Pharmacokinetics and pharmacodynamics: Maximizing the clinical potential of Erlotinib (Tarceva)

Pharmacokinetics and Pharmacodynamics: Maximizing the Clinical Potential of Erlotinib (Tarceva) Manuel Hidalgo and Duane Bloedow Pharmacokinetic and pharmacodynamic studies have an important role in the optimization of targeted agents. Phase I pharmacokinetic studies show that treatment with erlotinib HCl (Tarceva; Genentech Inc, South San Francisco, CA), an orally available epidermal growth factor receptor (HER1/EGFR)-tyrosine kinase inhibitor, on a daily, uninterrupted schedule is feasible. Also, plasma drug concentrations, likely to be clinically effective based on preclinical studies, are consistently achieved at the recommended phase II dose of 150 mg/day, the maximum tolerated dose. Pharmacodynamic studies are in progress to assess the activation of HER1/EGFR and associated downstream signaling pathways in tissue samples from patients treated with erlotinib. Expression of p27 is identified as a potential surrogate marker of erlotinib activity, and is a focus of ongoing and future studies. Also, studies indicate that skin may be a useful surrogate tissue for evaluating the pharmacodynamic effects of therapy. These studies will hopefully enable us to accurately assess the extent of target inhibition in patients treated with erlotinib and help optimize its clinical use. Semin Oncol 30 (suppl 7):25-33. © 2003 Elsevier Inc. All rights reserved.

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RLOTINIB HCl (Tarceva; Genentech, Inc, South San Francisco, CA) belongs to a new generation of powerful, targeted therapies for epidermal growth factor receptor (HER1/EGFR)driven cancer. Erlotinib is an orally available, quinazoline-based small molecule that inhibits ligand-induced phosphorylation by competing with adenosine triphosphate for binding with the intracellular catalytic domain of HER1/EGFR tyrosine kinase. The molecular structure of erlotinib is shown in Fig 1. In vivo and in vitro preclinical studies have provided a strong rationale for investigating erlotinib in the clinical setting. Phase I pharmacokinetic and pharmacodynamic studies with erlotinib provide information to define the optimal dosing schedule for patients with various types of solid tumors and establish the dose-limiting toxicities. This article reviews the phase I pharmacokinetic data and explores the pharmacodynamic effects of erlotinib on HER1/ EGFR activation and signaling in tissue samples from treated patients. In addition, use of the expression of certain molecules in the skin as surrogate markers of response to erlotinib therapy is discussed. The long-term goal of these marker Seminars in Oncology, Vol 30, No 3, Suppl 7 (June), 2003: pp 25-33

studies is to develop an ethical and reproducible method to assess target inhibition. Such a method would enable us to effectively optimize the use of these agents and monitor their activity. PHARMACOKINETIC STUDIES OF ERLOTINIB

The overall goal of these pharmacokinetic studies was to profile the absorption and systemic exposure characteristics of erlotinib and provide a context for considering whether an adequate amount of drug is delivered to the target tumor. To achieve maximum therapeutic effects, it is important that there is sufficient delivery of erlotinib to the tumor so that receptor phosphorylation and associated downstream signaling are blocked.1 In vivo preclinical studies in a murine human tumor xenograft model (HN5) showed, as expected, that a higher circulating plasma level, produced by daily dosing of erlotinib, is associated with greater inhibition of HER1/EGFR-associated phosphotyrosine.2 These data support a dosing strategy in cancer patients that maintains a continuously high circulating level of erlotinib and therefore sets the foundation for daily dosing. Phase I Pharmacokinetic Studies in Human Volunteers and Patients With Solid Tumors Four phase I studies have assessed the pharmacology, pharmacokinetics, and tolerability of erlotinib in human volunteers and patients with advanced solid tumors. Healthy volunteers participated in two clinical trials. In the first study, 51 volunteers received a single oral dose of erlotinib (1 to 1,000 mg/day). In the second study, eight

From the Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Baltimore, MD; and the Clinical and Experimental Pharmacology Department, Genentech, Inc, South San Francisco, CA. Dr Hidalgo has received research grant support and honoraria from Genentech Inc, OSIP, and Roche Pharmaceuticals. Address reprint requests to Manuel Hidalgo, MD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St, Room 1M88, Baltimore, MD 21231. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3003-0704$30.00/0 doi:10.1016/S0093-7754(03)00186-6 25

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Fig 1. Molecular structure of erlotinib [6,7-Bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl) amine hydrochloride; molecular weight 429.9].

