5900 - PTEN loss as Predictor of Tumor Heterogeneity (TH) and Poor Prognosis in EGFR-mutant Advanced Non-Small Cell Lung Cancer (ANSCLC) Patients (pts) Receiving Tyrosine-Kinase Inhibitors (TKIs).

Background

Although the dramatic activity of EGFR TKIs for EGFR-mutant ANSCLC, nearly 20% of pts do progress rapidly. Poor prognosis was demonstrated to be associated with TH, which may be mirrored by the co-existance of concomitant mutant drivers, such as PTEN. The aim of this analysis was to investigate the correlation between the loss of function of PTEN (as a mirror of TH), and the activity/efficacy of EGFR-TKIs for advanced EGFR mutant ANSCLC pts.

Methods

FFPE-tumor blocks of EGFR-mutant ANSCLC pts undergone upfront TKIs from 2015 to 2017 were retrospectively collected (follow-up >18 mo. was required for maturity). The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry (IHC) and it was correlated with objective response rate (ORR), overall- and progression-free-survival (OS/PFS). Kaplan-Maier (KM) analysis was performed for independent factors at multivariate analysis.

Results

Forty-two EGFR-mutant ANSCLC pts were included [median age 65 yrs (42-86); M/F: 45/55%; current/former/never smoker: 13.5/35/51.5%; PS (ECOG) 0/1/2/3: 30/55/12.5/2.5%; GEF/AFA/ERL: 72.5/25/2.5%; del19/L858R/rare: 60/35/5%]. At multivariate analysis, PTEN loss (HR 6.02, 95% CI 2.48-14.5, p < 0.0001) and metastatic sites >2 (HR 2.38, 95% CI 1.01-5.62, p = 0.048) were significantly associated with shorter PFS. At KM analysis, pts with PTEN loss (13) had a median PFS of 2.0 mo. (95% CI 0-5.4) and a 1-year PFS of 7.7%, in comparison with pts without (27), median PFS 18.3 mo. (95% CI 16.5-20.1), 1-year PFS 69.6% (log-rank p < 0.0001). Coherently, at the multivariate analysis, PTEN loss (HR 5.11, 95% CI 2.06-12.6, p < 0.0001) and PS of 2-3 (HR 6.57, 95% CI 2.01-21.5, p < 0.002) were significantly associated with shorter OS. Pts with PTEN loss had a median OS of 4.5 mo. (95% CI 0.2-8.9) and a 1-year PFS of 15.4%, in comparison with pts without, median OS 26.9 mo. (95% CI 16.7-37.1), 1-year OS 81.5% (log-rank p < 0.0001).

Conclusions

A low-cost and reproducible IHC assay for PTEN-loss analysis represents a potential tool for identifying TH of EGFR-mutant ANSCLC pts. A powered clinical validation is currently ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Emilio Bria.

Funding

Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

Disclosure

E. Bria: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.