Pemetrexed: Its Promise in Treating Non–Small-Cell Lung Cancer
Pemetrexed: Its Promise in Treating Non–Small-Cell Lung Cancer
Lung cancer, the most common
type of cancer in men, has increased
its incidence in women
over the past decade. Lung cancer is
the major cause of cancer-related
death in both North America and Europe,
and approximately 75% of lung
cancers are non-small-cell lung cancers
(NSCLC). NSCLC treatment
varies according to patient tumor stage
at time of diagnosis. Many patients
receive multimodality treatment consisting
of various combinations of surgery,
radiotherapy, and chemotherapy.
In early-stage (nonmetastatic)
NSCLC, combination chemotherapy
is being clinically assessed as an integral
part of multimodality treatment
regimens, either as neoadjuvant (inductive,
preoperative) or adjuvant
(postoperative) chemotherapy, or in
patients who are inoperable as concurrent
or sequential radiochemotherapy.[
In advanced (locally advanced or
metastatic) NSCLC, combination chemotherapy
containing platinum compounds
is an important component of
palliative therapy, since combination
chemotherapy improves survival, provides
symptom relief, and improves quality of life when compared with
best supportive care alone. As
chemotherapy gains wider acceptance
as a part of the initial treatment in
advanced and early-stage NSCLC, the
need for an effective second-line chemotherapy
grows. This is particularly true because increasing numbers of
patients receive combined-modality
therapy for early-stage NSCLC that
includes chemotherapy, and they may
be candidates for second-line treatment
at the time of disease progression
Preclinical and Early
Pemetrexed (Alimta) is a novel
acid) distinguished by a
unique 6-5-fused pyrrolo [2,3-d] pyrimidine
nucleus that differs from the
more common core structures of other
antifolates that have 6-6-fused pteridine
or quinazoline rings (Figure
1). Pemetrexed gains entry to the
cell via the reduced folate carrier, and
it is an excellent substrate for folylpolyglutamate
synthase once localized,
with the highest affinity of any
antifolate. Polyglutamation traps pemetrexed
and enhances its intracellular
retention. The parent drug is polyglutamated
90- to 195-fold more efficient
than methotrexate and 6- to
13-fold more efficient than the antipurine
5,6,7,8-tetrahydrofolic acid (lometrexol).[
5] The increased cellular retention
of pemetrexed forms may explain
the success of the 3-week
Pemetrexed inhibits multiple enzyme
targets involved in both pyrimidine
and purine synthesis, including
at least thymidylate synthase, dihydrofolate
carboxamide ribonucleotide formyltransferase,
and glycinamide ribonucleotide
targets are related to the cytotoxicity
of pemetrexed, as both thymidine and hypoxanthine are required to circumvent
death. Severe, unpredictable, and
occasionally fatal myelosuppression
and gastrointestinal toxicities have
been associated with antifolate agents.
Data accumulated in the past few years
suggest that plasma homocysteine is
a sensitive measure of the functional
folate status, and under conditions of
folate deprivation, plasma homocysteine
levels increase. Vitamin B12 and
B6 deficiencies can also result in high
Data from early pemetrexed trials
suggest that an elevated plasma homocysteine
concentration was indicative
of preclinical folate deficiency,
and resulted in a more severe toxicity
profile that typically included thrombocytopenia,
neutropenia, severe diarrhea,
and mucositis. Therefore, all
patients enrolled in pemetrexed clinical
trials over the past 2 to 3 years
received folic acid and vitamin B12
supplementation as follows: oral folic
acid at 350 to 1,000 μg administered
at least 5 continuous days prior to
pemetrexed and continuing throughout
therapy. Vitamin B12 at 1,000 μg
was administered intramuscularly with
folic acid and repeated every 9 weeks
while the patient was on study (Figure
2). Moreover, current data from
Vogelzang et al indicate that supplemental
use of vitamins can ameliorate
some of the severe drug-induced toxicity
effects resulting in improved
safety profile and efficacy for this
Pemetrexed is currently under clinical
investigation for a variety of solid
tumors, including NSCLC. Given
the important role of systemic chemotherapy
for the treatment of early
and advanced NSCLC, pemetrexed
has been tested in various doses and
several combinations in the first- and
second-line therapy settings.
