Randomized Phase II Trial of Three Schedules of Pemetrexed and Gemcitabine As Front-Line Therapy for Advanced Non–Small-Cell Lung Cancer
http://www.100md.com
《临床肿瘤学》
the Department of Oncology and Medicine, Mayo Clinic and Foundation, Rochester
Duluth Community Clinical Oncology Program (CCOP), Duluth
CentraCare Clinic, St Cloud, MN
Geisinger Medical Center, Danville, PA
Illinois Oncology Research Association CCOP, Peoria
Carle Cancer Center CCOP, Urbana, IL
Scottsdale CCOP, Scottsdale, AZ
Eli Lilly & Company, Indianapolis, IN
ABSTRACT
PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non–small-cell lung cancer.
PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8.
RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms.
CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.
INTRODUCTION
Non–small-cell lung cancer (NSCLC) is the leading cause of deaths related to cancer.[1] Despite the best available treatment regimens, prognosis for patients with locally advanced NSCLC not amenable to combined-modality therapy or metastatic disease is poor, with a median survival of 6 to 9 months. Several two-drug combinations, including docetaxel plus cisplatin, paclitaxel plus cisplatin, paclitaxel plus carboplatin, paclitaxel plus gemcitabine, cisplatin plus vinorelbine, gemcitabine plus cisplatin, docetaxel plus gemcitabine, and gemcitabine plus vinorelbine, seem to provide similar efficacy in randomized clinical trials.[2-7] The dismal outlook for patients with advanced lung cancer despite the best available therapy has prompted a search for new chemotherapeutic agents and combination regimens.
Pemetrexed is a novel multitargeted antifolate and inhibits a number of enzymes in the purine and thymidine synthesis pathways including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.[8,9] It has broad cytotoxic activity in a variety of tumor types including NSCLC[10,11] and breast,[12-14] colorectal,[15,16] head and neck,[17] gastric,[18] bladder,[19] cervix,[20] renal,[21] and pancreas cancers.[22] For chemotherapy-naive patients with advanced NSCLC, pemetrexed demonstrated an overall response rate (complete response [CR] + partial response [PR]) from 15.8% to 23.3% and median survival times of 7.2 and 9.2 months.[10,23] In the second-line setting for patients with advanced NSCLC, pemetrexed showed equivalent efficacy compared with docetaxel, with a response rate of 8.8%, but with significantly fewer side effects.[24] This resulted in the accelerated approval of pemetrexed by the US Food and Drug Administration as a single agent for patients with locally advanced or metastatic NSCLC after one prior chemotherapy.[25] The toxicities of pemetrexed are generally mild, and the drug is usually well tolerated. Myelosuppression, skin rash, and mucositis are the major toxicities observed, with neutropenia being the primary dose-limiting toxicity.[26-29]
Gemcitabine is a pyrimidine antimetabolite[30] that has broad activity in a variety of solid tumors.[31] Single-agent gemcitabine has a response rate of approximately 20% in front-line NSCLC. The toxicity of gemcitabine is mild, with myelosuppression being the dose-limiting toxicity. Preclinical studies have shown sequence-dependent cytotoxic synergy between gemcitabine and pemetrexed. However, conflicting data exist with regard to the optimum sequencing of these two agents. Clonogenic survival studies using HCT-8 colon carcinoma cells indicated cytotoxic synergy when gemcitabine exposure preceded that of pemetrexed, whereas an antagonistic effect occurred when pemetrexed was administered before gemcitabine.[32,33] On the basis of these results, a phase I study was conducted testing two different schedules of this combination with gemcitabine administered on days 1 and 8 and pemetrexed administered on day 1 (schedule 1) or 8 (schedule 2) 90 minutes after completion of the gemcitabine infusion.[32-34] Schedule 2 was better tolerated and was recommended for further study at doses of gemcitabine 1,250 mg/m2 and pemetrexed 500 mg/m2. However, a recent report demonstrated synergistic cytotoxicity for the opposite sequence of pemetrexed and gemcitabine in HT29 colon cancer cell lines and xenografts.[35] The primary goal of this phase II study was to evaluate the tumor response rate and toxicity of three different treatment schedules of gemcitabine and pemetrexed as front-line therapy in patients with advanced NSCLC and to identify the optimal schedule for future studies.
PATIENTS AND METHODS
Patient Selection
Patients with histologic or cytologic evidence of stage IIIB NSCLC who were not amenable to combined-modality therapy or stage IV metastatic NSCLC were eligible for this study. Other eligibility criteria included age 18 years; measurable disease; Eastern Cooperative Oncology Group performance status less than 2; prior radiotherapy to a different site must have been completed 4 weeks before random assignment with recovery from all acute toxic effects; adequate bone marrow (platelets 100 x 109 cells/L, absolute neutrophil count 1.5 x 109 cells/L, and hemoglobin 9 g/dL), hepatic (total bilirubin 1.5x the upper limit of normal; and AST, ALT, and alkaline phosphatase 3x the upper limit of normal or 5x the upper limit of normal if metastatic disease was present in the liver), and renal (estimated creatinine clearance 45 mL/min) functions; and a life expectancy of 3 months.
The exclusion criteria were as follows: inability to take folic acid or vitamin B12 supplementation; 4 weeks from major surgery to registration; prior chemotherapy, biologic therapy, or genetic therapy for lung cancer; radiation therapy to more than 25% of the bone marrow or prior radiation to the whole pelvis or radiation to the primary disease; uncontrolled infection or any chronic debilitating disease; clinically significant effusions (pericardial, pleural, and ascites), unless these could be drained; documented brain metastasis; aspirin or nonsteroidal anti-inflammatory agent ingestion 2 days before (5 days for long-acting agents such as piroxicam) plus the day of and 2 days after the day of pemetrexed administration; prior malignancy (except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancer from which the patient had been disease free for at least 5 years); pregnant or nursing women; men or women of childbearing potential or their sexual partners not using adequate protection; and weight loss 10% in last 6 weeks.
