Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Monnerat, C.
Right arrow Articles by Ettinger, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Monnerat, C.
Right arrow Articles by Ettinger, D. S.
Clinical Cancer Research Vol. 10, 5439-5446, August 15, 2004
© 2004 American Association for Cancer Research

Clinical Trials

Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer

Christian Monnerat1, Thierry Le Chevalier1, Karen Kelly2, Coleman K. Obasaju3, Julie Brahmer4, Silvia Novello1, Takashi Nakamura3, Astra M. Liepa3, Laurence Bozec5, Paul A. Bunn, Jr2 and David S. Ettinger4

1 Institut Gustave Roussy, Villejuif, France; 2 The University of Colorado Cancer Center, Denver, Colorado; 3 Eli Lilly and Company, Indianapolis, Indiana; 4 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; and 5 Eli Lilly and Company, St. Cloud, France


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Cisplatin is one of the most active agents for the treatment of non-small cell lung cancer (NSCLC). It is also known for significant toxicity, which makes it unsuitable for certain patients. Our purpose was to evaluate the efficacy and toxicity of a promising cisplatin-free combination, gemcitabine plus pemetrexed, in NSCLC.

Experimental Design: Chemo-naive patients with inoperable NSCLC were eligible for this study. Gemcitabine (1250 mg/m2) was given intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8. After inclusion of 13 patients, folic acid and vitamin B12 supplementation was added to lower pemetrexed-induced toxicity. Quality of life was assessed with the Lung Cancer Symptom Scale.

Results: Sixty patients enrolled; 58 were evaluable for response. All patients had a World Health Organization performance status of 0 or 1. Eighty-seven percent had stage IV disease. Nine patients had a confirmed partial response [overall response rate, 15.5%; 95% confidence interval (CI), 7.3–27.4%]. Twenty-nine (50.0%) patients had stable disease. Median overall survival was 10.1 months (95% CI, 7.9–13.0 months), with a 1- and 2-year overall survival of 42.6% (95% CI, 30.0–55.3%) and 18.5% (95% CI, 7.9–29.1%). Median progression-free survival was 5.0 months. Median response duration was 3.3 months. There were no deaths attributed to treatment. Common Toxicity Criteria grade 3/4 toxicities were neutropenia (61.7%), febrile neutropenia (16.7%), fatigue (23.3%), and elevations of aspartate aminotransferase (15.0%) and alanine aminotransferase (20.0%).

Conclusions: This combination had good tolerance and achieved promising overall survival with extended 1- and 2-year survival rates. This cisplatin-free regimen warrants further evaluation in randomized trials.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pemetrexed (LY231514, Alimta; Eli Lilly and Company, Indianapolis, IN) is a novel antifolate that is metabolized intracellularly to a pentaglutamate form. Pemetrexed inhibits three enzymes (thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide transferase) involved in folate metabolism and DNA synthesis (1, 2, 3) . The cytotoxicity of pemetrexed is caused by inhibition of both the pyrimidine and purine pathways. The maximum tolerated dose established in Phase I studies of pemetrexed was 600 mg/m2 every 3 weeks (4 , 5) . This dose was later reduced to 500 mg/m2 every 3 weeks in several Phase II trials, particularly when used in combination with other cytotoxic agents (6 , 7) . Folic acid and vitamin B12 supplementation became a requirement for pemetrexed-based therapy early in this study, when analysis of safety data from multiple pemetrexed trials suggested that supplementation may decrease toxicity (8) . Single-agent pemetrexed was tested in two Phase II non-small cell lung cancer (NSCLC) trials enrolling 92 chemo-naive patients (without vitamin supplementation) by Clarke et al. (9) and Rusthoven et al. (7) . Response rates of 15.8% and 23.3% and median survivals of 7.2 and 9.2 months were observed, respectively. In these two studies, the main toxicities reported were grade 3/4 neutropenia (42% and 39%) and grade 3/4 skin rash (31% and 39%).

Gemcitabine (Gemzar; Eli Lilly and Company) is a pyrimidine antimetabolite that is intracellularly transformed to difluorodeoxycytidine triphosphate. Its incorporation into DNA results in chain termination. Gemcitabine also inhibits ribonucleotide reductase, an enzyme required for deoxynucleoside formation and DNA synthesis (10) Gemcitabine has been widely explored in NSCLC, as a single-agent and in combination. The United States Food and Drug Administration-approved dose is 1000 mg/m2 weekly for 3 weeks every 4 weeks (11 , 12) or 1250 mg/m2 weekly for 2 weeks every 3 weeks (13) . In a Phase II study of gemcitabine (1250 mg/m2) weekly for 3 of 4 weeks enrolling 161 patients with advanced NSCLC, the response rate was 21.8%, and median survival was 11.5 months (13) . Main toxicities were grade 3 neutropenia, nausea, and elevations of hepatic transaminases.

