Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non-small cell lung cancer patients who have progressed following chemotherapy

• Published in: Cancer Immunology, Immunotherapy Vol. 63; no. 8; pp. 787 - 796
• Main Authors: Smith, David A., Conkling, Paul, Richards, Donald A., Nemunaitis, John J., Boyd, Thomas E., Mita, Alain C., de La Bourdonnaye, Guillaume, Wages, David, Bexon, Alice S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2014; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Cancer Research; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy; Dose-Response Relationship, Drug; Epidermal growth factor; Erlotinib Hydrochloride; Humans; Immunology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical research; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Neoplasm Metastasis; Oligonucleotides - administration & dosage; Oligonucleotides - adverse effects; Oligonucleotides - pharmacokinetics; Oncology; Original; Original Article; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Toll-Like Receptor 9 - agonists; Toxicity; Treatment Outcome; Vascular endothelial growth factor; United States > US; Switzerland; Recommended phase II dose; TLR9 agonist; Phase I; IMO-2055 (EMD 1201081); Advanced/metastatic NSCLC
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-014-1547-6

Background IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity. Results Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease ≥4 months. Conclusions IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC.