Improved efficacy of gefitinib therapy in phospho-Akt positive patients with advanced non-small cell lung cancer

Abstract

3004 Background: At the present time there is no reliable and identifiable marker that would help to identify those patients who are more likely to respond to gefitinib therapy. In some of the patients with NSCLC, EGFR may be the critical pathway signalling tumor growth. It is possible that responding patients are those in whom cell survival is maintained by activated EGFR-dependent pathways and in whom these pathways are suppressed by gefitinib. We investigated whether the evaluation of the Ras/raf/MAPK and the PI3K-AKT pathways before starting gefitinib therapy could help in identifying responding patients. This trial has been designed in order to possibly correlate Phospho-AKT/Phospho-MAPK status and gefitinib activity in terms of Response Rate (RR) and Time to Progression (TTP). Methods: Consecutive patients with NSCLC progressing or relapsing with standard therapy received gefitinib at a daily dose of 250 mg given until disease progression, unacceptable toxicity or refusal. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine P-AKT/P-MAPK status by immunohistochemistry. Results: One hundred-six NSCLC patients were enrolled onto the study in three Italian Institutions, and 103 were evaluable for P-AKT/P-MAPK status. P-AKT was positive in 51 (49.5%) and negative in 52 (50.5%) patients. P-MAPK resulted positive (2+/3+) in 23 (22.3%) and negative (0/1+) in 80 (77.7%). P-AKT positive status resulted significantly related to female gender (P<0.001), smoking history (P<0.05), and bronchioloalveolar histology (P<0.05). Compared to the P-AKT negative group, P-AKT positive patients had better RR (26.1% versus 3.9%, P=0.003), disease control rate (60.9% versus 23.5%, P<0.001), and significantly longer TTP (5.5 versus 2.8 months, P=0.004). No difference was observed in patients P-MAPK 0/1+ versus 2+/3 in terms of RR, disease control rate and TTP. Multivariate analysis confirmed that P-AKT positive status resulted in a significant reduction of disease progression risk (HR: 0.66, CI 95%:0.40–1.10). Conclusions: Gefitinib therapy resulted more active in P-AKT positive patients. No significant financial relationships to disclose.