volunteers received oral erlotinib at 200 mg/day for 14 days. Results of pharmacokinetic analyses from both trials show that erlotinib is absorbed rapidly, with peak concentration achieved within 4 hours, followed by a monophasic decline within approximately 9 hours. In the first study, doseindependent pharmacokinetics were found within the range of 3 to 30 mg, but nonlinear pharmacokinetics were observed at higher doses. Pharmacokinetic studies from the second study showed expected drug accumulation and continuous exposure with daily treatment. Results from both these studies show that erlotinib is well tolerated (data on file). Two clinical trials of erlotinib in patients with advanced, refractory solid tumors examined daily and weekly dosing, respectively. In the daily trial, 40 patients received escalating doses of erlotinib on three schedules designed to evaluate progressively longer treatment intervals. On the first schedule, escalating doses of erlotinib (25 to 100 mg/day) were administered daily for 3 days each week for 3 weeks, every 4 weeks. On the second schedule, patients received erlotinib doses ranging from 50 to 200 mg/day, administered once daily for 3 weeks, every 4 weeks. This schedule was designed to establish the maximum tolerated dose (MTD). On the third schedule, the MTD (as defined on the second schedule) was administered on a daily, uninterrupted basis.3 Results of pharmacokinetic analyses from the first and second schedules showed that the plasma level of erlotinib increased with dose, and daily dosing did not result in unexpected drug accumulation. Erlotinib was generally well tolerated in these studies; the dose-limiting toxicities were diarrhea and acneiform rash. Diarrhea was dose lim-

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iting at 200 mg/day on the daily dosing regimen. At 150 mg/day, diarrhea was manageable with loperamide. Rash was observed at all doses, but at 150 mg/day it was never greater than moderate in severity. Acneiform rash occurs with all HER1/ EGFR-targeted agents; it is likely to be a result of HER1/EGFR inhibition in the skin, although the precise mechanism is unknown.4,5 Diarrhea is common with orally administered HER1/EGFR agents.6,7 Based on these data, erlotinib 150 mg/ day was established as the MTD and recommended for use in future trials. In addition, encouraging antitumor activity was observed with erlotinib in patients with a wide range of solid tumors. Pharmacokinetics of Single-Dose Erlotinib To characterize the pharmacokinetics of a single, oral dose of erlotinib, plasma samples were collected on day 1 from patients treated on the second schedule of the daily dosing study (50 to 200 mg/day, administered once daily for 3 weeks, every 4 weeks). With erlotinib 150 mg, the maximum plasma concentration (Cmax) was 1.14⫾0.87 ␮g/mL, and the time to reach maximum plasma concentration (Tmax) was 4⫾3.46 hours, indicating rapid absorption; plasma exposure (the area under the plasma concentrationtime curve [AUC0 –24]) was 16.51⫾11.02 ␮g 䡠 h/L; and the elimination half-life (t1/2) was 20⫾9.7 hours.3 The relative clinical efficacy of drugs with similar mechanisms of action is often related to their pharmacokinetic properties. Differences in pharmacokinetics (eg, bioavailability) can affect the amount of drug actually delivered to the site of action and are, therefore, an important consideration. Gefitinib (Iressa; AstraZeneca, Wilmington, DE) is a quinazoline-based, small-molecule HER1/ EGFR inhibitor currently in advanced clinical development. Unlike erlotinib, the doses of gefitinib recommended for clinical use (250 and 500 mg/ day) are below its MTD of approximately 700 mg/day,5,7,8 although it is unclear whether this difference in dosing strategy affects efficacy. Recent data from two phase III clinical trials of gefitinib in combination with chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) were disappointing.9,10 When the exposure to erlotinib and gefitinib are compared after a single, oral dose of 150 mg3,11

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Table 1. Comparison of Erlotinib and Gefitinib Pharmacokinetics Following Administration of a Single Oral Dose in Patients With Advanced Solid Tumors*

Oral dose (mg) Cmax (␮g/mL) Tmax (hours) AUC0–24 (␮g 䡠 h/L) t1/2 (hours)

Erlotinib3 (Male and Female Patients)

Gefitinib11 (Male and Female Patients)

150 1.136 ⫾ 0.865 4.0 ⫾ 3.46 16.51 ⫾ 11.02 20.0 ⫾ 9.74

150 0.142 ⫾ 0.060 3–5† 1.97 ⫾ 0.84 33.9 ⫾ 7.6‡

*Arithmetic mean ⫾ SD unless otherwise indicated. †Range. ‡From 50 mg dose.