This trial was approved by the institutional review boards of all treatment centers. Written informed consent was obtained according to federal and institutional guidelines.
Experimental Treatment
Pemetrexed and gemcitabine were supplied as lyophilized powder forms by Eli Lilly & Company (Indianapolis, IN) through the North Central Cancer Treatment Group Coordinating Center Pharmacy. These agents were then reconstituted in sodium chloride solution before use. Patients were randomly assigned to receive one of the three different schedules of pemetrexed 500 mg/m2 (day 1 or 8) plus gemcitabine 1,250 mg/m2 intravenously (days 1 and 8) every 21 days. Schedule A was pemetrexed followed 90 minutes later by gemcitabine on day 1 plus gemcitabine on day 8; schedule B was gemcitabine followed 90 minutes later by pemetrexed on day 1 plus gemcitabine on day 8, and schedule C was gemcitabine on day 1 plus pemetrexed followed 90 minutes later by gemcitabine on day 8. In each schedule, administration of pemetrexed and gemcitabine was separated by approximately 90 minutes based on preclinical data.[32] Patients were administered 350 to 600 μg of oral folic acid daily and 1,000 μg of intramuscular vitamin B12 every 9 weeks starting 7 to 14 days before the first dose and until 3 weeks after the last dose of pemetrexed. Dexamethasone (4 mg) was administered orally every 12 hours on the day before, day of, and day after all doses of pemetrexed. Antiemetics were administered before chemotherapy on days 1 and 8 according to institutional guidelines. All patients were evaluated after two cycles of treatment, which was continued to a maximum of eight cycles or until disease progression, unacceptable toxicity, or patient refusal occurred. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2).
Clinical Care of Patients
Complete patient histories, physical examinations, CBC counts, chemistries (AST, ALT, alkaline phosphatase, total bilirubin, creatinine, and blood urea nitrogen), calculated creatinine clearance, homocysteine level, and chest x-ray were performed at baseline and, with the exception of chest x-ray, before each course of treatment. Bone scans, positron emission tomography scans, or magnetic resonance imaging of the brain were performed at the discretion of the treating physician if clinically indicated. CBC count was repeated weekly while patients were on study. Radiologic studies (roentgenograms, bone scans, and computed tomography scans or magnetic resonance imaging) were performed at baseline and after every two cycles of therapy to assess tumor response, which was defined according to the Response Evaluation Criteria in Solid Tumors criteria.[36]
Statistical Methods
A single-stage, randomized, phase II study with an interim analysis based on a modified Fleming design was conducted to assess the efficacy and toxicity of three different treatment schedules of pemetrexed in combination with gemcitabine in chemotherapy-na?ve patients with advanced or metastatic NSCLC.[37] Accrual was not suspended for the interim analysis evaluation; however, additional patients enrolled onto any schedule during this time were not included in the interim analysis. The two stratification factors were stage (IIIB v IV) and performance status (0 v 1). Patients were randomly assigned using a dynamic allocation procedure such that the marginal distributions of these stratification factors were balanced across the three schedules. The primary efficacy end point was the confirmed tumor response rate in each schedule. A treatment success was defined as either a CR or PR observed on two consecutive evaluations at least 4 weeks apart. This trial was designed to test the null hypothesis that the true treatment success rate in each schedule was at most 0.15 against the alternative that it was at least 0.30. On the basis of the Fleming design, a sample size of 55 patients in each schedule provided 90% power to test this hypothesis, with a two-sided = .10. A schedule was considered promising if at least 12 of the 55 assessable patients had a confirmed response. A planned interim analysis was conducted for each schedule after the first 19 assessable patients were observed for 6 months in that schedule. A regimen was considered promising if three or more confirmed responses were observed in the first 19 assessable patients, and accrual continued. A regimen with less than three confirmed responses was permanently closed to accrual because of lack of efficacy at the time of interim analysis.
Survival time was defined as the time from random assignment to death as a result of any cause. Time to progression (TTP) was defined as the time from random assignment to the date of first documented disease progression. If a patient died without documentation of disease progression, the patient was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude otherwise. In the case of a major treatment violation, the patient was censored for the event of interest on the date of the treatment violation. Any patient starting treatment and not returning for subsequent evaluations was censored for progression on day 1 after treatment. Duration of response was defined as the date from which the patient's objective status was first noted as a CR or PR to the date progression was first documented.
The results for the primary end point of confirmed tumor response rate, which was computed as the number of confirmed CR or PR divided by the total number of assessable patients, are analyzed separately within each schedule. Exact binomial CIs for the true treatment success rate were constructed according to the method of Duffy and Santner.[38] The distribution of TTP and overall survival time was estimated for each schedule using the Kaplan-Meier method.[39] Fisher's exact and 2 tests were used to compare the baseline characteristics and toxicity patterns between the arms. P < .05 was considered statistically significant. All patients were included in the analyses, except those patients who never received study treatment.
