Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas
represent the third leading cause of cancer mortality worldwide.
Despite significant therapeutic improvement, the outcome
of patients with advanced gastroesophageal adenocarcinoma
is poor. Randomized clinical trials failed to show a signi ficant survival benefit in molecularly unselected patients with
advanced gastroesophageal adenocarcinoma treated with anti EGFR agents.
Experimental Design: We performed analyses on four cohorts:
IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients),
COG (214 patients), and the Fondazione IRCCS Istituto Nazionale
dei Tumori (206 patients). Preclinical trials were conducted in
patient-derived xenografts (PDX).
Results: The analysis of different gastroesophageal adenocarci noma patient cohorts suggests that EGFR amplification drives
aggressive behavior and poor prognosis. We also observed that
EGFR inhibitors are active in patients with EGFR copy-number gain
and that coamplification of other receptor tyrosine kinases or KRAS
is associated with worse response. Preclinical trials performed on
EGFR-amplified gastroesophageal adenocarcinoma PDX models
revealed that the combination of an EGFR mAb and an EGFR
tyrosine kinase inhibitor (TKI) was more effective than each
monotherapy and resulted in a deeper and durable response. In
a highly EGFR-amplified nonresponding PDX, where resistance to
EGFR drugs was due to inactivation of the TSC2 tumor suppressor,
cotreatment with the mTOR inhibitor everolimus restored sensi tivity to EGFR inhibition.
Conclusions: This study underscores EGFR as a potential ther apeutic target in gastric cancer and identifies the combination of an
EGFR TKI and a mAb as an effective therapeutic approach. Finally,
it recognizes mTOR pathway activation as a novel mechanism of
primary resistance that can be overcome by the combination of
EGFR and mTOR inhibitors.