(Table 1), the plasma concentration (Cmax) and exposure (AUC0 –24) with erlotinib are substantially higher than with gefitinib. This suggests that oral erlotinib is well absorbed. Studies in rats and dogs show that erlotinib is highly bioavailable (rats 77%; dogs 88%) following oral administration (data on file). Studies to assess the bioavailability of erlotinib in humans are in progress. The oral bioavailability of gefitinib after a single dose of 250 mg in humans is approximately 57%.5 Pharmacokinetics of Multiple-Dose Erlotinib The plasma exposure to erlotinib during multiple daily dosing, measured on days 1 and 24 of the study, is shown in Fig 2.3 Exposure to erlotinib

Fig 2. Plasma concentrationtime curves of erlotinib and OSI420 on days 1 and 24 after treatment with erlotinib 150 mg/day on the second schedule (data are from a representative patient). (Source: Hidalgo M, et al: Phase I 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. Reprinted with permission of the American Society of Clinical Oncology.3)

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increased 2- to 7-fold following multiple dosing compared with single dosing. Importantly, there was no unexpected accumulation of erlotinib (at day 24, t1/2 ⫽ 18⫾6 hours), and steady-state was reached in approximately 7 days. The minimum plasma steady-state concentration (Cssmin) in most patients who received 150 mg/day exceeded 500 ␮g/mL, which is the concentration estimated in preclinical studies to provide a level of HER1/ EGFR inhibition that correlates with antiproliferative activity.3 In patients who received erlotinib 50 and 100 mg/day, Cssmin values of 500 ␮g/mL were achieved much less frequently. Therefore, these data support once-daily dosing of erlotinib at 150 mg/day. The pharmacokinetic properties of erlotinib and gefitinib following multiple daily dosing are compared in Table 2.3,5 The recommended dose of erlotinib (150 mg/day) provides higher AUC0 –24 and Cmax than with gefitinib at 225 and 525 mg/ day doses. These doses are close to the recommended therapeutic doses of 250 and 500 mg/day. It should also be noted that erlotinib 150 mg/day has a similar time to peak plasma concentration (Tmax) to gefitinib 250 mg and 500 mg/day, but it is eliminated faster. The higher peak plasma concentration and exposure with erlotinib does not appear to be associated with a greater incidence or severity of adverse events compared with gefitinib. Exposure to gefitinib 700 mg/day, the approximate MTD, is similar to that with erlotinib at 150 mg/day. However, the adverse events with gefitinib at this

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Table 2. Comparisons of Erlotinib and Gefitinib Pharmacokinetics Following Multiple Dosing in Patients with Solid Tumors*

Parameter

Erlotinib3 (Male and Female Patients)

Gefitinib5 (Male and Female Patients)

Gefitinib5 (Male and Female Patients)

Gefitinib5 (Male and Female Patients)

Dose (mg/day) Cmax (␮g/mL) Tmax (hours) AUC0–24 (␮g 䡠 h/L) t1/2 (hours)

150 (day 24) 2.12 ⫾ 1.52 2⫾0 38.42 ⫾ 29.55 18.18 ⫾ 5.74

225 (day 14) 0.307 (67)† 4 (1–5)‡ 5.041 (93)† 47 ⫾ 11

525 (day 14) 0.90 (28)† 5 (1–7)‡ 14.727 (40)† 56 ⫾ 11

700 (day 14) 2.15 (35)† 3 (3–5)‡ 36.08 (43)† 65 ⫾ 15

*Arithmetic mean ⫾ SD unless otherwise indicated. †Geometric mean ([%] coefficient of variation). ‡Median (range).

dose are more frequent and severe and, as a result, using gefitinib above 500 mg/day is not recommended.5,7,8,11 These data show that, at clinical doses, greater exposure to erlotinib than gefitinib is achieved. Furthermore, in vivo studies show that the tumorto-plasma ratio for erlotinib is 0.3 to 0.4; however, plasma concentration may not be a strong indicator of antitumor activity.2 In addition, it is currently unclear how much drug is required to inhibit the receptor maximally and what level of inhibition translates into clinical benefit. Therefore, it is too early to predict whether higher exposure to erlotinib than gefitinib will translate into greater clinical antitumor activity. Pharmacokinetics of the Principle Erlotinib Metabolite – OSI-420 The principal metabolite of erlotinib is OSI420, although there are several other active metabolites. The molecular structure of OSI-420 is shown in Fig 3. OSI-420 inhibits purified HER1/

Fig 3.

