Maintenance therapy in non-small cell lung cancer
Thoracic oncology, Departement for Surgery, Medical Center Mannheim, University Heidelberg, Mannheim, Germany
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Cite this article as: Schmid-Bindert G. Maintenance therapy
in non-small-cell lung cancer. Transl Lung Cancer Res
2012;1(2):105-110. DOI: 10.3978/j.issn.2218-6751.2011.10.02
Review Article
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Abstract
With standard doublet chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we have reached an outcome plateau of about 10 months median overall survival over the last decades. Several studies have now demonstrated some survival benefits for patients treated beyond induction chemotherapy. In the current discussion about treatment duration, the terms “switch” and “continuation” maintenance therapy are now most commonly used by the scientific community. Switch maintenance is the treatment with an agent with a different mode of action after completion of induction chemotherapy in patients who’s tumors have not progressed, whereas continuation maintenance is the continuation of one compound of the induction regimen. Chemotherapeutic compounds successfully investigated in the maintenance setting are Gemcitabine, Docetaxel and Pemetrexed. Targeted agents, recently investigated as maintenance therapy are Bevacizumab, Cetuximab and Erlotinib. New peer-reviewed publications of phase III randomized clinical trials on maintenance chemotherapy have led to a change in current practice guidelines and the use of maintenance therapy represents a new treatment option in advanced NSCLC. The pivotal trials are described and summarized in this review article.
Key words non-small-cell lung cancer; maintenance therapy; Gemcitabine; Docetaxel; Pemetrexed; Bevacizumab; Cetuximab; Erlotinib
Transl Lung Cancer Res Oct 31, 2011. DOI: 10.3978/j.issn.2218-6751.10.02
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Introduction
According to the American society of clinical oncology (ASCO) guidelines (1) standard first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) in a good performance status is a platinum containing doublet chemotherapy given for 4 to 6 cycles. Over the last decades this treatment strategy has reached an efficacy plateau of about 10 months of median overall survival in large randomized phase III trials. Many efforts have been undertaken to improve efficacy and prolong overall survival in this group of patients, for example by developing new cytotoxic agents, such as pemetrexed (2). Some new targeted agents, Cetuximab and Bevacizumab, have also demonstrated to significantly improve overall survival when combined with certain combinations of chemotherapy (3,4). However, targeted agents are always maintained until disease progression, bringing up again the question about the role of treatment duration and scheduling in advanced NSCLC. Up to date several studies have demonstrated, that extending the number of cycles did improve progression free survival (PFS) but did not result in a prolongation of overall survival (OS) (5-10).
The ASCO guidelines therefor have just been updated in 2011 particularly with regard to maintenance therapy: “For patients with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of these data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.”
The changes in the guidelines are in response to new peer-reviewed publications of phase III randomized clinical trials on maintenance chemotherapy published recently. The aim of this article is, to review all newsworthy data from maintenance phase III studies, that have led to a change in clinical practice.
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Maintenance therapy: definitions
What does maintenance therapy mean? A lot of different terms are used in the literature, such as switch and continuation maintenance, consolidation, alternating or sequential therapy or early second line therapy. There is no clear definition in the literature about these terms and a general consensus on which terms to use has not yet been reached (11,12).
In principle, maintenance therapy is the administration of
treatment after a defined number of chemotherapy cycles, when
a patients’ tumor has not progressed. The treatment is continued
until unacceptable toxicity or disease progression.
If the treatment is continued for a defined number of
cycles after the induction chemotherapy, this is usually called
consolidation therapy.
There are two different ways to continue treatment: either
with a compound from the induction regimen, or with an agent
with a different mode of action, not used in the first-line regimen.
These two approaches are called “continuation” or “switch”
maintenance therapy and these terms have emerged to be most
commonly used in the current discussion about maintenance
therapy.
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Cytotoxic agents asmaintenance therapy
A number of phase III trials have investigated the value
of cytotoxic agents, both in a “switch” maintenance or a
“continuation” maintenance approach. The most important trials
are summarized in Table 1.
