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The Oncologist, Vol. 10, No. 7, 467-470, August 2005; doi:10.1634/theoncologist.10-7-467
© 2005 AlphaMed Press
Commentary |
The Current Situation: Erlotinib (Tarceva®) and Gefitinib (Iressa®) in Non-Small Cell Lung Cancer
Drexel University College of Medicine, Clinical Trials Research Center, Philadelphia, Pennsylvania, USA
Correspondence: Robert L. Comis, M.D., Director, Drexel University College of Medicine, Clinical Trials Research Center, 1818 Market Street, Suite 1100, Philadelphia, PA 19013, USA. Telephone: 215-789-3609; Fax: 215-789-3655; e-mail: rcomis{at}ecogchair.org
Key Words. Non-small cell lung cancer • Erlotinib • Gefitinib • Epidermal growth factor receptor
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INTRODUCTION |
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 Top Introduction Changes/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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Molecular targeted therapies, such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), provide a different mechanism of action from chemotherapy and can be much more specific in their approach to cancer treatment. The New Drug Application (NDA) for erlotinib (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com; Hoffman-La Roche, Basel, Switzerland, http://www.roche.com; Genentech, Inc., South San Francisco, CA, http://www.gene.com) use for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen was approved in the United States on November 18, 2004, as well as in Switzerland on March 22, 2005. The dossier is currently undergoing review with the European Medicines Agency (EMEA). These approvals were based on data from the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Study BR.21, a randomized, double-blinded, placebo-controlled, phase III study of single-agent erlotinib at a dose of 150 mg daily in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen [1]. Erlotinib is the only EGFR TKI therapy shown in a randomized phase III trial to provide a survival benefit to NSCLC patients (hazard ratio [HR] = 0.73).
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CHANGES/ADVANCES IN TREATMENT OF NSCLC SINCE THE APPROVAL OF ERLOTINIB |
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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Erlotinib Versus Gefitinib: What Have We Learned?
Gefitinib (Iressa®; AstraZeneca, London, UK, http://www.astrazeneca.com) was the first oral EGFR inhibitor to come on the market. On May 5, 2003, it was granted Subpart H approval by the U.S. Food and Drug Administration (FDA) on the basis of response rate in patients with NSCLC refractory to both docetaxel (Taxotere®; Sanofi-Aventis, Paris, http://en.sanofi-aventis.com) and platinum [2].
On December 17, 2004, AstraZeneca announced, in a press release and a "Dear Doctor" letter, that analysis of the primary end point of the Iressa® Survival Evaluation in Lung Cancer (ISEL) study (Trial 709) showed that gefitinib did not significantly prolong survival in the overall study population (median, 5.6 versus 5.1 months for gefitinib and placebo, respectively; HR, 0.89; p = .11), or in patients with adenocarcinoma (median, 6.3 versus 5.4 months; HR, 0.83; p = .07) [2]. Subsequently, AstraZeneca withdrew its European Marketing Authorization Application (MAA) for gefitinib to treat patients with NSCLC from the EMEA [3].
The ISEL data were presented to the scientific community on April 19, 2005, at the Annual Meeting of the American Association of Cancer Research [4]. As disclosed previously, gefitinib did not confer an overall survival advantage; however, gefitinib-treated patients survived longer than placebo-treated patients in two specific patient subsets: patients of Asian origin (median, 9.5 versus 5.5 months, respectively; HR, 0.66; p = .010) and never-smokers (median, 8.9 versus 6.1 months, respectively; HR, 0.67; p = .012). As noted in the accompanying review article by Cohen et al. [5], the randomized, placebo-controlled study performed by the NCIC comparing erlotinib with placebo in patients after failure of at least one prior chemotherapy regimen did reveal a survival advantage for erlotinib, 6.67 months versus 4.70 months, respectively. The adjusted HR was 0.73 (p < .001). Erlotinib was also superior to placebo for progression-free survival and objective response rate. Interestingly, the HRs for erlotinib in the two patient subsets in which gefitinib appears to confer benefit, Asians and never-smokers, were 0.61 and 0.42, respectively. Also, in contrast to the ISEL results, erlotinib appears to prolong survival for most of the other patient subsets, although the sample size is too small in some of the subsets to draw a definitive conclusion.
