EDITORIALS
EDITORAL
Gefitinib Versus Cetuximab in Lung Cancer: Round One
John D. Minna, Michael J. Peyton, Adi F. Gazdar
Despite clinically significant advances in conventional forms
of chemotherapy (1), the prospects for long-term control of lung
cancer reside in therapies targeted to specific molecular changes
that are characteristic of the tumor and whose function the tumor
must maintain to survive (oncogenic changes to which the tumor
is “addicted”). Just over a year ago, intense excitement was generated by the finding that mutations in the tyrosine kinase (TK)
domain of the epidermal growth factor receptor (EGFR) gene are
highly predictive (in general) of clinical responses to EGFR TK
inhibitors (TKIs) (2,3). In this issue of the Journal, Mukohara
et al. (4) address the challenge of optimizing EGFR-targeted
therapy by comparing the effects of two different forms of therapies directed at EGFR, the TKI gefitinib (which binds to the intracellular TK domain, thus blocking signal transduction) and the
monoclonal antibody cetuximab (which binds to the extracellular
domain of EGFR and prevents ligand activation of the receptor).
They present both the findings of in vitro studies and a limited
amount of available patient response data.
EGFR is the prototype member of a family of four TK receptor molecules that activate multiple downstream signaling pathways involved in cell survival, proliferation, and angiogenesis
(5). On activation by any of several ligands, family members
form both homo- and heterodimers, resulting in a rich network
of possible activation pathways. The preferential heterodimerization partner for EGFR is HER2 (also known as EGFR2). Because EGFR is overexpressed in many tumor types, including
non–small-cell lung cancers (NSCLC), it was one of the first
molecules to be selected for the development of targeted therapies (6), more than two decades before the discovery of EGFR
mutations.
Of the several ways to specifically block EGFR function with
minimal effects on the activity of other family members, TKIs
and the EGFR monoclonal antibody approach have undergone
widespread clinical testing. The reversible quinazoline TKIs
gefitinib and erlotinib block phosphorylation and, thus, downstream signaling of EGFR. These compounds inhibit signaling
even in the presence of ligand (7). Suggestions that the use of the
monoclonal antibody cetuximab should be active in lung cancer
comes from two lines of evidence: Its use is of clinical benefit in
certain other tumors that overexpress EGFR, even though these
tumors lack EGFR mutations (8,9), and evidence exists for the
presence of autocrine loops in lung cancers (10). Cetuximab
interacts exclusively with the extracellular domain of EGFR,
partially occluding the ligand binding region (hence its potential
to block autocrine activities) and sterically preventing the receptor from adopting the extended conformation required for
dimerization (11). Trastuzumab, a monoclonal antibody directed
against HER2, has demonstrated clinical effectiveness in HER2overexpressing breast cancers (12). However, in the case of
cetuximab, initial results suggest that the responses to cetuximab
in NSCLC are modest, although trials are still ongoing (13).
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EDITORIALS
The TKIs gefitinib and erlotinib bind in the ATP binding
pocket and prevent phosphorylation, and hence activation, of the
EGFR. The most frequent mutations of EGFR increase the
efficacy of the TKIs in inhibiting EGFR activation. Consequently,
the mutant receptors are inhibited 10- to 100-fold more effectively
than the wild-type receptor. Although initial results indicated an
excellent correlation (>80%) between response to TKIs and positive mutational status of the cancers (14), more recent reports
have indicated an emerging role for other factors in determining
the response to TKIs, including increased copy number of both
EGFR and HER2 (15,16) and the status of HER3. In addition,
mutations occur in only 10%–20% of NSCLC patients, favoring
certain subpopulations (17). Furthermore, many patients treated
with these compounds develop resistance, in part due to secondary EGFR mutations, particularly the T790M mutation (18).
Finally, there are currently no data relating to increased longterm survival in patients treated with TKIs. These drawbacks
have led some to question proposals for the widespread general
use of TKIs in the treatment of NSCLC (19).
Mukohara et al. tested both targeted approaches (i.e., gefitinib
and cetuximab) on a variety of cell lines, some with mutant
EGFR and others with wild-type EGFR (4). They found that
gefitinib was effective at inhibiting growth at submicromolar
concentrations in EGFR mutant cell lines but was ineffective
against EGFR wild-type cell lines. Confirming our previous
observations, they found that only one EGFR mutant cell line
(HCC827) was inhibited by cetuximab, with none of the other
cell lines tested, either wild type or mutant, showing any substantial inhibition (20). These findings clearly have important clinical
implications because both drugs should, theoretically, block
EGFR signaling. Their patient data—i.e., the finding that gefitinib
gave partial responses, whereas cetuximab could produce only
stable disease—add important anecdotal evidence to support
the in vitro findings. Taken together, their observations suggest
gefitinib is superior in inhibiting lung cancer cells both in vitro
and in vivo.
Important questions that were not addressed in the studies of
Mukohara et al. include whether cetuximab would potentiate the
effects of standard chemotherapy regimens or the newer targeted
therapies, such as the TKIs, and the relative importance of autocrine production of EGFR family ligands in NSCLC. Although
there is one report with conflicting data (21), three publications
Affiliation of authors: Hamon Center for Therapeutic Oncology Research,
University of Texas Southwestern Medical Center, Dallas, TX.
