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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 759-761 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.903
Combining the Anti-EGFR Agent Gefitinib With Chemotherapy in Non–Small-Cell Lung Cancer: How Do We Go From INTACT to Impact?Vall d'Hebron University Hospital, Barcelona, Spain In this issue of the Journal of Clinical Oncology are the final results of two large phase III randomized controlled trials of the anti–epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in combination with chemotherapy in untreated patients with advanced non–small-cell lung cancer (NSCLC) [1,2]. In these two trials, with more than 2,000 patients combined, the addition of gefitinib to chemotherapy failed to meet either the primary end point of survival or the secondary end points of time to disease progression or response rates. There was not even a suggestion of a nonsignificant trend in any of these end points in favor of gefitinib. In addition, a similar absence of benefit of two comparable phase III studies in NSCLC with erlonitib, another EGFR tyrosine kinase inhibitor, has been recently reported. The two gefitinib trials, INTACT 1 and 2, were well designed, adequately powered, and well conducted. The conclusion that concomitant gefitinib administration does not add clinical benefit to conventional chemotherapy in NSCLC seems, therefore, irrefutable. These results would not have been readily anticipated a priori for a series of reasons: first, gefitinib has demonstrated well-documented activity as a single agent in the initial phase I studies that included a large number of patients with NSCLC, and the antitumor activity of gefitinib has been confirmed in two large phase II studies in the second- and third-line setting, with response rates ranging from 9% to 18%, depending on the study and the dose [3,4]. Second, unlike with triplet chemotherapy combinations, full doses of chemotherapy could be given in combination with gefitinib, because no overlapping toxicities between gefitinib and chemotherapy have been observed in the phase I studies with these combinations. Third, available preclinical data for gefitinib combined with chemotherapy were impressively additive [5,6]. Given the outcome of the INTACT trials, it is obvious that some of these observations were incorrect or that some additional key determinants had not been taken into account. The first criticism of these trials is the lack of selection of the subset of patients likely to respond to gefitinib. Unlike trastuzumab, there are not available predictive markers of sensitivity to anti-EGFR agents; in fact, there is evidence of a lack of correlation between EGFR expression levels in the tumor and response to anti-EGFR agents, and a retrospective analysis of tumor samples from the gefitinib phase II single agent studies in NSCLC has confirmed this lack of correlation with gefitinib as well [7,8]. It is, therefore, possible that in a situation in which the responding phenotype to gefitinib has not been yet characterized, the molecular heterogeneity of lung cancer could have resulted in a false-negative result in the overall study population [9]. Although there was no evidence of patient enrichment in the phase II studies in favor of treatment sensitive subtypes or a suggestion of a negative effect in nonresponders, it would have been extremely important to have collected tumor samples to allow for post hoc clinical correlations, assuming a molecular signature of receptor sensitivity is identified. However, let us go back to the trastuzumab comparison. The initial pivotal studies with trastuzumab showed single-agent activity and improvement in survival when combined with chemotherapy in a suboptimal population because, in addition to patients with 3+ HER2 overexpressing tumors, patients with 2+ HER2 ovexpressing tumors were also included [10,11]; it is now known that 2+ HER2 overexpressing, fluorescence in situ hybridization–negative tumors do not respond to trastuzumab [12]. The consequence was that the combined response rate in 2+ and 3+ HER2 overexpressing breast tumors to single agent trastuzumab in the second- and third-line setting was 15% [10], a response rate within the range of the observed response rate with single-agent gefitinib in the phase II studies in NSCLC [3,4]. Therefore, even if a gefitinib-sensitive population was diluted because of the lack of a predictive test, some trend should have emerged in favor of the combination in a fashion similar to what had been observed with trastuzumab. That this was not observed points to a potential antagonistic effect of the combination as an alternative explanation.
