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Regulatory Issues |
Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA
Correspondence: Correspondence: Martin H. Cohen, M.D., Food and Drug Administration, HFD-150 5600 Fishers Lane, Rockville, Maryland 20857, USA. Fax: 301-594-0499; e-mail: cohenma{at}cder.fda.gov
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ABSTRACT
On August 19, 2004, pemetrexed for injection (Alimta®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) received accelerated approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received prior chemotherapy.
Approval was primarily based on a single, controlled, unblinded trial. Five hundred seventy-one protocol-eligible patients were randomized to receive either pemetrexed or docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com). The primary efficacy end point was overall survival. The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm. Neither superiority nor noninferiority for overall survival could be demonstrated, the latter because a reliable and consistent survival effect of docetaxel could not be estimated and because of significant crossover of pemetrexed-treated patients to docetaxel after tumor progression. Comparable response rates, 9.1% for pemetrexed and 8.8% for docetaxel, times to progressive disease, and progression-free survival times supported the conclusion that an effect of pemetrexed on survival was reasonably likely, however.
In addition, pemetrexed was felt to have a more favorable safety profile than docetaxel. Of greatest importance, pemetrexed caused significantly less neutropenia, febrile neutropenia, neutropenic infections, and need for granulocyte/macrophage colony-stimulating factors.
INTRODUCTION
Pemetrexed (Alimta®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) is an antifolate antimetabolite that inhibits several key folate-dependent enzymes (thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase) required for de novo nucleotide biosynthesis [1]. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate-binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms. Polyglutamated metabolites have a long intracellular half-life, resulting in prolonged drug action in malignant cells.
In vitro studies have also suggested that pemetrexed may be active against certain tumor cells that are resistant to methotrexate, 5-fluorouracil, and raltitrexed (Tomudex®; AstraZeneca Pharmaceuticals, Wilmington, DE, http://www.astrazenecaus.com). Additionally, preclinical animal studies have suggested that folic acid and vitamin B12 supplementation reduce the risk for severe drug-induced toxicities while preserving the antitumor activity of pemetrexed.
The current pemetrexed submission to the U.S. Food and Drug Administration (FDA) was for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received prior chemotherapy.
PATIENTS AND METHODS
The safety and efficacy review of pemetrexed was primarily based on data from one multicenter, phase III, randomized trial in 571 patients, comparing pemetrexed alone with docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com) alone. Results of four supporting phase II NSCLC trials, two first-line and two second-line, were also provided.
In the phase III study, pemetrexed (500 mg/m2) was administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle. Patients receiving pemetrexed also received dexamethasone (Decadron®; Merck and Co., Inc., Whitehouse Station, NJ, http://www.merck.com) for skin rash prophylaxis as well as vitamin B12 and folic acid supplementation. Dexamethasone (4 mg) was given by mouth, twice daily, the day before, the day of, and the day after pemetrexed administration. Vitamin B12 (1,000 µg by i.m. injection) was given during the week preceding the first dose of pemetrexed and every three cycles thereafter. Folic acid (350–1,000 µg, most commonly 400 µg, daily) was initiated 5–7 days preceding the first dose of pemetrexed and was continued throughout therapy and for 21 days after the last dose of pemetrexed.
Docetaxel (75 mg/m2) was administered i.v. over 60 minutes on day 1 of a 21-day treatment cycle. Dexamethasone (8 mg) was given by mouth, twice daily, the day before, the day of, and the day after docetaxel administration as prophylaxis against fluid retention and hypersensitivity reactions.
Prerandomization stratification factors included performance status, disease stage, number of prior chemotherapy regimens, response to last prior chemotherapy, whether the patient had received prior platinum therapy, whether the patient had received prior paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) therapy, treatment site, and baseline homocysteine level. (Elevated pre-treatment homocysteine values had previously been shown to be an excellent predictor of pemetrexed treatment toxicity, and reduction in elevated homocysteine levels with folic acid and vitamin B12 was accompanied by a reduction in toxicity.)
The primary efficacy end point was overall survival. Secondary efficacy end points included response rate and duration, time to progression, progression-free survival time, and lung cancer symptoms measured by the lung cancer symptom scale.
Following disease progression, poststudy chemotherapy was permitted. Patients receiving pemetrexed could cross over to docetaxel treatment. Docetaxel-treated patients could not cross over to pemetrexed treatment.
RESULTS
One hundred thirty-five investigational sites in 23 countries participated in this study. Approximately 21% of the study population came from U.S. institutions.
Patient demographic and disease-related characteristics for the intent-to-treat population are summarized in Table 1
. Patients in the two treatment groups were comparable for the indicated characteristics.
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. There was no statistically significant difference between pemetrexed and docetaxel with respect to objective response rate, progression-free survival (PFS), and time to progressive disease.
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, 126 (48%) pemetrexed-treated patients and 107 (39%) docetaxel-treated patients received poststudy chemotherapy.
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The primary end point in this study was overall survival. The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (Table 2
and Fig. 1). Treatment with pemetrexed did not result in a statistically significant longer survival time than with docetaxel. As discussed below, noninferiority for overall survival could also not be demonstrated. Exploratory analyses of demographic effects on survival showed no significant differences between pemetrexed and docetaxel in patients over or under 65 years of age. There were too few nonwhite patients to assess possible ethnic differences. Regarding gender, females lived longer than males in both treatment groups. Adjusting for prognostic factors, however, there was no difference in survival between pemetrexed and docetaxel with respect to gender.
