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Cancer - 2002 - Kindler - The Pemetrexed Gemcitabine Combination in Pancreatic Cancer
Cancer - 2002 - Kindler - The Pemetrexed Gemcitabine Combination in Pancreatic Cancer
Hedy Lee Kindler, M.D. Gemcitabine has modest antitumor activity in advanced pancreatic cancer. New
agents are clearly needed. Pemetrexed (ALIMTA®) is a novel antifolate that inhibits
Director of Gastrointestinal Oncology, Section of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide
Hematology/Oncology, University of Chicago, Chi- formyltransferase. Pemetrexed has shown in vitro activity against pancreatic can-
cago, Illinois. cer cell lines. In a Phase I trial of pemetrexed, two patients with pancreatic cancer
achieved partial responses on the once every 21 days schedule. A Phase II trial of
pemetrexed in patients with advanced pancreatic cancer showed an objective
response rate of 6%, a one year survival of 28%, and a mild toxicity profile. The
combination of pemetrexed and gemcitabine is synergistic in vitro and was broadly
active in a Phase I trial. The pemetrexed/gemcitabine combination was evaluated
in a Phase II trial in 42 patients with advanced pancreatic cancer. The promising
activity observed in this study has led to an ongoing international, randomized,
Phase III trial in 520 patients comparing the pemetrexed/gemcitabine combination
with gemcitabine alone. Cancer 2002;95:928 –32.
© 2002 American Cancer Society.
DOI 10.1002/cncr.10755
FIGURE 1
of 18%, compared with an objective tumor response in a variety of in vitro tumor models, including pan-
rate of 0%, a clinical benefit response rate of 4.8%, and creatic cancer cell lines (generally considered che-
a one year survival of 2% for 5-FU. moresistant) in the human tumor cloning assay.10
The symptomatic benefit achieved with gemcitab-
ine and its mild toxicity profile have prompted numer- Phase I Trials of Single Agent Pemetrexed
ous investigators to combine other agents with gem- Three Phase I studies of pemetrexed have been con-
citabine in an effort to enhance its activity.2 ducted using three different schedules of administra-
tion: once every 21 days; weekly for 4 weeks every 42
Pemetrexed (ALIMTA®) days; and daily for 5 days every 21 days. Table 1
Pemetrexed (ALIMTA®; N-[4-[2-(2-amino-3,4-dihy- summarizes these studies.
dro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]- McDonald et al. administered a total of 116 cycles
benzoyl]-L-glutamic acid; Eli Lilly and Company, In- daily for 5 days every 21 days to 38 patients with
dianapolis, IN) is a novel pyrrolopyrimidine-based advanced malignancies refractory or not amenable to
antifolate.6 Pemetrexed enters cells via the reduced conventional therapy. Ten dose levels were evaluated,
folate carrier and undergoes intracellular polygluta- ranging from 0.2 to 5.2 mg/m2/d. Dose limiting toxic-
mation, resulting in prolonged intracellular retention.7 ities (DLTs) included neutropenia and reversible ele-
Pemetrexed and its polyglutamated metabolites in- vations of hepatic enzymes. The maximum tolerated
hibit several key folate-requiring enzymes, including dose (MTD) was 4.0 mg/m2/d. Minor responses were
thymidylate synthase (TS), dihydrofolate reductase, achieved in two patients, one each with nonsmall cell
glycinamide ribonucleotide formyltransferase, and lung cancer and colorectal cancer.11
aminoimidazole carboxamide ribonucleotide formyl- Fifty eight courses of pemetrexed were adminis-
transferase.7,8 Three of these pathways are illustrated tered to the 25 patients who received the weekly for 4
in Figure 1. The cytotoxicity of pemetrexed is thought weeks every 42 days schedule, as reported by Rinaldi
to be primarily mediated through TS inhibition.8 How- et al. Doses ranged from 10 to 40 mg/m2/wk. Neutro-
ever, inhibition of the other folate enzymes may also penia was dose-limiting at 40 mg/m2/week. Minor
be important, since pemetrexed is active against hu- responses were noted in two patients with colorectal
man cancer cell lines that are resistant to raltitrexed cancer.12
and 5-FU due to TS amplification.9 Pemetrexed shows The same group of investigators also treated 37
significant activity against a broad spectrum of tumors patients on the once every 21 days schedule. A total of
930 CANCER Supplement August 15, 2002 / Volume 95 / Number 4
TABLE 1
Phase I Trials of Pemetrexed
Author Schedule No. of patients MTD DLT Partial responses Minor responses
McDonald11 daily ⫻ 5 every 21 days 38 4 mg/m2/d neutropenia, elevated liver None One NSCLC one
enzymes colorectal cancer
Rinaldi12 weekly ⫻ 4 every 42 days 25 40 mg/m2/wk neutropenia None two colorectal cancer
Rinaldi13 once every 21 days 37 600 mg/m2 neutropenia, thrombocytopenia, two pancreatic cancer two six colorectal cancer
fatigue colorectal cancer
MTD: Maximum tolerated dose; DLT: dose-limiting toxicity; NSCLC: nonsmall-cell lung cancer.
