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Originally published as JCO Early Release 10.1200/JCO.2008.16.3972 on May 19 2008 © 2008 American Society of Clinical Oncology.
Dual-Agent Molecular Targeting of the ErbB2 Receptor: Killing One Bird With Two Stones
Department of Oncology, McMaster University, Hamilton, Ontario, Canada
Systemic Therapy Program, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario, Canada The phase I study by Storniolo et al in this issue of Journal of Clinical Oncology,1 which evaluates the combination of lapatinib (a selective small-molecule ErbB1 and ErbB2 tyrosine kinase inhibitor) and trastuzumab (an antibody blocking the extracellular domain of ErbB2) in patients with advanced ErbB2-positive breast cancer, is the first published study to our knowledge examining dual-agent molecular targeting of the ErbB2 receptor. The study demonstrated that there was clinical activity in a group of heavily pretreated patients and—using a toxicity end point—determined an optimally tolerated regimen for this combination of agents. The epidermal growth factor family of receptors plays a key role in regulating growth, survival, and resistance to chemotherapy in many epithelial malignancies.2 Approximately 25% of breast cancers overexpress ErbB2 or demonstrate ErbB2 gene amplification; ErbB2 is a key mediator of tumor cell growth and survival, and a predictor of poor outcome. Potential strategies to block peptide growth factor signaling pathways include (1) blocking or neutralizing the growth factor or its production, (2) blocking the receptor-binding site or prevention of receptor dimerization, (3) blocking the receptor tyrosine kinase domain, and (4) blocking downstream signaling pathways.3 The mechanism of action of trastuzumab is multifactorial and includes (1) antibody-dependent cellular cytotoxity, (2) modulation of ErbB2 signaling, (3) internalization of ErbB2 cell-surface protein, (4) reduction in proteolytic cleavage of the ErbB2 extracellular domain, and (5) interference with DNA damage repair.4 Small-molecule inhibitors such as lapatinib have an advantage over antibodies because they inhibit multiple signaling pathways at plasma concentrations achieved in the clinic. This is relevant because the survival of epithelial tumors is often dependent on the presence of redundant signaling pathways. Combining anti-ErbB2 antibodies with small-molecule tyrosine kinase inhibitors is an appealing strategy because both therapies exert their antitumor effects via distinct mechanisms of action and target ErbB2 at different sites. Combining distinct classes of inhibitors may not only potentiate cellular cytotoxicity, but may also assist in overcoming inherent or acquired resistance to one class of inhibitors. Mechanisms of resistance identified to date include activating mutations in the domain of the adenosine triphosphate–binding pocket for small-molecule tyrosine kinase inhibitors and the presence of truncated receptors for monoclonal antibodies.4 Dual-agent molecular targeting has been examined in preclinical models using the ErbB1 pathway as well as the ErbB2 pathway. With respect to the ErbB1 pathway, Huang et al5 and Matar et al6 studied the effect of cetuximab (an antibody that binds to the extracellular domain of ErbB1) in combination with either gefitinib or erlotinib (small-molecule inhibitors of the tyrosine kinase domain or ErbB1) against a panel of human cancer cell lines in culture and in tumor xenografts.5,6 The combination of cetuximab plus gefitinib or erlotinib enhances growth inhibition, in culture and in vivo, over that observed with either agent alone. Phosphorylation inhibition of downstream effector molecules (mitogen-activated protein kinase and AKT), and apoptosis was enhanced with the combination.5,6 In lung and head and neck tumor cells highly resistant to cetuximab, gefitinib, and erlotinib, but not cetuximab, retained the capacity to inhibit these tumor cells and were also able to further inhibit the activation of downstream effectors of ErbB1 signaling.5 When tested in vivo, single-agent therapy resulted in transient tumor regression only at the highest doses, whereas suboptimal doses of gefitinib and cetuximab in combination resulted in complete and permanent regression of large tumors.6 Contradictory results were obtained by Fishel et al7 who determined that gefitinib and cetuximab, when used in combination, were antagonistic when tested against two ErbB1-expressing epidermoid cell lines. The combination caused less apoptosis than gefitinib alone, and this appeared to be the result of overexpression of functional ErbB1 associated with the combination. It is likely that these discordant results were a result of the particular cell