Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 77-85
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.06.075
Multicenter Phase II Study of Erlotinib, an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck
Denis Soulieres,
Neil N. Senzer,
Everett E. Vokes,
Manuel Hidalgo,
Sanjiv S. Agarwala,
Lillian L. Siu
From the CHUM, Hospital Notre Dame, Montreal, Quebec; Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; US Oncology, Dallas; Cancer Therapy and Research Center, San Antonio, TX; the University of Chicago, Chicago, IL; and the Pittsburgh Clinical Research Network, Pittsburgh, PA.
Address reprint requests to Lillian L. Siu, MD, FRCPC, Princess Margaret Hospital, University Health Network, 610 University Ave, Suite 5-210, Toronto, Ontario, M5G 2M9 Canada; e-mail: lillian.siu{at}uhn.on.ca
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ABSTRACT
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PURPOSE: To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC).
PATIENTS AND METHODS: Patients with locally recurrent and/or metastatic HNSCC, regardless of their HER1/EGFR status, were treated with erlotinib at an initial dose of 150 mg daily. Dose reductions or escalations were allowed based on tolerability of erlotinib.
RESULTS: One-hundred fifteen patients were enrolled onto this study. Forty-seven percent of patients received erlotinib at 150 mg daily throughout the entire study, 6% had dose escalations, and 46% required dose reductions and/or interruptions. Five patients achieved partial responses on study, for an overall objective response rate of 4.3% (95% CI, 1.4% to 9.9%). Disease stabilization was maintained in 44 patients (38.3%) for a median duration of 16.1 weeks. The median progression-free survival was 9.6 weeks (95% CI, 8.1 to 12.1 weeks), and the median overall survival was 6.0 months (95% CI, 4.8 to 7.0 months). Subgroup analyses revealed a significant difference in overall survival favoring patients who developed at least grade 2 skin rashes versus those who did not (P = .045), whereas no difference was detected based on HER1/EGFR expression. Rash and diarrhea were the most common drug-related toxicities, encountered in 79% and 37% of patients, respectively, though the severity was mild to moderate in most cases.
CONCLUSION: Erlotinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization; hence, further evaluation of its role in this tumor type is warranted.
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INTRODUCTION
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The diagnosis of recurrent or metastatic squamous cell cancer of the head and neck (HNSCC) carries a limited prognosis, with a median survival of approximately 6 months. Conventional cytotoxic chemotherapeutic agents have produced objective response rates that varied from approximately 15% to 40%, and durations of response are typically brief. Furthermore, tumor shrinkage has not translated to significant improvements in the overall survival of this patient population [1,2]. Newer cytotoxic agents such as the taxanes have been evaluated, [3,4] but definitive results of their efficacy and toxicity are pending. Quality of life end points have not been well characterized, despite the concerns for chemotherapy-related toxicity, among patients whose performance statuses are often borderline because of existent comorbid illnesses. In this context, there are continual interests to search for new treatments which may provide a more favorable therapeutic index in these patients.
The epidermal growth factor receptor (HER1/EGFR) signal transduction pathways have been implicated in the regulation of various neoplastic processes, including cell cycle progression, inhibition of apoptosis, angiogenesis, tumor cell motility, invasion and metastasis [5-8]. Targeting HER1/EGFR as a therapeutic strategy against HNSCC is a rational approach substantiated by multiple lines of evidence. The overexpression of HER1/EGFR in 80% to 100% of HNSCCs corroborates the potential clinical relevance of this target [9]. Furthermore, elevated levels of HER1/EGFR and TGF- mRNA have been detected in tumors and in histologically normal mucosa from patients with HNSCC, when compared to control normal mucosa [10]. Importantly, several reports have provided support for a clinicopathologic association between HER1/EGFR overexpression and poorer prognosis, such as decreased chemosensitivity and shorter disease-free survival for patients with HNSCC [11-13].
Erlotinib hydrochloride (erlotinib) ([6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl]-[3-ethylphenyl]amine; formerly CP-358,774, OSI-774; Tarceva, OSI Pharmaceuticals, New York, NY) is an orally available, potent, reversible, and selective inhibitor of the EGFR tyrosine kinase. In preclinical xenograft models, the inhibition of HN5 head and neck tumor growth correlated with HER1/EGFR phosphotyrosine reduction by erlotinib [14]. A phase I clinical trial of erlotinib has been completed in patients with advanced solid tumors, diarrhea, and cutaneous toxicity were dose-limiting and the recommended dose of erlotinib for phase II evaluation is 150 mg per day on a continuous schedule [15]. Preliminary antitumor activity was observed, including one patient with HNSCC with progressive tumor growth before study entry who achieved disease stabilization for 15 months on erlotinib.
