Treatment rationale and study design for a phase III, double-blind,
placebo-controlled study of maintenance pemetrexed plus best supportive care
versus best supportive care immediately following induction treatment with
pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.
Author(s): Paz-Ares LG, Altug S, Vaury AT, Jaime JC, Russo F, Visseren-Grul C.
Affiliation(s): University Hospital - Virgen del Rocio, Seville, Spain. lpazares@hotmail.com
Publication date & source: 2010, BMC Cancer. , 10:85
BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small
cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after
initial induction chemotherapy in patients who did not progress during the
initial treatment, rather than waiting for disease progression to administer
second-line treatment. Maintenance therapy may consist of an agent that either
was or was not present in the induction regimen. The antifolate pemetrexed is
efficacious in combination with cisplatin for first-line treatment of advanced
NSCLC and has shown efficacy as a maintenance agent in studies in which it was
not included in the induction regimen. We designed a phase III study to determine
if pemetrexed maintenance therapy improves progression-free survival (PFS) and
overall survival (OS) after cisplatin/pemetrexed induction therapy in patients
with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression
levels of thymidylate synthase, the primary target of pemetrexed, may be
associated with responsiveness to pemetrexed, translational research will address
whether thymidylate synthase expression correlates with efficacy outcomes of
pemetrexed.
METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction
chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day
1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group
performance status of 0 or 1 who have not progressed during induction therapy
will randomly receive (in a 2:1 ratio) one of two double-blind maintenance
regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive
care (BSC) or placebo plus BSC. The primary objective is to compare PFS between
treatment arms. Secondary objectives include a fully powered analysis of OS,
objective tumor response rate, patient-reported outcomes, resource utilization,
and toxicity. Tumor specimens for translational research will be obtained from
consenting patients before induction treatment, with a second biopsy performed in
eligible patients following the induction phase.
DISCUSSION: Although using a drug as maintenance therapy that was not used in the
induction regimen exposes patients to an agent with a different mechanism of
action, evidence suggests that continued use of an agent present in the induction
regimen as maintenance therapy enables the identification of patients most likely
to benefit from maintenance treatment.
TRIAL REGISTRATION: Trial Registry: Clinicaltrials.gov REGISTRATION NUMBER:
NCT00789373 TRIAL ABBREVIATION: H3E-EW-S124.
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