Pemetrexed: Its Promise in Treating Non–Small-Cell Lung Cancer

Lung cancer, the most common type of cancer in men, has increased its incidence in women over the past decade. Lung cancer is the major cause of cancer-related death in both North America and Europe, and approximately 75% of lung cancers are non-small-cell lung cancers (NSCLC).[1] NSCLC treatment varies according to patient tumor stage at time of diagnosis. Many patients receive multimodality treatment consisting of various combinations of surgery, radiotherapy, and chemotherapy. In early-stage (nonmetastatic) NSCLC, combination chemotherapy is being clinically assessed as an integral part of multimodality treatment regimens, either as neoadjuvant (inductive, preoperative) or adjuvant (postoperative) chemotherapy, or in patients who are inoperable as concurrent or sequential radiochemotherapy.[ 2] In advanced (locally advanced or metastatic) NSCLC, combination chemotherapy containing platinum compounds is an important component of palliative therapy, since combination chemotherapy improves survival, provides symptom relief, and improves quality of life when compared with best supportive care alone.[3] As chemotherapy gains wider acceptance as a part of the initial treatment in advanced and early-stage NSCLC, the need for an effective second-line chemotherapy grows. This is particularly true because increasing numbers of patients receive combined-modality therapy for early-stage NSCLC that includes chemotherapy, and they may be candidates for second-line treatment at the time of disease progression or relapse. Preclinical and Early Clinical Development Pemetrexed(Drug information on pemetrexed) (Alimta) is a novel antifolate (N-[4-[2-(2-amino-3,4- dihydro-4-oxo-7H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl ]-benzoyl]-Lglutamic acid) distinguished by a unique 6-5-fused pyrrolo [2,3-d] pyrimidine nucleus that differs from the more common core structures of other antifolates that have 6-6-fused pteridine or quinazoline rings (Figure 1).[4] Pemetrexed gains entry to the cell via the reduced folate carrier, and it is an excellent substrate for folylpolyglutamate synthase once localized, with the highest affinity of any antifolate. Polyglutamation traps pemetrexed and enhances its intracellular retention. The parent drug is polyglutamated 90- to 195-fold more efficient than methotrexate(Drug information on methotrexate) and 6- to 13-fold more efficient than the antipurine antifolate (6R)-5,10-dideaza- 5,6,7,8-tetrahydrofolic acid (lometrexol).[ 5] The increased cellular retention of pemetrexed forms may explain the success of the 3-week administration schedule. Pemetrexed inhibits multiple enzyme targets involved in both pyrimidine and purine synthesis, including at least thymidylate synthase, dihydrofolate reductase, aminoimidazole carboxamide ribonucleotide formyltransferase, and glycinamide ribonucleotide formyltransferase.[6] These targets are related to the cytotoxicity of pemetrexed, as both thymidine and hypoxanthine are required to circumvent pemetrexed-induced cellular death.[7] Severe, unpredictable, and occasionally fatal myelosuppression and gastrointestinal toxicities have been associated with antifolate agents. Data accumulated in the past few years suggest that plasma homocysteine is a sensitive measure of the functional folate status, and under conditions of folate deprivation, plasma homocysteine levels increase. Vitamin B₁₂ and B₆ deficiencies can also result in high homocysteine levels. Data from early pemetrexed trials suggest that an elevated plasma homocysteine concentration was indicative of preclinical folate deficiency, and resulted in a more severe toxicity profile that typically included thrombocytopenia, neutropenia, severe diarrhea, and mucositis. Therefore, all patients enrolled in pemetrexed clinical trials over the past 2 to 3 years received folic acid(Drug information on folic acid) and vitamin B₁₂ supplementation as follows: oral folic acid at 350 to 1,000 μg administered at least 5 continuous days prior to pemetrexed and continuing throughout therapy. Vitamin B₁₂ at 1,000 μg was administered intramuscularly with folic acid and repeated every 9 weeks while the patient was on study (Figure 2). Moreover, current data from Vogelzang et al indicate that supplemental use of vitamins can ameliorate some of the severe drug-induced toxicity effects resulting in improved safety profile and efficacy for this drug.[8] Pemetrexed is currently under clinical investigation for a variety of solid tumors, including NSCLC. Given the important role of systemic chemotherapy for the treatment of early and advanced NSCLC, pemetrexed has been tested in various doses and several combinations in the first- and second-line therapy settings. Single-Agent Activity in NSCLC Initial phase II study results demonstrate that pemetrexed has singleagent activity in chemonaive and chemotherapy-pretreated patients. Two trials of single-agent pemetrexed were undertaken in previously untreated patients.