AKT phosphorylation and gefitinib efficacy in patients with advanced non-small cell lung cancer

Purpose: Aim of this trial was to evaluate correlation between P-AKT/P-MAPK status and gefitinib activity in terms of Response Rate (RR) and Time to Progression (TTP) in Non-Small Cell Lung Cancer (NSCLC) patients. Patients and 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. The multivariate analysis showed 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. The role of loss of PTEN and the impact of previous therapies on PI3K-AKT pathway activation should be addressed in further prospective trials.