The Emerging Role of Pemetrexed for the Treatment of Malignant Mesothelioma

Malignant mesothelioma is a devastating malignancy that affects approximately 2,500 Americans and 5,000 Western Europeans each year. It develops 20 to 60 years after asbestos exposure. Since workplace regulations limiting asbestos exposure were instituted earlier in the United States, the incidence of mesothelioma in the United States is believed to have peaked in the year 2000, while the peak incidence in Europe is not expected to occur until 2018 to 2025. Men are more commonly affected, reflecting occupational exposure. The median age of onset continues to rise. The median survival of patients with mesothelioma ranges from 6 to 15 months.[1] Numerous cytotoxic agents have been evaluated for the treatment of mesothelioma. Few drugs have consistently yielded response rates above 20%, which has led to considerable therapeutic nihilism. Antimetabolites are among the most active agents against mesothelioma; the antifolates are the most active and most widely studied group of antimetabolites (see Table 1). Pemetrexed(Drug information on pemetrexed) (Alimta), a new antifolate agent, may be more active than other antifolates against mesothelioma for several reasons. Pemetrexed targets more than one locus: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. A newly described cell membrane transporter found in mesothelioma is highly specific for pemetrexed.[2] The folate receptor alpha, which may be involved in pemetrexed transport, is highly activated in mesothelioma.[3] Methylthioadenosine phosphorylase (MTAP) is deleted in 66% of mesotheliomas, which may make these tumors particularly sensitive to inhibitors of de novo purine synthesis.[4] Completed Clinical Trials With Pemetrexed Several phase I, II, and III trials have evaluated pemetrexed alone or in combination with a platinum agent in patients with malignant mesothelioma. Phase I Trials
Pemetrexed has been evaluated in combination with a platinum agent in two phase I trials; vitamin supplementation was not utilized in either study. Thoedtmann and colleagues investigated the combination of pemetrexed and cisplatin(Drug information on cisplatin) in 54 patients with advanced solid tumors. Two cohorts were studied: in cohort 1, both drugs were given on day 1, using starting doses of pemetrexed and cisplatin of 300 and 60 mg/m², respectively. In cohort 2, pemetrexed at 500 or 600 mg/m² was administered on day 1, and cisplatin at 75 mg/m² was given on day 2.[5] Dose-limiting toxicity included neutropenic fever. Partial responses were observed in 5 of the 11 evaluable patients with mesothelioma. Hughes and colleagues evaluated pemetrexed in combination with carboplatin(Drug information on carboplatin) (Paraplatin) in a phase I trial performed exclusively in patients with malignant mesothelioma. Twentyseven patients were treated on five dose levels, ranging from pemetrexed at 400 mg/m² followed by carboplatin at an area under the concentration- time curve (AUC) of 4, to pemetrexed at 500 mg/m² and carboplatin at AUC 6; both agents were given every 21 days.[6] The maximum tolerated dose was pemetrexed 500 mg/m² and carboplatin AUC 6; the recommended phase II dose was pemetrexed 500 mg/m² and carboplatin AUC 5. Toxicities were principally hematologic, including grade 3/4 neutropenia in 70% of patients, leukopenia in 48%, and thrombocytopenia in 52%. Partial responses were observed in 32% of the patients in this phase I trial. The median survival was 451 days, and 70% of patients experienced symptomatic improvement. Phase II Trial
Single-agent pemetrexed has been evaluated in a multicenter phase II trial in 64 chemotherapy-naive patients with malignant pleural mesothelioma. Patients received pemetrexed 500 mg/m² intravenously over 10 minutes every 21 days.[7] Forty-three patients received vitamin supplementation with folic acid(Drug information on folic acid) and vitamin B₁₂. Partial responses were observed in 14% of patients, which is within the expected range for an antifolate agent in this disease (see Table 1). Median survival was 10.7 months; 1-year survival was 47.8%. Twenty-three percent of patients experienced grade 3/4 neutropenia. Phase III Trial
The largest clinical trial ever performed in patients with malignant mesothelioma was a pivotal, singleblind, placebo-controlled, international phase III trial which randomized 456 previously untreated patients with malignant pleural mesothelioma to either pemetrexed at 500 mg/m² followed by cisplatin at 75 mg/m², or placebo followed by cisplatin at 75 mg/m²; both regimens were administered intravenously every 21 days.[8] Vitamin supplementation with folate and vitamin B₁₂ was initiated in December 1999, after 117 patients had been enrolled, in order to reduce severe pemetrexed-related toxicity. Patients were stratified by performance status, histology, gender, white blood cell count, measurability of disease, and baseline homocysteine level. The primary objective was survival; secondary objectives included response rate, time to progression, toxicity, clinical benefit, and pulmonary function. The trial was well balanced with respect to baseline patient characteristics, including age, sex, performance status, histology, and stage. A total of 226 patients were randomized to the combination arm, and 222 to singleagent cisplatin. The response rate was significantly higher in the pemetrexed/ cisplatin arm compared with cisplatin alone (41% vs 17%; P < .001). Survival was significantly improved with combination chemotherapy: patients treated with pemetrexed/cisplatin had a median survival of 12.1 months com-pared with 9.3 months for cisplatin alone (P = .020; Figure 1). Time to progression also was improved with pemetrexed/cisplatin (5.7 vs 3.9 months, P = .001). Vitamin supplementation with folic acid and vitamin B₁₂ improved response rates and survival in both treatment arms (Table 2). Vitamin supplementation reduced the incidence of several grade 3/4 toxicities in the pemetrexed/cisplatin arm, including drug-related death, neutropenia, febrile neutropenia, thrombocytopenia, vomiting, stomatitis, and diarrhea (Table 3).