Because pemetrexed and gemcitabine have both shown single-agent activity against a wide range of solid tumors including NSCLC (7 , 9 , 11 , 12 , 14 , 15) , the combination of these two agents was evaluated in vitro, and cytotoxic synergy was found when gemcitabine exposure preceded that of pemetrexed (16) . Whereas preclinical studies suggested pemetrexed on day 1 with a 90-min interval between administrations, a Phase I study led to administration of pemetrexed on day 8 due to better hematological tolerance (16) . The recommended dose was gemcitabine (1250 mg/m2) on days 1 and 8, followed by pemetrexed (500 mg/m2) on day 8 of a 3-week cycle. The most common dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases (16) .

The objective of the present Phase II study was to determine the antitumor activity of the pemetrexed-gemcitabine combination, a cisplatin-free outpatient regimen, in chemo-naive patients with locally advanced or metastatic NSCLC. Secondary end points were to assess toxicity of treatment, evaluate overall and progression-free survival, and assess the impact on symptoms and quality of life.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection.
Eligible patients had histological or cytologic diagnosis of stage IIIB or IV NSCLC, with evidence of bidimensionally measurable disease. Any clinically significant effusion had to be drained and pleurodesis had to be performed at least 2 weeks before baseline imaging. Previous systemic chemotherapy, as well as prior radiation therapy to target lesions, was not permitted. Other eligibility criteria included the following: age ≥ 18 years; World Health Organization performance status of 0 or 1; calculated creatinine clearance ≥ 45 ml/min (based on modified Cockcroft and Gault method; Ref. 17 ); adequate hepatic function (i.e., serum bilirubin of ≤1.5 times the upper normal limit; alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase of ≤3.0 times the upper normal limit or ≤5.0 times the upper normal limit in case of liver metastases); adequate bone marrow function (absolute neutrophil count ≥ 1.5 x 109/liter, platelet count ≥ 150 x 109/liter, and hemoglobin ≥ 9 g/dl); albumin ≥ 3.0 g/dl; absence of >10% weight loss in the 6 weeks before inclusion; absence of serious concomitant illness that would compromise chemotherapy delivery; absence of second primary malignancy (except cervical carcinoma in situ and nonmelanomatous skin cancer that was adequately treated); absence of clinical evidence of brain metastases; effective contraceptive methods in patients with reproductive potential and negative pregnancy test for women before study entry; and written informed consent.

After this trial began, evidence of excessive pemetrexed-related toxicity in some patients treated in other studies was linked to folic acid and vitamin B12 deficiency, as measured by an elevated plasma homocysteine level (8) . Thus, after December 10, 1999, all pemetrexed-based trials were amended, and systematic folic acid and vitamin B12 supplementation was provided to all patients.

This study was conducted according to the Helsinki Declaration, and the protocol was approved by each local institutional review board and local ethical review committee.

Drug Administration.
Pemetrexed was supplied as a 40-mg/ml aqueous solution in vials of 200 or 1000 mg of the base compound. The appropriate dose of pemetrexed was added to 100 ml of normal saline for intravenous infusion. Gemcitabine was supplied as a lyophilized powder in 200- or 1000-mg vials. The appropriate dose was prepared with normal saline to make a solution containing approximately 10 mg/ml for intravenous infusion. Chemotherapy was given on a 3-week schedule and consisted of 1250 mg/m2 gemcitabine over 30 min on days 1 and 8 and 500 mg/m2 pemetrexed over 10 min on day 8, approximately 90 min after the gemcitabine infusion. Dose adjustments within a cycle were as follows: in case of Common Toxicity Criteria Version 2.0 (18) grade 3/4 neutropenia, thrombocytopenia, or nonhematological toxicity (except grade 3 transaminase elevation) after day 1, the day 8 doses were held until resolution of the toxicity, and pemetrexed and gemcitabine were given at full dose in case of a grade 3 toxicity and at 50% reduced dose in case of a grade 4 toxicity. No dose escalation was allowed after a dose reduction for the remainder of the study. The next cycle was not initiated until 14 days had elapsed from the administration of a delayed day 8 dose and until all toxicities resolved. Treatment could be delayed up to 35 days from the day 1 dose to allow a patient sufficient time to recover from all toxicities. If a further cycle could not be given by day 35, the patient was discontinued from study. For subsequent cycles, pemetrexed and gemcitabine doses were adjusted according to neutrophil and platelet nadir counts or maximum nonhematological toxicity from the preceding cycle. Treatment was interrupted for a persistent drop of creatinine clearance under 45 ml/min or the appearance of a clinically significant effusion. Beginning on December 10, 1999, folic acid (350–1000 µg/day orally) and vitamin B12 (1000 µg) i.m. every 9 weeks became mandatory, starting 1 to 2 weeks before initiation of chemotherapy. Dexamethasone (4 mg or equivalent) was given orally twice daily the day before, the day of, and the day after pemetrexed infusion to prevent rash. Antiemetic treatment with a 5HT3 antagonist and dexamethasone was recommended before each chemotherapy infusion. Dexamethasone was recommended for up to 2 days after the infusion. Salicylates or other nonsteroidal anti-inflammatory agents were interrupted 2 days before (5 days for long- acting agents), the day of, and 2 days after pemetrexed infusion to avoid any interaction with renal function.

