Molecular correlates of the EGFR signaling pathway in association with SWOG S0218: a phase II study of oral EGFR tyrosine kinase inhibitor OSI-774 (NSC-718781) in patients with malignant pleural mesothelioma (MPM)

Abstract

3007 Background: MPM is a tumor that shows high expression of EGFR. We evaluated OSI-774, a novel EGFR tyrosine kinase inhibitor (TKI) in MPM and correlated tumor molecular expression of the EGFR signaling pathway with clinical outcomes. Methods: Chemonaive MPM patients (pts) with PS 0–1, and adequate organ function were treated with continuous oral daily dosing with OSI-774 150 mg. Study endpoints were to estimate 1) 1 year and progression free survival (PFS), response rate, frequency and severity of toxicities; 2) To preliminarily correlate clinical outcome with molecular expression of the EGFR signaling pathway in tumor tissue. Results: 64 pts were enrolled between 5/02 and 4/03; 63 are eligible for analysis. Median age was 69.5 yrs; 47 (75%) were male. 30 pts with measurable disease are evaluable for response. No pts had objective responses; 47% had SD; 43% had PD. Survival data for 63 patients is as follows: There have been 32 deaths; 6 month survival is estimated at 60% (95% confidence interval 48%–73%); PFS is estimated at 28% (95%C.I. 16%–38%) at 6 months. For 60 pts, frequent toxicities were grades 1–3 rash (82%), fatigue (50%), diarrhea (53%), and pruritus (30%). One patient died of grade 5 respiratory failure. Tumor immunohistochemistries (IHC) are below: Conclusions: Lack of phosphorylation of AKT and lack of PTEN expression in the AKT pathway downstream of EGFR may be a mechanism of MPM's clinical resistance to OSI-774. ERK is variably activated among tumors; interestingly, it appears activated in the sarcomatous elements of MPM, suggesting that the ERK signaling pathway is important in the molecular pathogenesis of the more aggressive sarcomatous phenotype of MPM. No significant financial relationships to disclose.