Molecular structure of OSI-420.

EGFR with an IC50 of 2.5 nmol/L and HER1/ EGFR in intact cells with an IC50 of 14 nmol/L (data on file). These are similar to the values for erlotinib.12 These data suggest that OSI-420 may also block HER1/EGFR activation and associated downstream signaling events, thus, inhibiting tumorigenesis and contributing to the overall antitumor effect observed with erlotinib in vivo. OSI-420 has a similar pharmacokinetic profile to erlotinib (Fig 2). At 150 mg/day, the mean Cmax and AUC0 –24 values for OSI-420 on day 1 were 0.085⫾0.038 ␮g/mL and 1.69⫾1.42 ␮g 䡠 h/L, respectively. On day 1, the OSI-420:erlotinib AUC0 –24 ratio was, on average, 0.121 (range, 0.002 to 0.58), and the ratio was similar on subsequent days of treatment.3 METABOLISM

Most drugs undergo metabolic alteration, which occurs predominantly in the liver. As discussed, erlotinib is metabolized to several metabolites, including the predominant metabolite OSI-420, which are eliminated primarily in the bile. It is important to understand how erlotinib is metabolized and assess the effect that concomitant administration of other drugs may have on its metabolism. Approximately 80% of the metabolism of erlotinib occurs via cytochrome CYP3A4. CYP3A4 is also the common drug-metabolizing enzyme for other therapeutic agents that may be used concomitantly with erlotinib. Approximately 20% of erlotinib metabolism appears to be nonCYP3A4 dependent. Studies have shown that

MAXIMIZING THE CLINICAL POTENTIAL OF ERLOTINIB

cytochromes 1A2, 2C8, 2C9, 2C19, and 2D6 do not appear to be involved (data on file). Additional in vitro studies are underway. Potent inhibitors of CYP3A4 can affect the metabolism of erlotinib, altering the plasma exposure and, potentially, efficacy and tolerability. In vitro studies show that erlotinib metabolism is inhibited by ketoconazole, a strong 3A4 inhibitor (data on file). A study is in progress to assess the pharmacokinetics of erlotinib in combination with ketoconazole. Preliminary results indicate that the AUC0 –24 and Cmax of erlotinib are increased by ketaconazole. Other potent CYP3A4 inhibitors include systemic antifungals (fluconazole and itraconazole), erythromycin, troleandomycine, grapefruit juice, and some calcium channel blockers (verapamil and diltiazem). Other agents that could affect erlotinib metabolism are CYP3A4 inducers. Preclinical and early clinical studies show that CYP3A4 inducers increase erlotinib metabolism, thus, decreasing the plasma exposure (data on file). For example, the findings of a recent study show that exposure to erlotinib was reduced when a single, oral dose of erlotinib was administered after seven daily doses of rifampicin, a classic CYP3A4 inducer. These data suggest that a dose adjustment may be necessary when erlotinib is coadministered with potent CYP3A4 inhibitors, such as rifampicin (data on file). Other common CYP3A4 inducers include antiepileptics, (carbamazepine, barbiturates, and phenytoin). Studies are in progress to examine the effect of using erlotinib in combination with various other 3A4 substrates. PLASMA-PROTEIN BINDING

Phase I studies show that, in humans, 92% to 95% of erlotinib is bound to plasma-protein (data on file). Recent studies indicate that changes in plasma-protein binding as a result of drug– drug interactions are unlikely to influence clinical exposure to a therapeutic agent.13-15 Therefore, concomitant administration of agents that bind extensively to plasma-proteins, such as propranolol or warfarin, is not expected to necessitate an alteration in erlotinib dosing regimens. However, changes in the plasma-protein binding may affect certain individual pharmacokinetic parameters, which could result in changes in the concentration-time profiles.

