Lung cancer is the most fatal neoplasm worldwide, with nearly 1.3 million new cases annually. Overall survival is typically poor, and less than 14% of patients survive longer than 5 years. Non-small-cell lung cancer (NSCLC)-the most prevalent histologic form-accounts for 75% to 80% of lung cancers. The integration of combination chemotherapy and radiotherapy (RT) has now become a standard of care for patients with locally advanced NSCLC. Unfortunately, many patients are diagnosed with advanced, late-stage, metastatic disease; when untreated, their median survival time (MST) is 4 to 5 months. Many chemotherapy regimens have been investigated for NSCLC, but the ability of these treatments to improve overall survival is debatable. A meta-analysis (n = 52 randomized trials encompassing 9,387 patients) of the Non-Small-Cell Lung Cancer Collaborative Group indicated that cisplatin(Drug information on cisplatin)- based chemotherapy provides a significant survival benefit for patients with locally advanced or metastatic disease. In the past decade, several doublets, including a platinum compound (cisplatin or carboplatin(Drug information on carboplatin) [Paraplatin]) combined with a taxane (paclitaxel or docetaxel(Drug information on docetaxel) [Taxotere]), a vinca alkaloid (vinorelbine [Navelbine]), or an antimetabolite (gemcitabine [Gemzar]) demonstrated activity in several phase II and III clinical trials.[4,5] Schiller and colleagues of the Eastern Cooperative Oncology Group (ECOG) conducted a large randomized trial (ECOG 1594) to evaluate four commonly used combination regimens of chemotherapy in the firstline setting (n = 1,155); see Table 1 for summary. Three treatment protocols included combinations of paclitaxel(Drug information on paclitaxel) with cisplatin, gemcitabine(Drug information on gemcitabine) with cisplatin (GC), or docetaxel with cisplatin. The fourth combination regimen was paclitaxel with carboplatin (PCb), a standard therapy. Neither overall response rates, which were disappointingly low at 17% to 22%, nor median survival, which ranged between 7.4 and 8.1 months, was significantly different between arms (the 1- and 2-year survival percentages were also similar with the four regimens.) Although the PCb combination achieved lower toxicity, patients treated with GC showed a trend toward a slightly higher median time to progressive disease (ie, a 1-month improvement).
Kelly et al and the Southwest Oncology Group conducted a large randomized phase III trial comparing PCb to the standard regimen of vinorelbine and cisplatin (VC) (Table 1). Patients received paclitaxel at 225 mg/m2 over 3 hours with carboplatin at an area under the concentration-time curve (AUC) of 6, day 1 every 21 days (n = 206); or vinorelbine at 25 mg/m2/wk and cisplatin at 100 mg/m2/d, day 1 every 28 days (n = 202). The two groups responded similarly in terms of objective response rate (28% VC, 24% PCb), median survival time (approximately 8 months in both arms), and 1-year survival percentage (36% VC, 38% PCb). Patients in the VC arm experienced grade 3/4 hematologic toxicities, specifically leukopenia (P = .002) and neutropenia (P = .008) and grade 3 nausea (P = .001) and vomiting (P = .007) at significantly higher frequencies than patients receiving PCb. Grade 3 peripheral neuropathy was lower for patients in the VC arm (P < .001), while greater numbers of patients receiving VC discontinued therapy due to toxicity (P = .001). Quality-of-life measures were similar between the two arms, and overall costs were higher with the PCb regimen. The Italian Lung Cancer Project conducted a randomized phase III trial comparing platinum-based doublets as first-line treatment of advanced NSCLC (Table 1). Patients diagnosed with stage IIIB/IV disease (N = 607) were randomized to one of three treatment arms: GC, PCb, or VC. The objective response rate, overall survival, and 1-year survival percentages were similar among the three regimens. The percentages of cycles with reports of grade 3/4 neutropenia (17% and 35%, respectively) and anemia (6% and 2%, respectively) were lower than those reported in the VC arm (43% and 7%, P < .001), while grade 3/4 thrombocytopenia was higher in the GC and PCb study arms (16% and 3% vs 0.1%; P < .001). No serious hemorrhagic events were noted for patients receiving chemotherapy. Relatively low numbers of patients presented with febrile neutropenia (GC [n = 1], PCb , and VC ), generally similar among the three arms. Thirty percent of patients treated with PCb experienced grade 1-3 peripheral neuropathy. Fossella et al conducted a large international, randomized trial (N = 1,214) to investigate whether docetaxel plus platinum regimens improve survival and quality of life in the advanced first-line NSCLC setting compared with VC (Table 1). Patients with stage IIIB/IV disease were randomized to docetaxel at 75 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin AUC 6 mg/mL/min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks. The objective response rate was 32% for patients receiving DC vs 25% for VC (P = .029); response obtained