TABLE 3
Phase I Trial of Pemetrexed Plus Gemcitabine in Patients with Advanced Solid Tumors18
Patients 34 21
Cycles 164 85
Vitamin supplementation None None
Maximum tolerated dose Gemcitabine 1000 mg/m2 Days 1 and 8 Gemcitabine 1250 mg/m2 Days 1 and 8
2
Pemetrexed 500 mg/m Day 1 Pemetrexed 500 mg/m2 Day 8
Dose limiting toxicity Neutropenia Neutropenia
Partial responses 12: 3 colorectal cancer, 3 nonsmall cell lung cancer, 2 cholangiocarcinoma, 2 ovarian cancer,
1 mesothelioma, 1 breast cancer
Pemetrexed was delivered 90 minutes later in escalat- diet should not affect the efficacy of pemetrexed. B12 is
ing dose levels of 200, 300, 400, 500, and 600 mg/m2 on required for the 15% of patients who are B12-deficient.
Day 1 of a 21 day cycle (Group I). Since neutropenia
that developed on Day 8 led to reduction or omission Phase II Trial of Pemetrexed/Gemcitabine in
of the gemcitabine dose in more than 57% of treat- Pancreatic Cancer
ment courses, a second group of patients (Group II) Given the known, albeit modest, activity of both gem-
received pemetrexed on Day 8. The results of this trial citabine and pemetrexed in pancreatic cancer, the in
are summarized in Table 3. vitro synergy of the two agents, and the broad activity
In Group I, 35 patients received 164 cycles of of the combination observed in the Phase I trial, Kin-
pemetrexed/gemcitabine. Twenty one patients in dler et al. initiated a multicenter Phase II trial of gem-
Group II received 85 cycles of chemotherapy. Neutro- citabine plus pemetrexed in September 1999. The trial
penia was dose limiting. Other toxicities included enrolled 42 previously untreated patients with histo-
rash, fatigue, and increased transaminases. The rec- logically proven, locally advanced or metastatic pan-
ommended Phase II doses were 1250 mg/m2 of gem- creatic cancer. Patients were required to have a
citabine on Days 1 and 8 and 500 mg/m2 of pem- Karnofsky PS of at least 60%, a life expectancy of 12
etrexed given on Day 8. This combination showed weeks, bidimensionally measurable disease, and nor-
activity in a broad range of tumors. There were 12 mal hematologic, hepatic, and renal function.
partial responses in the 35 evaluable patients. Phar- Patients received gemcitabine 1250 mg/m2 by IV
macokinetic analysis determined that prior adminis- infusion over 30 minutes on Days 1 and 8 of a 21 day
tration of gemcitabine did not alter the disposition of cycle. Pemetrexed 500 mg/m2 was administered by IV
pemetrexed. infusion over 10 minutes on Day 8, 90 minutes after
gemcitabine. All patients received premedication with
Vitamin Supplementation in Pemetrexed Trials dexamethasone to prevent rash. In November 1999,
Folic acid administered with pemetrexed preserves when safety data determined that toxicity could be
antitumor activity and reduces toxicity in human tu- prevented with folate and B12 supplementation, all
mor cell lines and in tumor bearing mice.19 A very patients were administered dietary levels of these vi-
sensitive marker of folate status is plasma homocys- tamins. Computed tomography scans were obtained
teine. In multivariate analysis, a baseline homocys- every two cycles to assess for response. Clinical benefit
teine level ⱖ 12 M is a predictor of Grade 3/4 pem- response, assessed by changes in pain, PS, or weight
etrexed toxicities, including diarrhea, rash, change, was monitored weekly.
