Background: Hsp27 is over-expressed in many cancers and is associated with inhibition of chemotherapy-induced apoptosis. Apatorsen (A) is an antisense oligonucleotide that binds to Hsp27 mRNA and inhibits Hsp27 production; A has been shown to inhibit tumor growth and sensitize tumor cells to chemotherapy in numerous malignancies, including lung. Preclinical models demonstrate increased apoptosis with pemetrexed and platinum with A treatment. This study assessed the benefit of adding A to standard 1^st line chemotherapy for patients (pts) with advanced non-squamous non-small-cell lung cancer (NS-NSCLC). The primary endpoint was progression-free survival (PFS), with overall survival to be assessed later as a secondary endpoint. Methods: 155 pts with advanced NS-NSCLC were randomized 1:1, stratified by histology and smoking status. Pts received 3 IV loading doses of 600 mg A or placebo (PL) one week (wk) prior to chemotherapy. Pts received pemetrexed 500 mg/m², carboplatin AUC 6, and 600 mg A or PL on Day 1 every 3 wks. A or PL was also administered on days 8 and 15 of each cycle. Results: 155 pts were randomized. Demographics were similar between arms: median age 66 yr vs 67 yr; males 49% vs 49%; current/former smokers 70% vs 64% for A vs PL, respectively. Median PFS was A 6.0 months (mo) vs PL 4.9 mo; HR (2-sided 95% CI) was 0.922 (0.634, 1.340), p = 0.6687. Objective response rate: A 26% vs PL 31%. Median duration of treatment was A 15 wks vs PL 19 wks. High baseline serum Hsp27 levels ( > 9.3 ng/mL) were observed in 10% of pts. For pts with high Hsp27, median PFS was A 10.8 mo vs PL 4.8 mo. Grade 3/4 treatment-related toxicities were A thrombocytopenia (28%), neutropenia (27%), anemia (18%), leukopenia (12%), vs PL thrombocytopenia (30%), neutropenia (31%), anemia (20%), leukopenia (24%). Conclusions: A was not associated with a statistically significant improvement in PFS when added to 1^st line NS-NSCLC chemotherapy. Subset data suggest that high Hsp27 expression may be a method for optimally selecting pts for tx. OS data are pending and expected later this year. Clinical trial information: NCT01829113