Background: Hsp90 is a molecular chaperone recognized as a key facilitator of cancer cell growth and survival. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown single-agent activity in patients with lung, breast, and other cancers after progression on standard treatments. Ganetespib in combination with docetaxel induces synergistic efficacy in human non-small-cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and has not shown severe liver or common ocular toxicities reported for other Hsp90 inhibitors. Transient diarrhea is the most common adverse event, and is manageable with appropriate supportive care. A large randomized Phase 2 study of ganetespib in combination with docetaxel in advanced NSCLC patients (GALAXY-1 Trial) indicated good tolerability of the combination, and improvement in efficacy, including OS. Methods: GALAXY-2 is a randomized (1:1), international, open-label Phase 3 study enrolling patients who received and progressed on 1 prior systemic platinum-based combination therapy for advanced NSCLC of adenocarcinoma histology, were diagnosed ≥6 months before study entry, and whose tumors are negative for both EGFR mutations and ALK translocation (Target Patient Population [TPP]). Patients (N=700 TPP) are prospectively stratified for ECOG PS, total screening LDH, and geographic region (North America and Western Europe vs Rest of World). The primary endpoint is OS in the TPP. Key secondary endpoints include PFS, ORR, DCR, and DOR in the TPP. OS will also be analyzed in 3 subpopulations of the TPP: mKRAS, elevated LDH, and elevated LDH5. Patients in the control arm are treated with docetaxel 75 mg/m² on Day 1 of a 3-week cycle. In the combination arm, ganetespib 150 mg/m² is given on Day 1 with 75 mg/m² docetaxel, and ganetespib 150 mg/m² alone is given on Day 15 of each 3-week cycle. Two interim analyses for OS will be performed. Tumor tissue and blood samples will be collected for planned translational studies. Clinical trial information: NCT01798485.