Measurement of Study End Points.
This multicenter study had response rate as the primary end point, and the Simon optimum sequential two-stage design was used (19) . In stage 1, at least 7 of 30 enrolled patients had to have an objective tumor response to proceed to stage 2, where 30 additional patients were to be treated, for a total of 60 patients.

All patients who received one dose of chemotherapy were assessable for toxicity. A clinical and laboratory assessment was performed weekly, and toxicities were graded according to Common Toxicity Criteria. Within 3 weeks before the first cycle, tumor measurements were performed by computed tomography scan or magnetic resonance imaging. The same method of measurement was performed before every other cycle of therapy. Confirmation of response was performed 3–4 weeks after the first evidence of response. Patients were evaluable for response if they had a baseline exam and at least one follow-up exam and had received at least one cycle of chemotherapy. All sites with measurable lesions were followed for response. Measurements of unidimensional (i.e., single largest dimension) and bidimensional lesions (i.e., the product of the largest diameter and its largest perpendicular) were summed at each assessment, and the best response on study was recorded. A complete response required the disappearance of all clinical and radiological evidence of tumor for at least 3–4 weeks. A partial response required a ≥50% decrease in the sum of the products of the diameters of all measurable lesions for at least 3–4 weeks. Appearance of any new lesion or a ≥25% increase in the sum of the products of the diameters of measurable lesions compared with the smallest sum constituted progressive disease. Stable disease was a tumor decrease less than a partial response and a tumor increase less than progressive disease. Overall survival was defined as the time from study entry to the date of death or last follow-up. Progression-free survival was defined as the time from study entry until the date of disease progression or death from any cause or the date of last follow-up. Response duration was defined as the time of a complete response or partial response until disease progression. All survival estimates were calculated by the Kaplan-Meier method (20) .

Before each cycle, symptoms and quality of life data were collected with the Lung Cancer Symptom Scale (LCSS), as reported by patients and investigators (21) . The patient LCSS items are assessed as 100-mm visual analog scales, and scores were reported as 0 to 100, with 0 representing the best score. Clinically meaningful changes were defined as ≥10-mm changes from baseline that were maintained for at least two cycles. Patients were considered symptomatic if the baseline assessment was ≥10 mm. Observer LCSS scores were reported on 5-point categorical scales, and clinically meaningful changes were defined as ≥1-point changes from baseline that were maintained for at least two cycles. Patients with baseline assessment and at least one on-study assessment were evaluable for each of the LCSS analyses. Symptoms were classified as improved, worsened, or stable, based on the pattern of change; symptoms for patients without a confirmatory assessment were classified as unknown.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients.
From August 1999 to May 2001, 72 patients were considered for inclusion and signed informed consent. After fulfillment of all baseline exams, 11 patients did not meet the inclusion criteria (7 had inadequate organ function, 1 did not have histological/cytologic confirmation, 1 had inadequate performance status, 1 had excess weight loss, and 1 had both inadequate organ function and performance status), and 1 patient withdrew consent. The demographic and disease characteristics of the 60 eligible patients are listed in Table 1Citation . Among the 60 eligible patients, 47 received vitamin supplementation throughout their course of therapy, 10 received supplementation during part of their therapy, and 3 completed the study before vitamin supplementation was initiated.


View this table:
[in this window]
[in a new window]
  		Table 1 Patient and tumor characteristics

 
Drug Administration.
A total of 229 cycles were administered (median, 4; range, 1–12). Thirty-two patients (53.3%) received full doses of chemotherapy, 23 patients (38.3%) had dose reductions, and 5 patients (8.3%) had one omitted dose. Dose reduction was required in a total of 40 cycles (17.5%), 20 (50.0%) occurring at cycle 2, 6 occurring at cycle 3, 7 occurring at cycle 4, 3 occurring at cycle 5, and 1 each occurring at cycles 6, 9, 11, and 12. Reasons for dose reduction included neutropenia (82.5%), febrile neutropenia (7.5%), leukopenia (5.0%), and fatigue (5.0%). A dose delay was required in 28 patients (46.7%) and in 45 cycles (19.7%) . For pemetrexed, the theoretical dose intensity was 166.7 mg/m2/week, and the actual mean dose intensity received was 145.4 mg/m2/week, representing a relative dose intensity of 87.2%. For gemcitabine, the theoretical dose intensity was 833.3 mg/m2/week, and the actual mean dose intensity received was 644.0 mg/m2/week, representing a relative dose intensity of 77.3%.