Single-Agent Activity in NSCLC
Initial phase II study results demonstrate
that pemetrexed has singleagent
activity in chemonaive and
Two trials of single-agent pemetrexed
were undertaken in previously untreated
patients.[9,10] In Clarke et al's Australian/South African study,
all patients (n = 59) were treated with
pemetrexed at 600 mg/m2. Among 57
evaluable patients, overall response
rate was 16% (9 partial remissions),
median time to progression was 4.4
months, median duration of response
was 4.9 months, median survival was
7.2 months, and 1-year survival rate
In the Canadian trial (n = 33) of
Rusthoven and coworkers, patients
initially received pemetrexed at 600
mg/m2 IV for 10 minutes every 3
weeks. However, after three patients
were treated on this dose, it was reduced
to 500 mg/m2 IV due to toxicity.
Four of 33 patients assessable for
toxicity (13.3%) developed febrile
neutropenia and 13 patients (39%)
grade 3/4 neutropenia; four patients
experienced grade 4 thrombocytopenia.
The main nonhematologic toxicity
(> grade 2) was skin rash and
lethargy. Use of prophylactic dexamethasone
for 3 days starting the day
before pemetrexed significantly reduced
skin toxicity both in frequency
In 30 patients evaluable for response,
a partial response was obtained
in 23% of the patients, median
time to progression was 3.8 months,
median duration of response was 3.1
months, median survival was 9.2
months, and 1-year survival rate was
In chemotherapy-pretreated patients
with advanced NSCLC, Smit et
al conducted a large phase II trial of
pemetrexed as second-line treatment
in Europe and Australia. Patients
with stage IIIB or IV NSCLC were
eligible for accrual if they had relapsed
during or within 3 months of
prior chemotherapy. Patients with a
performance status of 2 were not enrolled.
Pemetrexed was administered
as a 10-minute IV infusion at a dose
of 500 mg/m2 every 3 days. Dexamethasone
4 mg was taken twice per
day orally on the day before, the day
of, and the day after each dose of
pemetrexed. Leucovorin administration
was recommended for any patients
who experienced grade 4
neutropenia, grade 4 thrombocytopenia,
or grade 3/4 mucositis. Antiemetic
medication was given according to standard recommendations. Vitamin
supplementation was not used.
Out of 79 patients considered evaluable
for efficacy, 44 had progressive
disease during or shortly after platinum-
containing therapy and 35 had
progressive disease during or shortly
after a non-platinum-containing regimen.
Six patients had partial responses
and one patient had a complete
response, for an overall response rate
of 8.9%. A total of 25 patients (31.6%)
achieved stable disease and 30 patients
(38%) had progressive disease.
Median duration of response was 6.8
months, median survival time was 5.7
months, and median time to progression
was 2 months (Table 1).
Based on these favorable results,
Hanna et al reported the results of the
largest phase III prospective randomized
trial ever conducted in secondline
NSCLC (n = 571). In this
registration trial, investigators compared
pemetrexed with the widely accepted
standard treatment docetaxel
(Taxotere). In the trial, 288 patients
were randomized to receive a
1-hour infusion of docetaxel at
75 mg/m2 on day 1 every 3 weeks.
The remaining 283 patients received
a 10-minute infusion of pemetrexed
at 500 mg/m2 on day 1 every 3 weeks.
Patients in both arms of the study received prophylactic dexamethasone;
only patients in the pemetrexed arm
received folic acid and vitamin B12
supplementation. The study was designed
to demonstrate an 80% chance
of superiority. The primary study end
point was survival; the secondary end
points were tumor response rate, progression-
free survival, and toxicity.
The results can be summarized as
follows: pemetrexed and docetaxel
have similar efficacy demonstrated for
response rates (9.1% vs 8.8%), median
survival (8.3 months vs 7.9 months;
Figure 3), and progression-free survival
(2.9 months each). The one-year
survival rate was 29.7% for each arm.
Pemetrexed had a more favorable hematologic
toxicity profile when compared
with docetaxel. Severe neutropenia
(grade 3/4) was seen in 5.3%
for the pemetrexed arm and 40.2%
for the docetaxel arm (P < .001). The
difference in the incidence of febrile
neutropenia and subsequent hospitalizations
between the pemetrexed and
docetaxel arms was also statistically significant (febrile neutropenia: pemetrexed
1.9%; docetaxel 12.7%; P < .001 [Table 2]; hospitalizations because
of febrile neutropenia: pemetrexed
1.5%; docetaxel 13.4%; P < .001). Patients on pemetrexed also required
significantly less granulocyte
colony-stimulating factor (G-CSF)
than patients on docetaxel (2.6% vs
19.2%; P < .001) (Table 3).