RESULTS
Patient Characteristics
A total of 157 patients (schedule A, n = 62; schedule B, n = 32; and schedule C, n = 63) were enrolled between September 2001 and May 2003. Seven patients (schedule A, n = 4; schedule B, n = 1; and schedule C, n = 2) were deemed ineligible because of low creatinine clearances (schedule A, n = 1; schedule C, n = 1), pleural effusions (schedule A, n = 1; never received study treatment), nonmeasurable disease (schedule A, n = 1; never received study treatment), and incorrect histology (schedule A, n = 1; schedule B, n = 1; and schedule C, n = 1; the patient in schedule A never received study treatment). In addition, two patients (one patient each in schedules B and C) never received study treatment, including one patient (schedule B) who had a grade 4 myocardial infarction before treatment started and another patient (schedule C) who had a performance status increase of 2 before study treatment. The baseline characteristics for the 152 assessable patients (excluding the three patients, one patient, and one patient in schedules A, B, and C, respectively, who never received any study treatment) are listed in [Table 1]. A majority of the patients had stage IV disease at the time of enrollment (schedule A, 86%; schedule B, 90%; and schedule C, 85%). The distribution of performance status was balanced across schedules A and C compared with schedule B (performance status of 0 and 1, 52% and 48%, respectively). This imbalance in the stratification factor in schedules A and C versus B is likely a result of the fact that schedule B was stopped early after the interim analysis. No statistically significant differences were observed among the three treatment schedules in the distribution of age, sex, race, and stage. Schedule B had fewer patients with elevated levels of homocysteine compared with schedules A and C (schedules A, B, and C: 17%, 10%, and 24%, respectively; two-sided 2 test, P = .05). The average lengths of follow-up for schedules A, B, and C were 17.1, 19.7, and 15.2 months, respectively ([Table 2]), and a median of five, two, and four cycles of treatment were administered, respectively. All patients were off active treatment at the time of this analysis. The percentages of patients who completed study per protocol in schedules A, B, and C were 20%, 13%, and 19%, respectively. A higher percentage of patients ended treatment early as a result of death, adverse events, and refusal in schedule B compared with schedules A and C (schedules A, B, and C: 24%, 42%, and 18%, respectively; schedule B v A, P = .07; schedule B v C, P = .01). Other follow-up data are listed in [Table 2].
Toxicities
Toxicity was defined as any adverse event deemed at least possibly related to treatment. [Table 3] lists the toxicities for the 152 assessable patients, both overall and by each schedule. Overall, 74% of patients experienced grade 3 and 4 hematologic toxicities, and 62% of patients experienced grade 3 and 4 nonhematologic toxicities. Schedule B had a significantly higher incidence of grade 3 and 4 febrile neutropenia (schedules A, B, and C: 5%, 19%, and 5%, respectively; P = .03). Patients on schedule A experienced less severe toxicity than schedule C (grade 3 and 4 events, 86% v 94%, respectively; grade 4 events, 39% v 48%, respectively); although this was not statistically significant (P = .19 and P = .30, respectively). There was one grade 5 event of pneumonitis in schedule C that was deemed at least possibly related to treatment.
The toxicity analysis was not adjusted for baseline homocysteine levels, although the distribution of baseline homocysteine levels across the three schedules was marginally significant. This is because there was no association between baseline homocysteine levels and occurrence of grade 3 and 4 toxicities across schedules (Cochran-Mantel-Haenszel statistics controlling for schedule; two-sided P = .8).
Hematologic Toxicity
The frequencies of the most common grade 3 and 4 hematologic toxicities (occurring in at least 10 of the 152 assessable patients) are listed in [Table 4] for each schedule. Neutropenia and leukopenia were the most common hematologic toxicities in each schedule (grade 3 and 4 neutropenia in schedules A, B, and C: 64.4%, 64.5%, and 69.4%, respectively; and grade 3 and 4 leukopenia in schedules A, B, and C: 44.1%, 42.0%, and 58.1%, respectively). Thrombocytopenia and anemia occurred less frequently (grade 3 and 4 thrombocytopenia in schedules A, B, and C: 8.5%, 12.9%, and 19.4%, respectively; and grade 3 and 4 anemia in schedules A, B, and C: 10.2%, 9.7%, and 4.8%, respectively). Packed RBC transfusion was required in 11.9% and 4.8% of patients in schedules A and C, respectively.
Nonhematologic Toxicity
The frequencies of the most common grade 3 and 4 nonhematologic toxicities (occurring in at least 10 of the 152 assessable patients) are listed in [Table 5] for each schedule. Among the grade 3 and 4 nonhematologic toxicities, fatigue (schedules A, B, and C: 11.9%, 22.6%, and 16.1%, respectively), dyspnea (schedules A, B, and C: 13.6%, 3.2%, and 11.3%, respectively), and AST/ALT elevation (schedules A, B, and C: 8.5%, 12.9%, and 6.5%, respectively) were the most common. Other nonhematologic toxicities occurring in at least 10 patients included nausea, vomiting, and rash.
Clinical Activity
One hundred fifty-two patients were assessable for response. The response data are listed in [Table 6]. No CR was observed. Schedule B was stopped early after interim analysis because of only one confirmed response in the first 19 assessable patients. Eighteen patients (31%) in schedule A had a confirmed PR; of these responses, 17 were observed in the first 55 patients (95% CI, 20% to 45%), thus meeting the success criteria of at least 12 confirmed responses in the first 55 patients. Only 10 confirmed PRs were observed in schedule C in the first 55 patients; therefore, this schedule failed to meet the cutoff criteria for further study (response rate, 16.1%; 95% CI, 11% to 34%). The median response duration was approximately 173 and 125 days for schedules A and C, respectively. An analysis of sex by response was conducted because there was a higher percentage of males in schedule B compared with schedules A or C (schedules A, B, and C: 53%, 74%, and 61%, respectively). Overall, there was no statistically significant association between sex and response (Cochran-Mantel-Haenszel statistics controlling for schedule; two-sided P = .65). Therefore, the difference in the response rates observed for different treatment schedules is unlikely caused by any effect from sex.