Antitumor Activity.
Fifty-eight patients were evaluable for tumor response (seven had baseline computed tomography scans performed within 28 days of initiation of chemotherapy, instead of 21 days as defined by the protocol). Two of the enrolled patients were not evaluable: one patient had a baseline computed tomography scan done 42 days before treatment; and the other had no baseline computed tomography scan available. No patient had a complete response, but 9 patients (7 of them from the 30 patients in stage I of the trial) had a confirmed partial response, for an overall response rate of 15.5% [95% confidence interval (CI), 7.3–27.5%]. Twenty-nine patients (50.0%) had stable disease, 12 patients (20.7%) had progressive disease, and 8 patients (13.8%) were not evaluated (6 patients went off study before tumor evaluation, and 2 patients did not have a subsequent measure of same lesions recorded at baseline). Therefore, 38 of the evaluable patients (65.5%) had either a partial response or stable disease. Responses were seen in lung, lymph nodes, liver, soft tissue, and pleura. Thirty-three patients received post-study chemotherapy, primarily platinum-based combination therapy. Median overall survival of all 60 patients was 10.1 months (95% CI, 7.9–13.0 months); median overall survival was 13.8 months (95% CI, 6.7–21.7 months) for partial response patients, 13.6 months (95% CI, 10.1–23.7 months) for stable disease patients, and 4.9 months (95% CI, 3.4–8.6 months) for progressive disease patients. The 1- and 2-year overall survival rates were 42.6% and 18.5%, respectively (see Fig. 1Citation ). Median progression-free survival was 5.0 months (95% CI, 3.5–6.3 months; see Fig. 2Citation ). Median duration of response was 3.3 months (95% CI, 2.7–7.1 months).



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1. Kaplan-Meier estimates for overall survival of all 60 patients.

 


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 2. Kaplan-Meier estimates for progression-free survival of all 60 patients.

 
Lung Cancer Symptom Scale.
Fifty-nine patients completed the patient LCSS at baseline. The percentage of patients considered symptomatic were as follows: anorexia, 63.7%; fatigue, 75.9%; cough, 67.2%; dyspnea, 83.1%; hemoptysis, 13.8%; and pain, 57.6%. Rates reported on the observer LCSS were similar. Fifty-five patients were included in at least one of the patient LCSS analyses. The results of the symptom items are displayed in Fig. 3Citation . Most patients reported their symptoms as stable or improved. The highest rates of improvement were seen with anorexia, cough, and pain. The majority of patients reported no hemoptysis at baseline, so they had no opportunity to improve. The highest rate of symptoms worsening was seen with fatigue. Similar results were seen with the observer LCSS. For the patient LCSS summary items (symptom distress, interference with activity level, and global quality of life), most patients reported these as stable or improved. Patients with a partial response were more likely to be classified as improved than stable for each of the LCSS items.



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 3. Summary of the changes in the patient LCSS. To be included in the analysis, patients must have had baseline and at least one post-baseline on-study assessment; patients not presented did not meet criteria for evaluation or were classified as "unknown."

 
Toxicity.
All 60 patients were assessable for toxicity. Hematological toxicities by worst grade for all patients are listed in Table 2Citation . Anemia was generally mild, with 9 patients (15.0%) requiring a blood transfusion. Grade 3 and 4 neutropenia was observed in 28.3% and 33.3% of the patients, respectively, and 9 patients (15.0%) experienced febrile neutropenia. Only 3 patients (5.0%) had grade 3/4 thrombocytopenia. There was no evidence of any cumulative hematological toxicity.


View this table:
[in this window]
[in a new window]
  		Table 2 Hematological toxicity (N = 60)

 
A summary of nonhematological and biochemical toxicity is listed in Table 3Citation . The regimen was generally well tolerated, with no grade 3/4 nausea, vomiting, or sensory neuropathy. Pemetrexed-related skin rash was frequent, occurring in 23 patients (38.3%), but only 2 cases (3.3%) were grade 3. Fatigue was the most frequent nonhematological toxicity. Grade 3 fatigue occurred in 14 patients (23.3%) after a median of 3 cycles and did not appear to be related to either age or gender. One patient on long-term corticosteroids for severe lung dyspnea was diagnosed with pneumocyctis carinii pneumonia at cycle 3, and two additional patients experienced documented pneumonitis of noninfectious origin. One patient experienced grade 4 diarrhea requiring hospitalization. Two patients developed pulmonary emboli, which were judged nonrelated to study medication; one resulted in death at cycle 1, and the other developed during a hospitalization for febrile neutropenia. There were no deaths attributed to chemotherapy treatment. Seven patients experienced alopecia; all but one were grade 1. Other toxicities were rare and generally mild. One patient with a history of past and present alcoholism had a grade 4 hyperbilirubinemia due to an underlying liver disorder and went off therapy at cycle 3.


