Background and Objectives: DV281 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Nivolumab is a PD-1 inhibitor that has demonstrated activity in advanced/metastatic NSCLC. Study DV9- NSC-01 (NCT03326752) is a phase 1b/2 study to assess safety and pharmacodynamic activity of DV281 in combination with nivolumab in patients with advanced or metastatic NSCLC and to determine the recommended dose for expansion.

Methods: Anti-PD-1/L1 experienced or naïve patients were enrolled in 2L or 3L NSCLC in the escalation phase, 3+3 design: 5 dose cohorts, with intra-patient dose escalation between the first 2 monotherapy doses: cohort 1: 1 mg; cohort 2: 1 to 3 mg; cohort 3: 3 to 10 mg; cohort 4: 10 to 15 mg; cohort 5: 15 to 25 mg. Nivolumab was administered at 240 mg Q2w. Safety was primary objective and pharmacodynamic effects including IFN-inducible gene expression were key secondary objective. DV281 is administered via inhalation, first alone, weekly for 2 doses, then 6 doses weekly with nivolumab, followed by a 5 week off period of DV281, while continuing nivolumab, then DV281 with intravenous nivolumab Q2w for an additional 24 weeks.

Preliminary Results from the Escalation phase: 22 patients have been enrolled to date: Cohort (C) 1: 4 patients; C 2: 3 pts; C3: 7 pts; C 4: 7 pts; C 5: 1pt, ongoing. Median age 67 y/o; male 50%; all ECOG PS0-1 (27.3/72.7%); non squamous 15 (68%), squamous 7 (32%); locally advanced 4 (18%), metastatic 18 (82%); PD-L1 expression: positive 12 pts (52%), negative 10 pts (48%); prior lines of therapy - 1 line: 10 pts (45.5%), 2 lines:12 (54.5%). Previous treatment with PD-1/PD-L1 inhibitors: 18 pts (9 as single agent, 9 in combination). Median treatment duration 11.5 weeks (1 to 38). Eighteen patients discontinued DV281: adverse event 2, PD 14, other 2. Safety profile of DV281 alone and combined with nivolumab with a median number of 5 doses (1.0 to 18.0): grade 1/ 2 chills (18%), fatigue (13.6%), flu-like symptoms (4.5%), diarrhea (13.6%) and rash (13.6%); no grade ≥3 DV281/nivolumab treatment related AE; no immune-related AEs. Pharmacodynamic (PD) assessment (IFN-induced genes) shows target engagement in all dose cohorts, with every patient showing evidence of target engagement in cohorts 3 and 4. A dose dependent increase in PD activity appears to begin to plateau at the 15 mg dose.

Conclusions: In this population of heavily pretreated patients, DV281 in monotherapy and in combination with nivolumab was well tolerated. Target engagement was observed at all dose levels. The expansion phase will use a modified dosing schedule, evaluating several groups of patients: non squamous resistant to PD-1/PD-L1 or to EGFR inhibitors; squamous experienced or naïve to anti PD-1/PD-L1.

Citation Format: Edward Garon, Alexander I. Spira, Melissa Johnson, Lyudmila Bazhenova, Joseph Leach, Albert Candia, Robert Coffman, Mary Janatpour, Erick Gamelin, Robert Janssen, Laura Q. Chow. Phase Ib/II, open label, multicenter study of inhaled DV281, a Toll-like receptor 9 agonist, in combination with nivolumab in patients with advanced or metastatic non small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT224.