[9,10] In Clarke et al's Australian/South African study,[10] all patients (n = 59) were treated with pemetrexed at 600 mg/m². Among 57 evaluable patients, overall response rate was 16% (9 partial remissions), median time to progression was 4.4 months, median duration of response was 4.9 months, median survival was 7.2 months, and 1-year survival rate was 32%. In the Canadian trial (n = 33) of Rusthoven and coworkers,[9] patients initially received pemetrexed at 600 mg/m² IV for 10 minutes every 3 weeks. However, after three patients were treated on this dose, it was reduced to 500 mg/m² IV due to toxicity. Four of 33 patients assessable for toxicity (13.3%) developed febrile neutropenia and 13 patients (39%) grade 3/4 neutropenia; four patients experienced grade 4 thrombocytopenia. The main nonhematologic toxicity (> grade 2) was skin rash and lethargy. Use of prophylactic dexamethasone(Drug information on dexamethasone) for 3 days starting the day before pemetrexed significantly reduced skin toxicity both in frequency and severity. In 30 patients evaluable for response, a partial response was obtained in 23% of the patients, median time to progression was 3.8 months, median duration of response was 3.1 months, median survival was 9.2 months, and 1-year survival rate was 25%. In chemotherapy-pretreated patients with advanced NSCLC, Smit et al conducted a large phase II trial of pemetrexed as second-line treatment in Europe and Australia.[11] Patients with stage IIIB or IV NSCLC were eligible for accrual if they had relapsed during or within 3 months of prior chemotherapy. Patients with a performance status of 2 were not enrolled. Pemetrexed was administered as a 10-minute IV infusion at a dose of 500 mg/m² every 3 days. Dexamethasone 4 mg was taken twice per day orally on the day before, the day of, and the day after each dose of pemetrexed. Leucovorin administration was recommended for any patients who experienced grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3/4 mucositis. Antiemetic medication was given according to standard recommendations. Vitamin supplementation was not used. Out of 79 patients considered evaluable for efficacy, 44 had progressive disease during or shortly after platinum- containing therapy and 35 had progressive disease during or shortly after a non-platinum-containing regimen. Six patients had partial responses and one patient had a complete response, for an overall response rate of 8.9%. A total of 25 patients (31.6%) achieved stable disease and 30 patients (38%) had progressive disease. Median duration of response was 6.8 months, median survival time was 5.7 months, and median time to progression was 2 months (Table 1). Based on these favorable results, Hanna et al reported the results of the largest phase III prospective randomized trial ever conducted in secondline NSCLC (n = 571). In this registration trial, investigators compared pemetrexed with the widely accepted standard treatment docetaxel(Drug information on docetaxel) (Taxotere).[12] In the trial, 288 patients were randomized to receive a 1-hour infusion of docetaxel at 75 mg/m² on day 1 every 3 weeks. The remaining 283 patients received a 10-minute infusion of pemetrexed at 500 mg/m² on day 1 every 3 weeks. Patients in both arms of the study received prophylactic dexamethasone; only patients in the pemetrexed arm received folic acid and vitamin B₁₂ supplementation. The study was designed to demonstrate an 80% chance of superiority. The primary study end point was survival; the secondary end points were tumor response rate, progression- free survival, and toxicity. The results can be summarized as follows: pemetrexed and docetaxel have similar efficacy demonstrated for response rates (9.1% vs 8.8%), median survival (8.3 months vs 7.9 months; Figure 3), and progression-free survival (2.9 months each). The one-year survival rate was 29.7% for each arm. Pemetrexed had a more favorable hematologic toxicity profile when compared with docetaxel. Severe neutropenia (grade 3/4) was seen in 5.3% for the pemetrexed arm and 40.2% for the docetaxel arm (P < .001). The difference in the incidence of febrile neutropenia and subsequent hospitalizations between the pemetrexed and docetaxel arms was also statistically significant (febrile neutropenia: pemetrexed 1.9%; docetaxel 12.7%; P < .001 [Table 2]; hospitalizations because of febrile neutropenia: pemetrexed 1.5%; docetaxel 13.4%; P < .001). Patients on pemetrexed also required significantly less granulocyte colony-stimulating factor (G-CSF) than patients on docetaxel (2.6% vs 19.2%; P < .001) (Table 3). In light of these magnitudes of significant difference compared to docetaxel, the authors concluded that pemetrexed possesses a more favorable toxicity profile than docetaxel, and is an effective second-line agent in NSCLC. Pemetrexed in Combination Pemetrexed is an attractive candidate for combination therapy, due to its unique mechanism of action and short infusion time. A number of different combination therapies have been investigated, eg, with gemcitabine (Gemzar), irinotecan(Drug information on irinotecan) (Camptosar), fluorouracil(Drug information on fluorouracil) (5-FU), or paclitaxel(Drug information on paclitaxel). Pemetrexed/Cisplatin
