Patients with non–small cell lung cancer (NSCLC) and progressive disease (PD) following programmed death 1 (PD-1) blockade therapy have a poor prognosis. CMP-001 is a CpG-A Toll-like receptor 9 (TLR9) agonist packaged within a virus-like particle. The multicenter, open-label, 2-part, Phase 1b CMP-001-003 study (NCT03438318) evaluated the safety and preliminary antitumor activity of CMP-001 plus atezolizumab with or without radiation in patients with advanced NSCLC. Eligible patients with PD following anti–PD-1/programmed death ligand 1 (PD-L1) therapy and ≥1 extra-central nervous system, non-bone metastasis amenable for intratumoral injection received CMP-001 and atezolizumab (Part A) or CMP-001, atezolizumab, and radiation (Part B). CMP-001 was administered at 5 mg subcutaneously once weekly during weeks 1 and 2, followed by 5 mg or 10 mg intratumorally once weekly during weeks 3-5 and every 3 weeks thereafter. Atezolizumab 1200 mg was administered intravenously once every 3 weeks starting on week 2. Radiation therapy in Part B consisted of 20 Gy delivered in 5 fractions starting ≥2 days prior to CMP-001 treatment. Following a safety run-in period (n=5), each Part enrolled additional patients in Stage 1; ≥2 of 12 patients were required to have a RECIST v1.1 response to proceed with Stage 2 enrollment. The primary objective was to evaluate the safety of CMP-001 and atezolizumab with or without radiation. A key secondary endpoint was best objective response per RECIST v1.1 as assessed by the investigator. Twenty-nine patients were enrolled in Stage 1 (Part A, n=13; Part B, n=16). The median number of prior lines of therapy received was 3 (range, 1-6); 31.0% of patients had ≥4 prior lines of therapy. Only 5 patients (17.2%) had response to any prior systemic therapy. The median number of CMP-001 intratumoral injections was 3 (Part A range, 1-12; Part B range, 1-6); 12 patients had a total of 65 injections into visceral lesions, including kidney, liver, lung, and pleura, which were safely performed. The most common treatment-related adverse events (TRAEs; ≥30%) overall were flu-like symptoms (ie, chills and pyrexia) and hypotension. Six patients (46.2%) in Part A and 8 patients (50.0%) in Part B had grade ≥3 TRAEs. Only 1 patient discontinued treatment due to TRAEs (Part A, grade 3 pneumonitis). As of April 15, 2020 (Part A median follow-up, 1.9 months [range, 1-19]; Part B median follow-up, 1.7 months [range, 1-4]), no objective responses were observed. Two patients (15.4%) and 4 patients (25.0%) had tumor shrinkage (<30% decrease in tumor size) in Parts A and B, respectively. Three patients (23.1%) and 8 patients (50.0%) had stable disease as best response in Parts A and B, respectively. Study enrollment was stopped after completion of Stage 1 due to lack of objective response. The cytokine response to CMP-001 treatment and tissue biopsy analyses will be presented. CMP-001 plus atezolizumab with and without radiation therapy had a manageable safety profile. Intratumoral injection of CMP-001 into visceral lesions was safely achieved, and stable disease was observed in heavily pretreated patients with PD-1/PD-L1 refractory NSCLC.