The review by Jan Buter andGiuseppe Giaccone in this issueof ONCOLOGY is an excellentoverview of the current statusof the anti–epidermal growth factorreceptor (EGFR) agents gefitinib (Iressa),erlotinib (Tarceva), and cetuximab(Erbitux). The authors addresssome of the most important issuesregarding anti-EGFR agents currently in clinical development. Key amongthese are the importance of patientselection and drug dosage in the successand failure of various clinicaltrials. This article raises several veryinteresting questions in the developmentof this class of agents.
The review by Jan Buter and Giuseppe Giaccone in this issue of ONCOLOGY is an excellent overview of the current status of the anti-epidermal growth factor receptor (EGFR) agents gefitinib (Iressa), erlotinib (Tarceva), and cetuximab (Erbitux). The authors address some of the most important issues regarding anti-EGFR agents currently in clinical development. Key among these are the importance of patient selection and drug dosage in the success and failure of various clinical trials. This article raises several very interesting questions in the development of this class of agents. Why Did Erlotinib Succeed and Gefitinib Fail in Placebo-Controlled Trials?
As discussed in the Buter/Giaccone article, the BR21 trial demonstrated a significant survival advantage for erlotinib compared to placebo as salvage therapy in 731 advanced non-small-cell lung cancer (NSCLC) patients, with a median survival of 6.7 and 4.7 months for the erlotinib and placebo groups, respectively (P < .001). However, the similarly designed ISEL trial, conducted with 1,692 advanced NSCLC patients, demonstrated a median survival of 5.6 months in the gefitinib group and 5.1 months in the placebo group (P = .11). Why did these two compounds that behave similarly in preclinical models, in single-arm clinical trials, and in randomized trials of first-line treatment with chemotherapy produce disparate results in the salvage single-agent setting? One hypothesis is that the patient populations enrolled in the two trials were different in a way that affected efficacy of the drugs. It was apparent from the first clinical studies utilizing gefitinib and erlotinib that certain patient characteristics, namely female gender, adenocarcinoma tumor histology, nonsmoking history, and East Asian race, predicted for better response to the drugs.[3,4] Somatic activating EGFR mutations were subsequently associated with dramatic response and survival benefits from gefitinib and erlotinib treatment compared to wild-type EGFR tumors; these mutations may underlie the initial correlation of patient characteris characteristics with response to tyrosine kinase inhibitors (TKIs).[5-8] More recently, increased EGFRgene copy number has been correlated with response to TKI treatment and survival, though it is not yet clear if copy number is reflective of patient characteristics to the degree reported with EGFRmutations.[9,10] The magnitude of benefit from TKI treatment to patients with varying clinical and molecular characteristics is a topic of much research and debate. Perhaps the BR21 and ISEL trials had enough differences in critical attributes between the treatment and placebo groups to yield different results. Of all the clinical characteristics of response to TKIs, nonsmoking status appears to be the most predictive of response to treatment and the most predictive of harboring a mutation. In BR21, never-smokers made up 21.3% of the erlotinib population and 17.3% of the placebo group. Never-smokers derived a greater reduction in the univariate hazard ratio of death (HR) with erlotinib treatment (HR = 0.4, 95% confidence interval [CI] = 0.3-0.6) than did the overall study population (HR = 0.7, 95% CI = 0.6-0.9). Among the patients with tumor samples available, increased gene copy number was associated with a survival advantage with erlotinib treatment but EGFRmutations were not, although the mutations identified by the BR21 group are aberrant within the in toto literature on EGFR mutations. In the ISEL trial, never-smokers comprised 21% of each treatment group and again derived a significant and greater reduction in the univariate hazard ratio of death with gefitinib treatment (HR = 0.67, 95% CI = 0.49-0.91) compared to the overall study population (HR = 0.89, 95% CI = 0.78-1.03). Analysis of EGFRmutation and gene amplification from ISEL is not yet available, but should be shortly. Because neither trial required its subjects to provide tissue for molecular analysis, analyses can only be performed in the subset of subjects with sufficient tissue. As a result, we cannot fully understand the molecular characteristics of the two trial populations and how they may have differed. The second hypothesis for the disparate trial outcomes is that a doseresponse relationship exists for TKIs and gefitinib was not given at a sufficient dose in the ISEL trial. The maximal tolerated dose of gefitinib is 800 mg/d. In early dose-escalation studies, gefitinib did not exhibit a clear increase in efficacy with increased dose, although the toxic side effects did increase. After two large randomized phase II studies exploring two dose levels, the dose of 250 mg was recommended for future study, including the ISEL trial.[3,4] In contrast, the maximum tolerated dose of erlotinib is 150 mg/d and this dose was used in subsequent clinical studies, including BR21. Further complicating the issue of effective dose is the recent observation that concomitant smoking can change the metabolism and possibly decrease the effectiveness of erlotinib.[ 14] It may be that patients with certain patient or molecular characteristics, like nonsmoking status or EGFR mutations, are especially sensitive to TKIs and treatment dose is not relevant to their outcome. However, in order to observe a population survival benefit with TKI treatment, dosing at the maximum tolerated dose may be required. In addition, one must also consider the possibility that inherent and true differences in the effectiveness of the drugs led to the success of BR21 and the failure of ISEL, and conversely that the drugs are equivalent and it was mere chance that produced different results. Future Directions
Epidermal growth factor receptor TKIs, particularly erlotinib, now have an established role in the salvage treatment of NSCLC. But it is imperative to apply the lessons learned about patient and molecular characteristics and TKIs toward future efforts to identify subsets of NSCLC patients that can benefit from these agents in other stages of disease. Although both gefitinib and erlotinib do not improve survival when added to chemotherapy in the first-line setting,[15-18] either TKI alone may be an effective primary treatment in a rationally selected subpopulation. For example, a subset analysis of never-smokers receiving first-line chemotherapy with or without erlotinib in a randomized controlled trial demonstrated an increased survival of 22.5 months with erlotinib compared to 10.1 months with placebo (P = .01). Similarly, a phase II study of first-line gefitinib in a clinically enriched Korean population of neversmoking patients with metastatic adenocarcinoma demonstrated a promising response rate of 69% and an estimated 1-year overall survival rate of 73%. To estimate the response rate in a molecularly defined population, a multicenter phase II study of first-line gefitinib for advanced NSCLC in patients known to harbor EGFR mutations is now under way. Additional ongoing studies include first-line erlotinib treatment in a population defined by clinical characteristics, and phase II and III clinical trials of TKIs in combination with chemotherapy as adjuvant and neoadjuvant therapy for earlier-stage disease. Conclusion
The gefitinib and erlotinib story thus far has served to remind scientists, clinicians, pharmaceutical companies, and patients that we often understand less about drugs and their targets than we think we do. Relationships between therapeutic agents and heterogeneous tumor cells are complex. With hundreds of novel targeted agents in the developmental pipeline, we should remember to be thoughtful and careful in the process of translating preclinical findings and early-phase clinical trial findings to randomized trials. A more thorough understanding of the molecular mechanisms of targeted agents and utilization of appropriate clinical trial design may lead to a higher success rate in future randomized trials. With its highs and lows, the gefitinib and erlotinib saga has energized translational research in lung cancer. It has inspired us to try to understand NSCLC not as an umbrella diagnosis, but as a collection of molecularly defined tumors that may require different treatment algorithms.
Dr. Sequist has acted as a consultant for Genentech. Dr. Lynch has acted as a consultant for Genentech, ImClone, and AstraZeneca; he has received clinical trial support from Genentech.
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