The existence of antagonism between cytostatic and cytotoxic agents has been demonstrated with tamoxifen and chemotherapy in the adjuvant treatment of breast cancer. In the Breast Intergroup Study 0100 [13], a regiment of six cycles of initial CAF (cyclophosphamide, doxorubicin, and fluorouracil) followed by tamoxifen was compared to concurrent chemohormonal therapy, followed by tamoxifen. The study demonstrated that delaying tamoxifen administration until after CAF resulted in a disease-free-survival advantage when compared with the concurrent use of chemotherapy and tamoxifen. A similar situation of schedule-dependent antagonism could have occurred with gefitinib. Gefitinib has both antiproliferative and pro-apoptotic effects. The antiproliferative effects are the result of p27 mediated G1 cell cycle arrest of EGFR-dependent tumor cells and—in a similar fashion as with tamoxifen—could render tumor cells less sensitive to cytotoxic agents. On the other hand, the pro-apoptotic effects of gefitinib could also be beneficial when trying to enhance the antitumor effects of chemotherapy. The challenge is how to dissociate the antiproliferative from the pro-apoptotic effects when gefitinib is to be used in combination with chemotherapy. Early preclinical studies in human tumor xenografts with the combination of gefitinib and chemotherapy suggest that intermittent gefitinib administration is significantly superior to continuous dosing [14]. Although in these studies all gefitinib schedules caused enhancement of paclitaxel antitumor activity, 2 days of gefitinib treatment before chemotherapy resulted in greater tumor regression and a higher percentage of complete responses. These results suggest that the antiproliferative effects of gefitinib may require continuous kinase inhibition to maintain cell cycle arrest while sensitization to apoptosis may require temporary inhibition of survival (antiapoptotic) pathways. In the INTACT 2 study, there was a trend toward improved survival in the subset of patients with adenocarcinoma histology who had received chemotherapy for A relevant issue is whether the negative INTACT data will be predictive of a similar lack of efficacy for concomitant administration of anti-EGFR monoclonal antibodies with chemotherapy in NSCLC. Although anti-EGFR monoclonal antibodies and low molecular weight tyrosine kinase inhibitors target the same receptor, they have non-overlapping mechanisms of action, which implies that this question will have to be addressed separately [7]. In fact, in a small randomized phase II trial, the anti-EGFR monoclonal antibody cetuximab in combination with cisplatin and vinorelbine was compared to the same schedule of chemotherapy given alone as first-line treatment in patients with NSCLC [15]. The response rates (53.3% v 32.2%) and disease control rates (93.3% v 77.4%) favored the cetuximab group, although progression-free and overall survival rates have not yet been reported. Further support for a concomitant chemotherapy and cetuximab approach stems from the increased efficacy of combined therapy in advanced colorectal cancer, compared with the antibody alone, rather than with chemoptherapy alone [16]. In summary, what have we learned from the INTACT trials, and how are we going to reduce the likelihood of more negative phase III trials with targeted agents? First, these studies are a demonstration that preclinical models, although certainly valuable, do not dependably predict human cancer biology. Therefore, it would seem appropriate not to commit large numbers of patients to phase III trials with targeted agents until some indication of preliminary activity has been gathered in the clinic with the combination under study. This could be achieved by conducting randomized phase II trials or by incorporating early stopping rules in phase III designs. Second, in an era where cDNA arrays and proteomic technology are becoming increasingly available and gene expression profiles in the tumor are being used to identify molecular signatures of prognosis [17] and prediction of response to conventional chemotherapy [18], it seems mandatory that we focus our efforts at identifying an "EGFR-dependent signature." Encouraging results have been reported with some predictive markers [19], but a much more comprehensive effort is required. Although fresh tumor tissue would be ideal, new technologies such as quantitative analysis of gene expression in paraffin-embedded tissue may also be useful to identify correlates of response to EGFR kinase inhibitors from formalin-fixed tumor samples [20]. It seems, therefore, reasonable that a "no tissue, no participation" rule should be strongly considered in trials with targeted agents. And third, we should be as determined as ever in integrating targeted therapies with conventional chemotherapy. From the absence of benefit in the INTACT studies, new mechanism-based models and hypotheses are emerging, and those with the greatest merit should undergo clinical evaluation. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have 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. Acted as a consultant within the last 2 years: Jose Baselga, AstraZeneca, Bristol-Myers Squibb. Received more than $2,000 per year from a company for either of the last 2 years: Jose Baselga, AstraZeneca, Merck KGaA, Bristol-Myers Squibb. REFERENCES
