Background: Notch signaling is implicated in cancer stem cell self-renewal and proliferation; thus being an appealing target in the treatment of SCLC. Tarextumab (TRXT), a fully human IgG2 antibody targeting Notch2 and 3 receptors, has shown preclinical efficacy in SCLC models with cisplatin. This Phase Ib study explores the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of TRXT with EP in chemo-naive ED-SCLC. Methods: Notch signaling is implicated in cancer stem cell self-renewal and proliferation; thus being an appealing target in the treatment of SCLC. Tarextumab (TRXT), a fully human IgG2 antibody targeting Notch2 and 3 receptors, has shown preclinical efficacy in SCLC models with cisplatin. This Phase Ib study explores the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of TRXT with EP in chemo-naive ED-SCLC. Results: By November 18, 2014, 27 pts were treated with TRXT at dose range 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. One DLT of Grade 3 nausea and vomiting was reported in the 10 mg/kg dose cohort. Frequently reported ( ≥ 15%) TRXT-related adverse events were: diarrhea (59.3%), fatigue (44.4%), nausea (40.7%), anemia (25.9%), decreased appetite (25.9%) and vomiting (25.9%); most were Grade 1 or 2 and managed with supportive care. The overall response rate was 84%. The median duration of treatment was 128 days (6 cycles) with mPFS and mOS of 124 and 228 days, respectively. The median follow-up for PFS and OS was of 86 and 107 days respectively. Conclusions: TRXT with EP is well tolerated. Encouraging anti-tumor activity has been observed. Final safety, efficacy, PK, immunogenicity and predictive biomarker results will be presented. TRXT at a dose of 15 mg/kg has been selected for the phase 2 randomized, placebo-controlled portion of the study, which is ongoing. Clinical trial information: NCT01859741