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The Oncologist, Vol. 9, No. 5, 482-488, September 2004; doi:10.1634/theoncologist.9-5-482
© 2004 AlphaMed Press

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FDA Commentary

FDA Drug Approval Summaries: Pemetrexed (Alimta®)

Maitreyee Hazarika, Robert M. White, John R. Johnson, Richard Pazdur

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Correspondence: Maitreyee Hazarika, M.D., U.S. Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: 301-594-2473; Fax: 301-594-0499; e-mail: HazarikaM{at}cder.fda.gov


   LEARNING OBJECTIVES
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 Learning Objectives
Abstract
 Introduction
 Background
 Phase III Study
 Randomized Clinical Trial...
 Discussion
 References
 
After completing this course, the reader will be able to:

  1. Explain the mechanism of action of a recently approved new cancer drug, pemetrexed.
  2. Describe the adverse-event profile of pemetrexed and a novel approach for toxicity reduction.
  3. Discuss the rationale for the FDA approval of pemetrexed.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
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 Learning Objectives
 Abstract
Introduction
 Background
 Phase III Study
 Randomized Clinical Trial...
 Discussion
 References
 
The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta®; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting.

On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m2 administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m2 infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B12 injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.

Key Words. Pemetrexed • Alimta® • Malignant pleural mesothelioma


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Background
 Phase III Study
 Randomized Clinical Trial...
 Discussion
 References
 
Malignant mesotheliomas arise primarily from the surface serosal cells of the pleural, peritoneal, and pericardial cavities and are highly aggressive neoplasms. The etiology of malignant mesothelioma is primarily exposure to asbestos fibers [1]. Simian virus 40 has also been implicated in the etiology [2]. Malignant pleural mesothelioma (MPM) most typically develops 20–50 or more years after the first documented asbestos exposure, commonly in the fifth to seventh decade of life. With median survival durations of 10–17 months from onset of symptoms and 9–13 months from diagnosis, the prognosis is poor for patients with these neoplasms.

Although the Cancer Committee of the College of American Pathologists provides a protocol for the examination of specimens from patients with MPMs, histological diagnosis remains difficult [3]. Earlier staging systems were not uniform, and the International Mesothelioma Interest Group Staging System (IMIG) updated several earlier staging systems after taking into consideration information about the impact of tumor (T) and nodal (N) status on survival [4]. Evaluations with two series of patients validated the staging system [5, 6].

Surgical resection of MPM is possible in only a minority of patients. Fewer than 15% of these patients live beyond 5 years [6, 7]. Curative radiotherapy, although available, is limited by the tumor volume to be treated and by toxicities to surrounding normal tissue [8]. Chemotherapy with single agents, such as doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), methotrexate with rescue, 5-azacytadine, 5-fluorouracil, cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ), and gemcitabine (Gemzar®; Eli Lilly; Indianapolis, IN), appears to have limited activity [9–11]. Combination chemotherapy regimens have shown response rates that range from 0%–48%, with the highest reported for cisplatin and gemcitabine (48% in 21 patients) [12, 13]. None of the single or combination chemotherapy regimens provide a survival benefit.

A New Drug Application for a first-line indication for pemetrexed (LY231514; MTA; Alimta®; Eli Lilly and Company; Indianapolis, IN) for patients with MPM not candidates for surgical resection was submitted to the U.S. Food and Drug Administration (FDA) in October 2002. At the time of the submission, there were no FDA-approved drugs for MPM. Response rate was originally proposed by the applicant as the primary end point for the randomized study, as they believed that unidimensional measurements were sufficient to provide information on response. Due to uncertainty about the application of unidimensional measurements of pleural rind for response assessments and uncertainty regarding the relationship of response to clinical benefit, the FDA required survival as the primary end point.


   BACKGROUND
Top
 Learning Objectives
 Abstract
 Introduction
 Background
Phase III Study
 Randomized Clinical Trial...
 Discussion
 References
 
Pemetrexed (pemetrexed disodium) (L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl]-, disodium salt) is a structurally novel antifolate that possesses the unique 6–5 fused pyrrolo [2,3-d] pyrimidine nucleus (Fig. 1Go). It is transported into cells by both the reduced folate carrier and membrane folate-binding protein transport systems. It was found to be one of the best substrates for the folylpoly-gamma-glutamate synthetase [14]. Polyglutamation and polyglutamated metabolites of pemetrexed are believed to have a role in the selectivity and antitumor activity of this agent. The polyglutamated forms have a greater affinity for thymidylate synthase and glycinamide ribonucleotide formyltransferase (GARFT) than pemetrexed monoglutamate. They inhibit thymidylate synthase, GARFT, and dihydrofolate reductase, all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides (Fig. 2Go).



