Background: Advanced NSCLC management has evolved toward individual tumor subtyping based on targetable oncogenic drivers. Most molecularly characterized lung adenocarcinoma patients (pts) could thus potentially benefit from targeted treatment. This study investigates the innovative paradigm of allocating pts to specific treatment arms based on their genetic profile. The targeted therapies AUY922 (HSP90 inhibitor[i]), BYL719 (PI3Ki), LDK378 (ALKi), INC280 (METi), and MEK162 (MEKi) will be evaluated in different pt subgroups with appropriate confirmed molecular aberrations, in a single cluster study. Methods: This Phase II, multiple arm, open-label study will enroll pts (aged ≥18 years, ECOG PS ≤2) with advanced (stage IIIB/IV) lung adenocarcinoma bearing different molecular alterations, who have failed prior treatment or are unsuitable for chemotherapy, and have received ≤2 prior lines of therapy. Pts must have locally obtained documentation of a relevant molecular alteration from either a new or the most recent archival tumor sample, using primary genetic profiling. Pts will be allocated to a specific treatment arm accordingly (AUY922, 70 mg/m² QW: activating EGFR mutation and resistant to EGFR inhibitors; BYL719, 350 mg QD: PIK3CA mutation/amplification [other PI3K pathway alterations may be eligible]; INC280, 600 mg BID: MET-positive tumors [by IHC or FISH]; LDK378, 750 mg QD: ALK or ROS1 rearrangement; MEK162, 45 mg BID: KRAS, NRAS or BRAF mutation). Sample size was calculated based on a Bayesian approach using either a minimally informative prior (BYL719, INC280 and MEK162; N=20 for each) or an informative prior using relevant historical data (AUY922 [N=30] and LDK378 [N=25]). The sample size will allow detection with high likelihood, of statistically and clinically relevant antitumor activity. Each treatment arm is independent from one another and will be analyzed separately. Study treatment is given until disease progression or discontinuation. The primary endpoint is overall response rate; secondary endpoints are overall survival, progression-free survival, disease control rate, duration of response, safety, and pharmacokinetics.