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.     

Multi-targeted-Enzyminhibition in der Tumortherapie

Pemetrexed is a newly developed therapeutic agent which inhibits several key enzymes in the folate metabolic pathway. In phase I trials, this novel multitargeted antifolate showed a broad antitumor activity as a single agent and in combination chemotherapy. Based on these findings, phase III studies have been conducted including patients with malignant pleural mesothelioma (MPM), non-small-cell lung cancer (NSCLC), and colorectal cancer. In a recent phase III trial in MPM, the combination of pemetrexed and cisplatin was significantly more efficacious than cisplatin alone. In addition, vitamin supplementation reduced treatment-associated toxicities with no apparent affect on activity. In patients with NSCLC, a phase III trial showed clinically equivalent efficacy of pemetrexed and docetaxel, but pemetrexed was associated with significantly fewer toxicities in second-line therapy. This review summarizes preclinical and clinical data to define the future role of pemetrexed in the treatment of tumor patients.     

Tsunami of immunotherapy reaches mesothelioma

Malignant pleural mesothelioma (MPM) is the most common type of malignant mesothelioma. It is a rare tumor linked to asbestos exposure and is associated with a poor prognosis. Until very recently, patients with advanced or unresectable disease had limited treatment options, primarily based on doublet chemotherapy with cisplatin and pemetrexed. In 2020 and 2021, after more than a decade with no major advances or new drugs, two phase III clinical trials published results positioning immunotherapy as a promising option for the first- and second-line treatment of MPM. Immunotherapy has revolutionized the treatment of many cancers and is also showing encouraging results in malignant mesothelioma. Both immune checkpoint inhibition and dual cytotoxic T-lymphocyte–associated antigen 4 and programmed death-ligand 1 pathway blockade resulted in significantly improved overall survival in randomized phase III trials. In the CheckMate 743 trial, first-line therapy with nivolumab plus ipilimumab outperformed standard chemotherapy, while in the CONFIRM trial, nivolumab outperformed placebo in patients previously treated with chemotherapy. These two trials represent a major milestone in the treatment of MPM and are set to position immunotherapy as a viable alternative for treatment-naïve patients and patients with progressive disease after chemotherapy.     

The role of Alimta in the treatment of malignant pleural mesothelioma: an overview of preclinical and clinical trials

Malignant pleural mesothelioma (MPM) is a rare tumor, but its annual incidence is rapidly increasing. While most patients have locally advanced disease at presentation, to date there is no proven standard chemotherapy for MPM that has shown to increase survival in randomized studies. Therefore, the development of new therapeutic agents is urgent for this disease. Alimta is a novel, multitargeted antifolate with activity as single agent in patients with MPM. Recently, a phase III trial showed that the combination of Alimta with cisplatin resulted in a significantly increased efficacy compared with cisplatin alone. In addition, vitamin supplementation reduced treatment associated toxicities with no apparent affect on activity. This review summarizes preclinical and clinical data to define the future role of Alimta in the treatment of patients with MPM.     

Overview on ongoing or planned clinical trials in Europe

Malignant pleural mesothelioma (MPM) is a locally invasive malignancy, but only a minority of patients can benefit by surgical resection. Among chemotherapeutic agents only vinorelbine, edatrexate, gemcitabine and raltitrexed have demonstrated response rates >20%. The largest randomised trial in MPM showed an improved median survival with cisplatin and pemetrexed versus cisplatin alone from 9.3 to 12.1 months. For the present overview about 70 requests of information were sent to the major European centres of thoracic oncology. The most widespread study treatment in Europe is an 'Extended Access Program (EAP)' evaluating pemetrexed alone or combined with cisplatin or carboplatin with about 1500 enrolled patients. Two other international randomized studies compare pemetrexed plus best supportive care (BSC) versus BSC alone, and the role of Ranpirnase (Onconase) in MPM. Important national trials are ongoing: in the UK the addressed questions were the role of radical surgery (MARS Trial), the role of chemotherapy (MS-01 trial) and the role of VATS on active treatment of pleural effusion. In Switzerland the SAKK group phase III study explores in a comparative way the value of hemithoracic radiotherapy after primary treatment with cisplatin/pemetrexed followed by surgery. In Italy, 2 phase II trials of neoadjuvant chemotherapy (pemetrexed plus cisplatin in Rome, pemetrexed plus carboplatin in Padua) followed by surgery and radiotherapy are active. With the important exception of UK, the most evident element is the overwhelming presence of pemetrexed in the ongoing and future clinical trials. Pemetrexed has influenced not only the clinical practice, but also the patient enrolment in clinical trials.     

