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Cite this article as: Stinchcombe TE. INFORM; C-TONG
0805: A multicenter, double blind randomized phase III trial of
maintenance gefitinib compared to placebo in advanced nonsmall
cell lung cancer. Transl Lung Cancer Res 2012;1(2):102-104. DOI: 10.3978/j.issn.2218-6751.2012.06.03
Research Highlight
INFORM; C-TONG 0805: A multicenter, double blind randomized
phase III trial of maintenance gefitinib compared to placebo in
advanced non-small cell lung cancer
Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, North Carolina, USA
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Submitted May 10, 2012. Accepted for publication Jun 08, 2012.
DOI: 10.3978/j.issn.2218-6751.2012.06.03 |
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The standard first-line therapy for patients with locally
advanced or metastatic non-small cell lung cancer
(NSCLC) is platinum-based chemotherapy (1). With
standard first line platinum-based therapy approximately
75% of patients will obtain disease control, the median
progression-free survival (PFS) is 4-6 months, and median
overall survival (OS) is 10-13 months (2-5). Phase III trials
that investigated a longer duration compared to a shorter
duration of platinum-based therapy failed to reveal an
improvement in OS with the longer duration of therapy
(6-9). This led to phase III trials of maintenance therapy
with single agent chemotherapy or epidermal growth factor
receptor tyrosine kinase inhibitors (EGFR TKI) to extend
the duration of therapy (10,11). The goal of maintenance
therapy is to delay disease progression and consequently
improve OS and maintain health-related quality of life
(HRQOL). In order to achieve these goals the therapy
must have a low rate of grade 3 or 4 toxicity and limited
cumulative toxicity so that patients can tolerate the extended
duration of therapy. A phase III trial of gefitinib compared
to docetaxel revealed the non-inferiority of gefitinib in an
unselected patient population, and a lower rate of grade 3
or 4 neutropenia and febrile neutropenia and of all grades
of asthenia (12). Thus, gefitinib is an attractive maintenance
agent.
The INFORM; C-TONG 0804 trial randomized
patients who had completed four cycles of platinum-based
therapy without disease progression or unacceptable toxicity
to gefitinib or placebo; the primary end-point was PFS (13). Patients assigned to the gefitinib arm (n=148) compared to
the placebo (n=148) had a significantly longer PFS (hazard
ratio (HR) of 0.42, 95% confidence interval of 0.33 to 0.55;
P<0.0001); the OS did not differ between the treatment
groups (HR of 0.84, 95% CI, 0.62 to 1.14; P=0.26). The
temptation is to compared the results of this trial to the
Sequential Tarceva in Unrectable NSCLC (SATURN)
trial which investigated maintenance erlotinib compared
to placebo after four cycles of platinum-based therapy
(n=889) (11). The SATURN trial revealed that maintenance
erlotinib compared placebo improved PFS (HR of 0.71,
95% CI, 0.62 to 0.82; P<0.0001) and OS (HR of 0.81,
95% CI, 0.70 to 0.95; P=0.0088). However, the clinical
characteristics of patient enrolled in the two trials differed
vastly, and most likely the prevalence of EGFR tyrosine
kinase (TK) mutations probably differed substantially. In
the SATURN trial the majority of patients were current or
former smokers (>80%), were Caucasian (84%), and only a
minority of patient’s tumor were adenocarcinoma histology
(45%). In contrast, in the INFORM trial all the patients
were Asian, the majority of patients had adenocarcinoma
(71%), and the majority of patients were never smokers
(54%). The numerical difference in the HR for PFS
between the two trials is most likely due to a difference in
the prevalence of EGFR TK mutations. The lack of OS
benefit observed in the INFORM trial could be due to
the smaller size of the trial and/or a high rate of EGFR
TKI therapy in the placebo arm at the time of disease
progression.
In both trials analyses based on EGFR TK mutation
status were performed, but only a small subset of patients
had confirmed EGFR TK mutant tumors. In the INFROM
trial, among patients with a known EGFR TK mutation,
patients in the gefitinib arm (n=15) compared to the placebo
arm (n=15) experienced a significantly longer PFS (HR of 0.17, 95% CI, 0.07 to 0.42). This is similar for to the
HR for PFS observed for patients with EGFR TK mutant
tumors in the SATURN trial (HR of 0.10, 95% CI, 0.04 to
0.25; P<0.0001) (11). The authors should be commended
for not performing an exploratory OS analysis in the EGFR
TK mutant since the small sample size, the confounding
factor on subsequent EGFR TKI therapy, and the limited
number of events would have made such an analysis
fundamentally flawed. Patients with EGFR TK wild-type
tumors in the gefitinib (n=25) compared to the placebo
arm (n=24) did not experience a statistically significant
improvement in PFS (HR of 0.86, 95% CI, 0.48 to 1.51);
OS analysis was not performed.
Patients’ HRQOL was assessed, and 81% of patients
had assessable HRQOL data; mean compliance with the
FACT-L questionnaire completion in the gefitinib and
placebo arms was 47% and 33%, respectively. Patients in
the gefitinib arm compared to the placebo arm experienced
a significantly relevant improvement in lung cancer
symptoms and median time to worsening in lung cancer
symptoms. The improvement in symptoms observed in the
gefitinib compared to the placebo arm is probably related
to the higher overall response rate observed in the gefitinib
arm (24% vs. 1%, P=0.0001), and the delay in time to
worsening of lung cancer symptoms is probably related to
the higher disease control rate (72% vs. 51%, P=0.0001).
The toxicities observed with consistent with previous trials
of gefitinib; three treatment-related deaths were observed
in the gefitinib arm.
The results of the INFORM trial provide evidence
of clinical benefit of maintenance gefitinib. However,
since the trial was designed and initiated there have been
significant changes in the treatment of advanced NSCLC.
The majority of patients with advanced NSCLC are
undergoing EGFR TK mutational testing at the time of
diagnosis, and patients with EGFR TK mutant tumors are
receiving EGFR TKI therapy as first-line therapy. Thus,
the role of EGFR TKI maintenance therapy in patients
with known EGFR TK mutant tumors is limited. In the
increasingly rare situation in which patients have completed
chemotherapy and are subsequently found to have an EGFR
TK mutation I initiate maintenance EGFR TKI therapy
based on the significant improvement in PFS observed in
this patient population. Thus, the more frequent clinical
question is the role of EGFR TKI therapy in patients with
EGFR wild-type tumors. Maintenance erlotinib compared
to placebo did demonstrate a statistically significant
improvement PFS and OS among patients with EGFR
wild-type tumors (n=388) in the SATURN trial. The lack
of a statistically significant benefit among EGFR wild-type
patients in the INFORM trial is most likely related to the
smaller size of the EGFR wild-type cohort. For the patients
who are candidates for maintenance therapy with confirmed
EGFR wild-type tumor and non-squamous histology,
I have generally used pemetrexed maintenance therapy
based on the larger improvement in PFS and OS observed
in the maintenance pemetrexed trials (10,14
). In patients
with EGFR wild-type tumors who are not candidates for
maintenance pemetrexed I discuss with the patient the
potential risks and benefits of maintenance EGFR TKI and
observation.
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Acknowledgements
Disclosure: The author declares no conflict of interest.
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References
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