Challenges and opportunities for erlotinib (Tarceva): What does the future hold?

Challenges and Opportunities for Erlotinib (Tarceva): What Does the Future Hold? Gabriel N. Hortobagyi and Guido Sauter The development of targeted agents has brought new opportunities and extraordinary therapeutic challenges to cancer therapy. Several agents that inhibit epidermal growth factor receptor (HER1/EGFR) tyrosine kinase have been developed and are advanced in their clinical development. Preclinical and clinical data show that these agents are selective for their target, have activity across many types of solid tumors, and are well tolerated compared with conventional cytotoxic chemotherapy. Attention is currently focused on optimizing the clinical use of these agents. This includes defining dosing schedules and appropriate combination partners, identifying predictive markers of response, developing techniques to accurately assess antitumor activity, and determining whether it is possible to preselect patients before therapy. Resolving these challenges will help us to realize the full potential of these agents. Semin Oncol 30 (suppl 7):47-53. © 2003 Elsevier Inc. All rights reserved.

CONTINUING TO BUILD A BASIS FOR THE CLINICAL USE OF ERLOTINIB

Erlotinib HC1 (Tarceva; Genentech, Inc, South San Francisco, CA) is a potent, selective, quinazoline-derived, small-molecule HER1/ EGFR-tyrosine kinase inhibitor. It is one of the most promising of a new generation of powerful, targeted therapies for HER1/EGFR-driven cancers. Extensive preclinical and early clinical data have shown that erlotinib is active against many types of cancer (data on file).1-3 Preclinical and phase I/II clinical trials show that erlotinib can be used as monotherapy or in combination with various cytotoxic drugs (data on file).1,2,4-6 In addition, erlotinib is well tolerated and does not exacerbate the toxicity of cytotoxic drugs. Also, based on phase I data, erlotinib 150 mg/day was established as the maximum tolerated dose and was recommended for future clinical trials.3 Phase II studies with erlotinib show antitumor activity in patients with advanced non–small cell lung cancer (NSCLC),7,8 ovarian cancer,9 head and neck squamous cell cancer,10,11 and colorectal cancer,12 respectively. In the NSCLC trial, survival with erlotinib was encouraging compared with other HER1/EGFR inhibitors,13,14 chemotherapeutic agents,15,16 and best supportive care in similar patient populations.17 Erlotinib is currently being investigated in four randomized, placebo-conSeminars in Oncology, Vol 30, No 3, Suppl 7 (June), 2003: pp 47-53

trolled, phase III clinical trials: second- or thirdline monotherapy in patients with advanced, refractory NSCLC (BR.21); first line in combination with carboplatin and paclitaxel in patients with advanced NSCLC (TRIBUTE); first line in combination with gemcitabine and cisplatin in patients with advanced NSCLC (TALENT); and in combination with gemcitabine in patients with advanced pancreatic cancer (PA.3). Early clinical data with erlotinib are encouraging, but data from these ongoing trials, and trials with other agents, are required to confirm the therapeutic potential of HER1/EGFR inhibitors. Also, continued preclinical investigation is vital to optimize the clinical use of these agents, particularly identifying markers that could be used to select patients most likely to benefit from erlotinib alone or in combination with other therapies; and the possible effect of differences in the administration schedule when using therapies in combination. For example, results from preclinical studies suggest that erlotinib is effective when administered concomitantly with cisplatin and before cisplatin (data on file).2 In the future, there is likely to be a wide range of targeted agents available for many types of cancer or, more specifically, for multiple molecular targets, necessitating a method to match the patient to the most appropriate treatment regimen. Hopefully, these combined regimens will inhibit different processes that are critical for tumor growth, resulting in an improved response to therapy. Combining agents that will work in the individual will optimize treatment and therefore, makes good economic as well as clinical sense. However, selecting the appropriate treatment regimen is likely to be complex, with factors such as

From The University of Texas, M. D. Anderson Cancer Center, Houston, TX; and the Institute of Pathology, University Hospital, Basel, Switzerland. Address reprint requests to Gabriel N Hortobagyi, MD, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 424, Houston, TX 77030-4009. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3003-0706$30.00/0 doi:10.1016/S0093-7754(03)00188-X 47