Based on the aforementioned rationale, further evaluation of erlotinib in patients with recurrent or metastatic HNSCC is warranted. The primary objective of this phase II trial was to determine the efficacy of erlotinib administered as a single agent in patients with recurrent and/or metastatic HNSCC. Secondary objectives were to measure stable disease rates, duration of responses, progression-free and overall survival. This study also sought to characterize the safety and pharmacokinetic profiles of erlotinib administered daily in this patient population.
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PATIENTS AND METHODS
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Eligibility
Patients with histologically or cytologically confirmed diagnosis of locally recurrent and/or metastatic HNSCC from any of the primary sites were candidates for this trial. Patients may have had prior induction or concurrent chemotherapy delivered as part of their primary treatment but must have completed primary therapy at least 6 months before study entry. Patients may have had up to one palliative regimen at least 4 weeks before study entry for recurrent or metastatic disease. HER1/EGFR overexpression was not an inclusion criterion for this study, but all patients must have archival or fresh tumor specimens available and evaluable for determination of expression of the HER1/EGFR by immunohistochemistry. Other eligibility criteria were the following: age 18 years or older; Eastern Cooperative Oncology Group performance status 0 to 2; ability to swallow tablets, or presence of a silicone-based gastrostomy or jejunostomy feeding tubes whereby tablets can be dissolved and administered; bidimensionally measurable disease; adequate hematopoietic (absolute neutrophil count  1.5 x 109/L; platelet count 100 x 109/L; and hemoglobin 9 g/dL); hepatic function (AST and ALT levels  2.5 times the upper normal limit and alkaline phosphatase 5 times the upper normal limit); renal function (creatinine concentration 1.5 mg/dL); for females, no pregnancy or lactation; no prior therapy with agents targeting the HER1/EGFR; and no abnormalities of the cornea based on history and/or slit-lamp examination using a vital dye and corneal sensitivity test. All patients gave written informed consent in accordance with the federal and institutional guidelines before study treatment.
Drug Administration
Erlotinib was administered in an open-labeled, unblinded fashion to all patients on study. All but one patient received erlotinib at an initial dose of 150 mg per day (one patient received 125 mg because of dosage error). Patients unable to swallow tablets or those who had silicone-based feeding tubes were allowed to dissolve the tablets in distilled water according to the instructions provided.
Dose reduction was based on the patient's tolerability of erlotinib treatment and could occur at any time during the study as guided by protocol. Dosing suspension was implemented for any National Cancer Institute Common Toxicity Criteria grade 4 toxicity. Rechallenge with study drug after dose interruption or suspension was allowed only if the investigator and medical monitor agreed it would be in the best interest of the patient to do so, and the patient had to provide updated written consent.
Dose escalation above 150 mg daily was allowed if the patient had been on a stable dose for 4 weeks and did not have any drug-related adverse events. The daily dose could be increased by 50 mg to a maximum of 250 mg per day.
Study treatment was planned for a minimum of 8 weeks and a maximum of 48 weeks. Continuation of study treatment beyond 48 weeks in patients with sustained tumor response or stabilization was allowed based on the assessments of the investigator and medical monitor.
Pretreatment and Follow-Up Studies
A complete history and physical examination including a skin assessment, complete blood counts with differential and platelet count, biochemical profile and urinalysis, were measured at screening, followed by weekly intervals at weeks 1 to 5, then every 4 weeks throughout the study, after any dose escalation, at study discontinuation, and as needed during the study. All patients underwent an ophthalmologic examination with a vital dye (fluorescein and/or Bengal-Rose) and slit-lamp assessment before study enrollment. In addition, a corneal sensitivity test to evaluate tear production (Schirmer's test) and a visual acuity test were performed before study enrollment to ensure eligibility. Ophthalmologic examinations were repeated at week 5 and within 2 weeks after any dose escalation, at study discontinuation, and as needed during the study.