Pemetrexed (Alimta®): a novel multitargeted antifolate agent

Pemetrexed (Alimta^®) is a novel, multitargeted antifolate that inhibits at least three of the enzymes involved in folate metabolism, and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated broad antitumor activity in Phase II trials in a wide variety of solid tumors, including mesothelioma, non-small cell lung, breast, cervical, colorectal, head and neck, and bladder cancers. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine (Gemzar^®). A pivotal Phase III study in mesothelioma has been presented. This study indicates the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. The most significant toxicities of pemetrexed, myelossuprresion and mucositis have been significantly ameliorated by folate and vitamin B12 supplementation. More importantly, vitamin supplementation has not demonstrated any adverse efficacy. This review discusses the biochemistry and clinical activity of pemetrexed.     

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.     

Pemetrexed (Alimta): a novel multitargeted antifolate agent

Pemetrexed (Alimta) is a novel, multitargeted antifolate that inhibits at least three of the enzymes involved in folate metabolism, and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated broad antitumor activity in Phase II trials in a wide variety of solid tumors, including mesothelioma, non-small cell lung, breast, cervical, colorectal, head and neck, and bladder cancers. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine (Gemzar). A pivotal Phase III study in mesothelioma has been presented. This study indicates the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. The most significant toxicities of pemetrexed, myelosuppression and mucositis have been significantly ameliorated by folate and vitamin B12 supplementation. More importantly, vitamin supplementation has not demonstrated any adverse efficacy. This review discusses the biochemistry and clinical activity of pemetrexed.     

Pemetrexed alone and in combination with platinum compounds in the management of malignant mesothelioma

Malignant pleural mesothelioma is an aggressive but rare malignancy with a dismal prognosis. It is traditionally resistant to chemotherapy. Antifolate agents have recently shown promising data in the treatment of this malignancy. Pemetrexed is a multitargeted antifolate inhibitor of thymidylate synthase and other folate-dependent enzymes that has emerged as one of the most active agents in this disease. Several phase I/II trials of pemetrexed as a single agent or in combination with a platinum drug have demonstrated considerable activity in mesothelioma. In a recently published phase III randomized study, pemetrexed/cisplatin showed a significant improvement in survival, response rate, and quality of life compared with single-agent cisplatin. In addition, several trials reported that folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed without affecting the efficacy of the drug.     

Retreatment of recurrent malignant pleural mesothelioma with cisplatin and pemetrexed

Combination chemotherapy with cisplatin and pemetrexed is the most active first-line regimen for malignant pleural mesothelioma (MPM). However, no drugs have been approved for second-line treatment of MPM, with effective regimens remaining to be identified for patients in relapse. We have now evaluated the combination of cisplatin and pemetrexed for retreatment of patients with recurrent MPM. Four men with MPM, all of whom received initial treatment with cisplatin and pemetrexed, underwent retreatment with this drug combination. Two of the patients achieved an objective response to the first-line chemotherapy with no evidence of disease progression for 6.4 or 11.4 months, respectively. The other two patients had stable disease with a duration of 7.8 or 5.0 months, respectively. The two patients who showed an objective response to first-line chemotherapy showed a partial response to retreatment, with a time to progression of 5.0 or 8.2 months, whereas the other two patients had progressive disease with a time to progression of 1.0 or 1.4 months, respectively. Retreatment with cisplatin plus pemetrexed was generally well tolerated. Retreatment with cisplatin and pemetrexed is a potential therapeutic option for certain patients with recurrent epithelioid MPM, possibly including those who show tumor regression with a time to progression of 6 months or more after the initial chemotherapy. Further studies are warranted to evaluate the efficacy of such retreatment and to clarify the criteria for patient selection.     

Pemetrexed

Pemetrexed (ALIMTA, LY231514) is a novel, multi targeted antifolate chemotherapy agent that is active in various tumors including mesothelioma, NSCLC, breast, colon and bladder carcinoma. Pemetrexed inhibits several enzymes in the folate pathway including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed is approved in the United States and a number of European Union countries for use in the treatment of mesothelioma, and the second-line treatment of advanced NSCLC. However, in Japan, pemetrexed was approved for use only in combination with cisplatin in the treatment of mesothelioma in January 2007. This approval was granted on the basis of a phase III trial of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Treatment with pemetrexed plus cisplatin and vitamin supplementation, resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone. In addition, in a phase III trial of pemetrexed versus docetaxel in patients with NSCLC previously treated with chemotherapy, treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects including grade 3 or 4 neutropenia , neutropenic fever, and alopecia, compared with docetaxel. Therefore, pemetrexed should be considered a standard treatment option for second-line NSCLC in US and most of EU. Addition of folic acid and vitamin B12 significantly reduced the toxicity of pemetrexed, especially hematologic toxicity and gastrointestinal toxicity. Pemetrexed is the expected agent for use in high risk patients, especially elderly or poor performance status patients.     

