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.

Abstract

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.

• Authors: David A Smith, Paul Conkling, Donald A Richards, John J Nemunaitis, Thomas E Boyd, Alain C Mita, Guillaume de La Bourdonnaye, David Wages, Alice S Bexon
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 63 Issue 8 Pg. 787-96 (Aug 2014) ISSN: 1432-0851 [Electronic] Germany
• PMID: 24770667 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• IMO-2055
• Oligonucleotides
• Protein Kinase Inhibitors
• Quinazolines
• TLR9 protein, human
• Toll-Like Receptor 9
• Bevacizumab
• Erlotinib Hydrochloride

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Bevacizumab
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Erlotinib Hydrochloride
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Middle Aged
• Neoplasm Metastasis
• Oligonucleotides (administration & dosage, adverse effects, pharmacokinetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Quinazolines (administration & dosage, pharmacokinetics)
• Toll-Like Receptor 9 (agonists)
• Treatment Outcome