HER1/EGFR staining of either original paraffin-embedded or newly biopsied tumor specimens was conducted by a central laboratory (IMPATH Inc, Los Angeles, CA) at screening. HER1/EGFR staining intensity were scored as follows: none = 0, weak = 1, weak to strong = 2, and strong = 3. The proportion score is a continuous variable from 0% to 100% staining positive. A hybrid-score (H-score) was calculated as the product of the HER1/EGFR intensity score and the proportion score, with a possible range of results from 0 to 300.
Tumor evaluations using consistent clinical examination and radiologic imaging of the head and neck, and chest, were performed at baseline before study treatment, every 8 weeks during treatment, and at study discontinuation. Objective tumor responses were determined according to the WHO criteria. Central radiology review was not performed.
Pharmacokinetic Sampling and Assay
Plasma levels of erlotinib and its metabolite OSI-420 were determined at various times relative to drug administration, dose escalation, and premature discontinuation from the study. Blood samples were taken randomly from one of three sampling windows (trough [ie, 20 to 25 hours postdose], Cmax window [ie, 2 to 5 hours postdose], or 5 to 10 hours postdose). During the study, the pharmacokinetic sampling should have covered all three windows for each patient. A randomization list was provided to specify the drug administration times relative to the clinic visits for each patient.
Plasma samples were analyzed by MDS Pharma Services (St Laurent, Quebec, Canada) for erlotinib and OSI-420 using a validated LC/MS/MS assay with a limit of quantitation of 1 ng/mL for each analyte. Briefly, an internal standard was added to aliquots of samples, calibration standards, and quality control samples, followed by liquid/liquid extraction with methyl t-butyl ether. The solvent layer was evaporated to dryness under nitrogen and reconstituted in mobile phase. The extracts were then analyzed by reverse-phase high-performance liquid chromatography with MS/MS detection using single reaction monitoring.
Statistical Analysis and Sample Size Determination
All patients were to be considered assessable for the primary efficacy analysis if they received study drug, had bidimensionally measurable disease, and had confirmation of disease diagnosis. Patients with disease progression earlier than the first 8 weeks were to be evaluated as "early progression." Progression-free survival (PFS), overall survival, 6-month, and 1-year rates were estimated from Kaplan-Meier curves. Kaplan-Meier analyses were performed using PROC LIFETEST in SAS (SAS/STAT User's Guide, Version 6; SAS Institute, Cary, NC, 1990). CIs reported for rates or proportions were calculated based on exact binomial distributions. The level of confidence for all CIs was selected at 95%.
A total of approximately 100 eligible patients were to be enrolled onto this single-arm study, to ensure that at least 40 would be HER1/EGFR+ patients.
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RESULTS
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Patient and Disease Characteristics
Table 1 summarizes the pretreatment patient and disease characteristics of 115 patients with recurrent and/or metastatic HNSCC who were enrolled in this phase II study. Evaluation of disease status at the time of study entry demonstrated that 53% of patients had locoregional recurrence, 23% had metastatic disease only, and 24% had both. As expected, the majority (87%) of patients had tumors that demonstrated strong HER1/EGFR staining intensity, whereas approximately half of the patients had 80% to 100% of their tumor cells stained positive for HER1/EGFR.
Summary of Previous Therapy
Table 2 provides a summary of prior therapy received by patients on study. All but one patient had received one or more treatment modalities before entering onto the study.
Treatment Compliance
Overall, treatment compliance was consistent with the protocol in the majority of study patients. All but three of the 115 patients received at least 1 week of erlotinib at the planned dose. Three patients (3%) received less than 1 week of erlotinib before discontinuation due to progressive disease or an adverse event. Two patients (2%) received erlotinib for more than 48 weeks. The median duration of treatment for all 115 patients was 10 weeks (range, 1 to 91 weeks).
Approximately half of the patients (55 [48%] of 115 patients) continued to receive 150 mg daily dose of erlotinib throughout the entire duration of the study, without any dose modifications.
For the eight patients(7%) who had dose escalations, erlotinib at 200 mg daily was administered for a range of 15 to 305 days, and the dose of one of these eight patients even escalated further to 250 mg per day for the last 28 days of treatment. Five of the eight patients tolerated the dose escalations without event, whereas the other three experienced severe, drug-related adverse events including one case of each of grade 3 fatigue, rash, and anemia.
Of the 35 patients (30%) who required dose reductions: 17 patients had their erlotinib dose reduced to 100 mg daily during their remaining course on study, five patients had their dose reduced to 100 mg daily but all were successfully rechallenged to 150 mg daily, nine patients had their dose reduced to 50 mg daily with one successfully rechallenged to 100 mg daily, and four patients had dose reduced for a 1 to 3 days only, because of drug dispensing problems. The majority of patients were dose reduced because of skin toxicities (21 [64%] of 33 patients).