with DCb (24%) was similar to that reported in patients receiving VC. There was a trend toward reduced median survival with DCb (9.4 months) compared to patients in the VC arm in one paired analysis (9.9 months; P = .657). Patients treated with DC had a significantly greater median survival of 11.3 vs 10.1 months for VC-treated patients (P = .044) in the second pairwise analysis. The 2-year survival rate was 21% for DC-treated patients and 14% for VCtreated patients. Neutropenia, thrombocytopenia,infection, and febrile neutropenia were similar with all three regimens. Grade 3/4 anemia, nausea, and vomiting were more common (P < .01) in the VC group than with either DC or DCb. Patients treated with either docetaxelcontaining regimen had consistently improved QOL scores when compared with those receiving VC, who experienced deterioration in QOL on-study. The potential of targeted chemotherapy appeared promising when the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib (Iressa) provided clinically meaningful symptom relief, improved survival, and improved tumor response in phase II studies in advanced NSCLC patients.[10,11] Unfortunately, when gefitinib was combined with active chemotherapy doublets (PCb or GC) in two randomized phase III studies (Iressa NSCLC Trial Assessing Combination Chemotherapy Trial-1 [INTACT-1; n = 1,093] and INTACT-2 [n = 1,037]) the agent failed to add significant benefit in median overall survival (and other clinical trial end points). Thus, despite noted improvements in tumor response rates achieved by new combination therapies, advanced metastatic NSCLC remains an incurable disease. A new treatment paradigm is warranted. Development of drug resistance is a major impediment to the success of some chemotherapy regimens. Future treatment regimens that target multiple metabolic and cellular functions might potentially lead to improvements in clinical outcome. Newer therapies ideally should possess potent antitumor activity, produce minimal toxicity (especially neurotoxicity), and be amenable to convenient administration schedules.
Pemetrexed: A Multitargeted Antifolate
Antifolate antimetabolites are widely used and are effective in treating a variety of solid tumors (ie, colon, breast, lung, head and neck, cervical cancers, etc). Unfortunately, drug resistance is a common problem that typically occurs after tumor cells adapt to maximize the use of one or more salvage pathways needed for DNA synthesis. Amplification of common target genes that code for key enzymes such as dihydrofolate reductase (DHFR) or thymidylate synthase (TS) has reduced the efficacy of some drugs. While a number of antifolates have been evaluated in clinical trials, further drug development has stopped or been delayed by the occurrence of life-threatening toxicities such as neutropenia, mucositis, and diarrhea. Pemetrexed(Drug information on pemetrexed), N-[4-[2-(2-amino- 3,4-dihydro-4-oxo-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-ethyl]-benzoyl]-L-glutamic acid, is a novel antifolate antimetabolite. It is distinguished by a unique 6-5-fused pyrrolo[2,3- d]pyrimidine nucleus, which differs from the more common core structures that contain 6-6-fused pteridine or quinazoline rings. This agent is also unique because it inhibits multiple folate-dependent enzyme pathways. Hanauske et al and Goldman and colleagues have published comprehensive reviews that provide detailed discussions of the molecular pharmacology of pemetrexed.[16,17]
Single-Agent Pemetrexed in Advanced NSCLC
Single-agent pemetrexed was evaluated in patients with NSCLC in two respective phase II trials: one conducted in Canada, the other in Australia and South Africa (Table 2).[18,19] Notably, both trials took place before routine supplementation with folic acid(Drug information on folic acid) and vitamin B12. In the study of Rusthoven et al and the National Cancer Institute of Canada Clinical Trials Group, chemonaive patients (n = 33) had stage IIIB/IV with locally advanced or metastatic bidimensionally measurable disease. (Prior adjuvant therapy was permitted.) Pemetrexed was given in 21-day cycles as a 10-minute intravenous (IV) infusion at 600 mg/m2. The scheduled dose was reduced to 500 mg/m2 after the first three patients received treatment due to unacceptable toxicities. Seven patients (23%) achieved partial responses. The median survival time was 9.2 months and the time to progression for all patients was 3.8 months. Patients with stage IIIB disease responded better than those with stage IV (67% vs 2.5%) to pemetrexed treatment. The predominant hematologic toxicity was neutropenia in 39% of patients; one patient suffered from grade 4 thrombocytopenia. The most common nonhematologic toxicity was skin rash, as expected. Most of these toxicities were manageable with supportive care. A retrospective analysis of this and another study revealed that patients receiving dexamethasone(Drug information on dexamethasone) during the first treatment cycle had fewer and less severe episodes of skin rash. Most of these toxicities were manageable with supportive care.
Clarke et al conducted the second phase II trial at three Australian and two South African institutions (n = 59 chemonaive patients with stage IIIA, IIIB, IV NSCLC).. The design was nearly identical to the study conducted by Rusthoven and coworkers, and in this study, the scheduled dose of 600 mg/m2 every 3 weeks was delivered to the full cohort without unacceptable toxicity. (Restaging was performed after every two cycles, and toxicity was assessed at each cycle.) In the absence of undue toxicity or disease progression, treatment continued for a maximum of 12 cycles. Study patients were treated with a median of four cycles of pemetrexed (21-day schedule). Patient eligibility criteria were similar to that used in the Canadian trial. Of the 57 patients evaluable for response/toxicity, nine achieved a partial response, yielding an objective response rate of 16%. The median survival time was 7.2 months, and median time to progressive disease was 4.4 months, with a median duration of response of 4.9 months. While the most common grade 3/4 toxicities reported were neutropenia (42%) and skin rash (32%), only 3% developed grade 3 infection. Eighteen patients (31%) developed grade 3/4 cutaneous toxicity that improved with prophylactic oral dexamethasone. The data from these two singleagent trials revealed consistent overall activity (objective response rates of 16% and 23%) and similar safety profiles. Together, they provided evidence of the single-agent activity of pemetrexed in the first-line treatment of advanced NSCLC.
Pemetrexed-Based Combinations in Advanced NSCLC
Pemetrexed/cisplatin doublet therapy has demonstrated antitumor activity in patients with advanced NSCLC in European (n = 36) and Canadian (n = 31) phase II trials (summarized in Table 3).[20,21] In these two studies, chemonaive patients were diagnosed with advanced NSCLC (stage IIIB/IV) and possessed good performance status . In both studies, the study regimen consisted of pemetrexed at 500 mg/m2 followed by cisplatin at 75 mg/m2 once every 21 days. Squamous-type carcinoma was more prevalent in the European study of Manegold et al, while a larger proportion of patients in the Canadian study of Shepherd and coworkers[ 21] had stage IV disease. Overall response rates were 39% and 45% (including 46% in stage IV disease) in the European and Canadian studies, respectively. Respective median survival time, median duration of response, and 1-year survival rate were 10.9 months, 10.4 months, and 50% in the European study compared to 8.9 months, 6.1 months, and 49% in the Canadian study. Grade 3/4 neutropenia was the predominant hematologic toxicity in both the European study (59%) and the Canadian study (37%). Fifty percent of the patients in the European study and 68% in the Canadian study experienced grade 2/3 fatigue. In the European study, nonhematologic toxicities included grade 3 nausea in 6% of patients and grade 3/4 diarrhea in 3% each. In the Canadian study, grade 3 nausea and emesis occurred in only two patients, grade 3/4 diarrhea in three, and grade 3 motor neuropathy in two. Both studies were completed before folic acid/vitamin B12 supplementation was routinely administered, and lower toxicities might be expected if the studies were conducted with the current schedule. Although they achieve activity, cisplatin- based combinations have proven to be problematic. Patients typically require extensive hydration before or after treatment, and severe toxicities are common. Consequently, pemetrexed is being evaluated either in combination with other platinum compounds (ie, carboplatin and oxaliplatin(Drug information on oxaliplatin)) or in cisplatin-free regimens. Koshy and Zinner et al from the University of Texas M. D. Anderson Cancer Center investigated pemetrexed/ carboplatin in patients with advanced or metastatic NSCLC (n = 50 chemonaive). Study patients received pemetrexed at 500 mg/m2 and carboplatin at AUC 6, both on day 1 of a 21-day cycle for up to six cycles, with vitamin supplementation, and achieved a 28.8% response rate (n = 49 evaluable) based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. With a minimum follow-up of 11 months, the median overall survival time was estimated at 13.5 months, with the 1-year survival rate estimated at 55.8%. Patients could elect to receive more than six cycles if they had no disease progression, although at study initiation, six cycles were intended. The median number of chemotherapy cycles that were administered was 6 (range: 1 to > 15). Fifteen patients (30%) received ≥ 8 cycles (8 cycles [n = 6]; 10 cycles ; 12 cycles ; 14 cycles ; 15 cycles ), and more than 277 cycles were administered. Grade 4 hematologic toxicity was reported in 10 patients: 6 with neutropenia and 4 with anemia. Ten percent of the patients experienced grade 3 or 4 nonhematologic toxicities, mainly represented by nausea and/or vomiting (three cases) and grade 3 fatigue (two cases). In three patients, deepvein thrombosis or pulmonary embolism was reported. In light of the absence of these toxicities in numerous other studies employing singleagent and doublet pemetrexed combinations, these were presumed to be unrelated to the pemetrexed/ carboplatin regimen. Note there were