Clinical Cancer Research Vol. 10, 4238S-4240S, June 15, 2004
© 2004 American Association for Cancer Research
Proceedings of the First International Conference |
The Role of Erlotinib (Tarceva, OSI 774) in the Treatment of Non-Small Cell Lung Cancer
Roman Perez-Soler
Gutman Professor of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York
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ABSTRACT
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Erlotinib (Tarceva) is a reversible and highly specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Phase I studies established a fixed daily oral dose of 150 mg as the recommended dose for Phase II studies. Using this dose and schedule, the response rate in a group of 57 patients with EGFR-positive non-small cell lung cancer after failure of platinum-containing chemotherapy was 12%. The median survival was 8.4 months, and the 1-year survival was 40%. Occurrence and severity of rash were correlated with an improved survival independently of performance status. Another ongoing Phase II study in 50 patients with bronchoalveolar carcinoma has shown a response rate of 26%. Results from two Phase III front-line studies in combination with chemotherapy, TALENT and TRIBUTE, have been recently reported. The addition of erlotinib did not improve response rate, time to progression, or survival. Efforts in the continued development of erlotinib should be focused on the following: (a) investigating the reasons for the lack of relationship between EGFR expression and clinical outcome; (b) the reasons for the failure of the front-line combination trials; and (c) confirming the rash/clinical outcome relationship. Progress in these tasks will allow a better selection of patients who can benefit from this therapy, permit the development of more effective combination schedules with cytotoxics, and define whether this agent should be used at the optimal biological dose or at the maximum-tolerated dose.
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INTRODUCTION
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Erlotinib (Tarceva) is a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in advanced stages of clinical development. Gefitinib (Iressa) shares with erlotinib both a common chemical backbone structure and a similar spectrum of clinical efficacy, at least in the clinical trials performed to date. Because gefitinib has been recently approved as a third-line therapy for non-small cell lung cancer (NSCLC) patients, it is pertinent to review the potential differences between these two agents that might have implications in their clinical use.
In the different preclinical studies performed, from cell-free systems to in vivo toxicity and efficacy studies, gefitinib was consistently 
2-fold less potent than erlotinib. Clinical studies have resulted in the selection of a continuous-fixed daily oral administration of 250 mg of gefitinib and 150 mg of erlotinib as the recommended dose and schedule for each of these agents. In the case of gefitinib, a dose of 250 mg is less toxic and as effective as a dose of 500 mg, as shown in two randomized Phase II studies in patients with NSCLC (IDEAL 1 and 2) (1
, 2)
. Therefore, 250 mg is close to an optimal biological dose. In the case of erlotinib, the dose of 150 mg meets the classical definition of maximum-tolerated dose (3)
. There are no clinical data comparing 150 mg to a lower dose. At the 150-mg dose, erlotinib results in a plasma area under the curve that is higher by one order of magnitude than the plasma area under the curve achieved with gefitinib. From a practical standpoint, this means that erlotinib is given to patients at a higher absolute dose than gefitinib.
Because of significant individual differences in absorption from the gastrointestinal tract and the use of a fixed dose rather than a dose calculated by body surface area, the actual dose range at which both these agents are used is unavoidably and unusually broad. Such a broad range may not be important if these agents exert their therapeutic effect more as antihormonal than as cytotoxic agents. However, this has not been proven.
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PHASE II STUDIES
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Five single-agent Phase II studies with gefitinib or erlotinib in patients with NSCLC have been reported. Three of these studies (two with gefitinib at two dose levels, 250 and 500 mg, and one with erlotinib at 150 mg; Refs. 1
, 2
, 4
) were performed in patients with all histologies as second- or third-line therapy (Table 1)
. Two studies (one with gefitinib at a dose of 500 mg and one with erlotinib at 150 mg) were performed in patients with bronchoalveolar carcinoma as front-line or second-line therapy (5
, 6)
. In none of these studies was degree of EGFR expression as measured by immunohistochemistry found to be a determinant of antitumor activity. Possible explanations for this surprising finding include, among others: (a) a significant proportion of sensitive tumors express a mutated form of EGFR that is not detected by the antibodies normally used for determination of EGFR expression; (b) coexpression with other members of the HER family of receptors or ligands is more important than expression of EGFR alone; (c) tumor cells have the ability to overcome the effect of the EGFR inhibitor by using or activating other signaling pathways that share common downstream elements; and (d) a highly overexpressed target may be an impediment for the agent to achieve complete inhibition and therefore is a determinant of resistance, as is the case for other antitumor agents that are specific enzyme inhibitors such as the thymidylate synthase inhibitors. In the gefitinib studies, female gender, adenocarcinoma histology, and no prior smoking were found to be strong predictors of clinical response. Similar trends, although not statistically significant, were observed in the Phase II study with erlotinib.
