Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer.

Abstract

BACKGROUND:

Preclinical pharmacological properties of mapatumumab (agonistic human monoclonal antibody to TRAIL-R1) suggest that this antibody reduces cell viability, induces cell death in many types of cancer cell lines in vitro, inhibits or reduces tumor growth in xenograft models of solid tumors, and can induce significant tumor regression in some models. The receptor for mapatumumab, TRAIL-R1, is expressed on NSCLC cell lines. This pharmacologic profile suggests that mapatumumab may have therapeutic benefit in the treatment of NSCLC.

METHODS:

This Phase 2 multi-center study was designed to evaluate the efficacy, safety, and tolerability of mapatumumab in patients with advanced non-small cell lung cancer (NSCLC) previously treated with at least 1 platinum-based regimen. Each patient was to receive mapatumumab at a dose of 10mg/kg administered intravenously (IV) every 21 days in absence of disease progression.

RESULTS:

A total of 32 patients with relapsed or refractory Stage IIIB or IV or recurrent NSCLC were enrolled. Patients had received a median of 3 previous therapeutic regimens (range 1-7). Mapatumumab was well tolerated by the patients in this study with no discontinuations due to adverse events. The most common adverse events reported, regardless of relationship, were fatigue, cough, nausea, dyspnea, constipation, and vomiting. Laboratory analyses revealed no appreciable evidence of hepatic or renal toxicity among the study patients. No patients developed anti-mapatumumab antibodies. The plasma mapatumumab concentrations observed in this study were consistent with the predicted exposures, based on Phase 1 pharmacokinetic results. None of the 32 treated patients showed a response according to the RECIST criteria. Nine patients (29%) had stable disease (SD).

CONCLUSION:

In a group of heavily pretreated NSCLC patients, no objective single agent activity of mapatumumab was demonstrated, but the drug was safe and well tolerated. Based on this favorable safety profile, and preclinical evidence of potential synergy in combination with agents commonly used to treat NSCLC, future evaluation of mapatumumab in combination with chemotherapy is warranted.

• Authors: F Anthony Greco, Philip Bonomi, Jeffrey Crawford, Karen Kelly, Yun Oh, Wendy Halpern, Larry Lo, Gilles Gallant, Jerry Klein
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 61 Issue 1 Pg. 82-90 (Jul 2008) ISSN: 0169-5002 [Print] Ireland
• PMID: 18255187 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• TNFRSF10A protein, human
• mapatumumab

Topics

• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Disease-Free Survival
• Female
• Humans
• Immunohistochemistry
• Lung Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor (drug effects, metabolism)