Overall survival (median survival times for patients in schedules A, B, and C: 11.4, 10.3, and 11.8 months, respectively) and TTP (median TTP for schedules A, B, and C: 4.7, 4.1, and 4.4 months, respectively) were similar among the three different schedules. The Kaplan-Meier curves for overall survival and TTP are shown in [Figures 1] and [2], respectively.
DISCUSSION
Patients with advanced NSCLC have a poor prognosis. Compared with best supportive care, systemic chemotherapy is associated with a small survival benefit, adding anywhere from 6 to 10 weeks to the median survival time.[40-42] Combination chemotherapy increases the response rate and prolongs survival when compared with single agents in randomized clinical trials in patients with good performance status.[43,44] Although platinum-based combination chemotherapy regimens are preferred, the survival advantage is modest, at best, when compared with nonplatinum combinations.[45] Currently, there is no single best treatment regimen for advanced NSCLC.
Our randomized, three-arm, phase II study was designed to identify the optimal schedule for the combination of gemcitabine and pemetrexed as front-line therapy for patients with advanced NSCLC. Patients were randomly assigned to receive one of the three different schedules of pemetrexed 500 mg/m2 (day 1 or 8) plus gemcitabine 1,250 mg/m2 intravenously (days 1 and 8) every 21 days with vitamin B12 and folate supplementation. Schedule A, with a response rate of 31%, compared with schedules B and C, with response rates of 6.5% and 16.1%, respectively, was the only arm that met the protocol-defined response criteria for further evaluation. Schedule B was discontinued after interim analysis because of a poor response rate. Regarding toxicities, schedule A resulted in less severe toxicity compared with schedule C. Schedule B, which had the lowest response rate, had the highest incidence of grade 3 and 4 febrile neutropenia (schedules A, B, and C: 5%, 19%, and 5%, respectively). Given the response criteria and the milder toxicity profile, schedule A is recommended for future studies of the combination of pemetrexed and gemcitabine.
The median survival time (schedules A, B, and C: 11.4, 10.3, and 11.8 months, respectively) and TTP (schedules A, B, and C: 4.7, 4.1, and 4.4 months, respectively) were similar among the three schedules, as seen in a number of recent comparative combination studies for advanced NSCLC,[2-7] in which improvement in objective response did not translate to improvement in survival or TTP. A plausible explanation for the similarity in survival in all three schedules may be the fact that a majority of patients (107 of 152 patients; 70%) received one or more subsequent therapies (schedules A, B, and C: 63%, 68%, and 79%, respectively).
The results of our phase II study are consistent with the previous phase I study testing two different schedules of this combination, with gemcitabine administered on days 1 and 8 and pemetrexed administered on day 1 (schedule 1) or 8 (schedule 2).[32-34] Schedule 1 of that phase I study is identical to schedule B of the current phase II study. Schedule 2 of that phase I study is similar to schedule C of the current phase II study, with the exception that pemetrexed was administered before gemcitabine on day 8 in schedule C. In both studies, schedule B yielded intolerable toxicities. In the present study, pemetrexed and gemcitabine were administered with a 90-minute interval between infusions. However, a recent phase IB study from our group of the pharmacokinetics of gemcitabine and pemetrexed in solid tumors demonstrated no pharmacokinetic interaction between the two drugs when administered in rapid sequence.[46] Therefore, it is reasonable to omit the 90-minute delay between the infusions for future studies of pemetrexed with gemcitabine.
Our results in schedule A compare favorably with a recently reported phase II study of the combination of pemetrexed and gemcitabine using a different treatment schedule in a similar patient population.[47] In that study, gemcitabine (1,250 mg/m2) was administered intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8, which is similar to our schedule C with the exception that gemcitabine was administered before pemetrexed on day 8.[47] After the initial accrual of 13 patients, folic acid and vitamin B12 supplementation were added. The efficacy in that study was similar to that seen on schedule C of the present study, with a response rate, overall survival time, and TTP of 15.5%, 10.1 months, and 5.0 months, respectively. Grade 3 and 4 toxicity was neutropenia (61.7%), which is also similar to our schedule C. However, there seemed to be a higher incidence of patients who experienced febrile neutropenia (16.7%), fatigue (23.3%), and elevations of AST (15.0%) and ALT (20.0%) in that study.
This randomized phase II study is the first report in the literature optimizing the administration schedule of the combination of pemetrexed and gemcitabine in the clinical trial setting. This study also demonstrates that the schedule of administration of certain chemotherapy agents may be important in terms of toxicity and, potentially, efficacy. In addition, our study demonstrates that a randomized phase II trial is an appropriate approach to selecting a regimen out of a number of possible regimens to be further studied. Schedule A seemed to have similar efficacy when compared with historical results with third-generation combination regimens including cisplatin/paclitaxel (response rate, overall survival time, and TTP: 21%, 7.8 months, and 3.4 months, respectively), cisplatin/gemcitabine (response rate, overall survival time, and TTP: 22%, 8.1 months, and 4.2 months, respectively), cisplatin/docetaxel (response rate, overall survival time, and TTP: 17%, 7.4 months, and 3.7 months, respectively), and carboplatin/paclitaxel (response rate, overall survival time, and TTP: 17%, 8.1 months, and 3.1 months, respectively) in similar patient populations.[2] Given the efficacy and toxicity profile, future studies aimed at incorporating pemetrexed and gemcitabine, administered as outlined in schedule A, into the therapy of NSCLC are needed.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the followig authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported in part by Public Health Service grant Nos. CA-25224, CA-37404, CA-15083, CA-35448, CA-35113, CA-35269, CA-35195, and CA-60276 from the National Institutes of Health and conducted as a collaborative trial of the North Central Cancer Treatment Group, Mayo Clinic, and Eli Lilly & Company, Indianapolis, IN.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Monnerat C, Le Chevalier T, Kelly K, et al: Phase II study of pemetrexed-gemcitabine combination in patients with advanced-stage non-small cell lung cancer. Clin Cancer Res 10:5439-5446, 2004(Cynthia X. Ma, Suresh Nai)
Duluth Community Clinical Oncology Program (CCOP), Duluth
CentraCare Clinic, St Cloud, MN
Geisinger Medical Center, Danville, PA
Illinois Oncology Research Association CCOP, Peoria
Carle Cancer Center CCOP, Urbana, IL
Scottsdale CCOP, Scottsdale, AZ
Eli Lilly & Company, Indianapolis, IN
ABSTRACT
PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non–small-cell lung cancer.
PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8.
RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms.
CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.
INTRODUCTION
Non–small-cell lung cancer (NSCLC) is the leading cause of deaths related to cancer.[1] Despite the best available treatment regimens, prognosis for patients with locally advanced NSCLC not amenable to combined-modality therapy or metastatic disease is poor, with a median survival of 6 to 9 months. Several two-drug combinations, including docetaxel plus cisplatin, paclitaxel plus cisplatin, paclitaxel plus carboplatin, paclitaxel plus gemcitabine, cisplatin plus vinorelbine, gemcitabine plus cisplatin, docetaxel plus gemcitabine, and gemcitabine plus vinorelbine, seem to provide similar efficacy in randomized clinical trials.[2-7] The dismal outlook for patients with advanced lung cancer despite the best available therapy has prompted a search for new chemotherapeutic agents and combination regimens.
Pemetrexed is a novel multitargeted antifolate and inhibits a number of enzymes in the purine and thymidine synthesis pathways including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.[8,9] It has broad cytotoxic activity in a variety of tumor types including NSCLC[10,11] and breast,[12-14] colorectal,[15,16] head and neck,[17] gastric,[18] bladder,[19] cervix,[20] renal,[21] and pancreas cancers.[22] For chemotherapy-naive patients with advanced NSCLC, pemetrexed demonstrated an overall response rate (complete response [CR] + partial response [PR]) from 15.8% to 23.3% and median survival times of 7.2 and 9.2 months.[10,23] In the second-line setting for patients with advanced NSCLC, pemetrexed showed equivalent efficacy compared with docetaxel, with a response rate of 8.8%, but with significantly fewer side effects.[24] This resulted in the accelerated approval of pemetrexed by the US Food and Drug Administration as a single agent for patients with locally advanced or metastatic NSCLC after one prior chemotherapy.[25] The toxicities of pemetrexed are generally mild, and the drug is usually well tolerated. Myelosuppression, skin rash, and mucositis are the major toxicities observed, with neutropenia being the primary dose-limiting toxicity.[26-29]
Gemcitabine is a pyrimidine antimetabolite[30] that has broad activity in a variety of solid tumors.[31] Single-agent gemcitabine has a response rate of approximately 20% in front-line NSCLC. The toxicity of gemcitabine is mild, with myelosuppression being the dose-limiting toxicity. Preclinical studies have shown sequence-dependent cytotoxic synergy between gemcitabine and pemetrexed. However, conflicting data exist with regard to the optimum sequencing of these two agents. Clonogenic survival studies using HCT-8 colon carcinoma cells indicated cytotoxic synergy when gemcitabine exposure preceded that of pemetrexed, whereas an antagonistic effect occurred when pemetrexed was administered before gemcitabine.[32,33] On the basis of these results, a phase I study was conducted testing two different schedules of this combination with gemcitabine administered on days 1 and 8 and pemetrexed administered on day 1 (schedule 1) or 8 (schedule 2) 90 minutes after completion of the gemcitabine infusion.[32-34] Schedule 2 was better tolerated and was recommended for further study at doses of gemcitabine 1,250 mg/m2 and pemetrexed 500 mg/m2. However, a recent report demonstrated synergistic cytotoxicity for the opposite sequence of pemetrexed and gemcitabine in HT29 colon cancer cell lines and xenografts.[35] The primary goal of this phase II study was to evaluate the tumor response rate and toxicity of three different treatment schedules of gemcitabine and pemetrexed as front-line therapy in patients with advanced NSCLC and to identify the optimal schedule for future studies.
PATIENTS AND METHODS
Patient Selection
Patients with histologic or cytologic evidence of stage IIIB NSCLC who were not amenable to combined-modality therapy or stage IV metastatic NSCLC were eligible for this study. Other eligibility criteria included age 18 years; measurable disease; Eastern Cooperative Oncology Group performance status less than 2; prior radiotherapy to a different site must have been completed 4 weeks before random assignment with recovery from all acute toxic effects; adequate bone marrow (platelets 100 x 109 cells/L, absolute neutrophil count 1.5 x 109 cells/L, and hemoglobin 9 g/dL), hepatic (total bilirubin 1.5x the upper limit of normal; and AST, ALT, and alkaline phosphatase 3x the upper limit of normal or 5x the upper limit of normal if metastatic disease was present in the liver), and renal (estimated creatinine clearance 45 mL/min) functions; and a life expectancy of 3 months.
The exclusion criteria were as follows: inability to take folic acid or vitamin B12 supplementation; 4 weeks from major surgery to registration; prior chemotherapy, biologic therapy, or genetic therapy for lung cancer; radiation therapy to more than 25% of the bone marrow or prior radiation to the whole pelvis or radiation to the primary disease; uncontrolled infection or any chronic debilitating disease; clinically significant effusions (pericardial, pleural, and ascites), unless these could be drained; documented brain metastasis; aspirin or nonsteroidal anti-inflammatory agent ingestion 2 days before (5 days for long-acting agents such as piroxicam) plus the day of and 2 days after the day of pemetrexed administration; prior malignancy (except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancer from which the patient had been disease free for at least 5 years); pregnant or nursing women; men or women of childbearing potential or their sexual partners not using adequate protection; and weight loss 10% in last 6 weeks.