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tumor phenotype, genotype, and disease stage having to be considered. While curing advanced metastatic cancer may be an unrealistic goal, we have real hope that with this type of approach it may become a chronic, manageable disease that can be controlled for extended periods of time. Similar targeted approaches may have a major role as part of curative, combined modality treatments of early primary cancers and, possibly, in cancer prevention strategies. This article discusses the challenges and opportunities that HER1/EGFR-targeted agents are encountering and are likely to face in the future. This article will focus in particular on the need to preselect patients for therapy, and the development of assays to identify markers that predict for response to therapy. The potential use of targeted agents in the future, such as for adjuvant/neoadjuvant therapy and patient-specific treatment cocktails, will also be considered. CAN WE IMPROVE OUTCOMES BY PRESELECTING PATIENTS?

The success of HER1/EGFR inhibitors may be dependent on our ability to identify and select those patients who are most likely to respond to therapy. Our experience with agents like trastuzumab (Herceptin; Genentech, Inc), an antiHER2 monoclonal antibody, show that phase III trials have the greatest chance of achieving a positive outcome if patients are enrolled based on their likelihood of response. In fact, it is likely that if patients were not preselected for therapy with trastuzumab, the development of this agent would have been unsuccessful. However, patient eligibility criteria for therapy with HER1/EGFR inhibitors requires complete understanding of the mechanisms of action of these agents, and the factors that affect this response – an understanding that we do not, as yet, possess. Trastuzumab was one of the first targeted agents to be licensed for clinical use. During its development and subsequent clinical use, many of the challenges facing clinicians who selected patients before therapy were highlighted. One of the key lessons was that screening for a marker of response before treatment is desirable. In the case of trastuzumab, this marker was relatively easily identified because it was the therapeutic target HER2. If patients are not selected before therapy, the number of patients responding, albeit to a high level,

may be so low that the trial does not have a positive outcome and a potential new treatment may be overlooked. It is estimated that in an unselected group of patients with advanced breast cancer, trastuzumab would have produced objective responses in 3% to 4% of patients, a rate too low to support further clinical development in the early 1990s. HOW IMPORTANT IS HER1/EGFR TUMOR EXPRESSION?

One of the main challenges with regard to the development of HER1/EGFR inhibitors is that a predictive marker for response to HER1/EGFR therapy has not been identified.18 Recent preclinical studies suggest that there is no correlation between HER1/EGFR overexpression and response to therapy.19-21 However, HER1/EGFR expression was initially used to preselect patients for therapy with some agents.7-9 In agreement with the preclinical studies, the results showed little difference in response between trials that did and did not select patients based on HER1/EGFR expression. One can argue that this is primarily because agents were being evaluated in tumors known to express high levels of HER1/EGFR (eg, head and neck squamous cell cancer and NSCLC); therefore, selection based on expression is of limited benefit. Interestingly, several studies suggest that increased HER1/EGFR expression correlates with poor disease prognosis and reduced survival, although the evidence is inconclusive.22,23 As a result of these data, patients for phase II/III trials are not generally selected on the basis of HER1/EGFR expression. However, it is hoped that patient samples from the erlotinib phase III trials, such as BR.21, TRIBUTE, TALENT, and PA.3, will allow us to further explore the relationship between clinical response and HER1/EGFR expression and perhaps identify markers that are predictive of response. The lack of correlation seen between HER1/ EGFR expression and response may be explained partly by the lack of standardized or validated methods to quantify HER1/EGFR expression. This limitation is also responsible for the wide variation of data on HER1/EGFR expression in various tumors. High-quality, reproducible, testing methods are critical if patients are going to be selected based on marker expression. The US Food and Drug Administration has approved an immunohis-

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Table 1. Various Methods to Detect/Quantitate HER1/EGFR Expression Method

Advantages

Disadvantages

IHC

Fast turnaround (can be automated) Low cost Suitable for formalin-fixed tissue Widely available/used Indefinite storage of slides Tissue morphology retained and visible

