Gefitinib Versus Cetuximab in Lung Cancer: Round One

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 HER2-overexpressing 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 ) .

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 long-term 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 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.

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