Correspondence to: John D. Minna, MD, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry
Hines Blvd., Dallas, TX 75309-8593 (e-mail: [email protected]).
See “Notes” following “References.”
DOI: 10.1093/jnci/dji247
© The Author 2005. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
Journal of the National Cancer Institute, Vol. 97, No. 16, August 17, 2005
indicate that cetuximab may act synergistically to potentiate the
activity of TKIs (22,23) and conventional cytotoxic therapies
(24) using lung or breast cancer cell lines. In addition, our results
(M. Peyton and J. Minna, unpublished data) show that cetuximab
consistently lowers the concentration of gefitinib required for
50% inhibition of cell growth by up to 10-fold in both EGFR
mutant and wild-type lung cancer cells. Although the optimal
combinational therapies and schedules need to be determined, as
well as the patient subpopulations that may derive the greatest
therapeutic benefit from such combinations, it is beginning to
appear that there is an emerging potential for cetuximab to play a
role in combination drug therapy. The first round clearly was won
by TKIs. However, cetuximab may still have an effective punch
if the right circumstances can be identified.
REFERENCES
(1) Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al.
Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung
cancer. N Engl J Med 2005;352:2589–97.
(2) Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA,
Brannigan BW, et al. Activating mutations in the epidermal growth factor
receptor underlying responsiveness of non-small-cell lung cancer to
gefitinib. N Engl J Med 2004;350:2129–39.
(3) Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR
mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.
(4) Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N,
et al. Differential effects of gefitinib and cetuximab on non–small-cell lung
cancers bearing epidermal growth factor receptor mutations. J Natl Cancer
Inst 2005;97:1185–94.
(5) Baselga J, Arteaga CL. Critical update and emerging trends in epidermal
growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445–59.
(6) Mendelsohn J. Antibody-mediated EGF receptor blockade as an anticancer therapy: from the laboratory to the clinic. Cancer Immunol Immunother
2003;52:342–6.
(7) Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Janne PA.
Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer
cell line H3255. Cancer Res 2004;64:7241–4.
(8) Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor
chimeric human-murine monoclonal antibody. Drugs Today (Barc) 2005;
41:107–27.
(9) Goldberg RM. Cetuximab. Nat Rev Drug Discov 2005;Suppl:S10–1.
(10) Riemenschneider MJ, Bell DW, Haber DA, Louis DN. Pulmonary adenocarcinomas with mutant epidermal growth factor receptors. N Engl J Med
2005;352:1724–5.
(11) Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM. Structural
basis for inhibition of the epidermal growth factor receptor by cetuximab.
Cancer Cell 2005;7:301–11.
(12) Altundag K, Esteva FJ, Arun B. Monoclonal antibody-based targeted therapy
in breast cancer. Curr Med Chem Anti-Canc Agents 2005;5:99–106.
(13) Govindan R. Cetuximab in advanced non-small cell lung cancer. Clin
Cancer Res 2004;10(12 Pt 2):4241s–4s.
(14) Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF
receptor gene mutations are common in lung cancers from “never smokers”
and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc
Natl Acad Sci U S A 2004;101:13306–11.
(15) Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al.
Epidermal growth factor receptor gene and protein and gefitinib sensitivity
in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–55.
(16) Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S,
Ceresoli GL, et al. Increased HER2 gene copy number is associated with
response to gefitinib therapy in epidermal growth factor receptor positive
non-small cell lung cancer patients. J Clin Oncol. In press 2005.
(17) Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II,
et al. Clinical and biological features associated with epidermal growth
factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:
339–46.
(18) Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M,
et al. EGFR mutation and resistance of non-small-cell lung cancer to
gefitinib. N Engl J Med 2005;352:786–92.
(19) Arteaga CL, Baselga J. Tyrosine kinase inhibitors: why does the current
process of clinical development not apply to them? Cancer Cell 2004;5:
525–31.
(20) Amann J, Kalyankrishna S, Massion PP, Ohm JE, Girard L, Shigematsu H,
et al. Aberrant epidermal growth factor receptor signaling and enhanced
sensitivity to EGFR inhibitors in lung cancer. Cancer Res 2005;65:226–35.
(21) Fischel JL, 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
2005;92:1063–8.
(22) Huang S, Armstrong EA, Benavente S, Chinnaiyan P, Harari PM. Dualagent molecular targeting of the epidermal growth factor receptor (EGFR):
combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res
2004;64:5355–62.
(23) Matar P, Rojo F, Cassia R, Moreno-Bueno G, Di Cosimo S, Tabernero J,
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 2004;10:6487–501.
(24) Raben D, Helfrich B, Chan DC, Ciardiello F, Zhao L, Franklin W, et al. The
effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005;11(2 Pt 1):795–805.
NOTES
Supported by Lung Cancer SPORE P50CA70907.
Conflicts of Interest: The authors are sponsored by grants from AstraZeneca
and ImClone, makers of gefitinib and cetuximab, respectively. The sponsors
played no role in the preparation of this manuscript.
Journal of the National Cancer Institute, Vol. 97, No. 16, August 17, 2005
EDITORIALS
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