The evidence suggests, therefore, that erlotinib may be a more efficacious agent than gefitinib. This apparent difference in efficacy may be in part attributable to the fact that erlotinib was dosed at its maximum-tolerated dose (MTD) [1], while gefitinib was dosed at about one third of its MTD [4]. Based on the data cited above, the FDA issued a New Labeling and Distribution Program for gefitinib on June 17, 2005, limiting the administration of gefitinib to patients in the following circumstances: patients currently receiving and benefiting from the drug; patients who have previously received and benefited from gefitinib; and previously enrolled patients or new patients in non-Investigational New Drug (IND) clinical trials approved by an Investigational Review Board (IRB) prior to June 17, 2005.
New patients may also be able to obtain gefitinib if AstraZeneca decides to make the drug available under the IND and the patients meet the criteria for clinical trial enrollment under the IND.
Erlotinib remains the only EGFR inhibitor approved for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.
Effect of Smoking Status on Pharmacokinetics from Erlotinib Study BR.21 and Phase I Pharmacokinetic Study
The effect of smoking history on erlotinib pharmacokinetics was explored in Study BR.21 [6, 7]. Patients achieved a survival benefit regardless of their smoking history, with HRs for current/ex-smokers and for never-smokers of 0.87 and 0.42, respectively. In a multivariate analysis controlling for patients’ baseline characteristics, the survival benefit was statistically significant for both patient subsets [7]. Former smokers or patients who had never smoked, however, had median erlotinib plasma concentrations that were approximately twice that of the patients who were current smokers. Greater survival benefit in nonsmokers may involve a lower incidence of certain gene mutation effects, such as those involving K-ras [8], and also the lack of induction of cytochrome P450 (CYP) 1A isoforms by cigarette smoke, which results in faster plasma clearance of erlotinib in smokers. The results of a phase I pharmacokinetics study in healthy volunteers confirm that the pharmacokinetics of erlotinib are different in smokers than in nonsmokers. The area under the concentration-versus-time curve from 0 to infinity (AUC0–inf) and the 24-hour concentration (C24h) were significantly lower in smokers than in nonsmokers. A 300-mg erlotinib dose produced approximately the same AUC in smokers as the 150-mg dose did in nonsmokers. While a statistically significant difference in the maximum concentration (Cmax) was observed, the magnitude of the overall effect was much smaller. These observations are consistent with the induction of a pathway that is involved in the clearance of a drug rather than in its absorption.
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MTD IS IMPORTANT AND DOSE ESCALATION MAY BE APPROPRIATE IN SMOKERS |
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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According to the erlotinib package insert [9], pretreatment with the CYP3A4 inducer rifampicin (Rifadin®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com) decreases the erlotinib AUC by about two thirds and may therefore necessitate treatment with an erlotinib dose greater than 150 mg. Given the observation of a markedly lower exposure to erlotinib in smokers than in nonsmokers and the greater survival benefit to never-smokers in Study BR.21, this adds to the hypotheses that exposure and efficacy of erlotinib might be related, and dosing may contribute to the differential efficacy between erlotinib and gefitinib. The MTD needs to be further defined in smokers, as this population of patients may require a higher erlotinib dose than that currently used to achieve the same level of drug exposure in nonsmokers. Preliminary results of a study of the feasibility of dose escalation with erlotinib in patients with NSCLC were presented at this year’s Annual Meeting of the American Society of Clinical Oncology [10].
Response Rate Is Not the Appropriate Surrogate for Survival
Since the BR.21 study was a placebo-controlled trial with the primary end point of survival, one has the opportunity to assess various factors as they relate to survival and other end points, including objective tumor response as determined by the Response Evaluation Criteria in Solid Tumors. The objective response rate for erlotinib was 8.9%, versus 0.9% for the placebo-treated group, and the median duration of response was better for the drug-treated patients, 34.3 weeks versus 15.9 weeks, respectively. It is quite unlikely that objective response alone can account for the overall impact of erlotinib on survival.