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PHARMACODIAGNOSTIC AND PHARMACODYNAMIC STUDIES

Based on the phase I data described previously, progression to phase II/IIII clinical trials was justified using the MTD of 150 mg/day. A phase II study in patients with non–small cell lung cancer showed antitumor activity and suggest a survival benefit.16,17 Phase III studies in this indication are in progress. Despite the selectivity of erlotinib for HER1/ EGFR, receptor expression was not an inclusion criterion for phase III trials because a strong relationship between expression and response was not reported in phase II trials.17-19 For example, in one of the phase II erlotinib monotherapy trials, patients with HER1/EGFR-positive and -negative head and neck squamous cell cancer were enrolled, and no relationship between HER1/EGFR expression and activity was detected.19 Despite the ubiquitous expression of the receptor, findings from trials in patients with various types of cancer indicate that only a relatively small proportion of patients will respond to therapy with HER1/EGFR inhibitors.20-22 Therefore, there is a need to identify and evaluate markers that predict for response to HER1/EGFR inhibitors. In the short term, such markers will facilitate the development and optimization of these agents, potentially enabling us to identify patients who are most likely to respond to therapy. Ultimately, because of the many targeted agents in development that are designed to block different tumorigenic pathways, screening before treatment will enable us to select the most appropriate agent or “therapeutic cocktail” for each patient. In general, marker identification may be approached in two different ways: examining markers in pretreatment tumor samples (pharmacodiagnostics/predictive diagnostics); or examining the effect of the drug in tissues (pharmacodynamics). For example, examining toxicity, measured after treatment in either tumor or validated normal tissue, which can then be correlated with activity and/or outcome. Ideally, studies to identify potential pharmacodynamic markers should be conducted in samples of the target tumor; however, this is rarely possible in clinical trials because of the ethical and physical limitations of performing invasive procedures to obtain serial tumor biopsies. The skin represents a

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Fig 4. The proportional variation in the quantitative expression of phosphorylated HER1/ EGFR (pHER1/EGFR) as a function of erlotinib dose.26

potential surrogate tissue because it contains a high level of HER1/EGFR, and HER1/EGFR inhibitors induce skin toxicity, which may correlate with antitumor response and/or survival.17,23,24 In addition, importantly, obtaining skin samples is minimally invasive. Therefore, the skin may be an appropriate tissue in which to explore the pharmacodynamic effect of HER1/EGFR inhibition.25 Several studies have assessed the ability of HER1/EGFR-targeted agents to inhibit HER1/ EGFR activation and signaling in skin samples.8,25-27 A recent phase I study in patients with advanced, solid tumors determined the effect of erlotinib on HER1/EGFR activation and signaling in epidermal samples.25 A total of 56 skin specimens were collected from 28 patients treated with erlotinib at doses ranging from 25 to 200 mg/day. The relationships between dose, plasma concentration, and biologic activity were explored. The expression and activation of HER1/EGFR, the downstream signaling intermediary extra-cytoplasmic regulated kinase (Erk), and the cell-cycle regulator p27 were all determined immunohistochemically.25 The immunohistochemistry data were analyzed using both a semiquantitative scoring system and an automatic, optical density, quantitative immunohistochemistry method.

A total of 12 (42.8%), seven (25%) and 14 (56%) patients had more than a 25% variation in phosphorylated (p) HER1/EGFR, pErk, and p27 expression, respectively. Interestingly, at the doses examined (25 to 200 mg/day) only up-regulation of p27 was dose related. The proportional variation in the quantitative expression of pHER1/ EGFR and p27 as a function of erlotinib dose is shown in Figs 4 and 5, respectively. Fig 6 shows immunoperoxidase staining for p27. In this study, no relationship was observed between the erlotinib plasma concentration and pharmacodynamic effect in the skin. Based on these findings, p27 expression has promise as a surrogate marker of response to erlotinib. Phase II studies are ongoing to evaluate the usefulness of p27 as a marker of clinical outcome.25 Using skin as a surrogate marker of response, however, has limitations. For instance, the relationship between the pharmacodynamic effect of erlotinib in skin biopsy samples and the target tumor is not known. It is possible that these tissues respond differently to HER1/EGFR inhibition,25 and the biodistribution of erlotinib between the skin and tumor compartments differs. Therefore, additional preclinical and clinical studies, in which tumor and skin samples are compared, are

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Fig 5. The proportional variation in the quantitative expression of p27 as a function of erlotinib dose.26

Fig 6. (A) Normal skin, (B) negative control, (C) pretreatment sample stained for p27, and (D) post-treatment sample stained for p27 (note the increase in the number of positive cells). Photographs are from a representative patient (magnified ⴛ400).26