[8] The median number of chemotherapy cycles delivered was also greater for patients on either arm who received vitamin supplementation. Treatment with pemetrexed plus cisplatin was associated with significant improvement in lung function as measured by FEV₁ (Figure 2) and vital capacity.[8] Tumor response correlated with lung function as measured by pulmonary function tests. Patients who had either a partial response or stable disease had better lung function than patients with progressive disease, regardless of treatment arm.[9] Most (93%) patients had three or more symptoms at study entry.[10]. Using the Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) instrument, Gralla and colleagues reported that global assessment of quality of life (P = .012) and symptom distress (P = .009) improved significantly with combination therapy at 18 weeks. Patients treated with the combination regimen experienced significant improvement (P < .001) in thoracic symptoms of pain, dyspnea, and cough as well as improvement in general symptoms including fatigue (P = .010), anorexia (P = .017), and activity level (P = .059). A Cox multiple regression analysis of the association between posttrial chemotherapy administration and survival found that second-line chemotherapy correlated with increased survival (P < .01).[11] Second-line chemotherapy was administered to 38% of patients in the pemetrexed plus cisplatin arm and 48% of patients in the single-agent cisplatin arm. The most commonly administered chemotherapy drugs were gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), and doxorubicin. Although fewer patients in the combination treatment arm received second-line chemotherapy, these patients still had a significantly longer survival compared with those treated with cisplatin alone (P = .02, log rank). Univariate and multivariate analyses confirmed that patients treated with pemetrexed plus cisplatin had significantly longer survival than patients treated with single-agent cisplatin. Vitamin supplementation, good Karnofsky performance status, early-stage disease, and epithelial histology were also associated with increased survival. Decreased survival was associated with elevated leukocyte counts and increased cystathionine.[12] Ongoing Clinical Trials With Pemetrexed Several ongoing phase II trials are evaluating pemetrexed in mesothelioma patients. Janne and colleagues are studying the combintion of gemcitabine and pemetrexed in a multicenter phase II trial in patients with peritoneal as well as pleural mesothelioma.[ 13] This is a logical combination to evaluate, since gemcitabine and pemetrexed are synergistic in vitro, and the combination demonstrated significant activity in a phase I trial.[14] Fifty-three chemonaive patients received gemcitabine at 1,250 mg/m² on days 1 and 8 and pemetrexed at 500 mg/m² on day 8. Grade 3/4 neutropenia developed in 33% of cycles. A response rate of 20% was observed in the first 34 evaluable patients. An alternate schedule of gemcitabine at 1,250 mg/m² on days 1 and 8 and pemetrexed at 500 mg/m² given on day 1 is currently being explored. The role of the pemetrexed plus cisplatin combination in neoadjuvant treatment is currently being explored in a multicenter US study. Most mesothelioma patients who receive extrapleural pneumonectomy develop local recurrence, while many patients who undergo extrapleural pneumonectomy followed by high-dose hemithoracic radiation therapy develop systemic recurrence. It is hypothesized that administering active systemic chemotherapy prior to surgery and radiation could facilitate resection and decrease recurrence. The primary objective of this study is pathological complete response rate (H₀ ≥ 1% vs H_a 6%). Secondary end points include disease-free and overall survival, response rate, toxicity, and pattern of relapse. Laboratory parameters being evaluated include thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, folylpolyglutamate synthetase, dihydropyrimidine dehydrogenase, reduced folate carrier, alpha folate receptor, and excision repair cross-complementation group 1 (ERCC1). Eligible patients will have International Mesothelioma Interest Group stage I to III disease, and adequate cardiopulmonary, bone marrow, hepatic, and renal function. Patients will receive 4 cycles of pemetrexed and cisplatin followed by extrapleural pneumonectomy 3 to 8 weeks after completion of chemotherapy, and hemithoracic radiation (54 Gy) 4 to 8 weeks following surgery. This is the first multicenter trial of multimodality treatment for mesothelioma ever performed in the United States. Conclusion Pemetrexed plus cisplatin is the first chemotherapy combination that has been demonstrated to improve survival in patients with malignant mesothelioma. Pemetrexed is thus a very important addition to the armamentarium of chemotherapy agents for this disease, and further study is warranted. Ongoing studies are evaluating pemetrexed in combination with gemcitabine and in the neoadjuvant setting; planned trials will assess pemetrexed in combination with other cytotoxic and targeted agents for this disease.