Small cell lung cancer (SCLC) is an unmet medical need, representing ∼15% of lung cancer diagnosed/year. Two-thirds of patients (pts) are diagnosed with extensive stage (ES) SCLC with a 2-year survival rate of 5%. Delta-like protein 3 (DLL3), an atypical Notch receptor family ligand, is highly expressed in SCLC and other neuroendocrine tumors with little to no expression in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate composed of a humanized DLL3-specific IgG1 monoclonal antibody tethered to a toxic DNA cross-linking agent. A Phase 1 study of Rova-T in SCLC pts showed encouraging progression-free and overall survival and a manageable safety profile1. Studies show that nivolumab (nivo, anti-PD-1 antibody) +/- ipilimumab (ipi, anti-CTLA-4 antibody) has antitumor activity and is well-tolerated in 2nd line SCLC. Given the complementary mechanisms of action and non-overlapping toxicities, futher study is warranted to evaluate if a combination of Rova-T and nivo, or all 3 agents leads to more pts with long-term responses and prolonged survival.
This Phase 1/2 study (NCT03026166) will enroll ∼90 pts in 3 cohorts. Each cohort will receive Rova-T 0.3 mg/kg IV on Day 1 of the 1st and 3rd 3-week cycle in combination with: nivo 360 mg/kg IV q3wk x 2 cycles (cohort 1) or nivo 1 mg/kg q3wk + ipi 1 mg/kg (cohort 2) or 3mg/kg (cohort 3) IV q3wk x 4 cycles. Maintenance nivo will be administered in all cohorts at 480 mg IV q4wk. The dose limiting toxicity (DLT) evaluation period is 12 weeks. Pt eligibility: ≥ 18 years; histologically or cytologically confirmed 2nd line or later ES SCLC; confirmed DLL3-positive status based on immunohistochemistry of baseline tumor tissue (for DLT evaluable pts); ECOG 0-1; no autoimmune disease; no prior exposure to immuno-oncology or pyrrolobenzodiazepine-based drugs. Primary and secondary objectives: assess safety and efficacy of Rova-T in combination with nivo or nivo + ipi. Exploratory objectives: assess expression of DLL3 and PD-L1 and their relationship to clinical outcome, pharmacokinetics, incidence of neutralizing antibodies, and effects on pharmacodynamic biomarkers. 1. Rudin et al., Lancet Oncol, 2016.
Clinical trial identification
Legal entity responsible for the study
C. Scripture, I. Lakatos, K. Boynton, S. Lally, T.H. Han, S.L. Peng, S.J. Dylla: Employee of AbbVie Stemcentrx and may own stock. G. Selvaggi: Employee of Bristol-Myers Squibb.