lines studied. Most relevant to the study being reviewed are the preclinical models examining dual targeting of the ErbB2 pathway. Xia et al4 treated ErbB2-overexpressing breast cancer cell lines with a combination of lapatinib and either trastuzumab or a polyclonal anti-ErbB2 antibody. The combination treatments led to enhanced tumor cell apoptosis, whereas treatment with the same doses of lapatinib, trastuzumab, or polyclonal anti-ErbB2 antibody alone led to minimal or no increase in apoptosis. They demonstrated that the enhanced tumor cell apoptosis after combination ErbB2-targeted therapies was most closely associated with downregulation of survivin protein. Konecny et al8 studied the combination of lapatinib and trastuzumab in a panel of human breast cancer cell lines. Synergistic activity was seen when the combination was tested in ErbB2-overexpressing cell lines. Of particular interest was that lapatinib retained activity in cell lines selected for resistance to trastuzumab. Storniolo et al1 have now tested dual-agent targeting of the ErbB2 pathway in the clinic. This approach demonstrated only modest activity (16% response in the 54 patients treated). However, these patients were heavily pretreated with chemotherapy (median of four prior cytotoxic regimens), and almost all of the patients (50 of 54) had been previously treated with trastuzumab; no information is available regarding whether these patients had developed resistance to trastuzumab. Thus, it is not clear whether the benefits seen were a result of the combined administration of lapatinib and trastuzumab, or from lapatinib alone. An optimally tolerated regimen was determined using a toxicity end point defined as a dose of lapatinib and trastuzumab at which no more than one of six patients experienced a dose-limiting toxicity. An optimal biologic dose was not determined in this study, which would have required serial tumor biopsies to determine this pharmacodynamic end point. Given how these end points are determined, an optimally tolerated dose or regimen would not necessarily correlate with an optimal biologic dose. This study demonstrated the feasibility of administering a combination of agents that target the ErbB2 pathway. However, to better determine the utility of this approach in the treatment of metastatic breast cancer, this would have to be studied in patients who have not previously been treated with an agent blocking the ErbB2 pathway, and would require obtaining serial tumor biopsies before and during therapy to determine optimal doses of each of the agents inhibiting the ErbB2 receptor and the downstream pathways mediating its effects when used in combination. Characterization of a "receptor-sensitive signature" would be of use in identifying tumors sensitive to such approaches in the clinic.6 The next step would be to study the dual-targeting approach in an ErbB2-positive population of patients who are ErbB2 inhibitor naive, with pharmacodynamic monitoring of effects on ErbB2 and downstream signaling pathways and correlating this with tumor response. To determine the contribution of lapatinib and trastuzumab in the clinical effect, it would be most appropriate to do this in a randomized setting in this population. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Hal W. Hirte, Sebastien J. Hotte Manuscript writing: Hal W. Hirte, Sebastien J. Hotte Final approval of manuscript: Hal W. Hirte, Sebastien J. Hotte NOTES published online ahead of print at www.jco.org on May 19, 2008. REFERENCES
1. Storniolo AM, Pegram MD, Overmoyer B, et al: Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 26:3317-3323, 2008 2. Yarden Y, Sliwkowski MX: Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2:127-137, 2001[CrossRef][Medline] 3. Harari PM, Allen GW, Bonner JA: Biology of interactions: Antiepidermal growth factor receptor agents. J Clin Oncol 25:4057-4065, 2007 4. Xia W, Gerard CM, Liu L, et al: Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24:6213-6221, 2005[CrossRef][Medline] 5. Huang S, Armstrong EA, Benavente S, et al: Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): Combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 64:5355-5362, 2004 6. Matar P, Rojo R, Cassia R, et al: Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): Superiority over single-agent receptor targeting. Clin Cancer Res 10:6487-6501, 2004 7. Fischel J-L, Formento P, Milano G: Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors. Br J Cancer 92:1063-1068, 2005 8. Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual kinase inhibitor (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66:1630-1639, 2006 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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