No standardized methodology (significant interlaboratory variations) No standardized method of quantitation Results susceptible to variation in methodology

FISH

Accurate and reproducible Easy to quantify Flexibility of application because of stability of DNA Tissue morphology retained and visible

Not widely used in routine pathology laboratories Requires training Signals decay over time Limited interpretation of morphology

Quantitative PCR

Fast turnaround (can be automated) Flexibility of application because of stability of DNA Widely available/used Relatively simple technique Quantitation possible

Morphology not maintained Selective analysis of tumor tissue is not possible, therefore use is limited (disintegrated tissue is analyzed)

ELISA

Fast turnaround (can be automated) Relatively simple technique Low cost Accurate and reproducible In routine use in most hospitals

Potentially useful for plasma or serum detection Selective analysis of tumor cells is not possible, therefore, use is limited (disintegrated tissue is analyzed)

Abbreviations: HER1/EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; FISH, fluorescence in-situ hybridization; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorption assay.

tochemical (IHC) test for HER2 expression (HercepTest; Dako, Carpinteria, CA). However, HER1/EGFR expression is proving more difficult to accurately quantitate and, although methods are available, they are not reproducible. This invalidates most cross-study comparisons. The most established and convenient method is IHC, which was originally developed for nonquantitative purposes; as a result, there is no standard scoring system or clearly defined cut-off range to define low, medium, or high expression. Furthermore, many parameters can influence IHC results, such as the time to fixation, type of fixative, and antigen retrieval method used. All of these factors can result in differences in assay sensitivity. Also, the assessment of the staining intensity can vary depending on the experience of the assessor, thus, it can be highly subjective. Despite these limitations, IHC analysis is currently the preferred method for assessing HER1/ EGFR expression in most laboratories. This is mainly because it does not involve costly equipment, a small amount of tissue is required, it is

applicable to formalin-fixed tissue, and costs are low compared with other techniques. The recent development of tissue microarrays allows for faster IHC analyses and a more comprehensive characterization of HER1/EGFR expression.24,25 Using tissue microarray technology, samples from up to 1,000 different tumors are arrayed in a recipient paraffin block, and sections can then be stained and quantified for HER1/EGFR expression. Tissue microarray allows a uniform, highthroughput IHC analysis of entire patient populations within a few hours. Other methods that could be used to identify responsive patients include fluorescence in-situ hybridization, quantitative polymerase chain reaction, and enzyme-linked immunosorption assay. The advantages and disadvantages of these methods are reviewed in Table 1. An important consideration when reviewing potential methods to preselect patients for therapy is the type of sample required for analysis. Some techniques, such as IHC, fluorescence in-situ hybridization, and polymerase chain reaction, can use formalin-fixed tis-

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sue. Other techniques, such as enzyme-linked immunosorption assay, require fresh tissue. Fresh tissue, although relatively difficult to obtain, reduces the variability resulting from tissue fixation procedures. Therefore, the type of tissue required for analyses is an important consideration when designing clinical trials. In summary, quantitation of HER1/EGFR expression is generally difficult, and more research is required before an optimal method and final conclusion regarding the predictive value of the level of expression or other receptor alterations are available. Because HER1/EGFR expression does not appear to drive tumor growth to the same extent as HER2, it is important to determine whether other signaling mediators, upstream or downstream of HER1/EGFR, would better define the group of tumors likely to respond to HER1/ EGFR-targeted therapy. However, if a suitable marker is not identified, an alternative approach is to determine whether crosstalk between HER1/ EGFR and other related pathways is associated with tumor growth. We can hypothesize that two or more markers may need to be present to predict for benefit with a HER1/EGFR-targeted agent. As a result, such relationships may require the use of combinations of targeted agents to achieve optimal clinical benefit. Therefore, research is urgently required to determine other molecular tumor characteristics that may predict for response to antiHER1/EGFR therapies. ONGOING STUDIES TO IDENTIFY PREDICTIVE MARKERS OF RESPONSE

