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Pemetrexed in Previously Treated Non–Small-Cell Lung Cancer

Pemetrexed in Previously Treated Non–Small-Cell Lung Cancer

ABSTRACT: Several decades of chemotherapy trials in non–small-cell lung cancer (NSCLC) have clearly shown a survival benefit for chemotherapy over best supportive care. However, only short-lived responses are attained, with an average of four cycles of chemotherapy, before tumor progression is observed. Second-line chemotherapy has been demonstrated to improve outcome, with docetaxel (Taxotere) as the predominant cytotoxic drug. A recent randomized trial in second-line NSCLC indicated that the novel drug pemetrexed (Alimta) attained the same response, time to progression, and survival as docetaxel. This finding ushers in a new age in second-line treatment that can be further invigorated by the addition of targeted agents. Accumulated evidence indicates that overexpression of epidermal growth factor receptor and HER2/neu, which occurs frequently in NSCLC, leads to the deregulation of PI3K and MAPK, activating Akt and enhancing chemoresistance. Future clinical trials in NSCLC will include tailored and multitargeted therapy and pemetrexed represents a significant step forS ward in this direction.

Second-line chemotherapy in
non-small-cell lung cancer
(NSCLC) is a relatively new
approach. For a long time, it was not
recognized that cisplatin-based chemotherapy
improved survival in the
metastatic setting. A Canadian
study[1] showed a median survival of
4 months with best supportive care
and 8 months (P = .01) with vindesine
(Eldesine) at 3 mg/m2 weekly
* 4 and then every 2 weeks plus cisplatin
at 120 mg/m2, days 1 and 21
and then every 6 weeks. One-year
survival rates were 10% and 22%,
respectively.

The cisplatin-based chemotherapy
meta-analysis[2] of cisplatin combined
with vinca alkaloids or etoposide
showed a chemotherapy benefit
with a hazard ratio of 0.73 and an
increase in median survival of 1.5
months. The response rate with gemcitabine
(Gemzar)/cisplatin was higher
than with etoposide/cisplatin (41%
vs 22%; P = .02) and time to progression
was also longer in the gemcitabine
arm (6.9 vs 4.3 months; P =
.01).[3] In the British study, median
survival was 6.7 months with mitomycin
(Mutamycin)/ifosfamide (Ifex)/
cisplatin (MIC) as compared to 4.8
months with best supportive care (P =
.03).[4]

In the Southwest Oncology Group study,[5] cisplatin-based chemotherapy
was a strong significant prognostic
factor for survival. Furthermore,
in cisplatin-treated patients, three different
prognostic subsets were observed
based on performance status,
age, hemoglobin, and lactate dehydrogenase
(LDH), with 1-year survival
of 27%, 16%, and 6% (P

More recently, overexpression of
genes involved in the nucleotide excision
repair pathway has been related
to cisplatin response and survival.
In gemcitabine/cisplatin-treated patients,
overexpression of excision repair
cross-complementing 1 (ERCC1)
mRNA was associated with a median
survival of 5 months, in contrast with
15 months in patients with normal
ERCC1 mRNA levels (P = .009).[6]
In spite of the statistically demonstrated
benefit of cisplatin chemotherapy,
patients often perceive a
relatively small benefit, and hence are
reluctant to receive chemotherapy.

In scripted interviews, when patients
were asked to indicate the benefit
required to accept the toxicity
associated with chemotherapy, only
22% chose chemotherapy over best
supportive care for a survival benefit
of 3 months.[7] Moreover, in a British
study, patients were randomized
to receive three or six cycles of mitomycin/
vinblastine/cisplatin (MVP); no
differences were observed in time to
progression (5 months in both arms)
or in median survival (6 vs 7
months).[8]

No single chemotherapy combination
has demonstrated an overall superiority
to any other in survival
benefit[9,10] or in quality of life[10]
in metastatic NSCLC. The average
time to progression ranged from 3.4
to 5.5 months, median survival from
7.4 to 9.9 months, 1-year survival from
31% to 43%, and 2-year survival from
10% to 13%.[9,10] In these studies, a
fraction of patients received poststudy
therapy, mainly with crossover doublet
combinations.[10] However, no
consistent second-line treatment had
been undertaken until recently. The
British randomized study[8] highlighted
the point that time to progression
occurred early on, after three to five
cycles of chemotherapy.