Our German/Austrian study was the first phase II study of pemetrexed/ cisplatin(Drug information on cisplatin) completed in advanced NSCLC.[13] The dose and schedule selected for the study were based on the experience reported by Thodtmann and collegues in their clinical/pharmacokinetic phase I study of pemetrexed plus cisplatin.[14] Thus, all patients received pemetrexed at 500 mg/m² IV over 10 minutes, followed by cisplatin at 75 mg/m² 30 minutes later; treatment was preferably administered on an outpatient basis every 21 days. Cisplatin administration and pre- and posthydration were performed according to local policy. Patients also received dexamethasone at 4 mg orally twice per day on the day before, the day of, and the day after pemetrexed administration. Antiemetic medications were administered according to standard. Vitamin supplementation was not used, and G-CSF was not recommended routinely. A total of 36 chemotherapynaive patients were enrolled (all evaluable for response). Fourteen (39%) patients achieved partial remission, and 17 (47%) patients had stable disease as their best response. The median duration of response was 10.4 months, with 75% of patients having response duration exceeding 9 months. The median time to progression was 6.3 months, 56% of patients remained progression-free at 6 months, 36% at 9 months, and 33% at 1 year, respectively. The median survival was 10.9 months, and the 1-year survival percentage was 50%. Twenty-one (59%) patients experienced grade 3/4 granulocytopenia without fever or infection. Four (11%) and six (17%) patients experienced grade 3 anemia and grade 3/4 thrombocytopenia, respectively. Nonhematologic toxicity included grade 3 nausea in two (6%) patients, and grades 3/4 diarrhea in one (3%) patient each. One patient each experienced grade 4 alanine aminotransferase (ALT), grade 3 bilirubin, and grade 3 aspartate aminotransferase (AST) elevations. Shepherd and colleagues of the National Cancer Institute of Canada Clinical Trials Group used an identical study design in the second phase II study of pemetrexed and cisplatin (n = 31).[15] Out of 29 patients evaluable for response, 13 (45%) obtained a partial response. Median duration of response was 6.1 months, median time to progression was 5.8 months, median survival time was 8.9 months, and 1-year survival rate was 49%, respectively. Grade 3/4 anemia was observed in 5/1 patients, and grade 3/4 granulocytopenia in 7/4 patients, respectively. Grade 3 nausea and emesis occurred in only two patients, grade 3/4 diarrhea in 3 patients, and two patients had grade 3 motor neuropathy. It is fair to conclude that these phase II studies demonstrate that pemetrexed/ cisplatin is effective and welltolerated. Response rates obtained are almost twice as high as single-agent pemetrexed and are comparable to the response rates shown by other new drugs, which have been tested in combination with cisplatin. The outpatient feasibility provided by the short infusion time of pemetrexed and the treatment schedule of once every 3 weeks further enhances the convenience of this regimen. Pemetrexed/Carboplatin
For the carboplatin(Drug information on carboplatin) (Paraplatin)/ pemetrexed combination, the phase II recommended study dose is pemetrexed at 500 mg/m² and carboplatin at an area under the concentrationtime curve (AUC) of 5, given in 3- week intervals with both drugs administered on day 1.[16] A recent phase II trial from Scagliotti et al indicated that pemetrexed/carboplatin is effective and well tolerated as frontline chemotherapy in patients with locally advanced NSCLC (n = 80).