no grade > 1 alopecia or neurosensory toxicities. In our group's multicenter phase II randomized study, 80 chemonaive patients with locally advanced or metastatic NSCLC received either pemetrexed at 500 mg/m2 plus carboplatin at AUC 6 (arm A, 39 patients) or pemetrexed at 500 mg/m2 plus oxaliplatin at 120 mg/m2 (arm B, 41 patients) on day 1 of a 21-day cycle for up to six cycles. Vitamins and dexamethasone were provided per pemetrexed therapy. Principal patient characteristics were as follows: males, 75%; median age, 60 years (range: 36-79 years); ECOG performance status 0/1, 99%; and stage IV 64%. Confirmed response rate and stable disease in arm A were 33% and 44%, respectively, compared to 29% and 46% in arm B. The primary grade 3/4 hematologic toxicities in arm A included neutropenia (26%), febrile neutropenia (3%), thrombocytopenia (18%), and anemia (8%). In arm B, neutropenia (2%) was the sole grade 4 hematologic toxicity, with grade 3 neutropenia (5%), thrombocytopenia (2%), and anemia (2%). Primary nonhematologic toxicities included grade 3 fatigue (8%) and stomatitis (3%) in arm A, with grade 3 vomiting (7%), neuropathy (2%), diarrhea (2%), and hypersensitivity reactions (2%) in arm B. Median time to progression was 5.7 and 5.5 months, respectively, for arms A and B. Median overall survival time was 10.5 for both arms. The 1-year survival rate was 43.9% for arm A and 49.9% for arm B. Adjei et al conducted a phase I study with pemetrexed and gemcitabine in the treatment of solid tumors.[ 24] The study evaluated two different dosing schedules with patients in cohort 1 receiving gemcitabine on days 1 and 8 and pemetrexed on day 1 of a 21-day cycle. Cohort 2 received gemcitabine on days 1 and 8 and pemetrexed on day 8. Six different dose levels were evaluated, with gemcitabine given at either 1,000 or 1,250 mg/m2 and pemetrexed doses ranging from 200 to 600 mg/m2. (The study was conducted before the administration of vitamin supplements was instituted as routine practice.) The maximum tolerated dose for both cohorts was gemcitabine/pemetrexed at 1,250/500 mg/m2, and the recommended dose and schedule was gemcitabine at 1,250 mg/m2 on days 1 and 8 and pemetrexed at 500 mg/m2 on day 8. The combination had broad activity in different tumors, with 13 objective responses in 55 evaluable patients. Of the eight patients with NSCLC, three achieved a partial response. Neutropenia was the most common doselimiting toxicity. Nausea, fatigue, rash, and elevated hepatic transaminase were also observed. The day 8 administration of pemetrexed improved tolerability. In a phase II study, Adjei et al further investigated tumor response, and compared toxicities among patients receiving three schedules of pemetrexed at 500 mg/m2 plus gemcitabine at 1,250 mg/m2 in 148 stage III/IIIB patients. Pemetrexed plus gemcitabine were administered 90 minutes apart, on an every-21-day cycle: schedule A, pemetrexed followed by gemcitabine on day 1, gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1, gemcitabine on day 8; schedule C, gemcitabine on day 1, pemetrexed followed by gemcitabine on day 8. Arm B was closed at the time of interim analysis due to its decreased efficacy (less than 3 responses in the first 19 patients). Patients in arm A achieved a partial response rate of 29%, while those in arm C had a partial response rate of 17% (which did not meet the protocol- defined efficacy criteria). Median survival at the current median followup was 11.4 months. Overall, 74% patients experienced grade > 3 hematologic toxicity, and 62% reported grade > 3 nonhematologic toxicity (commonly fatigue [17.6%], dyspnea [11.5%], and rash [8.1%]). The rates of grade > 3 febrile neutropenia (arm A = 5%, arm B = 20%, arm C = 5%; P = .03) were significantly different. Patients in arm A also reported fewer adverse events than those in arm C (grade > 3: 86% vs 93%; grade > 4: 40% vs 50%). The authors concluded that sequence and schedule of administration critically determines the efficacy and toxicity of pemetrexed/gemcitabine, and that schedule A (pemetrexed followed by gemcitabine on day 1, gemcitabine on day 8) was optimal (based on preliminary efficacy and toxicity data) and should be further investigated. Monnerat et al also implemented the day 8 administration of pemetrexed in combination with gemcitabine in a multicenter phase II study in non-small-cell lung cancer. A total of 60 patients were enrolled, and 54 were evaluable for efficacy. Final results from this study have not yet been published, but preliminary data indicated promising survival data with a median survival time of 11.3 months, despite a relatively low overall response rate (17%). Conclusions In the phase II setting, pemetrexed has demonstrated consistent results in response and survival both as a single agent and in combination with platinum agents. Pivotal data have demonstrated the feasibility of its association with gemcitabline or radiotherapy. The routine practice of vitamin supplementation has reduced toxicity while maintaining activity. Ongoing and future studies will seek to maximize efficacy of pemetrexed through the implementation of pharmacogenomic approaches (a strategy detailed elsewhere in this supplement).