Most of the patients who required erlotinib dose interruptions did so for less than 2 weeks, mainly because of drug availability issues or adverse events which interfered with compliance. Seven patients (6%) were permanently discontinued from the study, primarily because of adverse events; three of those patients had adverse events believed to be related to erlotinib.
Objective Tumor Response
No complete response was reported among the 115 patients on this study, whereas five patients achieved a best response of partial response, for an overall objective response rate of 4.3% (95% CI, 1.4% to 9.9%) by intention-to-treat analysis. The median duration of response was 9.7 weeks (range, 5.1 to 26.4 weeks). None of the five responders had their erlotinib dose escalated. One patient received treatment at 150 mg daily for the entire study period, whereas the other four patients have had dose reductions and/or dose interruptions.
Forty-four patients (38.3%) had a best response of stable disease for a median duration of 16.1 week (range, 9.6 to 89.6+ weeks). Seventy-seven percent of the patients with stable disease had disease stabilization lasting for at least 3 months. Fifty-four patients (47%) had progressive disease on study, and the 12 remaining patients were considered not assessable for response, because tumor measurements were not repeated before they were declared off-study.
Progression-Free Survival and Overall Survival
The median progression-free survival for the entire study population was 9.6 weeks (95% CI, 8.1 to 12.1 weeks; Fig 1). The 6-month and 1-year progression-free survival rates were 10.4% (95% CI, 5.5% to 17.5%) and 0.9%, respectively. The median overall survival was 6.0 months (95% CI, 4.8 to 7.0 months; Fig 2). The 6-month and 1-year survival rates were 50% (95% CI, 41% to 60%) and 20% (95% CI, 13% to 28%), respectively. At the time of data analysis, a total of 108 patients had a reported date of death, and seven patients were still alive and had been followed on study for 11.1 to 28.4 months.
Subgroup Analysis
HER1/EGFR expression.
When survival was analyzed as a function of the HER1/EGFR intensity or proportion scores, no difference was observed (Fig 3A and B, respectively).
Skin rash.
When analyzed as a function of rash severity, the median survival durations of patients with no skin rash, grade 1 skin rash, and grades 2 to 4 skin rashes were 4.0 months, 5.0 months, and 7.4 months, respectively. There was a statistically significance difference in overall survival between patients with no rash versus those with grades 2 to 4 skin rash (P = .045). The difference was not statistically significant between patients with no rash versus those with grade 1 skin rash (P = .14). Figure 4 illustrates the Kaplan-Meier curves of survival as stratified by grade of skin rash.
HER1/EGFR expression and skin rash.
The relationship between HER1/EGFR expression and the severity of skin rash was explored. The median HER1/EGFR H-scores for patients who developed no skin rash, grade 1 skin rash, and grade 2 or worse skin rashes were 210, 180, and 210, respectively, suggesting that there are no significant associations between these two parameters (P = .98).
Toxicity
Table 3 displays the incidence of the most common nonhematolologic toxicities considered to be drug-related or with unknown relationships encountered during the study. Rash and diarrhea were the principal drug-related toxicities, reported in 79% and 37% of the patients, respectively, although the severity was mild to moderate in most cases. Ten percent of patients experienced grade 3 skin rash, and one patient (1%) developed a grade 4 rash on erlotinib 150 mg daily and required dose interruption followed by subsequent dose reduction to 100 mg daily. Grade 3 diarrhea occurred in four patients (3%), and no patient had grade 4 diarrhea. The median time to the first occurrence of rash regardless of severity was 8 days (range, 2 to 73 days). The median time to the first occurrence of diarrhea regardless of severity was 12 days (range, 1 to 174 days). Other common toxicities, including dry skin, pruritus, stomatitis, and nausea and fatigue, all generally of mild to moderate intensity, were noted in approximately 15% to 30% of the study patients. There were no treatment-related deaths.
Biochemical Changes
The shifts from baseline grade to worst grade on study for ALT, AST, alkaline phosphatase, and total bilirubin values are listed in Table 4. Abnormalities observed in these hepatic parameters were mostly mild to moderate, even in patients who had elevated values at baseline. Grade 3 elevations in these parameters were infrequent and sporadic; most were due to disease progression in the liver and were deemed as erlotinib-related only in two patients.
