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Originally published as JCO Early Release 10.1200/JCO.2005.03.6129 on November 21 2005 © 2005 American Society of Clinical Oncology.
Epidermal Growth Factor Receptor Inhibitors in Lung Cancer: Smaller or Larger Molecules, Selected or Unselected Populations?University of Colorado Cancer Center, Aurora, CO Epidermal growth factor receptor (EGFR) inhibitors, including the small-molecule tyrosine kinase inhibitors (EGFR TKIs) erlotinib (Tarceva; OSI Pharmaceuticals Inc, Melville, NY) and gefitinib (Iressa; AstraZeneca, Macclesfield, United Kingdom), and the monoclonal antibodies directed at the receptor such as cetuximab (Erbitux; Bristol-Myers Squibb, Princeton, NJ), have demonstrated promising effects in some patients with non–small-cell lung cancer (NSCLC) and other solid tumors. In patients with NSCLC, both erlotinib and gefitinib produced objective response in a minority of patients (9% to 20%). In subsequent randomized trials comparing these agents versus placebo, erlotinib produced a significant survival benefit (hazard ratio [HR] = 0.73), but gefitinib failed to produce a significant survival advantage (HR = 0.89) in unselected patients.1,2 Data on cetuximab have been more sparse. Table 1 lists published, ongoing, and planned NSCLC studies with cetuximab. As a single-agent treatment in chemotherapy-refractory patients, Hanna et al7 reported an objective response rate of 4.5% and a disease control rate of 35%, which is similar to but numerically lower than that reported from the phase II studies with EGFR TKIs.
In this issue of Journal of Clinical Oncology, Robert et al6 present results of a phase I/II a study of cetuximab in combination with carboplatin and gemcitabine in patients with advanced NSCLC who were EGFR positive by immunohistochemistry (IHC). The drug combination was well tolerated, with acceptable toxicity. Objective response was reported in 10 of 35 patients (28.6%) and an additional 21 patients had stable disease, yielding a disease control rate of 88.6%. As listed in Table 1, the combination studies so far reported have given consistent objective responses of 26% to 35% and median survivals of 7 to 11 months. The question is whether these results are better than chemotherapy alone in unselected or selected patient populations. With cetuximab, there are as yet no phase III study results reported. In a randomized phase II study, which compared vinorelbine/cisplatin alone with the same combination plus cetuximab, the addition of cetuximab resulted in a slightly superior response and survival, leading to initiation of an ongoing randomized phase III trial. Currently, several other randomized studies are ongoing or completed accrual, and more results are waiting. Combination of cytotoxic chemotherapy with EGFR TKIs failed to improve outcome in advanced NSCLC, but there might be significant differences in the mechanisms of sensitivity between monoclonal antibodies and the EGFR TKIs. For example, a recent study showed that EGFR mutations were associated with gefitinib sensitivity in vitro, but this was not the case for cetuximab.8 Much has to be learned about the combinations of chemotherapy and targeted therapies, and some of the questions that need to be resolved include the following. Do the EGFR monoclonal antibodies provide synergy in combination with chemotherapy? What is the optimal scheduling of chemotherapy and EGFR inhibitors in combination? (A targeted therapy given concomitantly with chemotherapy might produce antagonism, whereas sequential treatment might give synergy as demonstrated in breast cancer and antihormonal therapy.9) What is the importance of selecting subgroups of patients to these treatments? The study by Robert et al6 was performed in an enriched population based on EGFR protein expression detected by IHC. The role of EGFR protein expression for prediction of outcome after EGFR inhibitors has been a subject of debate. In patients with colorectal cancer, the US Food and Drug Administration (FDA) label indicates that patient selection by a Dako test kit (Dako A/S, Glostrup, Denmark) should be used for this particular indication, but no studies has so far provided the scientific rational for using IHC as a selection criteria in unselected patients with colorectal cancer, given that most of the clinical trials with cetuximab required EGFR IHC positivity for study entry. In NSCLC, conflicting data are reported, and no test has been approved by the FDA for selecting patients to receive any EGFR inhibitor. The lack of standardized methods for IHC assessments provides several potential reasons for the conflicting data presented in the literature. Factors that might influence the positive yields are the choice of antibody, scoring criteria and definition of positive and negative result, and patient/tumor material. Robert et al6 applied an IHC method using the Impath Predictive Oncology Inc, and no association was seen between EGFR protein expression and response. The FDA approval of IHC in the label for patients with colorectal cancer treated with cetuximab was based on the Dako EGFR pharm Dx method (Dako A/S, Glostrup, Denmark). This method was used in most analyses of EGFR protein expression in NSCLC studies of EGFR inhibitors and a positive yield up to 90% is reported.4 By using the Dako EGFR pharm Dx kit, no association with clinical outcome after EGFR TKIs was seen in most NSCLC studies.10-12 However, others reported that EGFR protein expression was associated with clinical outcome using other methodologies.13 Whether the methodology will make a difference has not been examined in larger studies. In a preliminary report presented at the 2005 American Society of Clinical Oncology meeting, a comparison between Dako PharmDx kit and the EGFR antibody from Zymed Laboratories (San Francisco, CA) was done in colorectal cancer, and the sensitivity was found to be higher with the use of the Zymed antibody.14 Similar comparisons have not yet been done in NSCLC. Whether differences in the scoring criteria make a difference in outcome has not been studied carefully, but most likely different outcome will be seen depending on the definitions of a positive result. In the study by Robert et al,6 a positive result was defined by staining of 10% or more of the cells, in which the membrane staining had an intensity of 1+ or more.