In addition, when one evaluates the HRs in various subgroups that have a wide differential in objective response, there appears to be little relationship between objective response and overall survival. For instance, the objective response rates for females and males were 14.4% and 6.0%, respectively, whereas the HRs totally overlapped at 0.80 and 0.76, respectively. Similarly, patients with adenocarcinoma or squamous cell carcinoma had response rates of 13.9% and 3.85%, respectively, with overlapping HRs of 0.71 and 0.67, respectively.
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UPDATED INFORMATION ON EGFR TKIS RELEASED SINCE THE APPROVAL OF ERLOTINIB |
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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EGFR Expression—Positive Versus Negative EGFR Immunohistochemistry Is Proving to Be an Inadequate Method for Assessment of EGFR Status
EGFR expression, generally measured by immunohistochemistry (IHC), has long been associated with a poor prognosis in several solid tumor types [11, 12]. It had been hoped that there would also be a clear association between EGFR expression, as measured by IHC, and the activity of targeted EGFR inhibitors. This has not been the case in most studies of targeted EGFR inhibitors, whether they be small molecules or antibodies. This is true in both lung cancer trials and colon cancer studies [13–16]. Determination of EGFR status by IHC or other extracellular detection methods does not reflect the intracellular pathways of tyrosine kinase phosphorylation or, necessarily, the critical oncogenic role played by EGF in EGF-dependent tumors.
In the BR.21 trial, however, the duration of survival was longer in the EGFR-positive patient subset that was treated with erlotinib, compared with those treated with placebo (median, 10.7 months versus 3.8 months, respectively; HR, 0.65; p = .033). There was no apparent erlotinib survival advantage in the EGFR-negative patient subset. However, the subset analysis that compared survival in the EGFR-positive and EGFR-negative groups revealed such wide confidence intervals that one cannot conclusively exclude an erlotinib effect, even in the EGFR-negative group.
More recently, there have been data derived from the BR.21 trial concerning the potential value of fluorescence in situ hybridization (FISH) [17]. One-hundred twenty-five of 221 patient slides that were usable for FISH analysis were successfully analyzed. Forty-five percent of the specimens revealed either high polysomy or amplification. A univariate analysis was performed comparing erlotinib-treated patients with placebo-treated patients in these subgroups. The objective response rate for those with a high copy number was significantly greater than the rate for those with a low copy number (20% versus 2.4%, respectively; p = .03); as well, there was a significant difference in the HR for those with high and low copy numbers (0.44 versus 0.86, respectively; p = .008). Once again, there was substantial overlap in the 95% confidence intervals such that one cannot conclusively state that there was no erlotinib effect in those with a low copy number.
EGFR mutational status in NSCLC has been and continues to be of considerable interest, since there is evidence of a strong association between EGFR mutations and objective response to both gefitinib [18–20] and erlotinib [20]. Once again, because the BR.21 study was a placebo-controlled trial with survival as the primary end point, important information can be derived concerning the impact of mutational status on survival, as well as response, a secondary end point. A mutational analysis was successfully performed in 177 of 197 specimens suitable for analysis in the BR.21 trial [17]. Overall, 40 patient samples analyzed (23%) revealed a mutation. There was no statistically significant difference when objective response rate was compared between wild-type patients (7.4%) and patients harboring the mutation (15.8%), possibly because of the small sample size and correspondingly wide confidence intervals. More importantly, the HRs for survival comparing those with wild-type and those with mutated EGFR were superimposable, 0.73 and 0.77, respectively.
From the existing data, there appear to be several paths at the present time that can be pursued with the primary axioms being: (a) there are no clear cut factors that predict objective response, time to progression, and survival; (b) there are factors, such as IHC positivity and FISH positivity for EGFR, that might be able to select out the patients who are least likely to derive benefit; (c) patients with mutated EGFR, if properly evaluated and studied, might derive great benefit from EGFR-directed therapy; (d) patients who are female, who are nonsmokers, and who have adenocarcinoma (particularly, if they are of Asian decent) might derive the most benefit; and most important, based on the erlotinib BR.21 data, (e) the vast majority of lung cancer patients do not fit into the categories of patients that might derive benefit from erlotinib-based interventions for advanced lung cancer and less advanced disease. So, at the present time, in spite of the best efforts of science, we are left with a collage of factors, both clinical and laboratory, that must be considered in the design of clinical trials and in evaluating our patients for treatment outside a protocol. The positive factor, though, is that an addition has been made to the treatment armamentarium for lung cancer.