One or more sporadic creatinine elevations above the normal range were observed in 12 patients on study. The highest creatinine level observed in this group was 1.8 mg/dL (grade 1), and creatinine levels returned to a normal range by the end of the study in the majority.
Hematologic Toxicity
Overall, erlotinib therapy was not associated with any significant myelotoxicity. No patients developed febrile neutropenia or thrombocytopenic bleeding or required platelet transfusions on study.
Pharmacokinetic Analysis
Steady-state plasma concentrations of erlotinib and its metabolite OSI-420 were available for a limited number of patients at various sampling time points postdose. The median values of individual patient results are presented in three windows: 2 to 5 hours (n = 82 patients), 5 to 10 hours (n = 51 patients), and 20 to 25 hours (n = 44 patients). Tables 5 and 6 demonstrate the median plasma concentrations of erlotinib and OSI-420 at the three sampling windows, analyzed by grade of skin rash and HER1/EGFR H-score, respectively. There were no statistically significant differences in any of the median plasma concentrations between patient subgroups whether stratified by grade of skin rash or by HER1/EGFR H-score. When hazard ratios of survival are analyzed according to the pharmacokinetic results, the median plasma concentrations of both erlotinib and OSI-420 at the 5 to 10 hour postdose window, as well as those of OSI-420 at the trough (ie, the 20 to 25 hour window), predict for improved survival (Table 7).
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Table 5. Median Pharmacokinetic Concentrations of Erlotinib (OSI-774) and Erlotinib Metabolite (OSI-420) by Grade of Skin Rash
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Table 6. Median Pharmacokinetic Concentrations of Erlotinib (OSI-774) and Erlotinib Metabolite (OSI-420) by HER1/EGFR H-Score
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Table 7. Overall Survival by Pharmacokinetic Concentrations of Erlotinib (OSI-774) and Erlotinib Metabolite (OSI-420)
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DISCUSSION
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This multicenter phase II trial met its objectives to determine the efficacy, safety, and pharmacokinetic profiles of erlotinib administered as a single agent in patients with refractory, recurrent and/or metastatic HNSCC. Although the objective response rate of 4.3% observed on this study, lower than that achievable with conventional cytotoxic chemotherapy, indicates that erlotinib as a single agent is marginally cytoreductive in this patient population, it is notable that disease stabilization with a median duration of 16.1 weeks was achieved in 38% of patients. Furthermore, the median overall survival of 6 months and the 1-year survival rate of 20% are comparable to those attainable by palliative chemotherapy in this population. Given that the patients on this study were heavily pretreated and that the current results demonstrated the static effects of erlotinib against refractory HNSCC, continual evaluation of erlotinib in this disease site is warranted. Other EGFR-targeted therapies, such as the monoclonal antibody IMC-C225 and another tyrosine kinase inhibitor, gefitinib, have also shown antitumor activity in HNSCC [9,16,17], corroborating further investigations of this class of agents in this malignancy.
Based on the typical experience with toxicity from standard chemotherapeutic agents, the toxicity profile of erlotinib observed on this study was favorable, with mild to moderate rash and diarrhea being the most prevalent, as predicted from phase I trial results and class effects expected of this agent. Due to the uncontrolled nature of this single arm phase II trial, meaningful interpretation of data based on patients' health-related quality of life and clinical benefit would be difficult. Future trial options in recurrent and/or metastatic HNSCC may include combining erlotinib with tolerable doses of chemotherapy or with other relevant molecular targeted agents, in an attempt to enhance the therapeutic index and to avoid overlapping toxicities. At present, a phase I/II trial of erlotinib administered in combination with cisplatin as first-line palliative therapy is ongoing in this patient population (http://www.nci.nih.gov/cancerinfo/pdq). Validated measures of health-related quality of life and clinical benefits should be included in any controlled randomized trial designs that are employed to further evaluate the tolerability and efficacy of this agent alone or in combination with other therapeutic modalities.