In light of these magnitudes of significant
difference compared to docetaxel,
the authors concluded that
pemetrexed possesses a more favorable
toxicity profile than docetaxel,
and is an effective second-line agent
Pemetrexed in Combination
Pemetrexed is an attractive candidate
for combination therapy, due to
its unique mechanism of action and
short infusion time. A number of different
combination therapies have
been investigated, eg, with gemcitabine
(Gemzar), irinotecan (Camptosar),
fluorouracil (5-FU), or
Our German/Austrian study was the first phase II study of pemetrexed/ cisplatin completed in advanced NSCLC. The dose and schedule selected for the study were based on the experience reported by Thodtmann and collegues in their clinical/pharmacokinetic phase I study of pemetrexed plus cisplatin. Thus, all patients received pemetrexed at 500 mg/m2 IV over 10 minutes, followed by cisplatin at 75 mg/m2 30 minutes later; treatment was preferably administered on an outpatient basis every 21 days. Cisplatin administration and pre- and posthydration were performed according to local policy. Patients also received dexamethasone at 4 mg orally twice per day on the day before, the day of, and the day after pemetrexed administration. Antiemetic medications were administered according to standard. Vitamin supplementation was not used, and G-CSF was not recommended routinely. A total of 36 chemotherapynaive patients were enrolled (all evaluable for response). Fourteen (39%) patients achieved partial remission, and 17 (47%) patients had stable disease as their best response. The median duration of response was 10.4 months, with 75% of patients having response duration exceeding 9 months. The median time to progression was 6.3 months, 56% of patients remained progression-free at 6 months, 36% at 9 months, and 33% at 1 year, respectively. The median survival was 10.9 months, and the 1-year survival percentage was 50%. Twenty-one (59%) patients experienced grade 3/4 granulocytopenia without fever or infection. Four (11%) and six (17%) patients experienced grade 3 anemia and grade 3/4 thrombocytopenia, respectively. Nonhematologic toxicity included grade 3 nausea in two (6%) patients, and grades 3/4 diarrhea in one (3%) patient each. One patient each experienced grade 4 alanine aminotransferase (ALT), grade 3 bilirubin, and grade 3 aspartate aminotransferase (AST) elevations. Shepherd and colleagues of the National Cancer Institute of Canada Clinical Trials Group used an identical study design in the second phase II study of pemetrexed and cisplatin (n = 31). Out of 29 patients evaluable for response, 13 (45%) obtained a partial response. Median duration of response was 6.1 months, median time to progression was 5.8 months, median survival time was 8.9 months, and 1-year survival rate was 49%, respectively. Grade 3/4 anemia was observed in 5/1 patients, and grade 3/4 granulocytopenia in 7/4 patients, respectively. Grade 3 nausea and emesis occurred in only two patients, grade 3/4 diarrhea in 3 patients, and two patients had grade 3 motor neuropathy. It is fair to conclude that these phase II studies demonstrate that pemetrexed/ cisplatin is effective and welltolerated. Response rates obtained are almost twice as high as single-agent pemetrexed and are comparable to the response rates shown by other new drugs, which have been tested in combination with cisplatin. The outpatient feasibility provided by the short infusion time of pemetrexed and the treatment schedule of once every 3 weeks further enhances the convenience of this regimen. Pemetrexed/Carboplatin
For the carboplatin (Paraplatin)/ pemetrexed combination, the phase II recommended study dose is pemetrexed at 500 mg/m2 and carboplatin at an area under the concentrationtime curve (AUC) of 5, given in 3- week intervals with both drugs administered on day 1. A recent phase II trial from Scagliotti et al indicated that pemetrexed/carboplatin is effective and well tolerated as frontline chemotherapy in patients with locally advanced NSCLC (n = 80). In this study, 39 patients in the pemetrexed/ carboplatin arm (arm A) received pemetrexed at 500 mg/m2 and carboplatin at AUC 6 on day 1 of a 21-day cycle for up to six cycles of therapy. (Arm B consisted of 41 patients receiving pemetrexed at 500 mg/m2 plus oxaliplatin [Eloxatin] at 120 mg/m2.) Vitamins and dexamethasone were provided per pemetrexed therapy. The confirmed response rate was 33% (vs 27% for arm B), with stable disease reported for 41% (vs 44%) of patients, respectively. Neither time to disease progression nor survival data have been reported yet. For the pemetrexed/carboplatin arm, the