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Gemcitabine
Three phase III trials have investigated gemcitabine as a
“continuation” maintenance therapy in advanced NSCLC (Table 1). One randomized phase III study by Brodowicz et al. (14)
was performed to show significant difference in median time to
progression (TTP) in patients with advanced NSCLC treated
with single-agent Gemcitabine maintenance therapy versus best
supportive care following Gemcitabine plus Cisplatin initial firstline
therapy. 352 patients were enrolled. After initial therapy, 206
patients were randomized and treated with Gemcitabine or best
supportive care (BSC). Time to progression (TTP) throughout
the study period was 6.6 and 5 months for Gemcitabine and
BSC arms, respectively, while values for the maintenance period
were 3.6 and 2.0 months (for P<0.001 for both). Median OS
throughout study was 13.0 months for Gemcitabine and 11.0 months for BSC arms (P=0.195). The toxicity profile was mild,
with neutropenia being most common grade 3/4 toxicities.
Another trial by Belani et al. (15) with a similar trial design
failed to demonstrate a difference in PFS or OS between the
Gemcitabine and the BSC group. However, in this study only
16% of patients in the treatment arm and 16% in the BSC arm
received further treatment, which may be explained by the low
overall performance status of patients.
In a maintenance trial by Perol et al. Gemcitabine and
Erlotinib were compared to best supportive care (BSC). 464
patients were randomized to receive either Erlotinib (switch
maintenance), Gemcitabine (continuation maintenance) or no
further treatment (BSC). Unlike previous maintenance trials,
pemetrexed was predefined as second-line therapy in all arms.
Primary endpoint was PFS, which was significantly improved for
both maintenance arms, Gemcitabine and Erlotinib compared
to the observation arm (3,7 vs. 2,8 months vs. 2,1 months
respectively). Overall survival data have not yet been reported.
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Docetaxel
A phase III study compared immediate with delayed Docetaxel
after front-line therapy with Gemcitabine plus Carboplatin
(17). 566 chemotherapy-naïve patients with squamous or nonsquamous
NSCLC, stage IIIB with pleural effusion or stage IV,
were enrolled. Gemcitabine (1,000 mg/m2) was administered
on days 1 and 8 followed by Carboplatin (AUC 5) on day 1.
After four 21-day cycles, patients who did not have progression
were randomly assigned either to an immediate Docetaxel group
(Docetaxel 75 mg/m2 on day 1 every 21 days, with maximum
of six cycles) or to a delayed Docetaxel group. The primary end
point was OS measured from random assignment. Additional
analyses included tumor response, toxicity, progression-free
survival (PFS), and quality of life (QOL).
398 patients completed Gemcitabine plus Carboplatin
and 309 patients were randomly assigned equally to the two
Docetaxel treatment groups. Median PFS for immediate
Docetaxel (5,7 months) was significantly greater (P<0.0001) than for delayed Docetaxel (2.7 months). Median OS for
immediate Docetaxel (12.3 months) was greater than for delayed
Docetaxel (9.7 months), but the difference was not statistically
significant (P<0.0853). QOL results were not statistically
different (P=0.76) between the two groups. It has to be pointed
out that the number and percentage of patients who finally
assigned and were treated with Docetaxel was different between
the two study arms. In the delayed Docetaxel group only 98 of
154 patients have been treated with Docetaxel.
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Pemetrexed
In a multicenter randomized double blind placebo controlled
phase III trial (JMEN) 663 patients with all NSCLC histological
subtypes were included who had not progressed after four
cycles of chemotherapy with Cisplatin combined with either
Gemcitabine, Paclitaxel or Docetaxel (18). After the induction
chemotherapy the efficacy and toxicity of maintenance therapy
with Pemetrexed 500 mg/m2 plus BSC to that of placebo plus
BSC were compared. The patients were randomized 2:1 and
441 patients received Pemetrexed plus BSC, 222 placebo plus
BSC. In the maintenance treatment, patients received a median
number of 5 cycles Pemetrexed and 3,5 cycles placebo. 48.3% of
patients received 6 cycles or more of Pemetrexed and 23,4% of
patients 10 cycles or more. Pemetrexed significantly improved
PFS (4,3 months vs. 2,6 months; hazard ratio [HR] 0,50, 95%
CI 0,42–0,61, P<0.0001) and OS (13,4 months vs. 10,6 months;
HR 0.79, 0,65–0,95, P=0.012) compared to placebo in the ITT
population. Fewer patients on Pemetrexed compared to placebo
received systemic post-study therapy (227 [51%] vs. 149 [67%];
P=0.0001). In patients with predominantly non-squamous
histology median OS was 15,5 vs. 10,3 months (P=0.002). In
July 2009 Pemetrexed was approved for maintenance treatment
in first-line NSCLC stage IIIb/IV.