1. Giaccone G, Herbst RS, Manegold C, et al: A phase III clinical trial of Gefitinib, an EGFR inhibitor, in combination with gemcitabine and cisplatin in advanced non–small-cell lung cancer (INTACT 1). J Clin Oncol 22:777-784, 2004
2. Herbst RS, Giaccone G, Schiller J, et al: Gefitinib in Combination With Paclitaxel and Carboplatin in Chemotherapy-Naive Patients With Advanced Non-Small-Cell Lung Cancer: Results from a Phase III Clinical Trial (INTACT 2). J Clin Oncol 22:785-794, 2004
3. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003
4. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003
5. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000
6. Sirotnak FM, Zakowsky MF, Miller VA, et al: Efficacy of cytotoxic agents against human tumor xenographs is markedly enhanced by coadministration of ZD1839 (Iressa) an inhibitor of tyrosine kinase. Clin Cancer Res 6:4885-4892, 2000
7. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003 8. Bailey LR, Kris M, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving Gefitinib (Iressa, ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 44, 2003 (abstr LB-170)
9. Betensky RA, Louis DN, Cairncross JG: Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol 20:2495-2499, 2002
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11. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001
12. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002 13. 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, 2002 (abstr 143) 14. Solit DB, She Y, Moasser M, et al: Pulsatile administration of the EGF receptor inhibitor (Iressa, ZD1839) is significantly more effective that continuosly dosing for sensitizing tumors to Taxol. AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics, 2003 (abstr 83) 15. Gatzemeier U, Rosell R, Ramlau R, et al: Cetuximab (C225) in combination with cisplatin/vinorelbine alone in the first-line treatment of patients with epidermal growth factor (EGFR) positive advanced non–small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 22:642, 2003 (abstr 2582) 16. Cunningham D, Humblet Y, Siena S, et al: Cetuximab (Erbitux) in combination with irinotecan or as single agent in patients with EGFR-expressing, irinotecan-refractory metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:252, 2003 (abstr 1012)
17. van de Vijver MJ, He YD, van't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002 18. Pusztai L, Ayers M, Simmans FW, et al: Emerging science: Prospective validation of gene expression profiling-based prediction of complete pathologic response to neoadjuvant paclitaxel/FAC chemotherapy in breast cancer. Proc Am Soc Clin Oncol 22:1, 2003 (abstr 1) 19. Tabernero J, Rojo F, Jimenez E, et al: A phase I PK and serial tumor and skin pharmacodynamic (PD) study of weekly (q1w), every 2-week (q2w) or every 3-week (q3w) 1-hour (h) infusion EMD72000, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced tumors. Proc Am Soc Clin Oncol 22:172, 2003 (abstr 770) 20. Natale RB, Shak S, Aronson N, et al: Quantitative gene expression in non–small-cell lung cancer from paraffin-embedded tissue specimens: Predicting response to gefitinib, an EGFR kinase inhibitor. Proc Am Soc Clin Oncol 22:170, 2003 (abstr 763) Related Articles
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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90 days in the gefitinib arms. This indicates a possible effect of gefitinib monotherapy as maintenance therapy once chemotherapy had been completed. Taken together, these observations suggest that instead of concomitant administration of gefitinib and chemotherapy, pulse gefitinib-chemotherapy schedules or sequential chemotherapy followed by gefitinib should be studied in lung cancer. The sequential approach will be tested in a US Intergroup phase III study in which patients will be randomly assigned to gefitinib or placebo following chemoradiotherapy and consolidation docetaxel in patients with inoperable stage III NSCLC. 