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needed. To this end, an ongoing study is examining the ability of erlotinib to inhibit HER1/EGFR activation and signaling in tumor and skin samples from patients with head and neck squamous cell cancer.26 This study will examine the expression of pHER1/EGFR, pErk, and pAkt. Other studies are ongoing to define the relationship between HER1/ EGFR inhibition and steady-state plasma drug concentrations, drug-induced effects in tumor and skin, and the correlation between HER1/EGFR inhibition and treatment outcome. In addition, various clinical trials examining surrogate markers of response to erlotinib are in progress in patients with various types of cancers. The pharmacodynamic effects of other HER1/ EGFR-targeted agents in patients with solid tumors are also being explored, although, there is currently no clear evidence regarding a surrogate or predictive marker of response to any HER1/ EGFR-targeted agent. In agreement with data from a phase II trial with erlotinib in patients with non–small cell lung cancer,17 findings from recent phase II studies with two anti-HER1/EGFR monoclonal antibodies (cetuximab and ABX-EGF) indicate that skin rash may correlate with response and/or survival. In a phase II trial examining cetuximab and irinotecan (Camptosar; Pfizer Inc, New York, NY) in 121 patients with colorectal cancer, response rates were 3.8% in those with no skin rash, 14% in patients with grade 1 rash, 23.5% in patients with grade 2 rash, and 70.6% in those with grade 3 rash. A similar correlation was found between rash and median duration of survival (124, 193, 320, and 395 days, respectively).24 A relationship between skin rash and response was also noted with ABX-EGF in patients with renal cancer.23 Thus, further investigation of rash as a potential pharmacodynamic surrogate marker of activity is warranted. DISCUSSION

Pharmacokinetic and pharmacodynamic studies are essential to help determine the optimal dosage of targeted agents. Moreover, in the future the identification of surrogate or predictive markers of response may help evaluate the efficacy of these agents more accurately and enable us to preselect patients who are most likely to respond to therapy. Phase I pharmacokinetic studies have shown that treatment with erlotinib on a once-daily, uninterrupted, dose schedule is well tolerated. Fur-

thermore, clinically effective plasma drug concentrations are consistently achieved at the recommended phase II dose of 150 mg/day. Despite erlotinib being investigated in numerous phase II and III studies, further studies will help optimize its use. Central to this is understanding the downstream mechanism of action of erlotinib and how these processes influence its antitumor activity. Pharmacodynamic assays have been developed to examine variations in potential marker expression in tissue samples before and after treatment with erlotinib. Activation of HER1/EGFR and various downstream signaling pathways have been quantified using immunohistochemistry to try to identify a suitable marker. However, while these experiments are promising, staining and quantification procedures need to be validated before firm conclusions can be drawn. At present, a clear surrogate or predictor marker of activity has not been identified, although expression of p27 is the most promising marker recognized so far. Also, data from various studies show that using normal skin samples for biologic studies could be a useful tool for the development of HER1/EGFR inhibitors. ACKNOWLEDGMENT The authors thank Sean Kelley for the evaluation and interpretation of pharmacokinetic data.

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774). Final report of a phase II study. Presented at the American Society of Clinical Oncology Molecular Therapy Symposium, San Diego, CA, November 8-10, 2002 18. Finkler N, Gordon A, Crozier M, et al: Phase 2 evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced ovarian carcinoma. Proc Am Soc Clin Oncol 20:208a, 2001 (abstr 831) 19. Hidalgo M: Phase I studies/combination therapy with Tarceva (erlotinib HCl;OSI-774) in head and neck cancer. Presented at the First Annual Opinion Leader Consort on Novel and Targeted Therapies for Head and Neck Cancer, San Juan, Puerto Rico, February 5-9, 2003 20. Senzer NN, Soulieres D, Siu L, et al: Phase 2 evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 20:2a, 2001 (abstr 6) 21. Fukouka 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 21:298a, 2002 (abstr 1188) 22. Kies MS, Arquette M, Nabell L, et al: Final report of the efficacy and safety of the anti-epidermal growth factor antibody, cetuximab (IMC-C225), in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 21:232a, 2002 (abstr 925) 23. Rowinsky E, Schwartz G, Dutcher J, et al: ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFr) monoclonal antibody: Phase II clinical trials in renal cell cancer (RCC). Eur J Cancer 38:57, 2002 (suppl 7) (abstr 178) 24. Saltz L, Rubin M, Hochster H: Acne-like rash predicts response in patients treated with cetuximab (IMC-C225) plus irinotecan (CPT-11) in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Clin Cancer Res 7:3766, 2001 (suppl) (abstr 559) 25. 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) 26. Hidalgo M, Malik S, Rowinsky E, et al: Inhibition of the epidermal growth factor receptor (EGFR) by OSI-774, a specific EGFR inhibitor in malignant and normal tissues of cancer patients. Proc Am Soc Clin Oncol 20:71a, 2001 (abstr 281) 27. 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