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  		Figure 1. Chemical structure of pemetrexed (pemetrexed sodium).

 


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  		Figure 2. Inhibition of multiple folate-requiring enzymes by pemetrexed and its polyglutamates.

 
Pemetrexed is primarily eliminated in the urine, with 70%–90% of the dose recovered as unchanged parent drug within the first 24 hours. It is not metabolized to any appreciable extent. It does not inhibit the cytochrome P-450 (CYP) isoenzymes CYP3A4, CYP2D6, CYP1A2, or CYP2C9. The terminal half-life from plasma is 3.5 hours in patients with normal renal function. It is approximately 81% bound to plasma proteins. Total plasma clearance of pemetrexed decreases as renal function decreases. There have been no pharmacokinetic evaluations in patients with third-space accumulations.


   PHASE III STUDY
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 Learning Objectives
 Abstract
 Introduction
 Background
 Phase III Study
Randomized Clinical Trial...
 Discussion
 References
 
Patients with histologically confirmed MPMs who were not candidates for curative surgery were enrolled and were randomized equally between the two treatment arms of pemetrexed plus cisplatin and cisplatin alone. Clinical staging was done using the IMIG staging criteria. Patients were entered and randomly assigned to a treatment arm based on local pathology; independent centralized pathology review was carried out on patients only when feasible. Eligibility criteria required the presence of unidimensionally and/or bidimensionally measurable disease. Patients were excluded if they had received prior systemic chemotherapy, intracavitary cytotoxic drugs, or immunomodulators. The primary end point was survival. The results of the phase III trial were previously reported [15].

Between May 1999 and November 2001, 456 patients were considered eligible for the trial, and they constituted the intent-to-treat population. Of these, 448 patients were treated and were considered assessable for efficacy and toxicity analyses: 226 patients in the pemetrexed plus cisplatin arm and 222 patients in the cisplatin alone arm. The primary safety analysis was performed on a subset of patients who had received supplementation with folic acid and vitamin B12 injections: 168 patients on the pemetrexed plus cisplatin arm and 163 patients on the cisplatin alone arm. The patients were predominantly male, Caucasian, with good performance status scores (Table 1Go). Median age was 61 years (range 19–85 years). In the pathologically confirmed mesothelioma patients, 85% had epithelial histologies. In confirmed mesothelioma pathology patients, 78% had stage III or stage IV disease. In the randomized and treated population, 7.5% of patients had received prior chemotherapy for the purpose of pleurodesis, while 9.7% had received prior radiotherapy that had concluded at least 4 weeks before enrollment.


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  		Table 1. Summary of patient characteristics
 
In the pemetrexed plus cisplatin treatment arm, pemetrexed was administered at a dose of 500 mg/m2 diluted in approximately 100 ml of normal saline as a 10-minute i.v. infusion followed by the administration of cisplatin 30 minutes later at a dose of 75 mg/m2 over 2 hours. In the cisplatin alone treatment arm, approximately 100 ml of normal saline were given as an i.v. infusion over approximately 10 minutes followed 30 minutes later by the same dose of cisplatin as used in the alternate treatment arm.

Folic acid and vitamin B12 supplements were introduced into the trial for safety reasons. The sponsor initiated a multivariate analysis in 1997 to assess the relationships between vitamin metabolites, drug exposure, and other baseline patient characteristics and toxicity following therapy with pemetrexed [16]. It was concluded that toxicity from pemetrexed therapy appeared to be higher in patients with elevated pretherapy homocysteine levels and that elevated baseline homocysteine levels correlated with severe toxicities, such as febrile neutropenia, grade 4 neutropenia, thrombocytopenia, and diarrhea. As a result, vitamin supplementation was given to patients in both treatment arms to preserve blinding. Folic acid (350–1,000 µg daily) was given orally, daily starting 7 days before the first dose of chemotherapy and was continued while the patient was on therapy and for 21 days after cessation of therapy. Vitamin B12 injections (1,000 µg i.m.) were started 1 week before the first dose of chemotherapy and were repeated every 3 cycles while the patient was on therapy.

Patients were also given dexamethasone the day before, the day of, and the day after chemotherapy administration to reduce the risk of skin rashes. Dexamethasone was given to all patients in both arms.


   RANDOMIZED CLINICAL TRIAL RESULTS
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 Learning Objectives
 Abstract
 Introduction
 Background
 Phase III Study
 Randomized Clinical Trial...
Discussion
 References
 
Methods
The pemetrexed marketing application was based on a single, randomized, single-blind, phase III, multicenter study that included 88 principal investigators who enrolled 574 patients in 20 countries.