While phase II and III clinical trials are examining the relationship between HER1/EGFR expression and clinical response, several other routes of investigation are also being used to identify markers predictive of response. The first approach aims to identify genotypes or phenotypes that characterize tumors highly dependent on HER1/EGFR signaling and build a molecular profile of tumors that are potentially responsive to HER1/EGFR-targeted therapies. The first stage in this process is to identify the key regulators of tumorigenic development more accurately. To this end, large-scale expression analyses using data from large series of patients with various types of cancer are in progress at various establishments, including Genentech, Inc. These data are derived from public and private gene-chip and expressed

sequence-tag databases that contain information about several thousand normal and tumor tissue specimens. Probing these databases allows: largescale comparisons of gene expression across different tumor and tissue types; tumor and normal tissue; and different pathologic and histologic subtypes of cancer. These databases enable data from various indications to be summarized, so key regulators in tumorigenesis can be identified rapidly and accurately. Molecular profiling can be performed using gene-chip arrays to determine whether certain genetic profiles are predictive of tumor response or resistance to therapy. Tumor samples from patient or preclinical models can be analyzed using this approach. However, experience with erlotinib and other HER1/EGFR inhibitors suggests that preclinical data from established tumor cell lines may not accurately represent the clinical setting. Therefore, using patient specimens for analyses is preferred and this approach is being evaluated. Central to this is the collection of tissue samples, pre- and post-treatment, from patients participating in clinical trials. The molecular data from these samples can then be correlated with clinical response. However, collecting and analyzing patient tumor samples for molecular profiling presents many difficulties. An alternative approach that may provide further insight into the correlation between tumor response and molecular profile is the use of primary tumor explants, which may be used as xenografts in vitro or in vivo. In a recent study, tumor explants from patients were treated with chemotherapeutic agents to determine their sensitivity in vitro.26,27 The donor patients were subsequently treated with the same agents and segregated in accordance with their clinical response to chemotherapy. It was found that in vitro resistance to chemotherapy was strongly correlated with a lack of clinical response. Therefore, molecular profiling of primary tumor explants and correlation with their degree of resistance or sensitivity to growth inhibition by HER1/EGFR-targeted therapies could be used to identify predictive markers of patient response or resistance to therapy. ARE WE ABLE TO ASSESS ANTITUMOR ACTIVITY ACCURATELY?

Traditional anticancer therapies have defined tumor regression as the primary endpoint of phase

CHALLENGES AND OPPORTUNITIES FOR ERLOTINIB

II clinical trials. This is because tumor regression is relatively easy to measure and quantitate, occurs early during treatment, and generally correlates with symptomatic improvement. Prolongation of disease-free and overall survival can only be determined much later in the course of a clinical trial, requiring extended monitoring and follow-up. However, the traditional approach to clinical trial design may not be appropriate for the evaluation of targeted agents because they are more likely to cause disease stabilization rather than extensive tumor regression. Therefore, it is important to select primary endpoints for phase II/III clinical trials that are more appropriate for these agents. Preclinical studies show that, in mice bearing human tumor xenografts, erlotinib treatment produces tumor stasis and, at higher doses, tumor regression.2 Other HER1/EGFR inhibitors show similar antiproliferative activity in preclinical studies.28 Findings from clinical trials, in agreement with preclinical studies of erlotinib and other HER1/EGFR inhibitors, suggest that the most likely outcome is disease stabilization,7-11 with fewer patients having tumor regression. Therefore, a challenge for clinicians is to select the most appropriate endpoints for clinical trials to quantify the activity of these agents accurately in the clinical setting. Previous experience with radiotherapy and chemotherapy led to the classification of a reduction in tumor volume as a response to therapy, but agents that reduce the rate of tumor growth without producing tumor regression are unfamiliar to oncologists. Because tumor growth rate in vivo cannot be measured accurately, patients who progress to any extent on therapy are usually categorized as treatment failures, even if growth rate is reduced. For these types of agents, using time to progression in randomized trials would be a more appropriate way to determine clinical activity than objective response rate. Therefore, there is a need to develop methods to measure subclinical tumor response. One promising method being investigated at present is positron emission tomography. Preclinical studies with erlotinib are in progress to develop a model for positron emission tomography scanning of patients with various tumors enrolled in phase II/III trials. In the future, it will hopefully be possible to assess not only tumor regression and stable disease, but also reduction in tumor growth, because this would affect overall survival. The phase III first-line combination trials with erlo-