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OTHER MOLECULAR TARGETED AGENTS FOR NSCLC WITH PRELIMINARY, PREAPPROVAL DATA |
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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Bevacizumab (Avastin®; Genentech, Inc.) in combination with paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) plus carboplatin (Paraplatin®; Bristol-Myers Squibb) as first-line therapy showed encouraging results in a randomized phase II/III trial for the treatment of patients with advanced NSCLC performed by the Eastern Cooperative Oncology Group (ECOG) [21]. Erlotinib is being evaluated in combination with bevacizumab [22] for the treatment of NSCLC. Now that we have two new agents, erlotinib and bevacizumab, that have proven survival benefits in various stages of NSCLC, it is important to explore how both agents can be combined to further improve treatment outcome in the early stages of the disease.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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Dr. Comis has served as a consultant for OSI Pharmaceuticals; Genentech, Inc.; and Bristol-Myers Squibb.
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REFERENCES |
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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- Shepherd FA, Pereira J, Ciuleanu TE et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. J Clin Oncol 2004;22(suppl 14):12.
- U.S. Food and Drug Administration. IRESSA® (ZD1839, gefitinib) Tablets. Oncologic Drugs Advisory Committee (ODAC) Meeting Briefing Document, March 4, 2005. Available at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_01_01-AstraZeneca-Iressa.pdf. Accessed July 12, 2005.
- AstraZeneca Pharmaceuticals. Gefitinib (IressaTM) Marketing Authorisation Application Withdrawn in EU. Press Release, January 4, 2005. Available at http://www.astrazeneca.com/pressrelease/4442.aspx. Accessed July 12, 2005.
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[Abstract/Free Full Text] - Hamilton M, Wolf JL, Zborowski D et al. TarcevaTM (erlotinib) exposure/effects (EE) analysis from a phase III study in advanced NSCLC: effect of smoking on the PK of erlotinib. Proc Am Assoc Cancer Res 2005;46:56.
- Clark GM, Zborowski D, Santabarbara P et al. Smoking history is more predictiveofsurvivalbenefitfromerlotinibforpatientswithnon-smallcell lung cancer (NSCLC) than EGFR expression. J Clin Oncol 2005;23(suppl 16):628.
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- Chung KY, Shia J, Kemeny NE et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803–1810.
[Abstract/Free Full Text] - Saltz LB, Meropol NJ, Loehrer PJ Sr et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–1208.
[Abstract/Free Full Text] - Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.
[Abstract/Free Full Text] - Hecht JR, Patnaik A, Malik I et al. ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): an updated analysis. J Clin Oncol 2004;22(suppl 14):248.[CrossRef]
- Tsao MS, Sakurada A, Lorimer I et al. Molecular analysis of the epidermal growth factor receptor (EGFR) gene and protein expression in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial BR.21. J Clin Oncol 2005;23(suppl 16):622.
- Lynch TJ, Bell DW, Sordella R 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;350:2129–2139.
[Abstract/Free Full Text] - Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
[Abstract/Free Full Text] - Pao W, Miller V, Zakowski M 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;101:13306–13311.
[Abstract/Free Full Text] - Sandler AB, Gray R, Brahmer J et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. J Clin Oncol 2005;23(suppl 16):2.
- Tsao AS, Herbst R, Sandler A et al. Phase I/II trial of bevacizumab plus erlotinib for patients with recurrent non-small cell lung cancer: correlation of treatment response with mutations of the EGFR tyrosine kinase gene. J Clin Oncol 2005;23(suppl 16):643.
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TopIntroductionChanges/Advances in Treatment of...MTD Is Important and...Updated Information on EGFR...Other Molecular Targeted Agents...Disclosure of Potential...ReferencesRelated Articles in The... |
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Cohen, Martin H., Johnson, John r., Chen, Yeh-Fong et al. FDA Drug Approval Summary: Erlotinib (TarcevaR) Tablets. The Oncologist 2005;10:461–466.
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