Interestingly, as consistent with the results from phase II trials of erlotinib in other disease sites, [18] and from other EGFR-targeted therapies, [17,19] clinical outcome of erlotinib in the current study correlated with the development of skin rash. Histologic examination has revealed a neutrophilic infiltration of dermal tissues, particularly in the infundibular portion of hair follicles, [15] but the pathogenesis of this cutaneous toxicity remains unclear. Whether the rash reflects the local effects of EGFR blockade in skin or represents a systemic inflammatory reaction to this class of agents, it appears to serve as a clinically important pharmacodynamic marker of target inhibition. The development and the severity of skin rash were generally independent of the median plasma concentrations of erlotinib or its metabolite, OSI-420. Previous results from the phase I evaluation of erlotinib demonstrated statistically significant, borderline trend and nonsignificant relationships between AUC0-24 (area under the plasma concentration-time curve from time 0 to 24 hours), Cmax and Cssmin, respectively, with the development of cutaneous toxicity [15]. Unfortunately the limited sampling schedule used in this study precluded further conclusions on the relationships between various pharmacokinetic parameters and skin toxicity. In addition to pharmacokinetic reasons, the variability observed in skin toxicity may be related to pharmacodynamic differences or pharmacogenetic heterogeneity among patients. The observation that patients with at least grade 2 skin rash had better survival outcome in this study is hypothesis generating and supports the rationale of "physiologic dosing till rash development" in future trials of erlotinib, providing that other drug-related toxicities are manageable.
Notably, when the paired associations between skin rash, pharmacokinetic data, and survival are reviewed, there appears to be a lack of consistency among these outcome parameters. Even though there are statistically significant associations demonstrated between skin rash and survival, as well as between the 5 to 10 hour postdosing plasma concentrations of elotinib/OSI-420 and survival, no such association was observed between the pharmacokinetic data and skin rash. Evidently, this type of indirect inference is not an objective of the current trial and the study is not powered accordingly. Moreover, pharmacokinetic analyses presented here are preliminary and conducted through a less than optimal approach. These relationships will be re-examined once the population pharmacokinetic analysis of erlotinib has been completed. Also, it is possible that pharmacokinetic measurements of plasma drug concentrations do not reflect variations in drug activity accountable by pharmacodynamic or pharmacogenetic differences at the target level.
The finding that neither HER1/EGFR staining intensity nor proportion score predicted for clinical outcome in this study raises hypotheses about this target for cancer therapy. Although measurement of HER1/EGFR expression by immunohistochemistry can be variable and has not been standardized among different laboratories, [20] this parameter may not be the relevant determinant of tumor sensitivity to EGFR-targeted therapies. HNSCC is known to be a prototype among epithelial malignancies with a high prevalence of HER1/EGFR overexpression, and patients enrolled in the current study possessed HER1/EGFR expression profiles typical for this tumor site. HER1/EGFR polymorphism could, conceptually, explain differences in skin toxicity and tumor response observed among patients on study. Although existent data on HER1/EGFR polymorphism in HNSCC are insufficient, mutated forms of HER1/EGFR (eg, vIII) are particularly interesting and could result from specific clonal events that are important and necessary for tumor proliferation [21-24]. Furthermore, the lack of correlation between HER1/EGFR expression as evaluated by immunohistochemistry and survival outcome would suggest that other measures may represent better predictors of response to erlotinib and other EGFR-targeted therapies. Besides the possibility of HER1/EGFR mutated variants, another potential predictive marker to determine the dependence of the tumor on the HER1/EGFR pathway is the extent of its tyrosine kinase phosphorylation. Although the measurement of phospho-EGFR is technically more challenging in the laboratory, it may provide better assessments of the functional status of the receptor as well as the dependence of the tumor on the HER1/EGFR pathway. The utility and validity of this and other predictive markers warrant further evaluations in clinical studies. In optimistic anticipation, molecular profiling analysis and other technical advancements will ultimately unravel the complexity of the HER1/EGFR signaling cascade and provide appropriate predictors of response to erlotinib and other EGFR-targeted therapies.
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Authors' Disclosures of Potential Conflicts of Interest
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The following authors 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. Performed contract work within the last 2 years: Manuel Hidalgo, OSIP, Genentech. Received more than $2,000 a year from a company for either of the last 2 years: Lillian L. Siu, Genentech; Manuel Hidalgo, OSIP, Genentech.
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Acknowledgment
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We thank Gary Clark, PhD, Mieke Ptaszynski, MD, and Don Albert for their assistance with the manuscript.
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NOTES
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Supported by OSI Pharmaceuticals Inc; Hoffman-La Roche Inc; and Genentech Inc.
Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Submitted June 17, 2003;
accepted October 29, 2003.
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TOP
ABSTRACT
INTRODUCTION
