Sir,

Platelet-derived growth factor receptor (PDGFR) and C-kit are two tyrosine kinase receptors that have been implicated in several malignancies, including malignant mesothelioma (MMe).

Indeed, overexpression of PDGF-β 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 β-chain of PDGF; finally, blocking either PDGFR-β or PDGFR-α resulted in MMe growth inhibition [1].

Regarding C-kit, despite a large amount of uncertainty concerning the entity, type, and even the presence, of its expression in MMe [2], 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 agents [3].

We thus performed a pilot study of single-agent imatinib mesylate (Gleevec™), a tyrosine kinase inhibitor that targets both PDGF-R and C-kit, in naïve as well as pre-treated MMe patients.

Eligibility criteria included: histologically proven, PDGFR-β and/or C-kit-positive, unresectable or recurring 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 expectancy, 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 modified RECIST criteria for MMe.

Treatment-related toxic effects 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.

Table 1 Patients’ characteristics
Full size table

No objective responses were observed, the best result obtained being disease stabilization in four patients only (36.3%); the remaining seven patients (63.6%) progressed, despite treatment.

Median time to progression (TTP) was 8 weeks (average 10.9 ± 4.39, range 7–19), while median overall survival was 20 weeks (average 22.09 ± 11.16, range 9–42), fairly better for those who obtained a disease stabilization (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 chemotherapy and, until the recent registration of Pemetrexed, 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 field to test new therapeutic strategies, including molecularly targeted treatments.

In accordance with two previous experiences [4], [5], we demonstrated no activity of single-agent Gleevec in MMe patients. However, recent data from our laboratory suggest that Gleevec could synergize with some chemotherapeutic agents, at least in vitro [6]. Thus, despite the above results, the inhibition of the PDGFR and C-kit pathways deserves further studies in MMe.