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tinib (TALENT and TRIBUTE) are designed to allow for a reduction in tumor growth rate because treatment with erlotinib beyond progression is permitted. It will be interesting to see whether this improves survival in patients who, in other trials, would have been classified as having experienced treatment failure and their therapy withdrawn. Other ways to evaluate antitumor activity indirectly include the use of surrogate markers of activity. Several studies with HER1/EGFR agents show that the skin could be a surrogate tissue in which to evaluate the pharmacodynamic effects of therapy and identify easily quantifiable surrogate markers of response.29-31 The acneiform rash that commonly occurs with HER1/EGFR-targeted agents has been highlighted as a possible surrogate marker (data on file).8,11 However, the relationship between rash and response to therapy/survival appears to vary with different agents, and further investigation is required before the potential of this marker is realized. Moreover, a potential problem associated with using skin as a surrogate tissue is that it is currently unclear whether the extent of inhibition achieved in the skin biopsy sample and target tumor is similar. Thus, potential surrogate tissues such as skin and surrogate markers need to be carefully validated. Preclinical studies are in progress to assess the effect of erlotinib treatment on HER1/EGFR and its associated downstream signaling intermediaries in skin and tumor samples. The expression and activation of HER1/EGFR, the downstream signaling intermediary extra-cytoplasmic regulated kinase (Erk), and the cell-cycle regulator (p27), have all been investigated as potential surrogate markers of activity to erlotinib. At this stage there is no definitive result, but p27 shows some promise and more studies are investigating this in greater detail. After a marker is identified, a process of clinical validation will be required to ensure that it is a reliable predictor of delayed tumor growth, tumor regression, and ultimately clinical outcome. Finally, in addition to skin, studies are also in progress to assess the use of hair follicles and samples from buccal biopsies as surrogate tissues. ARE WE EVALUATING AGENTS IN THE MOST APPROPRIATE PATIENT POPULATION?

Another factor that requires consideration is the patient population in which HER1/EGFR

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inhibitors are evaluated and optimized. Conventionally, clinical trials with most anticancer agents are conducted in heavily pretreated patients with metastatic cancer. Evidence of efficacy in this population provides the rationale for the agent to be examined in other groups. This approach is appropriate for nonspecific agents because, as discussed, these agents are likely to cause tumor regression, which is relatively easy to detect. However, this is not an ideal population in which to test targeted therapies that may require prolonged administration to realize their maximum antitumor activity and are dependent on tumor characteristics that may change with disease progression. Therefore, under these conditions, it is likely that the potential value of targeted agents will be underestimated. Many studies suggest that growth factor receptor abnormalities play a key role in transformation, early tumorigenesis, and metastasis.32,33 As the tumor becomes more advanced and is exposed to various therapeutic regimens, it is likely to have many more genetic abnormalities than less advanced, untreated tumors. Consequently, it is much less likely that a single molecular lesion, such as HER1/EGFR overexpression, will be a dominant driver of tumor growth. If there are multiple drivers of tumor growth, inhibition of one pathway or process is much less likely to have clinical consequences. Therefore, HER1/EGFR-tyrosine kinase inhibition may be most effective in early stage, premetastatic disease, or the adjuvant/ neoadjuvant or preventative settings,34 and trials should be designed accordingly. THE FUTURE – THE NEXT 5 TO 10 YEARS

Many target-based agents have been identified and evaluated in preclinical and clinical studies. The clinical development of these agents is still in its infancy, but ongoing clinical trials with erlotinib and other HER1/EGFR inhibitors should provide a clearer understanding of their efficacy and how they should be used to achieve maximum clinical benefit. Maximizing response includes implementing well-designed clinical trials, using appropriate patient populations, identifying optimal regimens and schedules, and defining predictive markers that could be used in the future to select patients who are most likely to respond to treatment.