Customized chemotherapy can
help to improve outcome by selecting
patients[11] and planning second-line
treatment in all clinical trials. There
are only a few drugs that have demonstrated
activity in the second-line approach, and there is some evidence
of activity for cisplatin-based chemotherapy
in patients receiving frontline
noncisplatin combinations.[12]

Phase II Second-Line
Trials in NSCLC

Multiple phase II studies have been
performed with almost all available
cytotoxic drugs. The majority of these
studies included vinorelbine (Navelbine),
gemcitabine, paclitaxel, and
docetaxel (Taxotere). A complete review[
13] found that with the exception
of docetaxel, the response in some
of these studies was null. Median survival
from the time of starting second-
line treatment ranged from 3 to
11 months (Table 1). Many of these
early phase II studies included a small
number of patients. Moreover, from
the inclusion criteria, it is difficult to
discern whether the patients were cisplatin-
refractory (no response was
observed) or cisplatin-resistant (a prior
response was attained), as there
was no common agreement on the
concept of cisplatin-resistant and
-refractory tumors.[13] The largest
gemcitabine study, including 83 patients,
attained a partial response of
19%, including patients who had previously
responded to gemcitabine/cisplatin
chemotherapy.[14]

Pemetrexed (Alimta) has been tested
in patients with progressive disease
within 3 months after first-line
chemotherapy or progression while
being treated with first-line chemotherapy.[
15] Patients were stratified
according to whether the first-line
treatment included a platinum regimen.
Pemetrexed was administered at
500 mg/m2 every 21 days. The response
rate was 4.5% in the platinumpretreated
group and 14% in the
non-platinum-pretreated group. Median
survival was 6.4 and 4 months,
respectively. Time to progression was
2.3 and 1.6 months, respectively (Table
1). In this trial, no folic acid or
vitamin B12 was administered. Vitamin
supplementation with daily folic
acid (350 μg) and vitamin B12 (1,000
μg) every 9 weeks significantly lowered
homocysteine levels and reduced
severe myelosuppression and gastrointestinal
toxicity.[16]

Randomized Second-Line
Trials in NSCLC

To date, the only drug approved
for second-line treatment of NSCLC
is docetaxel, based on the results of
two phase III randomized studies (Table
2).[17,18] Among the many intriguing
questions surrounding this
point, perhaps the most salient is why
paclitaxel has not been identified as a
potential second-line treatment. Several
lines of evidence indicate that
HER2/neu overexpression is related
to paclitaxel resistance.

Prez-Soler et al reported that in
NSCLC heterotransplants in nude
mice, lack of HER2/neu expression
was linked to better response to paclitaxel
(0% of responding tumors and
48% of nonresponders expressed
HER2/neu).[19] Furthermore, paclitaxel
yielded a significantly lower
growth inhibition than docetaxel in
HER2/neu-overexpressing MCF/18
cells (a MCF-7 human breast cancer
cell line transfected with HER2/
neu).[20] Growth factor receptor-mediated
signal transduction has been
involved in chemoresistance. The
HER2/neu/phosphatidylinositol-3 kinase
(PI3K)/Akt pathway mediates
resistance to chemotherapy and EGFR inhibitors. Overexpression of Akt confers
chemoresistance in NSCLC.[21]
Akt regulates cell survival by phosphorylating
downstream apoptotic targets
(BAD, procaspase 9, Forkhead
family of transcription factors, NFkappaB
regulator IKK) (Figure 1).[22]
The loss of phosphatase PTEN leads
to activation of Akt.[23] In breast cancer
cell lines, expression of both
HER2/neu and HER3 caused a PI3Kdependent
activation of Akt that was
linked to increased resistance to paclitaxel,
doxorubicin, fluorouracil (5-
FU), etoposide, and camptothecin.[24]

These preclinical lines of evidence
have led some investigators to design
second-line studies of gefitinib (Iressa,
an EGFR inhibitor) plus trastuzumab
(Herceptin, a HER2/neu
inhibitor). HER2/neu has been studied
by immunohistochemistry in resected
NSCLC tumors, and 2+ or 3+
overexpression was found in 17%.[25]
However, with real-time quantitative
polymerase chain reaction (RTQPCR),
HER2/neu mRNA expression
was detected in 100% of specimens
analyzed. HER2/neu expression level
segregated patients into poor and good
prognostic subgroups. The segregation
method used a tumor-normal tissue
ratio of 1.8 as a cutoff value.[26]
Almost 35% of patients had high
HER2/neu expression, and nearly 38%
had high epidermal growth factor receptor
(EGFR) expression. High
HER2/neu expression was associated
with inferior survival in this group of
resected NSCLC patients.