Audit of patients with mesothelioma treated with pemetrexed in a single institution in Western Australia

Malignant pleural mesothelioma (MPM) is a devastating malignancy that until recently has had no effective treatment. Pemetrexed in combination with cisplatin entered routine clinical practice following reports of efficacy in 2003. We performed a retrospective analysis of all patients with malignant mesothelioma at a single institution treated with pemetrexed in any combination or as monotherapy between 2004 and 2007. During this period, 62 patients received pemetrexed-based chemotherapy for MPM, most of whom were male (87%), treated in the palliative setting (84%) and received pemetrexed in combination with a platinum agent (95%). Pemetrexed was found to be well tolerated and produced clinical benefit and response rates similar to other published studies for its use in MPM in the phase IV or community practice settings. Patients with progressive disease as their best radiological response had very poor outcomes, while patients with stable disease had similar outcomes to those with responses. We confirmed that survival after commencement of pemetrexed-based chemotherapy remains under one year in this group of patients, somewhat less than the survival reported in phase III trials that currently inform clinical decision making. Further research is required to identify those patients who might benefit from pemetrexed based on molecular predictive markers.     

Medical Treatment of Mesothelioma: Anything New?

In the present report, we review the current standard and investigational treatments of malignant pleural mesothelioma (MPM). Several studies have reported the use of gemcitabine and cisplatin as an induction chemotherapy in combination with extrapleural pneumonectomy (EPP) and thoracic radiation in a combined-modality approach for resectable MPM. Since the combination of cisplatin with pemetrexed was applied as the standard first-line regimen for unresectable MPM, the combination as an induction chemotherapy regimen has been proven effective in phase 2 trials. In addition, intensity-modulated radiation therapy and proton therapy have been introduced as new radiation methods into the combined modality. Hyperthermic intraoperative chemotherapy following EPP appears effective with acceptable toxicity. In addition, clinical studies that include molecular targeting agents, immunotherapy, and gene therapy have all been conducted. Thus, although there are numerous hopeful treatments for MPM, the benefits of these regimens remain to be proven in a randomized clinical setting.     

Peritoneal Mesothelioma

OPINION STATEMENT: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatment options are unsatisfactory, and new approaches are needed. Recent publications have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC). We have noted at our institution prolonged survival in selected patients after intensive multimodality treatment. Our most recently reported trial included initial laparatomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Portacath; repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy; and intraoperative hyperthermic perfusion with mitomycin and cisplatin, followed by whole abdominal radiation. To date there have been no universally accepted treatments for MPM. Unless referred to a specialty center, patients are routinely treated with pemetrexed and cisplatin which has been shown to increase survival in pleural mesothelioma.     

Chemotherapy for malignant pleural mesothelioma: past results and recent developments

This review summarises the results of previously conducted clinical trials, and subsequently presents data arising from all phase II-III studies on chemotherapy of malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the antimetabolites, and in particular to pemetrexed that produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine-applied as a single agent or in combination with cisplatin-as well as vinorelbine appear to improve the quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. The publication of pemetrexed with cisplatin phase III results in a peer-reviewed journal may soon establish a standard of care.     

Chemotherapy for malignant pleural mesothelioma: past results and recent developments

This review summarises results of previously conducted clinical trials and subsequently presents data arising from all phase II-III studies on chemotherapy for malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear somewhat more promising. This applies especially to the antimetabolites, and in particular to pemetrexed which produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine--applied as a single agent or in combination with cisplatin--as well as vinorelbine appear to improve quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. Publication of results from a phase III trial of pemetrexed with cisplatin in a peer reviewed journal may soon establish a standard of care.     