neutropenia, thrombocytopenia, mucositis, and fa- The results of this trial will be presented at the
tigue.20 Supplementation with dietary levels of folate 2002 Meeting of the American Society of Clinical On-
and B12 significantly decreases toxicities related to cology.
pemetrexed.19 Since November 1999, all patients on
pemetrexed trials have received oral supplementation Phase III Trial of Pemetrexed/Gemcitabine
with 350-1000 g of folic acid daily and 1000 g B12 Promising results obtained in the Phase II trial of the
intramuscularly every nine weeks beginning at least combination of pemetrexed plus gemcitabine led to
one week prior to chemotherapy and continuing the development of an ongoing Phase III international
throughout treatment. It is thought that supplemen- trial in 520 patients. Previously untreated patients
tation of folic acid at a level equivalent to an American with locally advanced or metastatic pancreatic cancer
932 CANCER Supplement August 15, 2002 / Volume 95 / Number 4
are randomized by PS, disease stage, investigational ]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate
center, and baseline homocysteine level to one of two synthase. J Med Chem. 1992;35:4450 – 4454.
7. Mendelsohn LG, Shih C, Chen VJ, Habeck LL, Gates SB,
treatment regimens: gemcitabine 1,000 mg/m2 by IV
Shackelford KA. Enzyme inhibition, polyglutamation, and
infusion weekly on Days 1, 8, and 15 every 28 days, or the effect of LY231514 (MTA) on purine biosynthesis. Semin
gemcitabine 1,250 mg/m2 by IV infusion on Days 1 Oncol. 1999;26(2 Suppl 6):42– 47.
and 8 of a 21 day cycle plus pemetrexed 500 mg/m2 by 8. Shih C, Chen VJ, Gossett LS, et al. LY231514, a pyrrolo[2,3-
IV infusion on Day 8. Patients on the combination arm d]pyrimidine-based antifolate that inhibits multiple folate-
also receive vitamin supplementation with folate and requiring enzymes. Cancer Res. 1997;57:1116 –1123.
9. Schultz RM, Patel VF, Worzalla JF, Shih C. Role of thymidy-
B12. End points include overall survival, progression
late synthase in the antitumor activity of the multitargeted
free survival, objective response rate, quality of life, antifolate, LY231514. Anticancer Res. 1999;19:437– 443.
and toxicity. 10. Britten CD, Izbicka E, Hilsenbeck S, et al. Activity of the
multitargeted antifolate LY231514 in the human tumor clon-
CONCLUSIONS ing assay. Cancer Chemother Pharmacol. 1999;44:105–110.
11. McDonald AC, Vasey PA, Adams L, et al. A Phase I and
Pemetrexed, a new generation antifolate antimetabo-
pharmacokinetic study of LY231514, the multitargeted anti-
lite, has activity in pancreatic cancer. The 6% response folate. Clin Cancer Res. 1998;4:605– 610.
rate, while modest, is similar to other single agents in 12. Rinaldi DA, Burris HA, Dorr FA, et al. Initial Phase I evalu-
previously untreated patients with this disease, while ation of the novel thymidylate synthase inhibitor, LY231514,
the 28% one year survival is promising. Pemetrexed is using the modified continual reassessment method for dose
synergistic with gemcitabine in vitro, and the combi- escalation. J Clin Oncol. 1995;13:2842–2850.
13. Rinaldi DA, Kuhn JG, Burris HA, et al. A Phase I evaluation of
nation of these two drugs was broadly active and well
multitargeted antifolate (MTA, LY231514) administered ev-
tolerated in a Phase I study. The pemetrexed/gemcit- ery 21 days, utilizing the modified continual reassessment
abine combination has been evaluated in a recently method for dose escalation. Cancer Chemother Pharmacol.
completed Phase II trial. An ongoing Phase III trial 1999;44:372–380.
that compares the combination of pemetrexed/gem- 14. Miller KD, Picus J, Blanke C, et al. Phase II study of the
multitargeted antifolate LY231514 (ALIMTA, MTA, pem-
citabine to single agent gemcitabine will help to de-
etrexed disodium) in patients with advanced pancreatic
termine whether this combination improves survival cancer. Ann Oncol. 2000;11:101–103.
and quality of life for patients with advanced pancre- 15. Teicher BA, Chen V, Shih C, et al. Treatment regimens
atic cancer. including the multitargeted antifolate LY231514 in human
tumor xenografts. Clin Cancer Res. 2000;6:1016 –1023.
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