In the future, cancer treatment is likely to become more patient specific, with treatment regimens being tailored specifically to the patients’ tumor genotype and phenotype. Therefore, it is important to investigate whether these agents can be safely and effectively combined with other targeted agents. Against this background, continued preclinical investigation is vital to optimize the use of these agents. In addition, it is essential to obtain fresh tumor tissue samples from patients to document successful modulation of the target and assess clinical response. Moreover, it is important to evaluate the potential adverse effects of prolonged inactivation of HER1/EGFR function in individuals with cancer, should be evaluated because HER1/EGFR is a ubiquitous cellular signaling system. Thus, there are still many challenges facing researchers and many questions that remain unanswered. However, our increasing understanding of the biology of HER1/EGFR signaling and its role in the development and progression of various malignancies suggests that HER1/EGFR inhibitors, alone or in combination with other agents, will improve outcomes for patients with many types of solid tumors. REFERENCES 1. Moyer JD, Barbacci EG, Iwata KK, et al: Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838-4848, 1997 2. Pollack VA, Savage DM, Baker DA, et al: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: Dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739-748, 1999 3. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 4. Mita A, Farouzesh B, Hidalgo M: Phase I, pharmacokinetic (PK), and biological studies of the epidermal growth factor receptor-tyrosine kinase (HER1/EGFR-TK) inhibitor erlotinib (OSI-774; Tarceva) in combination with docetaxel. Eur J Cancer 38:53, 2002 (suppl 7) (abstr 168) 5. Patnaik A, Goetz A, Hammond L, et al: Phase I, pharmacokinetic (PK) and biologic study of OSI-774 (Tarceva), a selective epidermal growth factor receptor (EGFR) tyrsoine kinase (TK) inhibitor in combination with paclitaxel and carboplatin in patients with advanced solid malignancies. Eur J Cancer 38:54, 2002 (suppl 7) (abstr 169) 6. Ratain MJ, George CM, Janisch L, et al: Phase I trial of erlotinib (OSI-774) in combination with gemcitabine (G) and

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mal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 61:88878895, 2001 20. Christensen JG, Schreck RE, Chan E, et al: High levels of HER-2 expression alter the ability of epidermal growth factor receptor (EGFR) family tyrosine kinase inhibitors to inhibit EGFR phosphorylation in vivo. Clin Cancer Res 7:4230-4238, 2001 21. Moasser MM, Basso A, Averbuch SD, et al: The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184-7188, 2001 22. Nicholson RI, Gee JM, Harper ME: EGFR and cancer prognosis. Eur J Cancer 37:9-15, 2001 23. Cooke T, Reeves J, Lannigan A, et al: The value of the human epidermal growth factor receptor-2 (HER2) as a prognostic marker. Eur J Cancer 37:S3-10, 2001 (suppl 1) 24. Kononen J, Bubendorf L, Kallioniemi A, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844-847, 1998 25. Nocito A, Kononen J, Kallioniemi OP, et al: Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer 94:1-5, 2001 26. Kern DH, Weisenthal LM: Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J Natl Cancer Inst 82:582588, 1990 27. Mehta RS, Bornstein R, Yu IR, et al: Breast cancer survival and in vitro tumor response in the extreme drug resistance assay. Breast Cancer Res Treat 66:225-237, 2001 28. Levitt ML, Koty PP: Tyrosine kinase inhibitors in preclinical development. Invest New Drugs 17:213-226, 1999 29. Malik S, Siu L, Rowinsky E, et al: Pharmacodynamic evaluation of the epidermal growth factor inhibitor OSI-774 (Tarceva) in human epidermis of cancer patients. Clin Cancer Res (in press) 30. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292-4302, 2002 31. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110-124, 2002 32. Wells A, Kassis J, Solava J, et al: Growth factor-induced cell motility in tumor invasion. Acta Oncol 41:124-130, 2002 33. Kim H, Muller WJ: The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Exp Cell Res 253:78-87, 1999 34. Lonardo F, Dragnev KH, Freemantle SJ, et al: Evidence for the epidermal growth factor receptor as a target for lung cancer prevention. Clin Cancer Res 8:54-60, 2002