main grade 3/4 hematologic toxicity included neutropenia (26%) and thrombocytopenia (18%). Main nonhematologic toxicities consisted of grade 3 fatigue (8%) and stomatitis (32.6%). In the pemetrexed/oxaliplatin arm, no grade 4 hematologic toxicities were reported, with grade 3 neutropenia (5%), thrombocytopenia (2%), and anemia (2%). Main nonhematologic toxicities were grade 3 vomiting (7%), neuropathy (2%), diarrhea (2%), and hypersensitivity reactions (2%). Another phase II study (n = 50) by Zinner et al used pemetrexed at 500 mg/m2 administered on day 1 followed by carboplatin at AUC 6 given on day 1, every 3 weeks, for six cycles. The overall response rate was 28%, with a median time to progression of 4.8 months. Five patients (10%) had grade 3/4 nonhematologic toxicity, with mild alopecia and sensory neuropathy. Two patients had grade 3 thrombocytopenia and 15 experienced grade 3/4 neutropenia. Pemetrexed/Gemcitabine
Both the suggested preclinical synergy and the documented efficacy in advanced NSCLC provided the rationale to investigate pemetrexed and gemcitabine (Gemzar) in combination. Adjei et al identified a dose for phase II studies as gemcitabine at 1,250 mg/ m2 days 1 and 8 and pemetrexed at 500 mg/m2 (90 minutes after gemcitabine) on day 8, every 3 weeks. Based on the phase I combination trial results (objective responses obtained in three NSCLC patients), Ettinger and coworkers initiated a multicenter phase II trial combining pemetrexed and gemcitabine in chemonaive patients with stage IIIB/ IV NSCLC (n = 60). The dose and schedule was gemcitabine at 1,250 mg/m2 as a 30-minute IV infusion on days 1 and 8 and pemetrexed at 500 mg/m2 as a 10-minute IV infusion, 90 minutes after gemcitabine, on day 8 every 3 weeks with prophylactic dexamethasone. Vitamin supplementation with folic acid and vitamin B12 was initiated after the trial began due to pemetrexed-related toxicity. The data so far indicate that pemetrexed/gemcitabine is active and possesses a comparable toxicity pro-file to other relevant doublets. Out of 54 patients evaluable for response, 9 (17%) had a partial response, with 29 (54%) with stable disease. Median progression-free survival was 4.9 months, median overall survival 11.3 months, and 1-year survival 44%. Median duration of response was 3.3 months. The observed grade 3/4 hematologic toxicities in 60 patients evaluable for toxicity were neutropenia in 29%/34% of the patients, neutropenic fever in 13%/2%, thrombocytopenia in 5%/0%, and anemia in 12%/0% of the patients. Reported grade 3/4 nonhematologic toxicities reported were AST/ALT elevations in 16/21%, diarrhea in 3/2%, fatigue in 23/0%, and skin rash in 3/0% of patients. Pemetrexed/Vinorelbine
Clarke et al conducted a phase II study to determine the response rate of the platinum-free combination pemetrexed/vinorelbine (Navelbine) in the first-line treatment of advanced NSCLC. Patients received pemetrexed at 500 mg/m2 day 1 and vinorelbine at 30 mg/m2 days 1 and 8 as a 10-minute IV infusion every 3 weeks. Folic acid and vitamin B12 supplementation were given to reduce the hematologic toxicities noted in previous pemetrexed studies. Efficacy and toxicity results were reported for 34 of the 36 enrolled patients. Grade 4 hematologic toxicities included neutropenia in 15 patients and leukopenia in six. Grade 3/4 nonhematologic toxicities included fatigue (n = 7), dyspnea (5), nausea (3), and stomatitis (1). Two patients discontinued treatment due to toxicity (neutropenic sepsis, stomatitis) and one discontinued due to fatigue. Twelve patients achieved a partial remission and eight patients had stable disease. The authors concluded that pemetrexed in combination with vinorelbine is well tolerated and has promising activity. Conclusions In non-small-cell lung cancer, pemetrexed has shown promising activity and can safely be administered as either a single-agent or in combination for first- and second-line chemotherapy. Pemetrexed's toxicity profile improves significantly with the concomitant administration of dexamethasone, vitamin B12, and folic acid. In second-line chemotherapy, singleagent pemetrexed may be a candidate to replace docetaxel as a standard treatment because of lower toxicity and increased patient feasibility. For first-line chemotherapy, the role of platinum-based and platinum-free pemetrexed combinations still needs to be defined in randomized phase III studies. However, phase II data indicate high efficacy with favorable toxicity profile for pemetrexed combined with cisplatin, carboplatin, oxaliplatin, gemcitabine, and vinorelbine.
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