The Shepherd et al study[17] demonstrated
that docetaxel at 75 mg/m2 every 3 weeks yielded a 6% response.
When compared with best supportive
care, time to progression was 3 vs 1.7
months, median survival was 7.5 vs
4.6 months, and 1-year survival was
37% vs 12%. These differences were
all statistically significant. Better outcome
was observed in patients with a
performance status of 1, those who
had responded to prior cisplatin treatment,
those who had received only
one prior chemotherapy regimen,
those who had no weight loss, or those
with normal LDH (Table 2). The Fossella
et al [18] study showed as well
that docetaxel at 75 mg/m2 every 3
weeks achieved a 7% response rate,
with a median survival of 5.7 months
and a 1-year survival of 30%, while
vinorelbine or ifosfamide yielded a
1% response rate, with a median survival
of 5.6 months and a 1-year survival
of 20%. The differences at 1
year were significant. In this study,
prior paclitaxel treatment did not influence
the responses attained with
docetaxel (Table 2).

The Camps et al[27] phase III study
compared two different docetaxel dose
schedules (75 mg/m2 every 3 weeks
vs 36 mg/m2 weekly for 6 weeks, every
8 weeks). Preliminary observations
in 179 patients show response
rates of 11% and 7%, time to progression
of 3.4 and 3.5 months, and median
survival of 6.3 and 6.1 months, respectively.
Eighteen percent of patients had
received prior paclitaxel-based treatment.
No substantial differences in toxicity
were observed (Table 2).

Hanna et al conducted the largest
phase III randomized trial in secondline
treatment,[28] comparing docetaxel
at 75 mg/m2 every 3 weeks with
pemetrexed at 500 mg/m2 every 3
weeks. In the pemetrexed arm, folic
acid (350-1,000 μg daily) and vitamin
B12 (1,000 μg every 9 weeks)
were administered. Patients were stratified
according to performance status,best response to prior chemotherapy,
number of prior chemotherapy
regimens, time since last chemotherapy,
prior platinum- and taxane-based
chemotherapy, and baseline homocysteine
serum levels. Ninety percent of
patients had received prior cisplatin
treatment and 26% had received prior
taxanes. The median number of cycles
administered was 4 in both arms.

Response rates were 8.8% in the
docetaxel arm and 9.1% in the pemetrexed
arm, respectively. Time to progression
was 2.9 months in both arms.
Median survival was 7.9 and 8.3
months, respectively. One-year survival
was 29.7% in both arms (Table
2). While response, time to progression,
and survival were similar in the
two arms, in the pemetrexed arm less
severe neutropenia, fewer hospitalizations,
and less need for ancillary measures
were observed. This study opens
the gates for new second-line chemotherapy
combinations (Figure 2).

A phase II second-line randomized
trial of irinotecan/cisplatin vs cisplatin
alone was carried out in patients
pretreated with taxanes/gemcitabine.[
29] Response rates were 24% and
8.3%, respectively. Time to progression
was 2.5 and 2 months, respectively.
Median survival was identical
in both arms (9 months). One-year
survival was 40.5% and 31.2%, respectively
(Table 2). Although the number
of patients included in the trial was
small, the results were promising for
the use of the novel combination.

EGFR inhibitors have also been
used as targeted therapies, attaining
meaningful response rates ranging
from 11% to 18.4%, with median survival
times of 6.5 to 8.4 months, and
1-year survival rates of 29% to
40%.[30,31] These outcomes are relevant,
especially considering that most
of these patients had received more
than two prior chemotherapy regimens.
Skin toxicity was linked to better
survival in some of these trials
(Table 2). The combination of cetuximab
(Erbitux), the monoclonal antibody
against the extracellular
ligand-binding domain of EGFR, plus
docetaxel yielded a 25% response rate
with a 7.5-month median survival.[32]

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