This trial was approved by the institutional review boards of all treatment centers. Written informed consent was obtained according to federal and institutional guidelines.
Experimental Treatment
Pemetrexed and gemcitabine were supplied as lyophilized powder forms by Eli Lilly & Company (Indianapolis, IN) through the North Central Cancer Treatment Group Coordinating Center Pharmacy. These agents were then reconstituted in sodium chloride solution before use. Patients were randomly assigned to receive one of the three different schedules of pemetrexed 500 mg/m2 (day 1 or 8) plus gemcitabine 1,250 mg/m2 intravenously (days 1 and 8) every 21 days. Schedule A was pemetrexed followed 90 minutes later by gemcitabine on day 1 plus gemcitabine on day 8; schedule B was gemcitabine followed 90 minutes later by pemetrexed on day 1 plus gemcitabine on day 8, and schedule C was gemcitabine on day 1 plus pemetrexed followed 90 minutes later by gemcitabine on day 8. In each schedule, administration of pemetrexed and gemcitabine was separated by approximately 90 minutes based on preclinical data.[32] Patients were administered 350 to 600 μg of oral folic acid daily and 1,000 μg of intramuscular vitamin B12 every 9 weeks starting 7 to 14 days before the first dose and until 3 weeks after the last dose of pemetrexed. Dexamethasone (4 mg) was administered orally every 12 hours on the day before, day of, and day after all doses of pemetrexed. Antiemetics were administered before chemotherapy on days 1 and 8 according to institutional guidelines. All patients were evaluated after two cycles of treatment, which was continued to a maximum of eight cycles or until disease progression, unacceptable toxicity, or patient refusal occurred. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2).
Clinical Care of Patients
Complete patient histories, physical examinations, CBC counts, chemistries (AST, ALT, alkaline phosphatase, total bilirubin, creatinine, and blood urea nitrogen), calculated creatinine clearance, homocysteine level, and chest x-ray were performed at baseline and, with the exception of chest x-ray, before each course of treatment. Bone scans, positron emission tomography scans, or magnetic resonance imaging of the brain were performed at the discretion of the treating physician if clinically indicated. CBC count was repeated weekly while patients were on study. Radiologic studies (roentgenograms, bone scans, and computed tomography scans or magnetic resonance imaging) were performed at baseline and after every two cycles of therapy to assess tumor response, which was defined according to the Response Evaluation Criteria in Solid Tumors criteria.[36]
Statistical Methods
A single-stage, randomized, phase II study with an interim analysis based on a modified Fleming design was conducted to assess the efficacy and toxicity of three different treatment schedules of pemetrexed in combination with gemcitabine in chemotherapy-na?ve patients with advanced or metastatic NSCLC.[37] Accrual was not suspended for the interim analysis evaluation; however, additional patients enrolled onto any schedule during this time were not included in the interim analysis. The two stratification factors were stage (IIIB v IV) and performance status (0 v 1). Patients were randomly assigned using a dynamic allocation procedure such that the marginal distributions of these stratification factors were balanced across the three schedules. The primary efficacy end point was the confirmed tumor response rate in each schedule. A treatment success was defined as either a CR or PR observed on two consecutive evaluations at least 4 weeks apart. This trial was designed to test the null hypothesis that the true treatment success rate in each schedule was at most 0.15 against the alternative that it was at least 0.30. On the basis of the Fleming design, a sample size of 55 patients in each schedule provided 90% power to test this hypothesis, with a two-sided = .10. A schedule was considered promising if at least 12 of the 55 assessable patients had a confirmed response. A planned interim analysis was conducted for each schedule after the first 19 assessable patients were observed for 6 months in that schedule. A regimen was considered promising if three or more confirmed responses were observed in the first 19 assessable patients, and accrual continued. A regimen with less than three confirmed responses was permanently closed to accrual because of lack of efficacy at the time of interim analysis.
Survival time was defined as the time from random assignment to death as a result of any cause. Time to progression (TTP) was defined as the time from random assignment to the date of first documented disease progression. If a patient died without documentation of disease progression, the patient was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude otherwise. In the case of a major treatment violation, the patient was censored for the event of interest on the date of the treatment violation. Any patient starting treatment and not returning for subsequent evaluations was censored for progression on day 1 after treatment. Duration of response was defined as the date from which the patient's objective status was first noted as a CR or PR to the date progression was first documented.
The results for the primary end point of confirmed tumor response rate, which was computed as the number of confirmed CR or PR divided by the total number of assessable patients, are analyzed separately within each schedule. Exact binomial CIs for the true treatment success rate were constructed according to the method of Duffy and Santner.[38] The distribution of TTP and overall survival time was estimated for each schedule using the Kaplan-Meier method.[39] Fisher's exact and 2 tests were used to compare the baseline characteristics and toxicity patterns between the arms. P < .05 was considered statistically significant. All patients were included in the analyses, except those patients who never received study treatment.