[17] In this study, 39 patients in the pemetrexed/ carboplatin arm (arm A) received pemetrexed at 500 mg/m² and carboplatin at AUC 6 on day 1 of a 21-day cycle for up to six cycles of therapy. (Arm B consisted of 41 patients receiving pemetrexed at 500 mg/m² plus oxaliplatin(Drug information on oxaliplatin) [Eloxatin] at 120 mg/m².) Vitamins and dexamethasone were provided per pemetrexed therapy. The confirmed response rate was 33% (vs 27% for arm B), with stable disease reported for 41% (vs 44%) of patients, respectively. Neither time to disease progression nor survival data have been reported yet. For the pemetrexed/carboplatin arm, the main grade 3/4 hematologic toxicity included neutropenia (26%) and thrombocytopenia (18%). Main nonhematologic toxicities consisted of grade 3 fatigue (8%) and stomatitis (32.6%). In the pemetrexed/oxaliplatin arm, no grade 4 hematologic toxicities were reported, with grade 3 neutropenia (5%), thrombocytopenia (2%), and anemia (2%). Main nonhematologic toxicities were grade 3 vomiting (7%), neuropathy (2%), diarrhea (2%), and hypersensitivity reactions (2%). Another phase II study (n = 50) by Zinner et al used pemetrexed at 500 mg/m² administered on day 1 followed by carboplatin at AUC 6 given on day 1, every 3 weeks, for six cycles.[18] The overall response rate was 28%, with a median time to progression of 4.8 months. Five patients (10%) had grade 3/4 nonhematologic toxicity, with mild alopecia and sensory neuropathy. Two patients had grade 3 thrombocytopenia and 15 experienced grade 3/4 neutropenia. Pemetrexed/Gemcitabine
Both the suggested preclinical synergy and the documented efficacy in advanced NSCLC provided the rationale to investigate pemetrexed and gemcitabine(Drug information on gemcitabine) (Gemzar) in combination. Adjei et al identified a dose for phase II studies as gemcitabine at 1,250 mg/ m² days 1 and 8 and pemetrexed at 500 mg/m² (90 minutes after gemcitabine) on day 8, every 3 weeks.[19] Based on the phase I combination trial results (objective responses obtained in three NSCLC patients), Ettinger and coworkers initiated a multicenter phase II trial combining pemetrexed and gemcitabine in chemonaive patients with stage IIIB/ IV NSCLC (n = 60).[20] The dose and schedule was gemcitabine at 1,250 mg/m² as a 30-minute IV infusion on days 1 and 8 and pemetrexed at 500 mg/m² as a 10-minute IV infusion, 90 minutes after gemcitabine, on day 8 every 3 weeks with prophylactic dexamethasone. Vitamin supplementation with folic acid and vitamin B₁₂ was initiated after the trial began due to pemetrexed-related toxicity. The data so far indicate that pemetrexed/gemcitabine is active and possesses a comparable toxicity pro-file to other relevant doublets. Out of 54 patients evaluable for response, 9 (17%) had a partial response, with 29 (54%) with stable disease. Median progression-free survival was 4.9 months, median overall survival 11.3 months, and 1-year survival 44%. Median duration of response was 3.3 months. The observed grade 3/4 hematologic toxicities in 60 patients evaluable for toxicity were neutropenia in 29%/34% of the patients, neutropenic fever in 13%/2%, thrombocytopenia in 5%/0%, and anemia in 12%/0% of the patients. Reported grade 3/4 nonhematologic toxicities reported were AST/ALT elevations in 16/21%, diarrhea in 3/2%, fatigue in 23/0%, and skin rash in 3/0% of patients. Pemetrexed/Vinorelbine
Clarke et al conducted a phase II study to determine the response rate of the platinum-free combination pemetrexed/vinorelbine (Navelbine) in the first-line treatment of advanced NSCLC.[21] Patients received pemetrexed at 500 mg/m² day 1 and vinorelbine at 30 mg/m² days 1 and 8 as a 10-minute IV infusion every 3 weeks. Folic acid and vitamin B₁₂ supplementation were given to reduce the hematologic toxicities noted in previous pemetrexed studies. Efficacy and toxicity results were reported for 34 of the 36 enrolled patients. Grade 4 hematologic toxicities included neutropenia in 15 patients and leukopenia in six. Grade 3/4 nonhematologic toxicities included fatigue (n = 7), dyspnea (5), nausea (3), and stomatitis (1). Two patients discontinued treatment due to toxicity (neutropenic sepsis, stomatitis) and one discontinued due to fatigue. Twelve patients achieved a partial remission and eight patients had stable disease. The authors concluded that pemetrexed in combination with vinorelbine is well tolerated and has promising activity. Conclusions In non-small-cell lung cancer, pemetrexed has shown promising activity and can safely be administered as either a single-agent or in combination for first- and second-line chemotherapy. Pemetrexed's toxicity profile improves significantly with the concomitant administration of dexamethasone, vitamin B₁₂, and folic acid. In second-line chemotherapy, singleagent pemetrexed may be a candidate to replace docetaxel as a standard treatment because of lower toxicity and increased patient feasibility. For first-line chemotherapy, the role of platinum-based and platinum-free pemetrexed combinations still needs to be defined in randomized phase III studies. However, phase II data indicate high efficacy with favorable toxicity profile for pemetrexed combined with cisplatin, carboplatin, oxaliplatin, gemcitabine, and vinorelbine.