of patients with advanced NSCLC, especially those with an interval time to progression greater than 6 months.     

Final overall survival results and effect of prolonged (≥ 1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial

The ATHENA study expanded on the safety and efficacy data derived from first-line trials of bevacizumab combined with standard chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC). In ATHENA, 2,264 patients received first-line bevacizumab-containing therapy in routine oncology practice. Overall survival (OS) data are now mature; additional analyses from this large data set can provide insights into treatment duration and the effect of prolonged bevacizumab exposure, where data are currently limited. Patients with HER2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We performed subgroup analyses on data from patients treated for ≥12 months and those who continued single-agent bevacizumab after stopping chemotherapy. After median follow-up of 20.1 months, median OS was 25.2 months (95% confidence interval [CI] 24.0–26.3 months) in the entire population. Median OS was 30.0 months (95% CI 28.5–32.7 months) in 1,205 patients who continued bevacizumab after discontinuation of chemotherapy and 18.4 months (95% CI 17.2–19.7 months) in 1,058 patients who discontinued bevacizumab before or at the same time as stopping chemotherapy. Bevacizumab treatment was continued for ≥12 months in 473 patients (21%). In most, bevacizumab was administered as monotherapy for extended periods after stopping chemotherapy. In the subgroup of patients treated for ≥12 months, the median time to onset of grade 3–5 adverse events was 5.0 months. There was no evidence that first onset of adverse events of special interest, except for proteinuria, was more common in later than earlier cycles. No relationship was detected between development of hypertension and OS. Findings from these analyses suggest that patients with LR/mBC can receive bevacizumab for prolonged periods without major toxicity or progression of disease. In the absence of progression, continuation of single-agent bevacizumab appears to be a reasonable approach, with minimal toxicity and the possibility of long-term disease control.