A Randomized Open Label Phase II Trial Comparing BIBW2992 Plus Simvastatin With BIBW2992 Plus Best Supportive Care in Previously Treated Patients With Advanced (Stage IIIB/IV) Non-adenocarcinomatous Non-small Cell Lung Cancer (NSCLC)
One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that
there are alternative mechanisms for persistent activating EGFR downstream signaling,
including both RAS/Erk and PI3K/Akt kinase pathways. Therefore, simultaneous inhibition of
both pathways would be necessary to reduce tumor cell survival more effectively. One of the
candidate combinations is concurrent use of EGFR-TKIs and statins, which are irreversible
inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been used
to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Beside
the cholesterol lowering effect, statins have been shown to induce apoptosis in several
tumor types. It affects the synthesis of other products of the mevalonate pathway such as
isoprenoids, which are used as substrates for prenylation. Attachment of isoprenoids to RAS
proteins facilitates their anchoring to the cell membrane where they carried out their
roles. By interrupting the biosynthesis of mevalonate, statins inhibit activation of RAS and
downstream signaling cascades, including the RAF/MEK/ERK and PI3K/AKT, which play critical
roles in regulation of cell survival and proliferation. Therefore, it seems to be a
promising therapeutic approach overcoming tumor resistance to EGFR-TKIs, which is associated
with RAS activation.
According to the recent clinical result of phase II trial, a randomized phase II study of
gefitinib with or without simvastatin in previously treated patients with advanced NSCLC
conducted by Han et al.37 gefitinib plus simvastatin combination produced higher response
rates than gefitinib alone in patients with non-adenocarcinoma (5/13 [39%] v 1/13 [8%],
P=0.06). This finding suggests that simvastatin may enhance sensitivity to gefitinib in
non-adenocarcinoma that is relatively resistant to gefitinib. Moreover, by Mantha et al.35
demonstrated that the combination of gefitinib and lovastatin showed significant synergic
cytotoxic effects in vitro in a total of 16 squamous cell carcinomas, NSCLC, and colon
carcinoma cell lines. Of special interest, these cell lines did not possess the activating
mutations of EGFR, which confer increased sensitivity to gefitinib. Nevertheless, combining
lovastatin with gefitinib induced more significant inhibition of AKT activation than either
agent alone. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib
treatment regardless PTEN loss in glioblastoma cell lines. These results suggest that
statins can augment EGFR inhibition.
Interventional
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Objective response rate
Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
each 8 weeks
No
JI-YOUN HAN, M.D. PhD.
Principal Investigator
National Cancer Center
Korea: Food and Drug Administration
NCCCTS-10-489
NCT01156545
October 2010
December 2015
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