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Table 4 summarizes all toxicities experienced by study patients, regardless of causality, based on National Cancer Institute (NCI) Common Toxicity Criteria (CTC) grade. There was no significant difference between pemetrexed and docetaxel for CTC grade 1 and grade 2 toxicities. For CTC grade 3 toxicity, grade 4 toxicity, and grade 3/4 toxicity, pemetrexed was significantly less toxic than docetaxel. Pemetrexed’s safety advantage for CTC grade 3 or 4 toxicity came primarily from less neutropenia, less febrile neutropenia, and less infection accompanying neutropenia.
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provides the clinically relevant adverse effects that were reported in 265 patients randomly assigned to receive single-agent pemetrexed with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel.
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The incidence of CTC grade 3/4 hypertension was the only finding demonstrating an age difference in patients treated with pemetrexed and was greater in patients 65 years or older than in younger patients. There were insufficient numbers of nonwhite patients to assess ethnic differences. The incidence of CTC grade 3/4 dyspnea was higher in males for both treatment arms.
DISCUSSION
The primary study end point was overall survival. Superiority in the survival of pemetrexed-treated patients compared with docetaxel-treated patients was not demonstrated. Noninferiority in the survival of pemetrexed-treated patients compared with docetaxel-treated patients also was not demonstrated. Demonstration of noninferiority requires that the survival effect of docetaxel be precisely determined. This generally requires the availability of multiple historical studies to evaluate interstudy variability and to assess constancy of results [2].
Two docetaxel second-line NSCLC studies were conducted, only one of which demonstrated a statistically significant docetaxel survival benefit. That trial, reported by Shepherd and colleagues [3], enrolled stage IIIB/IV patients with performance status scores of 0–2 who had failed one or more platinum-based chemotherapy regimens. Patients were initially randomized to receive docetaxel at a dose of 100 mg/m2 or best supportive care (BSC). Because of early toxic deaths, the protocol was amended to reduce the docetaxel dose to 75 mg/m2. After the amendment, there were 55 patients who received docetaxel at a dose of 75 mg/m2 and 49 patients who received BSC. Docetaxel treatment gave a response rate of 5.5%. The median survival time was 7.5 months for docetaxel versus 4.6 months for BSC. The difference in overall survival was statistically significant (p = .01). The 1-year survival rates were 37% and 12% (p < .05) for docetaxel and BSC, respectively.
The second study was reported by Fossella and colleagues [4]. It was a randomized trial comparing docetaxel at a dose of 100 mg/m2 or 75 mg/m2 with the physician’s choice of either vinorelbine (Navelbine®; GlaxoSmithKline, Philadelphia, http://www.gsk.com) or ifosfamide (Ifex®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com). The study population had a higher percent of stage IV patients and more patients who had received two or more prior regimens than did the study population in the Shepherd et al. [3] study. The 100-mg/m2 docetaxel dose again was associated with early toxic deaths. The patients treated with the 75-mg/m2 docetaxel dose had an objective response rate of 5.7% compared with 0.8% for the physician’s choice arm. The median survival times were 5.7 and 5.6 months and the 1-year survival rates were 30% and 20% for the 75-mg/m2 docetaxel arm and the physician’s choice arm, respectively. The difference in overall survival between the two treatments was not statistically significant (p = .13). The p value for the 1-year survival difference was .025.
Hanna and coinvestigators, in their publication of study results [5], claimed that noninferiority in survival of pemetrexed-treated patients to docetaxel-treated patients was demonstrated. Their analysis was based on a 50% retention of control (docetaxel) effect. However, the Hanna et al. fraction retention noninferiority analysis was based on a questionable estimate of control effect (middle value of 95% confidence interval of log-hazard ratio). Since the active control effect is estimated based on only one small historical trial, however, the point estimate of the hazard ratio may not be appropriate to establish the control effect. To minimize the risk of overestimation of control effect, a 95% lower confidence limit is generally used as an estimate of the control effect. That analysis fails to demonstrate noninferiority.
The noninferiority of survival analysis was also confounded by the 32% crossover rate of pemetrexed-treated patients to docetaxel after tumor progression and by the greater number of docetaxel-treated patients who did not receive any poststudy chemotherapy.
Accelerated approval differs from regular approval in that the latter requires demonstration of clinical benefit, such as increased survival, symptom relief, or delay in the time to symptom occurrence. Accelerated approval applies to therapies developed for the treatment of serious and life-threatening diseases in patients who are unresponsive to, or intolerant of, existing therapy or for whom no existing therapy exists. Under accelerated approval regulations, a new drug or biologic agent may be approved on the basis of adequate trials establishing that the drug product has an effect on a surrogate end point that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit. Accelerated approval requires that the applicant study the drug further to verify and describe its clinical benefit (phase IV commitments). Such studies must be adequate (i.e., randomized) and well controlled. The applicant must carry out any such studies with due diligence (as rapidly as possible) [6].
The effects of pemetrexed on surrogate efficacy end points (response rate and PFS rate) and on safety support the conclusion that an effect of pemetrexed on survival or on disease-related symptoms is reasonably likely.
ACKNOWLEDGMENT
The views expressed herein are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.
REFERENCES
314.510 and 21CFR 601.41. Available at http://www.gpoaccess.gov/cfr/index.html.This article has been cited by other articles:
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5% of patients (% incidence)