Although the intent-to-treat population numbered 456 patients, the applicant’s efficacy claim was based on the 448 patients in the randomized and treated population. The primary analysis was a comparison of survival times between the two treatment arms in the randomized and treated group. Differences were assessed using a two-sided log-rank test. A planned interim analysis was conducted and presented to the Data Safety Monitoring Board. Because of this interim analysis, the final comparison of survival was tested at the {alpha} = 0.0476 level.

Survival
In the 448 randomized and treated patients, the survival time for patients treated with pemetrexed plus cisplatin was longer than the survival time for patients treated with cisplatin alone—median 12.1 months versus 9.3 months (p = 0.021, hazard ration [HR] = 0.77, 95% confidence interval [CI] of HR = 0.61–0.96) (Table 2Go). In the subgroup of the fully folic acid- and vitamin B12-supplemented patients (n = 331), the median survival times for patients treated with pemetrexed plus cisplatin and cisplatin alone were 13.3 months and 10 months, respectively (p = 0.051, HR = 0.76, 95% CI of HR = 0.57–1.0).


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  		Table 2. Efficacy of pemetrexed plus cisplatin versus cisplatin in MPM patients
 
Since only 67% of the randomized and treated patients had the diagnosis of mesothelioma confirmed by independent review, the FDA conducted an independent survival analysis on the pathologically confirmed mesothelioma subset. In the randomized and treated patients (n = 303), the median survival times for patients treated with pemetrexed plus cisplatin and cisplatin alone were 13 months and 10.2 months, respectively (p = 0.066). In the subgroup of the fully folic acid- and vitamin B12-supplemented patients (n = 220) that were pathologically confirmed, the median survival times for patients treated with pemetrexed plus cisplatin and cisplatin alone were 14.4 months and 10.3 months, respectively (p = 0.058).

The FDA also found the intent-to-treat analysis (with the inclusion of the eight patients, i.e., n = 456) comparable with the randomized and treated analysis (n = 448) of survival. Kaplan-Meier survival curves for the randomized and treated group are shown in Figure 3Go.



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  		Figure 3. Kaplan-Meier survival curves for all randomized treated patients.

 
Safety
The primary safety analysis was done on the fully vitamin-supplemented subgroup, which consisted of 168 patients on the pemetrexed plus cisplatin arm and 163 on the cisplatin alone arm.

Neutropenia (24.4%), fatigue (17.3%), leukopenia (15.5%), nausea (11.9%), dyspnea (11.3%), and vomiting (10.7%) were the most commonly reported grade 3 and 4 adverse events (Table 3Go). Febrile neutropenia and neutropenic sepsis were relatively infrequent. The incidences of grade 3 and 4 anemia and thrombocytopenia were 6% and 5.4%, respectively, in patients on the pemetrexed plus cisplatin arm (Table 4Go). The most common clinical cause of dose delay in both arms was neutropenia, followed by reduced creatinine clearance, leukopenia, anemia, stomatitis, and infection. Cycle 4 was the cycle of therapy with the most clinical delays in both treatment arms.


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  		Table 3. Common adverse events (>10% of patients) in fully vitamin-supplemented patients
 

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  		Table 4. Adverse events in fully supplemented patients
 
Toxicities were higher in the pemetrexed plus cisplatin arm than in the cisplatin alone arm. Severe toxicities were reduced with the use of folic acid and vitamin B12 supplementation.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Background
 Phase III Study
 Randomized Clinical Trial...
 Discussion
References
 
In a single, randomized, single-blind trial, the combination of pemetrexed and cisplatin, compared with cisplatin alone, showed a statistically significant longer overall survival in MPM patients. Pemetrexed plus cisplatin is the first treatment for MPM to demonstrate a survival benefit. The trial was changed while ongoing, and supplementation with folic acid and vitamin B12 was added.

Although a single trial, a large number of independent investigators from multiple international centers contributed data to the trial, and there was a substantial increment in survival of 3 months. The efficacy of pemetrexed was supported by an improvement in pulmonary function tests.

Survival analyses in all intent-to-treat patients and in the randomized and treated patients both favored the pemetrexed plus cisplatin group at a statistically significant level. Survival analyses in the fully vitamin-supplemented subgroup and in the subgroup with a confirmed histologic diagnosis of MPM also favored the pemetrexed plus cisplatin group at a borderline statistical significance level.

