The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.
In this issue of ONCOLOGY, Saba et al provide a comprehensive review of epidermal growth factor receptor (EGFR) biology, the scientific rationale behind inhibition of the receptor, and clinical trials using EGFR inhibitors in squamous cell carcinoma of the head and neck (SCCHN) and non-small-cell lung cancer (NSCLC). They conclude that EGFR is a valid target of anticancer therapy and that patient selection in clinical trials is important. We agree that further studies are required to fully understand the role of EGFR inhibitors in the treatment of SCCHN and NSCLC. In this commentary, we will elaborate further on the issue of patient selection and future directions in the development of EGFR inhibitors.
SCCHN and NSCLC are biologically heterogeneous diseases with variable clinical behavior and outcome, even within comparable disease stages and treatment. On the other hand, targeted agents such as EGFR inhibitors, by definition, provide selective benefit depending on the presence of the target. Therefore, a uniform clinical response is unlikely with the expected heterogeneity of tumors. For example, tamoxifen is not effective in breast cancer patients with estrogen receptor-negative tumors. Without patient selection based on the presence of HER2/neu gene amplification, the efficacy of trastuzamab (Herceptin) for the treatment of breast cancer would not have been detected because of dilution of the net-clinical activity.
Proper patient selection for a given therapy can be achieved based on clinical criteria, or through biomarkers of response or resistance. Since we have more information in NSCLC compared to SCCHN regarding selection criteria, we will discuss lung cancer first.
Response Markers of NSCLC
As mentioned by Saba et al, several large trials have used the EGFR tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) and gefitinib (Iressa), with modest objective response rates (8.9%-19%) as single agents in recurrent/metastatic NSCLC.[2-4] However, a subset analysis of the multicenter phase II trial of gefitinib has shown that Japanese patients had higher response rates compared to non-Japanese patients (27.5% vs 10.4%, P = .0023). In addition, receiving prior immuno/hormonal treatment, being female, and having adenocarcinoma were associated with higher response rates. Subsequent analyses suggest "never-smokers" respond at a higher rate as well.
In addition to these clinical characteristics of TKI response, somatic gain-of-function mutations in the tyrosine kinase (TK) domain of the EGFR gene were identified by three independent groups and shown to be associated with clinical response to gefitinib.[5-7] These mutations are thought to enhance TK activity; therefore, the tumors with the mutation are more dependent on the EGFR pathway and more sensitive to gefitinib. When the EGFR-TK domain was sequenced from genomic DNA collected from patients in Japan, Taiwan, the United States, and Australia, the mutations were detected in 21% of specimens with NSCLC, whereas none were detected in nonmalignant lung tissue from the same patients and other carcinomas. The mutations were more frequent in patients of East Asian ethnicity, females, patients with adenocarcinoma, and in never-smokers.
These findings were consistent with the clinical findings in the gefitinib trials. Furthermore, Cappuzzo et al showed that the presence of EGFR gene amplification or high degree of polysomy and high levels of protein expression were associated with a higher rate of response to gefitinib (36% vs 3%) and longer survival (18.7 vs 7 months, P = .03). A Southwest Oncology Group study of patients with bronchoalveolar carcinoma or adenocarcinoma with features of bronchoalveolar carcinoma also showed the association of increased EGFR gene copy number with prolonged survival (18 vs 8 months, P = .042) after gefitinib treatment.
These mutation studies provided insight into resistance to TKI treatment as well, which may suggest a rationale for new agents or combination regimens to overcome the resistance. Pao et al found this acquired resistance to be associated with a second mutation in addition to the primary drug-sensitizing mutation in patients whose disease progressed after the initial response to gefitinib or erlotinib. These data suggest that the acquired resistance is due to the emergence of a resistant cell clone developing the additional mutation during treatment. One other important finding is that EGFR mutations and K-ras oncogene mutations (which represent an important step in the carcinogenesis of NSCLC) were mutually exclusive.[8,12] While EGFR mutations are common in never-smokers, K-ras mutation is common in smokers.[7,8]
Therefore, emerging evidence suggests that one can select NSCLC patients based on clinical characteristics and/or biomarkers for erlotinib or gefitinib response. However, we have insufficient data on anti-EGFR antibodies such as cetuximab (Erbitux) and newer multitargeted TKIs.
Response Markers of SCCHN
The objective response rate in SCCHN with EGFR inhibitors is similar to that in NSCLC, ranging from 4.3% to 16.5%.[13-15] However, the EGFR mutations and amplifications found in NSCLC are rare in SCCHN. Lee et al reported an EGFR mutation rate of 7.3% in a Korean population, but the demographics in this study were different from the NSCLC studies. Of 41 patients, 3 had the same mutation (E746_A750del) and all were male current smokers.
EGFR gene amplification has been reported to be 12.7% in SCCHN. The EGFR sequence and gene copy number analyses from the phase II gefitinib trial are currently ongoing. In addition, polymorphic variations in intron 1 of the EGFR gene may be associated with the response to TKIs by affecting the transcription efficiency of the gene. The correlation between polymorphic variation and TKI response is currently being investigated in a clinical trial. Nonetheless, there are no defined clinical criteria or bio-markers for patient selection in SCCHN.
Future Clinical Trials
With this mounting evidence, we have begun to apply these findings to clinical trials in NSCLC. Phase II NSCLC trials are studying erlotinib and cetuximab in patients enriched by clinical characteristics such as female nonsmokers with adenocarcinoma, and bronchoalveolar carcinoma or adenocarcinoma with features of bronchoalveolar carcinoma. However, debate continues over whether to test all patients for the EGFR mutation, gene copy number, or protein overexpression, because some patients without these genetic changes still respond to TKI treatment to a certain extent. To add one more layer of complexity, it is unclear whether we need to exclude patients with secondary resistance or K-ras mutations from treatment with TKIs.
Strong evidence suggests that there are genetic changes associated with clinical response, and we must select patients accordingly to avoid ineffective and costly therapy. Also, we must learn from the experience with gefitinib and erlotinib for new agents currently in development. Future clinical trials with targeted agents should be on a smaller scale with clinical specimen collection and correlative studies rather than premature large randomized trials. Many biomarker discoveries were only made possible by correlative studies with clinically well-characterized patient specimens. For the multitargeted TKIs, such correlative studies will be even more important because different receptors are inhibited at different dose levels and the accurate clinical assessment of end results after multipathway inhibition can only be determined in clinical trials.
We face many challenges in the development of EGFR inhibitors-for example, determining the best tests with which to predict outcome, awaiting the maturation of scientific evidence before moving forward to prospective studies, and dealing with the cost of the trials and correlative studies. Despite these challenges, we must continue to rigorously validate our predictive/prognostic markers in retrospective studies and move forward to rationally designed prospective studies.
-Christine H. Chung, MD
-David H. Johnson, MD
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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