The question whether patients who receive Pemetrexed in
the induction chemotherapy would benefit from “continuation”
maintenance treatment with Pemetrexed has currently been
investigated in the PARAMOUNT trial (19). The primary
endpoint was PFS. After the induction chemotherapy with
Pemetrexed plus Cisplatin those 539 patients whose tumors
were not progressing were randomized 2:1 to receive either
Pemetrexed maintenance therapy or placebo until disease
progression. The median number of cycles in the maintenance
phase was 4 cycles for both arms. 23% of patients treated with
Pemetrexed received more then 6 cycles of maintenance versus
14% in the placebo arm. The study reached its primary endpoint,
demonstrating a benefit in PFS for Pemetrexed over placebo (3,9
vs. 2,6 months). Overall survival data are not yet mature.
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Targeted agents as maintenance therapy
Targeted agents, recently investigated as maintenance therapy are
listed in Table 2.
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Erlotinib
Maintenance Erlotinib was investigated in both, the Saturn and
Atlas trial (21,24). In the Saturn trial Erlotinib was compared
to placebo after first-line chemotherapy and given until disease
progression in patients with advanced NSCLC in both squamous
and non-squamous histology, who had not progressed after
initial treatment. Patients were stratified prior to randomization,
using the adaptive method of Pocock and Simon, to ensure
balance between treatment groups for EGFR protein expression
by IHC (EGFR Positive versus EGFR Negative versus EGFR
undetermined); Stage of disease at start of chemotherapy (IIIb
versus IV); ECOG PS (0 versus 1); Chemotherapy regimen
(Gemcitabine plus Cisplatin versus Carboplatin plus Docetaxel versus other); Smoking status (current smoker [includes patients
who had stopped smoking within a year] versus former smoker
versus never smoked); and Region (North America, South
America, Western Europe, Eastern Europe, South East Asia and
Africa). All patients were required to provide a tumor sample
for analysis of EGFR protein expression by IHC. Treatment
was continued until progression, death or unacceptable toxicity.
There was an improvement in PFS (HR 0.71; P<0.0001) and
overall survival was 12 vs. 11 month (HR 0.81; P=0.008)
in favour of Erlotinib. In a subgroup of patients with tumors
positive for EGFR protein expression the PFS hazard ratio was
0,69 (P<0.0001), whereas in the subgroup with negative EGFR
protein expression HR is only 0.91. In the subgroup of patients
with tumors positive for EGFR mutation the PFS hazard ratio
was best with 0,1 (P<0.0001), whereas in the subgroup with
EGFR wildtype HR is 0.78 (P=0.0185) . In the non-squamous
subgroup the benefit of OS was 13,7 vs. 10.5 month (P=0.0194),
in the squamous histology the difference was modest. OS for
Erlotinib was 11.3 month and for Placebo 11.1 month, HR 0.86
(0.68,1.10), P=0.2369. The ATLAS (21) trial confirmed the
significant survival benefit shown in the SATURN trial.
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Monoclonal Antibodies
A series of randomized studies have exlpored Cetuximab, a
monoclonal antibody against the epidermal growth factor
receptor (EGFR) in the treatment of advanced NSCLC. In
the first-line setting, the phase III FLEX study (First- Line
Erbitux in Lung Cancer) randomized 1125 patients with EGFRexpressing
tumors in stage‚ wet IIIB/IV, including all NSCLC
histologies. The study showed that the addition of Cetuximab to
cisplatin and vinorelbine followed by Cetuximab maintenance
therapy significantly improved survival when compared with
Cisplatin plus vinorelbine alone (11,3 vs. 10,1 months, HR
0.87, P=0.044) (4). Another study with a similar study design,
BMS099 (Bristol-Myers Squibb 099), exploring Paclitaxel plus
Carboplatin with or without Cetuximab, showed a comparable
numeric overall survival benefit for the patients treated with
Cetuximab. However, this difference was not statistically
significant, assumably due to the significantly lower number of
patients (median OS 9,7 versus 8,4 months, HR 0.89, P=0.169)
(23).