View this table:
[in this window]
[in a new window]
  		Table 3 Nonhematological and biochemical toxicity (N = 60)

 
Vitamin Supplementation.
Because vitamin supplementation was complete for 47 patients, partial for 10 patients, and absent for 3 patients, we examined whether vitamin supplementation had an effect on the clinical outcome and rate of toxicities. No numerical difference (data not shown) was noticed for the response rate, overall survival, LCSS scores, median number of chemotherapy cycles administered, or toxicity rates.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study was designed to confirm preclinical data suggesting synergistic activity of pemetrexed and gemcitabine and to evaluate both clinical activity and tolerance of this regimen in the treatment of advanced NSCLC. The most accepted end point of patient benefit in advanced lung cancer trials is overall survival. Although there is heterogeneity in the patients enrolled in different clinical trials, the heterogeneity tends to be least in trials of chemo-naive patients and in multicenter trials. Most Phase II and III trials of standard doublet chemotherapy combinations in advanced, chemo-naive NSCLC patients show median survival times of 8–10 months. In this trial, the median survival was 10.1 months. The 1-year survival rate was 43%, the 2-year survival rate was 19%, and the 3-year survival rate was 11%. These results compare favorably with studies with the most active doublet combinations in the literature.

The time to progression (TTP) or progression-free survival is another well-accepted end point in advanced lung cancer trials. The TTP is not influenced by subsequent therapies given after progression. In most multicenter trials of double chemotherapy combinations in advanced, chemo-naive NSCLC patients, the median TTP is 4–5 months. Generally, patient survival is about twice the duration of the median TTP. In some Phase II trials in which survival has been considerably more than twice the TTP, subsequent Phase III trials have failed to confirm patient benefit. In this trial, the median TTP was 5.0 months, which was approximately half of the overall median survival. This median TTP compares favorably with other doublet combinations in the literature.

Response rates in advanced NSCLC have not always correlated well with patient survival and are thus not accepted as definitive evidence of patient benefit by United States regulatory agencies. In this study, the objective response rate was 15.5%, and the disease stabilization rate was 50%. This response rate is somewhat lower than that reported in many trials of other active doublet combinations (20–30%). The 21% rate of disease progression compares more favorably with results from other active doublets. Otherwise, there is not a clear explanation for the lower than anticipated response rate.

Recently, a new end point of clinical benefit has emerged in the management of advanced NSCLC. As in our study, it has been seen that chemotherapy regimens with modest response profiles may be associated with prolonged survival. Carboplatin, for instance, was quoted with a low 9% response rate but was associated with longer survival than multidrug regimens (22) . As demonstrated for single-agent topotecan, patients who achieved a stabilization of their disease have an overall survival identical to that of patients with a partial response (23) . In our study, two-thirds of patients achieved either partial response or stable disease, and their median overall survival was identical (13.8 months for partial response patients and 13.6 months for stable disease patients). Most of these patients also experienced symptom improvement or stabilization.

Although second-line therapies can produce a small improvement in survival, the influence of second-line chemotherapy on survival in this study is not possible to evaluate (24) . Assessment of clinical benefit brought by new chemotherapy should not be restricted to an evaluation of response rate and duration of survival but should also be balanced by measures of treatment-related toxicities, disease-related symptoms, and quality of life (25) . Recently, the results of a randomized study comparing docetaxel with pemetrexed in the second-line setting were published (26) . Pemetrexed treated patients had equivalent efficacy, as evidenced by response rates, time to progression, and survival, but with significantly reduced rates of hematological and nonhematological toxicity.

Assessment of lung cancer-related symptoms revealed improvements in pain, cough, and anorexia and worsening of fatigue. Evaluation of these end points is limited by the small number of patients symptomatic at baseline and by the lack of a comparison in the setting of a Phase II trial.