Similar to the approved label of pemetrexed, numerical values for response rate are not mentioned in the body of this article. As anticipated prior to the study, there was considerable discrepancy in tumor response evaluations among the study investigators, the study independent reviewers, and the FDA reviewers. The FDA review of the submitted images could confirm tumor response in only 47 of the 94 patients in the pemetrexed plus cisplatin treatment group for whom the applicant claimed a tumor response. Although tumor response rate appeared higher in the pemetrexed plus cisplatin treatment group, the exact numbers are very uncertain.

Following therapy with pemetrexed, toxicities appeared to be higher in patients with elevated pretherapy homocysteine levels. Elevated baseline homocysteine levels (≥10 µmol/l) highly correlated with severe hematological and nonhematological toxicities. Thus, every patient since December 1999 treated in the trial with pemetrexed was supplemented with folic acid and vitamin B12 to improve patient safety.

In patients treated with the combination therapy with full vitamin supplementation, the common adverse events were neutropenia, fatigue, leukopenia, nausea, vomiting, and dyspnea. In comparison with the nonsupplemented subgroup of patients, toxicities were reduced by folate and vitamin B12 supplementation. Despite supplementation, the combination of pemetrexed and cisplatin produces a high degree of toxicity.

For MPM, the recommended dose of pemetrexed is 500 mg/m2 administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle followed by cisplatin at a dose of 75 mg/m2 infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Folic acid (350–1,000 µg daily) orally, daily must be started 1–3 weeks before the first dose of chemotherapy and continued while the patient is on therapy. Vitamin B12 (1,000 µg i.m.) injections must be started 1–3 weeks before the first dose of chemotherapy and repeated every 9 weeks while the patient is on therapy. Patients should also be given dexamethasone on the day before chemotherapy for a total of 3 days to reduce the risk of skin rash.

On February 4, 2004, the FDA approved pemetrexed for use in combination with cisplatin for the treatment of MPM in patients whose disease is either unresectable or who are not otherwise candidates for curative surgery. Approval was based on a longer survival time for patients treated with pemetrexed plus cisplatin than for those treated with cisplatin alone.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Background
 Phase III Study
 Randomized Clinical Trial...
 Discussion
 References
 
The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. FDA.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Background
 Phase III Study
 Randomized Clinical Trial...
 Discussion
 References
 

  1. Craighead JE, Mossman BT. The pathogenesis of asbestos-associated diseases. N Engl J Med 1982;306:1446–1455.[Medline]
  2. Carbone M, Fisher S, Powers A et al. New molecular and epidemiological issues in mesothelioma: role of SV40. J Cell Physiol 1999;180:167–172.[CrossRef][Medline]
  3. Nash G, Otis CN. Protocol for the examination of specimens from patients with malignant pleural mesothelioma: a basis for checklists. Cancer Committee, College of American Pathologists. Arch Pathol Lab Med 1999;123:39–44.[Medline]
  4. Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest 1995;108:1122–1128.[Abstract/Free Full Text]
  5. Rusch VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996;111:815–825; discussion 825–826.[Abstract/Free Full Text]
  6. Pass HI, Temeck BK, Kranda K et al. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998;115:310–317; discussion 317–318.[Abstract/Free Full Text]
  7. Sugarbaker DJ, Garcia JP, Richards WG et al. Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma: results in 120 consecutive patients. Ann Surg 1996;224:288–294; discussion 294–296.[CrossRef][Medline]
  8. Maasilta P. Deterioration in lung function following hemithorax irradiation for pleural mesothelioma. Int J Radiat Oncol Biol Phys 1991;20:433–438.[Medline]
  9. Solheim OP, Saeter G, Finnanger AM et al. High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study. Br J Cancer 1992;65:956–960.[Medline]
  10. Planting AS, Schellens JH, Goey SH et al. Weekly high-dose cisplatin in malignant pleural mesothelioma. Ann Oncol 1994;5:373–374.[Abstract/Free Full Text]
  11. Kindler HL, Millard F, Herndon JE 2nd et al. Gemcitabine for malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B. Lung Cancer 2001;31:311–317.[CrossRef][Medline]
  12. Chahinian AP, Antman K, Goutsou M et al. Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol 1993;11:1559–1565.[Abstract/Free Full Text]
  13. Byrne MJ, Davidson JA, Musk AW et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999;17:25–30.[Free Full Text]
  14. 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 1997;57:1116–1123.[Abstract/Free Full Text]
  15. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–2644.[Abstract/Free Full Text]
  16. Niyikiza C, Baker SD, Seitz DE et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002;1:545–552.[Abstract/Free Full Text]
Received June 8, 2004; accepted for publication July 20, 2004.




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