Cancer Chemother Pharmacol (2007) 59: 149–150
LETTER TO THE EDITOR
Camillo Porta · Luciano Mutti · Gianfranco Tassi
Negative results of an Italian Group for Mesothelioma (G.I.Me.)
pilot study of single-agent imatinib mesylate in malignant pleural
Received: 18 February 2006 / Accepted: 24 March 2006 / Published online: 25 April 2006
© Springer-Verlag 2006
Platelet-derived growth factor receptor (PDGFR)
and C-kit are two tyrosine kinase receptors that have
been implicated in several malignancies, including malig-
nant mesothelioma (MMe).
Indeed, overexpression of PDGF- receptors has
been demonstrated in MMe cell lines, xenografts as well
as in patient specimens. Furthermore, one of the most
common genetic abnormalities observed in MMe
involves chromosome 22q13, which codes for the -chain
of PDGF; Wnally, blocking either PDGFR- or
PDGFR- resulted in MMe growth inhibition .
Regarding C-kit, despite a large amount of uncer-
tainty concerning the entity, type, and even the presence,
of its expression in MMe , transfection of C-kit in
MMe cells, in the presence of its ligand stem cell factor
(SCF), up-regulates the transcriptional repressor Slug
and increases the resistance to several chemotherapeutic
We thus performed a pilot study of single-agent
imatinib mesylate (Gleevec™), a tyrosine kinase inhibi-
tor that targets both PDGF-R and C-kit, in naïve as well
as pre-treated MMe patients.
Eligibility criteria included: histologically proven,
PDGFR- and/or C-kit-positive, unresectable or recur-
ring MMe, measurable disease, an ECOG Performance
Status of · 2, a CALGB prognostic score of · 4,
age ¸ 18 and < 70 years, at least 12 weeks’ life expec-
tancy, as well as a written informed consent; patients
were also required to have adequate organ function.
Gleevec™, directly purchased by G.I.Me., was given,
per os, at the dose of 200 mg b.i.d.; disease status was
evaluated at baseline and then every 2 months on spiral
high-resolution CT images using the recently developed
and validated modiWed RECIST criteria for MMe.
Treatment-related toxic eVects were recorded and
reported according to the NCI-CTC version 3.0.
Eleven patients were enrolled in this pilot study,
whose characteristics are reported in Table 1.
No objective responses were observed, the best result
obtained being disease stabilization in four patients only
(36.3%); the remaining seven patients (63.6%) pro-
gressed, despite treatment.
Median time to progression (TTP) was 8 weeks (aver-
age 10.9 § 4.39, range 7–19), while median overall sur-
vival was 20 weeks (average 22.09 § 11.16, range 9–42),
fairly better for those who obtained a disease stabiliza-
tion (average 29.5 vs. 14 weeks).
Treatment was well tolerated, with few cases of grade
3/4 toxicities (nausea 2/11, i.e., 18.1%; neutropenia,
fatigue, edema and rash 1/11, i.e., 9% each).
Malignant mesothelioma is relatively resistant to che-
motherapy and, until the recent registration of Pemetr-
exed, no regimen has emerged as a standard of care.
Even though a real breakthrough, these results should
still be considered as unsatisfactory; thus, MMe is still an
ideal Weld to test new therapeutic strategies, including
molecularly targeted treatments.
In accordance with two previous experiences ,
, we demonstrated no activity of single-agent Glee-
vec in MMe patients. However, recent data from our
laboratory suggest that Gleevec could synergize with
some chemotherapeutic agents, at least in vitro .
Thus, despite the above results, the inhibition of the
PDGFR and C-kit pathways deserves further studies
C. Porta (&)
Medical Oncology, I.R.C.C.S. San Matteo University Hospital,
Piazzale C. Golgi, 27100 Pavia, Italy
Local Health Authority 11, Piedmont, Italy
Pneumology, Civic Hospital, Brescia, Italy