RESULTS
Patient Characteristics
A total of 157 patients (schedule A, n = 62; schedule B, n = 32; and schedule C, n = 63) were enrolled between September 2001 and May 2003. Seven patients (schedule A, n = 4; schedule B, n = 1; and schedule C, n = 2) were deemed ineligible because of low creatinine clearances (schedule A, n = 1; schedule C, n = 1), pleural effusions (schedule A, n = 1; never received study treatment), nonmeasurable disease (schedule A, n = 1; never received study treatment), and incorrect histology (schedule A, n = 1; schedule B, n = 1; and schedule C, n = 1; the patient in schedule A never received study treatment). In addition, two patients (one patient each in schedules B and C) never received study treatment, including one patient (schedule B) who had a grade 4 myocardial infarction before treatment started and another patient (schedule C) who had a performance status increase of 2 before study treatment. The baseline characteristics for the 152 assessable patients (excluding the three patients, one patient, and one patient in schedules A, B, and C, respectively, who never received any study treatment) are listed in [Table 1]. A majority of the patients had stage IV disease at the time of enrollment (schedule A, 86%; schedule B, 90%; and schedule C, 85%). The distribution of performance status was balanced across schedules A and C compared with schedule B (performance status of 0 and 1, 52% and 48%, respectively). This imbalance in the stratification factor in schedules A and C versus B is likely a result of the fact that schedule B was stopped early after the interim analysis. No statistically significant differences were observed among the three treatment schedules in the distribution of age, sex, race, and stage. Schedule B had fewer patients with elevated levels of homocysteine compared with schedules A and C (schedules A, B, and C: 17%, 10%, and 24%, respectively; two-sided 2 test, P = .05). The average lengths of follow-up for schedules A, B, and C were 17.1, 19.7, and 15.2 months, respectively ([Table 2]), and a median of five, two, and four cycles of treatment were administered, respectively. All patients were off active treatment at the time of this analysis. The percentages of patients who completed study per protocol in schedules A, B, and C were 20%, 13%, and 19%, respectively. A higher percentage of patients ended treatment early as a result of death, adverse events, and refusal in schedule B compared with schedules A and C (schedules A, B, and C: 24%, 42%, and 18%, respectively; schedule B v A, P = .07; schedule B v C, P = .01). Other follow-up data are listed in [Table 2].
Toxicities
Toxicity was defined as any adverse event deemed at least possibly related to treatment. [Table 3] lists the toxicities for the 152 assessable patients, both overall and by each schedule. Overall, 74% of patients experienced grade 3 and 4 hematologic toxicities, and 62% of patients experienced grade 3 and 4 nonhematologic toxicities. Schedule B had a significantly higher incidence of grade 3 and 4 febrile neutropenia (schedules A, B, and C: 5%, 19%, and 5%, respectively; P = .03). Patients on schedule A experienced less severe toxicity than schedule C (grade 3 and 4 events, 86% v 94%, respectively; grade 4 events, 39% v 48%, respectively); although this was not statistically significant (P = .19 and P = .30, respectively). There was one grade 5 event of pneumonitis in schedule C that was deemed at least possibly related to treatment.
The toxicity analysis was not adjusted for baseline homocysteine levels, although the distribution of baseline homocysteine levels across the three schedules was marginally significant. This is because there was no association between baseline homocysteine levels and occurrence of grade 3 and 4 toxicities across schedules (Cochran-Mantel-Haenszel statistics controlling for schedule; two-sided P = .8).
Hematologic Toxicity
The frequencies of the most common grade 3 and 4 hematologic toxicities (occurring in at least 10 of the 152 assessable patients) are listed in [Table 4] for each schedule. Neutropenia and leukopenia were the most common hematologic toxicities in each schedule (grade 3 and 4 neutropenia in schedules A, B, and C: 64.4%, 64.5%, and 69.4%, respectively; and grade 3 and 4 leukopenia in schedules A, B, and C: 44.1%, 42.0%, and 58.1%, respectively). Thrombocytopenia and anemia occurred less frequently (grade 3 and 4 thrombocytopenia in schedules A, B, and C: 8.5%, 12.9%, and 19.4%, respectively; and grade 3 and 4 anemia in schedules A, B, and C: 10.2%, 9.7%, and 4.8%, respectively). Packed RBC transfusion was required in 11.9% and 4.8% of patients in schedules A and C, respectively.
Nonhematologic Toxicity
The frequencies of the most common grade 3 and 4 nonhematologic toxicities (occurring in at least 10 of the 152 assessable patients) are listed in [Table 5] for each schedule. Among the grade 3 and 4 nonhematologic toxicities, fatigue (schedules A, B, and C: 11.9%, 22.6%, and 16.1%, respectively), dyspnea (schedules A, B, and C: 13.6%, 3.2%, and 11.3%, respectively), and AST/ALT elevation (schedules A, B, and C: 8.5%, 12.9%, and 6.5%, respectively) were the most common. Other nonhematologic toxicities occurring in at least 10 patients included nausea, vomiting, and rash.
Clinical Activity
One hundred fifty-two patients were assessable for response. The response data are listed in [Table 6]. No CR was observed. Schedule B was stopped early after interim analysis because of only one confirmed response in the first 19 assessable patients. Eighteen patients (31%) in schedule A had a confirmed PR; of these responses, 17 were observed in the first 55 patients (95% CI, 20% to 45%), thus meeting the success criteria of at least 12 confirmed responses in the first 55 patients. Only 10 confirmed PRs were observed in schedule C in the first 55 patients; therefore, this schedule failed to meet the cutoff criteria for further study (response rate, 16.1%; 95% CI, 11% to 34%). The median response duration was approximately 173 and 125 days for schedules A and C, respectively. An analysis of sex by response was conducted because there was a higher percentage of males in schedule B compared with schedules A or C (schedules A, B, and C: 53%, 74%, and 61%, respectively). Overall, there was no statistically significant association between sex and response (Cochran-Mantel-Haenszel statistics controlling for schedule; two-sided P = .65). Therefore, the difference in the response rates observed for different treatment schedules is unlikely caused by any effect from sex.