The pemetrexed-gemcitabine regimen was well tolerated in our experience. The only significant grade 3/4 clinical toxicities encountered in >10% of the patients were fatigue and febrile neutropenia. Fifty percent of the dose reductions occurred at cycle two. Cumulative myelosuppression was not observed. There were no severe cases of anorexia, edema, fever, or stomatitis. The only case of severe diarrhea occurred in a patient with an elevated homocysteine level. The number of patients who completed or began treatment without vitamin supplementation is too small in this study for a meaningful comparison of supplemented versus nonsupplemented patients. However, folic acid and vitamin B12 supplementation has been shown to dramatically reduce the incidence of grade 3/4 hematological and nonhematological toxicities in other studies (27, 28, 29) . Because nearly all patients received vitamin supplementation, changes in dose or schedule would be required to reduce the rates of neutropenia.

The utility of cisplatin-free combinations in the treatment of advanced NSCLC is still a matter of debate. There is no question that cisplatin is currently the drug of choice for metastatic NSCLC (30 , 31) . Nevertheless, some plateau in the overall survival has been reached with the use of cisplatin-based combinations (32, 33, 34, 35, 36) . The many toxicities of cisplatin, including severe nausea and vomiting, renal toxicity often requiring hospitalization for intravenous hydration, and long-lasting ototoxicity and neuropathy, are all detrimental to the patient’s quality of life. Furthermore, cisplatin resistance has been found to be associated with elevated excission repair cross-complement group 1 (ERCC1) mRNA levels in tumor tissue (37 , 38) . High ERCC1 level has also been associated with shorter survival in NSCLC patients treated with gemcitabine plus cisplatin (39) . Theoretically, NSCLC patients with high levels of ERCC1 could benefit more from effective non-platinum-based cytotoxic therapy.

Other Phase II studies of cisplatin-free regimens in NSCLC have recently been reported. The combination of gemcitabine and vinorelbine has been investigated in previously treated and untreated patients with stage IIIb and IV disease (40) . In the untreated group, 16 of 42 patients (36%) experienced a partial response, median overall survival was 10.1 months, and 1- and 2-year survival was 42.9% and 31.6%. A randomized Phase II study in untreated advanced NSCLC of gemcitabine plus irinotecan or docetaxel has been conducted and reported by the Cancer and Leukemia Group B (41) . In this study, gemcitabine and irinitoecan produced an overall response rate of 12.8%, and gemcitabine and docetaxel produced an overall response rate of 23.1%. Median overall survival was 7.95 months and 12.8 months, respectively. Estimated 1-year survival was 23% and 51%, respectively.

To move beyond the apparent plateau in NSCLC, cytotoxic agents are being used in combination with agents having novel mechanisms of action. An example of this is the study of cisplatin, vinorelbine, and bexarotene, a novel retinoid X receptor agent, in advanced NSCLC. This regimen produced an overall response rate of 25%, a median survival time of 14 months, and 1-year, 2-year, and projected 3-year survival rates of 61%, 32%, and 30%, respectively. This apparent advance is encouraging, but due to the presence of cisplatin, this regimen would not be a treatment option for all patients. An effective, platinum-free cytotoxic regimen to be combined with such a novel agent is still needed.

Pemetrexed has now clearly demonstrated antitumor activity against NSCLC, either as a single agent or in association with cisplatin or gemcitabine (7 , 9 , 16 , 26 , 42) . Evidence for non-cross-resistance of pemetrexed in NSCLC has been suggested by its activity in cisplatin-pretreated patients (42) . Combination studies associating pemetrexed with other active agents, such as paclitaxel, docetaxel, irinotecan, vinorelbine, and carboplatin, are being pursued (5) . Antitumor activity of these new regimens is awaited to further confirm the role of pemetrexed in the treatment of NSCLC.

Selection of day 8 pemetrexed administration was based on Phase I data of Adjei et al. (16) . However, those data were produced without vitamin supplementation. A randomized, three-arm study of pemetrexed and gemcitabine is currently being conducted that should further define the optimal schedule for this combination regimen. Another Phase I/II study in NSCLC is testing the administration of these two agents on a biweekly schedule. In addition, results from a Phase I and pharmacokinetic study testing the necessity for the 90-min delay between administrations should be available in the near future.

Despite the disappointing response rate, this cisplatin-free regimen is characterized by promising overall survival, progression-free survival, and time to progressive disease, which are better indicators of efficacy than response. In addition, this regimen offers good tolerance and convenient outpatient administration. Our study showed the activity of the pemetrexed-gemcitabine combination in advanced NSCLC. Its 10.1-month median survival warrants further evaluation in a randomized fashion against the current platinum-based standards, once the optimal administration schedule is established.


   ACKNOWLEDGMENTS
 
We thank Patrick McAndrews and Donna L. Miller for assistance in preparing the manuscript.