The authors do not report how many patients they had to screen to include the 35 eligible patients. In another study, in which a positive association was seen between clinical outcome and EGFR protein expression, a multiplicity of frequency of positive cells (0% to 100%) and the intensity (1+ to 4+) was made for the final score (range, 0 to 400), and a score of The main question is whether we have identified a marker or combination of markers that can be used to enrich the study populations for EGFR inhibitor studies. In the National Cancer Institute of Canada study BR-21, which demonstrated an overall survival benefit for patients who were treated previously with erlotinib compared with placebo, approximately 30% of the patients did not have any clinical benefit from the therapy and had an early death.1 The challenge is how to identify these 30% of the patients who will not benefit from EGFR-blocking therapy. Most likely a single test cannot be used, but a combination of tests might be more effective. However, which combination of tests should be used has not yet been identified. Preliminary data from 204 NSCLC patients demonstrated that a combination of IHC and FISH can be used to identify patients who will not benefit from gefitinib EGFR inhibitor therapy because those patients whose tumors with low or no EGFR gene copy number and low or no EGFR protein expression had a similar outcome as patients treated with placebo in the National Cancer Institute of Canada BR-21 study.17 Thus, the combination of FISH and IHC seems to be a reasonable candidate panel of markers to be used for selection of patients to EGFR inhibitors, which is similar to what today is clinical practice for selection of breast cancer patients to anti-HER2 therapy. Although, the use of EGFR protein expression as a selection criteria has been appealing based on the suggestive target for the EGFR antibodies, it is still a debatable issue. The results from the study of Robert et al6 in this issue of the Journal of Clinical Oncology are encouraging and deserve additional exploration, but many questions still remain to be answered. Among them is whether the same results can be achieved with chemotherapy alone in the EGFR-negative population. Authors' Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 2. Thatcher N, Chang A, Parikh P, et al: ISEL: A phase III survival study comparing gefitinib (IRESSA) plus best supportive care (BSC) with placebo plus BSC, in patients with advanced non-small-cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens. Lung Cancer 49:S4, 2005 (abstr Pr4) 3. Kim ES, Mauer AM, Tran HT, et al: A phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer: Final report. Proc Am Soc Clin Oncol 22:642s, 2003 (abstr 2581) 4. Rosell R, Daniel C, Ramlau R, et al: Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small-cell lung cancer (NSCLC). J Clin Oncol 22:620, 2004 (suppl; abstr 7012) 5. Kelly K, Hanna N, Rosenberg A, et al: A multi-center phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small cell lung cancer. Proc Am Soc Clin Oncol 22:644s, 2003 (abstr 2592) 6. Robert F, Blumenstein G, Herbst R, et al: Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naïve advanced non–small-cell lung cancer. J Clin Oncol 23:9089-9096, 2005 7. Hanna N, Bonomi P, Lynch TJ, et al: A phase II trial of cetuximab as therapy for recurrent non-small cell lung cancer (NSCLC). Lung Cancer 49:S38, 2005 (abstr O-106) 8. Mukohara T, Engelman JA, Hanna NH, et al: Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 97:1185-1194, 2005 9. Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143) 10. Bailey LR, Kris MG, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (‘Iressa’, ZD1939) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL1 and 2. 94th Annual Meeting of the American Association for Cancer Research, Washington DC, 2003 (abstr LB-170), July 13, 2003 11. Cappuzzo F, Gregorc V, Rossi E, et al: Gefitinib in pretreated non-small-cell lung cancer (NSCLC): Analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 21:2658-2663, 2003 12. Parra HS, Cavina R, Latteri F, et al: Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer. Br J Cancer 91:208-212, 2004[Medline] 13. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005 14. Tse C, Treaba DO, Goldstein LC, et al: Sensitivity of immunohistochemical detection of EGFR could impact patient eligibility for anti-EGFR therapy. J Clin Oncol 23:272, 2005 (suppl; abstr 3607) 15. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol 23:6838-6845, 2005 16. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 17. Hirsch FR, McCoy J, Cappuzzo F, et al: FISH and immunohistochemistry can be used to select NSCLC patients, who will not benefit from gefitinib treatment. Lung Cancer 49:S38, 2005 (abstr O-107)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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200 was considered as positive. By using these criteria for a positive result, approximately 60% of the patients will fall into the positive category.