A Phase II Trial of Nivolumab With Chemotherapy Followed by Maintenance Nivolumab in Patients With Pleural Mesothelioma After Surgery: The NICITA Study Protocol

BackgroundIn selected patients with early-stage malignant pleural mesothelioma (MPM), a multimodal therapy that includes surgical cytoreduction, chemotherapy, and/or radiotherapy is recommended. Several clinical trials have demonstrated the beneficial effects of immune checkpoint inhibitors in pretreated MPM patients with advanced disease. Recent clinical data have suggested that the combination of chemotherapy and checkpoint inhibition might improve efficacy.Trial DesignThe NICITA (nivolumab with chemotherapy in pleural mesothelioma after surgery) trial is a prospective, 1:1 randomized, open-label, multicenter phase II clinical trial (ClinicalTrials.gov identifier, NCT04177953). Ninety-two patients with MPM epithelioid subtype, who had undergone extended pleurectomy and decortication with or without hyperthermic intrathoracic chemoperfusion, will be included to receive adjuvant treatment. All patients will receive ≤ 4 cycles of platinum-based chemotherapy with pemetrexed (arms A and B). Patients in arm B will additionally receive nivolumab, together with the adjuvant chemotherapy, and subsequently for ≤ 12 cycles as maintenance therapy. The primary endpoint of this study is the time-to-next-treatment. The secondary endpoints include progression-free survival, overall survival, proportion of patients with treatment beyond progression, duration of treatment beyond progression in this population, and quality of life.ConclusionThis prospective trial will contribute data to assess the efficacy of standard chemotherapy combined with nivolumab in the context of multimodal management of early-stage MPM. The study is currently enrolling patients.     

Induction chemotherapy, extrapleural pneumonectomy, and radiotherapy in the treatment of malignant pleural mesothelioma: the Memorial Sloan-Kettering experience

Approximately 25% of patients with malignant pleural mesothelioma (MPM) prove unresectable at surgery and the median survival of stage III MPM is <12 months even after complete resection by extrapleural pneumonectomy. From 1939-2004, a series of sequential clinical trials has been performed at our institution. The surgical procedure has been modified and improved upon, and adjuvant hemithoracic radiation (RT) standardized. The evolution of our current standard of care for MPM is discussed. Improving chemotherapy for MPM led us to test induction chemotherapy followed by EPP and adjuvant RT for locally advanced MPM to assess feasibility. Patients with T3-4 or N2 MPM by CT and PET scans were enrolled on a phase II study. Induction therapy was: gemcitabine (1250 mg/m2 days 1, 8) and cisplatin (75 mg/m2 day 8)x2-4 cycles. Patients underwent EPP 3-5 weeks after induction therapy, then 54 Gy RT 4-6 weeks postop. At surgery, 8/9 had complete resection by EPP with no postoperative deaths. All received planned adjuvant RT. This combined modality approach is feasible for locally advanced MPM, and initial analysis suggests improved resectability. This experience supports additional studies of induction and multimodality therapy, especially with regimens such as cisplatin and pemetrexed which may be better tolerated and more effective.     

Malignant Pleural Mesothelioma: Medical Treatment Update

Malignant pleural mesothelioma (MPM) is a disease usually unaffected by current therapeutic strategies, but for the majority of patients, the use of systemic chemotherapeutic drugs remains the only therapeutic option available. During the past 15-20 years, many phase II and a few phase III clinical trials have studied a large variety of drugs such as anthracyclines, alkylating agents, platinum compounds, taxanes, vinka alkaloids, and antifolates as single agents and in combination, with the aim to increase responses and survival. The combination of pemetrexed and cisplatin tested in the largest phase III randomized trial of malignant pleural mesothelioma ever conducted has become the current standard of care. New targeted therapeutic approaches with a variety of anti–growth factor drugs are currently undergoing investigation worldwide.     

The emerging role of antifolates in the treatment of malignant pleural mesothelioma

Clinicians have long regarded malignant pleural mesothelioma as a chemoresistant neoplasm and as a result no standard chemotherapy regimen has emerged. Antifolates such as methotrexate are among the most active compounds in mesothelioma, albeit based only on phase II data. Recently two antifolate-based combinations with apparently higher efficacy than older regimens have emerged: the pemetrexed/cisplatin regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials with pemetrexed combined with either cisplatin or carboplatin responses occurred in five of 11 and nine of 29 patients, respectively. In a phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with mesothelioma achieved a partial response. In a phase II trial of raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72 patients (25%) with malignant pleural mesothelioma. Indeed, responses were seen in cisplatin-refractory patients. Based on the promising results from these combination trials, two large phase III studies have begun. The first study was a multicenter, multinational trial sponsored by Eli Lilly and Company, which randomized more than 430 patients with malignant pleural mesothelioma to cisplatin with or without pemetrexed. That trial completed enrollment in February 2001 and is the largest trial ever conducted in mesothelioma. The second trial is being conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and compares cisplatin with or without raltitrexed with planned accrual of 240 patients. In both trials, survival is the main endpoint. These trials will help to define the role of these new antifolates in malignant pleural mesothelioma.