   FOOTNOTES
 
Grant support: Supported by Eli Lilly and Company (Indianapolis, IN). T. Le Chevalier, P. Bunn, and D. Ettinger have acted as consultants of Eli Lilly and Company.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Thierry Le Chevalier, Department of Medicine, Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif Cedex, France. Phone: 33-142-114322; Fax: 33-142-115219; E-mail: tle-che{at}igr.fr

Received 2/ 4/04; revised 4/ 6/04; accepted 4/13/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Chen VJ, Bewley JR, Gossett L, et al Activity of LY231514 against several enzymes in the folate-dependent pathways. Proc Am Assoc Cancer Res, 37: 381 1996.
  2. Grindey GB, Shih C, Barnett CJ, et al LY231514, a novel pyrrolopyrimidine antifolate that inhibits thymidylate synthase (TS). Proc Am Assoc Cancer Res, 33: 411 1992.
  3. Shih C, Chen VJ, Gossett LS, et al LY231514, a pyrrolo[2,3-D]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res, 57: 1116-23, 1997.[Abstract/Free Full Text]
  4. Rinaldi DA, Kuhn JG, Burris HA, et al A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol, 44: 372-80, 1999.[CrossRef][Medline]
  5. Adjei AA. Pemetrexed (Alimta®): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther, 3: 145-56, 2003.[CrossRef][Medline]
  6. Cripps C, Burnell M, Jolivet J, et al Phase II study of first-line LY231514 (multi-targeted antifolate) in patients with locally advanced or metastatic colorectal cancer: an NCIC Clinical Trials Group study. Ann Oncol, 10: 1175-9, 1999.[Abstract/Free Full Text]
  7. Rusthoven JJ, Eisenhauer E, Butts C, et al Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: a phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 17: 1194 1999.[Abstract/Free Full Text]
  8. Niyikiza C, Baker SD, Seitz DE, et al Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther, 1: 545-52, 2002.[Abstract/Free Full Text]
  9. Clarke SJ, Abratt R, Goedhals L, et al Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non-small-cell lung cancer. Ann Oncol, 13: 737-41, 2002.[Abstract/Free Full Text]
  10. Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anticancer Drugs, 6(Suppl 6): 7-13, 1995.
  11. Gatzemeier U, Shepherd FA, LeChevalier T, et al Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study. Eur J Cancer, 32A: 243-8, 1996.
  12. Manegold C, Bergman B, Chemaissani A, et al Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer. Ann Oncol, 8: 525-9, 1997.[Abstract/Free Full Text]
  13. Cardenal F, Lopez-Cabrerizo MP, Anton A, et al Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol, 17: 12-8, 1999.[Abstract/Free Full Text]
  14. Guchelaar HJ, Richel DJ, van Knapen A. Clinical, toxicological and pharmacological aspects of gemcitabine. Cancer Treat Rev, 22: 15-31, 1996.[CrossRef][Medline]
  15. Adjei AA. Pemetrexed: a multitargeted antifolate agent with promising activity in solid tumors. Ann Oncol, 11: 1335-41, 2000.[Abstract/Free Full Text]
  16. Adjei AA, Erlichman C, Sloan JA, et al Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors. J Clin Oncol, 18: 1748-57, 2000.[Abstract/Free Full Text]
  17. Shargel L, Yu AB. Dosage adjustment in renal disease Shargel L Yu AB eds. . Applied biopharmaceutics and pharmacokinetics, 2nd ed. p. 305-30, Appleton-Century-Crofts Norwalk, CT 1985.
  18. . National Cancer Institute: common toxicity criteria (version 2), Division of Cancer Treatment and Diagnosis, National Cancer Institute Bethesda, MD 1999.
  19. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials, 10: 1-10, 1989.[Medline]
  20. Kaplan EL, Meier P. Non-parametric estimation of incomplete observations. J Am Stat Assoc, 53: 457-81, 1958.[CrossRef]
  21. Hollen PJ, Gralla RJ, Kris MG, et al Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Psychometric assessment of the Lung Cancer Symptom Scale. Cancer (Phila), 73: 2087-98, 1994.
  22. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol, 7: 1602-13, 1989.[Abstract]
  23. Cesano A, Lane SR, Ross GA, Fields SZ. Stabilization of disease as an indicator of clinical benefit associated with chemotherapy in non-small cell lung cancer patients. Int J Oncol, 17: 587-90, 2000.[Medline]
  24. Huisman C, Smit EF, Giaccone G, Postmus PE. Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol, 18: 3722-30, 2000.[Abstract/Free Full Text]
  25. Gridelli C, Perrone F, Nelli F, Ramponi S, De Marinis F. Quality of life in lung cancer patients. Ann Oncol, 12(Suppl 3): S21-5, 2001.
  26. Hanna N, Shepherd FA, Fossella FV, et al Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol, 22: 1589-97, 2004.[Abstract/Free Full Text]