In the NSCLC trials with gefitinib and erlotinib, the response rate ranged from 9 to 19% for gefitinib (1
, 2)
and was 12% for erlotinib (4)
. The median survival ranged between 5.9 and 8 months in the gefitinib trials and was 8.4 months in the erlotinib trial. In the bronchoalveolar carcinoma trials, the response rates were 12–19% for gefitinib (5)
and 26% for erlotinib (6)
. A definitive randomized Phase III trial of erlotinib in second-/third-line therapy versus a best supportive care placebo control is being performed in patients with all histologies by the National Cancer Institute of Canada. Survival is the primary end point. The study is powered to detect a 33% improved median survival. Accrual of 700 patients has been completed, and the results will be available in the first quarter of 2004. A positive result of this trial is essential to establish the value of this class of agents in the treatment of patients with NSCLC as second/third line. In a previous study performed by the same group in a similar patient population, the median survival of the best supportive care placebo control group was 4.6 months (7)
. There is, therefore, a reasonable chance that this study will meet the survival end point. However, if this trial does not show an improved survival in the patients treated with single-agent erlotinib, patient preselection based on tumor molecular determinants of response will probably remain the only valid strategy to save this class of antitumor agents for the treatment of relapsed NSCLC.
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CORRELATION BETWEEN RASH AND SURVIVAL
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In the erlotinib study in patients with NSCLC and the gefitinib study in patients with bronchoalveolar carcinoma, a statistically significant relationship between occurrence of skin rash and survival was identified. In the other three NSCLC and bronchoalveolar carcinoma trials, this relationship was not analyzed or has not been reported. This relationship between rash and survival has been confirmed in four additional Phase II single-agent studies with erlotinib, gefitinib, or cetuximab (Erbitux), three Phase II combination studies with cetuximab, and one Phase III study with cetuximab (8, 9, 10)
. There are currently no single-agent studies with any of these agents in which this correlation was looked for and not found. Information regarding such a correlation in the Phase II studies of gefitinib in NSCLC patients (IDEAL 1 and 2) is eagerly awaited. However, the fact that no differences in survival were found in the IDEAL trials between the low-dose and high-dose arms despite a slight difference in the incidence of rash (10%) suggests that such a correlation may not exist in these trials and that the relationship between skin rash and survival may be a differential aspect of erlotinib and cetuximab compared with gefitinib. This is potentially important for the development of agents in which this relationship exists because it provides a rational basis for exploring the possibility of enhancing their antitumor activity by escalating the dose in individual patients to a level that causes detectable skin rash.
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FRONT-LINE COMBINATION STUDIES
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Four front-line randomized chemotherapy combination trials with gefitinib (INTACT 1 and 2) and erlotinib (TALENT and TRIBUTE) have definitely shown no benefit to adding the EGFR inhibitor to standard combination chemotherapy in patients with NSCLC. The rationale for these studies was based on preclinical in vivo evidence of synergism between cytotoxic agents and the EGFR tyrosine kinase inhibitors in human xenografts with high levels of EGFR expression. The reasons for these failures are speculative and include, among others: (a) A combination schedule significantly different from that in the preclinical studies was used, which could be antagonistic. In the preclinical studies, animals did not receive the EGFR inhibitor for 48 h (Saturday and Sunday) before the weekly administration of the cytotoxic agents, thus probably releasing the tumor cells from G1-S arrest and sensitizing them to the effects of the cytotoxic agents. In the clinical studies, the EGFR inhibitor was given continuously without interruptions. (b) There is also the possibility, unexamined thus far, that these agents are more active in chemotherapy-refractory patients than in chemotherapy-naïve patients; (c) Furthermore, there may be no advantage to adding a third agent to a cytotoxic doublet because of redundancy or duplication in the mechanism of cytotoxicity, i.e., induction of apoptosis that is independent of EGFR expression.
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FUTURE PROSPECTS
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The philosophical foundation of the field of anti-EGFR therapy was based on the following three main pillars: (a) maximum antitumor activity should be observed at a dose devoid of toxicity, the so-called optimal biological dose; (b) EGFR expression should be a major determinant of antitumor activity; and (c) combinations with cytotoxic agents should maximize the therapeutic potential of EGFR inhibitors. The mounting evidence that the survival of patients treated with EGFR blockers correlates with damage to a surrogate tissue such as the skin, the unquestionable fact that the antitumor activity of EGFR blockers is not related to extent of EGFR expression and the failure of four large front-line randomized trials of EGFR blockers combined with chemotherapy in NSCLC patients are forcing us to rethink the strategy for the development and use of these agents. There is a general consensus that tumor tissue studies aimed at identifying determinants of response to these agents should be given a high priority to define specific patient populations with a higher probability of response. Hopefully, the results of the National Cancer Institute of Canada study will definitely establish the therapeutic value of this class of compounds in a non-preselected population of patients with NSCLC and such complicated studies can be justified as undertaken to additionally improve these objective levels of efficacy rather than as attempts to rescue a class of barely active agents.
