Background: Notch signaling is implicated in cancer stem cell self-renewal and proliferation, thus it is an appealing target in the treatment of SCLC. TRXT, a fully human IgG2 antibody targeting Notch2 and 3 receptors, has shown preclinical efficacy in SCLC models in combination with cisplatin. This Phase Ib study explores the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of TRXT with EP in chemo-naive ED-SCLC. Here we report updated safety and efficacy data. Methods: Cohorts of 3 to 6 pts were treated at each dose level using a standard 3+3 design. TRXT was given IV on Day 1 of each 21 day cycle with etoposide 100 mg/m² (Days 1- 3) and cisplatin 80 mg/m² or carboplatin at AUC 5 (Day 1). After 6 cycles, those pts without disease progression or unacceptable toxicities continued TRXT alone every 21 days. Once the MTD of TRXT with etoposide and cisplatin was established, the MTD of TRXT plus etoposide and carboplatin was evaluated in a cohort of 6 subjects. Results: As of November 17, 2015, 27 pts were treated with TRXT doses ranging from 5 mg/kg to 15 mg/kg. The MTD was not reached and TRXT 15 mg/kg was determined to be the Phase 2 dose. Frequently reported ( ≥ 15%) TRXT-related adverse events were: diarrhea (63%), fatigue (44.4%), nausea (37%), anemia (33.3%), decreased appetite (29.6%), vomiting (29.6%), alopecia (22.2%) and thrombocytopenia (22.2%); most were Grade 1 or 2, and reversible.The median number of TRXT doses received was 6. The overall response rate was 73%. By January 12, 2016, the mOS was 10.3 months with median follow up of 9.8 months for all pts. The mOS was 16.0 months for pts receiving TRXT doses at ≥ 12.5 mg/kg, and 7.6 months for pt at < 12 mg/kg. Conclusions: TRXT with EP was well tolerated. Dose dependent antitumor activity was seen. Updated PK/PD, safety, and efficacy data as well as exploratory predictive biomarker data and correlation with clinical response will be presented. A randomized placebo-controlled phase 2 study with this regimen is ongoing. Clinical trial information: NCT01859741