Overall survival (median survival times for patients in schedules A, B, and C: 11.4, 10.3, and 11.8 months, respectively) and TTP (median TTP for schedules A, B, and C: 4.7, 4.1, and 4.4 months, respectively) were similar among the three different schedules. The Kaplan-Meier curves for overall survival and TTP are shown in [Figures 1] and [2], respectively.
DISCUSSION
Patients with advanced NSCLC have a poor prognosis. Compared with best supportive care, systemic chemotherapy is associated with a small survival benefit, adding anywhere from 6 to 10 weeks to the median survival time.[40-42] Combination chemotherapy increases the response rate and prolongs survival when compared with single agents in randomized clinical trials in patients with good performance status.[43,44] Although platinum-based combination chemotherapy regimens are preferred, the survival advantage is modest, at best, when compared with nonplatinum combinations.[45] Currently, there is no single best treatment regimen for advanced NSCLC.
Our randomized, three-arm, phase II study was designed to identify the optimal schedule for the combination of gemcitabine and pemetrexed as front-line therapy for patients with advanced NSCLC. Patients were randomly assigned to receive one of the three different schedules of pemetrexed 500 mg/m2 (day 1 or 8) plus gemcitabine 1,250 mg/m2 intravenously (days 1 and 8) every 21 days with vitamin B12 and folate supplementation. Schedule A, with a response rate of 31%, compared with schedules B and C, with response rates of 6.5% and 16.1%, respectively, was the only arm that met the protocol-defined response criteria for further evaluation. Schedule B was discontinued after interim analysis because of a poor response rate. Regarding toxicities, schedule A resulted in less severe toxicity compared with schedule C. Schedule B, which had the lowest response rate, had the highest incidence of grade 3 and 4 febrile neutropenia (schedules A, B, and C: 5%, 19%, and 5%, respectively). Given the response criteria and the milder toxicity profile, schedule A is recommended for future studies of the combination of pemetrexed and gemcitabine.
The median survival time (schedules A, B, and C: 11.4, 10.3, and 11.8 months, respectively) and TTP (schedules A, B, and C: 4.7, 4.1, and 4.4 months, respectively) were similar among the three schedules, as seen in a number of recent comparative combination studies for advanced NSCLC,[2-7] in which improvement in objective response did not translate to improvement in survival or TTP. A plausible explanation for the similarity in survival in all three schedules may be the fact that a majority of patients (107 of 152 patients; 70%) received one or more subsequent therapies (schedules A, B, and C: 63%, 68%, and 79%, respectively).
The results of our phase II study are consistent with the previous phase I study testing two different schedules of this combination, with gemcitabine administered on days 1 and 8 and pemetrexed administered on day 1 (schedule 1) or 8 (schedule 2).[32-34] Schedule 1 of that phase I study is identical to schedule B of the current phase II study. Schedule 2 of that phase I study is similar to schedule C of the current phase II study, with the exception that pemetrexed was administered before gemcitabine on day 8 in schedule C. In both studies, schedule B yielded intolerable toxicities. In the present study, pemetrexed and gemcitabine were administered with a 90-minute interval between infusions. However, a recent phase IB study from our group of the pharmacokinetics of gemcitabine and pemetrexed in solid tumors demonstrated no pharmacokinetic interaction between the two drugs when administered in rapid sequence.[46] Therefore, it is reasonable to omit the 90-minute delay between the infusions for future studies of pemetrexed with gemcitabine.
Our results in schedule A compare favorably with a recently reported phase II study of the combination of pemetrexed and gemcitabine using a different treatment schedule in a similar patient population.[47] In that study, gemcitabine (1,250 mg/m2) was administered intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8, which is similar to our schedule C with the exception that gemcitabine was administered before pemetrexed on day 8.[47] After the initial accrual of 13 patients, folic acid and vitamin B12 supplementation were added. The efficacy in that study was similar to that seen on schedule C of the present study, with a response rate, overall survival time, and TTP of 15.5%, 10.1 months, and 5.0 months, respectively. Grade 3 and 4 toxicity was neutropenia (61.7%), which is also similar to our schedule C. However, there seemed to be a higher incidence of patients who experienced febrile neutropenia (16.7%), fatigue (23.3%), and elevations of AST (15.0%) and ALT (20.0%) in that study.
This randomized phase II study is the first report in the literature optimizing the administration schedule of the combination of pemetrexed and gemcitabine in the clinical trial setting. This study also demonstrates that the schedule of administration of certain chemotherapy agents may be important in terms of toxicity and, potentially, efficacy. In addition, our study demonstrates that a randomized phase II trial is an appropriate approach to selecting a regimen out of a number of possible regimens to be further studied. Schedule A seemed to have similar efficacy when compared with historical results with third-generation combination regimens including cisplatin/paclitaxel (response rate, overall survival time, and TTP: 21%, 7.8 months, and 3.4 months, respectively), cisplatin/gemcitabine (response rate, overall survival time, and TTP: 22%, 8.1 months, and 4.2 months, respectively), cisplatin/docetaxel (response rate, overall survival time, and TTP: 17%, 7.4 months, and 3.7 months, respectively), and carboplatin/paclitaxel (response rate, overall survival time, and TTP: 17%, 8.1 months, and 3.1 months, respectively) in similar patient populations.[2] Given the efficacy and toxicity profile, future studies aimed at incorporating pemetrexed and gemcitabine, administered as outlined in schedule A, into the therapy of NSCLC are needed.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the followig authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported in part by Public Health Service grant Nos. CA-25224, CA-37404, CA-15083, CA-35448, CA-35113, CA-35269, CA-35195, and CA-60276 from the National Institutes of Health and conducted as a collaborative trial of the North Central Cancer Treatment Group, Mayo Clinic, and Eli Lilly & Company, Indianapolis, IN.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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