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OPEN DISCUSSION
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Dr. Eric Rowinsky: I’m still not convinced that there are data that really close the door on any correlation between receptor expression and benefit. I think that we may be fooling ourselves here. There is the idea going around that receptor expression does not confer responsiveness. But the data come out of all these small studies or from the INTACT trials, where as we’ll probably see with TRIBUTE and TALENT, chemotherapy is a confounder. Certainly in vitro receptor expression, when you quantitate receptors, even by immunohistochemistry, it loosely correlates with cytotoxicity. So I think we need to do a plain old-fashioned randomized trial to really discern whether that correlation exists.
Dr. Perez-Soler: The issue is raised by the fact that there have been responders with no detectable EGFR expression by immunohistochemistry. It would be important to reanalyze these tumor samples again to confirm that they are EGFR negative. If they are negative on reanalysis, we must accept that these agents may have a non-EGFR-related mechanism of action.
Dr. Thomas Lynch: Along those same lines, you may remember that the percentage of people for whom we had specimens in the IDEAL trial, where it was reported that there was no relation between immunohistochemistry and outcome, was 50–60% at most. It was a trial of 200 patients with only 10 responders. So you’re looking at a very small sample, and there’s the selection bias in terms of the patients for whom you get a specimen. You have specimen on people who happen to have big tumors taken out or maybe longer lead time as opposed to someone who comes in with widely metastatic disease. It’s not like you have tissue on 40 randomly selected patients. Your point is well taken that chemotherapy confounds things. What do other people think? Have we answered this question of expression of EGFR?
Dr. Rowinsky: There are cell line studies and there are xenografts with the Abgenics antibody and also with ImClone’s antibody that show the opposite with actually counting receptors.
Dr. John Heymach: Just to raise a mechanism that hasn’t gotten a lot of attention, we know endothelial cells actually express EGF receptor. There are data from Isaiah Fidler’s lab at M. D. Anderson and others that EGFR inhibitors slow endothelial proliferation and can have antiangiogenic effects, particularly in tumors that express transforming growth factor 
. We know EGF actually drives endothelial cells no matter what system you are using. So, it seems reasonable that there is a mixture of different responses. We may have cases in which the antitumor effects are purely through inhibition of EGFR on tumor cells and other cases in which the antiendothelial effects predominate.
Dr. Rowinsky: EGF also decreases vascular endothelial growth factor production in nonendothelial cells.
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FOOTNOTES
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Presented at the First International Conference on Novel Agents in the Treatment of Lung Cancer, October 17–18, 2003, Cambridge, Massachusetts.
Requests for reprints: Roman Perez-Soler, Chairman, Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467-2490. Phone: (212) 920-4001; Fax: (718) 798-7474; E-mail: rperezso{at}montefiore.org
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REFERENCES
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- Fukuoka M, Yano S, Giaccone G, et al Final results from a Phase II trial of ZD1839 (Iressa) for patients with advanced non-small cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol, 21: 298 2002.
- Kris MG, Natale RB, Herbst RS, et al A Phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer patients who had failed platinum- and docetaxel-based chemotherapy regimens (IDEAL 2). Proc Am Soc Clin Oncol, 21: 292 2002.
- Hidalgo M, Siu LL, Nemunaitis J, et al Phase I and pharmacology study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced solid malignancies. J Clin Oncol, 19: 3267-79, 2001.[Abstract/Free Full Text]
- Perez-Soler R, Chachoua A, Huberman M, et al Finals results of a Phase II study of erlotinib (Tarceva) monotherapy in patients with advanced non-small cell lung cancer following failure of platinum-based chemotherapy (abstract P-611). Lung Cancer, 41(Suppl. 2): S246 2003.
- Patel JD, Miller VA, Kris MG, et al Encouraging activity and durable responses demonstrated by the EGFR tyrosine kinase inhibitor erlotinib (Tarceva TM, OSI-774) in patients with advanced bronchioalveolar (BAC) cell carcinoma. Lung Cancer, 41(Suppl.): S56 2003.
- West HL, Franklin WA, Gumerlock P, et al ZD 1839 (Iressa) in advanced bronchioalveolar carcinoma (BAC): a preliminary report of SWOG S0126. Lung Cancer, 41(Suppl.): S56 2003.
- Shepherd FA, Dancey J, Ramlau R, et al Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol, 18: 2095-103, 2000.[Abstract/Free Full Text]
- Saltz L, Kies M, Abbruzzese JL, Azarnia N, Needle M The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol, 22: 204 2003.
- Cohen EE, Rosen F, Stadler WM, et al Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol, 21: 1980-7, 2003.[Abstract/Free Full Text]
- Clark GM, Perez-Soler R, Siu L, Gordon A, Santabarbara P Rash severity is predictive of increased survival with erlotinib HCl. Proc Am Soc Clin Oncol, 22: 196 2003.
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ABSTRACT
INTRODUCTION