The vascular endothelial growth factor has also been
proven to be an effective therapeutic target in this setting. The
Eastern Cooperative Oncology Group (ECOG) 4599 study
demonstrated, that the addition of Bevacizumab to Paclitaxel
plus carboplatin followed by Bevacizumab maintenance
therapy significantly improved overall survival compared to
Paclitaxel plus Carboplatin alone. (12.3 vs. 10.3 months, HR
0.79, P=0.003) (3). Another study, AVAiL (Avastin in Lung
Study), investigated Cisplatin plus Gemcitabine with either Bevacizumab, at 7.5 or 15 mg/kg, or placebo (each administered
concurrently with chemotherapy and as a maintenance treatment
until disease progression). Patients treated with Bevacizumab had
a significant improvement in PFS compared with chemotherapy
plus placebo, for either the 7.5 or 15 mg/kg Bevacizumab
regimens (13.6 and 13.4 versus 13.1 months, HR 0.93 and HR
1.03, P=0.420 and P=0.761, respectively). However, overall
survival was not different between the treatment arms.
From the design of these four randomized studies no
conclusions can be drawn as to whether the clinical benefit
associated with the addition of the targeted agent to standard
first-line chemotherapy was conferred to the induction
chemotherapy, maintenance, or indeed both phases of treatment.
To demonstrate if those agents are effective as maintenance
therapy, alternative study designs are needed.
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Summary
Two randomized phase III studies have recently investigated
Pemetrexed and Erlotinib as “switch” maintenance therapy. Both
trials have met their primary endpoints and overall survival
was significantly improved in the maintenance arms. Based
on this convincing data these two compounds have now been
registered for “maintenance therapy”. A recently presented study
has now demonstrated also survival benefit for Pemetrexed in
a “continuation” maintenance approach, when Pemetrexed was
used already in the induction regimen. Thus, Pemetrexed could
be a new option for both strategies, switch and continuation
maintenance therapy.
According to the European Medicines Agency (EMA) “Alimta
now is indicated as monotherapy for the maintenance treatment
of locally advanced or metastatic non-small cell lung cancer other
than predominantly squamous cell histology in patients whose
disease has not progressed immediately following platinumbased
chemotherapy. First line treatment should be a platinum
doublet with Gemcitabine, Paclitaxel or Docetaxel”.
Regarding Erlotinib the Committee for Medicinal Products
for Human Use (CHMP) adopted a new indication as follows:
“Tarceva is indicated as monotherapy for maintenance treatment
in patients with locally advanced or metastatic non-small cell
lung cancer with stable disease after four cycles of standard
platinum-based first-line chemotherapy. When prescribing
Tarceva, factors associated with prolonged survival should be
taken into account”.
Bevacizumab, a monoclonal antibody against VEGF, and
Cetuximab, a monoclonal antibody against EGFR, have
demonstrated clinical benefit for patients, when added to firstline
chemotherapy and continued until disease progression.
However, to clarify whether the effect of the targeted agents
is attributed to the maintenance of the agents after induction
therapy, alternative study designs are required.
Bevacizumab is registered in the following indication:
“Bevacizumab in addition to platinum-based chemotherapy, is
indicated for first-line treatment of patients with unresectable
advanced, metastatic or recurrent non-small cell lung cancer
other than predominantly squamous cell histology”.
Although Cetuximab has reached its primary endpoint in the
phase III trial, it has not yet been approved for the treatment of
lung cancer in Europe.
A recent meta-analysis by Zhang et al. (25) has statistically
analyzed most of the above randomized controlled trials
altogether. The results of this meta-analysis suggest, that OS
and PFS are clearly in favor of maintenance therapy for both,
switch and continuation strategy. However, to give a clear
recommendation for the future, many other aspects like costeffectiveness
and toxicity must be taken into account.
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References
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