  27. Bunn PA, Jr, Paoletti P, Niyikiza C, et al Vitamin B12 and folate reduce toxicity of AlimtaTM (pemetrexed disodium, LY231514, MTA), a novel antifolate/antimetabolite. Proc Am Soc Clin Oncol, 20: 76a 2001.
  28. Scagliotti GV, Shin DM, Kindler HL, et al Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol, 21: 1556-61, 2003.[Abstract/Free Full Text]
  29. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al A phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol, 21: 2636-44, 2003.[Abstract/Free Full Text]
  30. Johnson DH. Evolution of cisplatin-based chemotherapy in non-small cell lung cancer: a historical perspective and the Eastern Cooperative Oncology Group experience. Chest, 117: 133S-7S, 2000.[Abstract/Free Full Text]
  31. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-Small Cell Lung Cancer Collaborative Group. Br Med J, 311: 899-909, 1995.[Abstract/Free Full Text]
  32. Schiller JH, Harrington D, Belani CP, et al Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 346: 92-8, 2002.[Abstract/Free Full Text]
  33. Kelly K, Crowley J, Bunn PA, Jr, et al Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol, 19: 3210-8, 2001.[Abstract/Free Full Text]
  34. Scagliotti G, De Marinis F, Rinaldi M, et al Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol, 20: 4285-91, 2002.[Abstract/Free Full Text]
  35. Fossella F, Pereira JR, von Pawel J, et al Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol, 21: 3016-24, 2003.[Abstract/Free Full Text]
  36. Smit EF, van Meerbeeck JP, Lianes P, et al Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group–EORTC 08975. J Clin Oncol, 21: 3909-17, 2003.[Abstract/Free Full Text]
  37. Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Investig, 94: 703-8, 1994.
  38. Metzger R, Leichman CG, Danenberg KD, et al ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol, 16: 309-16, 1998.[Abstract/Free Full Text]
  39. Lord RV, Brabender J, Gandara D, et al Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res, I: 2286-91, 2002.
  40. Herbst RS, Khuri FR, Lu C, et al The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: potential for decreased toxicity and combination with biological therapy. Cancer (Phila), 95: 340-53, [erratum in Cancer (Phila) 2003;97:1367]. 2002.
  41. Rocha Lima CM, Rizvi NA, Zhang C, et al Randomized phase II trial of gemcitabine plus irinotecan or docetaxel in stage IIIB or stage IV NSCLC. Ann Oncol, 15: 410-8, 2004.[Abstract/Free Full Text]
  42. Smit EF, Mattson K, von Pawel J, et al ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study. Ann Oncol, 14: 455-60, 2003.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JCOHome page
G. R. Simon, C. F. Verschraegen, P. A. Janne, C. J. Langer, A. Dowlati, S. M. Gadgeel, K. Kelly, G. P. Kalemkerian, A. M. Traynor, G. Peng, et al.
Pemetrexed Plus Gemcitabine As First-Line Chemotherapy for Patients With Peritoneal Mesothelioma: Final Report of a Phase II Trial
J. Clin. Oncol., July 20, 2008; 26(21): 3567 - 3572.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Y. Seiwert, P. P. Connell, A. M. Mauer, P. C. Hoffman, C. M. George, L. Szeto, R. Salgia, K. E. Posther, B. Nguyen, D. J. Haraf, et al.
A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non-Small Cell Lung or Esophageal Cancer
Clin. Cancer Res., January 15, 2007; 13(2): 515 - 522.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. Hendricksen, P. M.J. Moonen, A. G. van der Heijden, J. Molkenboer-Kuenen, C. A. Hulsbergen-van de Kaa, and J. A. Witjes
Potential and Toxicity of Intravesical Pemetrexed: a Preclinical Study in Pigs
Clin. Cancer Res., April 15, 2006; 12(8): 2597 - 2601.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
C. X. Ma, S. Nair, S. Thomas, S. J. Mandrekar, D. A. Nikcevich, K. M. Rowland, T. R. Fitch, H. E. Windschitl, S. L. Hillman, S. E. Schild, et al.
Randomized Phase II Trial of Three Schedules of Pemetrexed and Gemcitabine As Front-Line Therapy for Advanced Non-Small-Cell Lung Cancer
J. Clin. Oncol., September 1, 2005; 23(25): 5929 - 5937.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
S. Dubey and J. H. Schiller
Three Emerging New Drugs for NSCLC: Pemetrexed, Bortezomib, and Cetuximab
Oncologist, April 1, 2005; 10(4): 282 - 291.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Monnerat, C.
Right arrow Articles by Ettinger, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Monnerat, C.
Right arrow Articles by Ettinger, D. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online