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© 2003 American Society for Clinical Oncology Pilot Trial of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib Plus Carboplatin and Paclitaxel in Patients With Stage IIIB or IV Non–Small-Cell Lung Cancer
From the Thoracic Oncology Service, Departments of Medicine and Radiology, Memorial Sloan-Kettering Cancer Center; Weill Medical College of Cornell University; the Division of Medical Oncology, Vanderbilt University Medical School and the Vanderbilt-Ingram Cancer Center, New York, NY; and AstraZeneca Pharmaceuticals, Wilmington, DE. Address reprint requests to Vincent A. Miller, MD, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: millerv{at}mskcc.org.
Purpose: Gefitinib is an oral agent that inhibits the tyrosine kinase of the epidermal growth factor receptor. In phase I trials gefitinib was well tolerated and antitumor activity was seen in pretreated non–small-cell lung cancer (NSCLC) patients. Preclinical studies indicated enhanced effects when gefitnib was added to carboplatin or paclitaxel. This pilot trial combined gefitinib with carboplatin and paclitaxel to define the toxicities of the combination and assess drug-drug interactions in untreated advanced NSCLC patients. Patients and Methods: Initially (part 1) patients were randomly assigned to receive intermittent gefitinib with cycle 1 or 2 of chemotherapy. Thereafter (part 2), the highest dose of gefitinib that was given without dose-limiting toxicity (DLT) from part 1 was administered continuously beginning with the first cycle of chemotherapy. Three sequentially enrolled cohorts received gefitinib 250 and 500 mg (intermittently) and 500 mg (continuously). Results: We treated 24 patients; nine patients with 250 mg and 15 patients with 500 mg (nine patients continuous). Two occurrences of DLT were observed. One patient (500 mg, part 1) developed grade 3 rash and another patient (part 2) developed prolonged neutropenia. Steady-state gefitinib levels did not affect exposure to chemotherapy. In a limited sample, chemotherapy modestly increased the gefitinib area under concentration-time curve at steady-state and minimum steady-state trough concentration. Partial responses were observed in five of 24 patients. The median survival was 8 months. Conclusion: The gefitinib with carboplatin and paclitaxel regimen was generally well tolerated and no unanticipated toxicities or clinically relevant pharmacokinetic interactions were observed. Both doses of gefitinib were believed to be safe for further study with chemotherapy. This regimen was thus tested in a completed randomized phase III trial.
LUNG CANCER remains the leading cancer killer of both men and women in the United States and the majority of patients will have advanced disease at diagnosis or develop recurrence, neither of which is amenable to curative approaches.1 The use of cisplatin-based chemotherapy developed in the 1970s and 1980s led to an approximate 2-month prolongation in median survival and a doubling of 1-year survival proportion from 10% to 20% when given to patients with advanced non–small-cell lung cancer (NSCLC).2 When newer active agents such as docetaxel, gemcitabine, and paclitaxel were then added as components of regimens, additional improvement was seen, with median survivals of 8 to 9 months and 1-year survivals of 35% widely reported.3 However, more recent phase III trials indicate that a therapeutic plateau may have been reached with this approach.4 The incorporation of targeted biologically based therapies into active chemotherapy regimens offers a promising approach to advance progress more rapidly in treatment of this disease. The epidermal growth factor receptor (EGFR) is a member of the type I family of transmembrane glycoproteins (human epidermal growth factor receptor 2 [HER-2], 3, and 4 are other family members) possessing tyrosine kinase activity that is present on nearly all NSCLC specimens and is overexpressed in about 25% of specimens.5 The receptor consists of an extracellular ligand-binding domain, a transmembrane lipophilic segment, and an intracellular kinase domain with autocatalytic activity. When bound by ligand, EGFR homo- or heterodimerizes with another family member, the kinase domain is activated, and tyrosine residues in the intracytoplasmic tail are phosphorylated. This leads to downstream signaling and a variety of changes characteristic of malignant progression including upregulation of ras, raf, mitogen-activated phosphorylated (MAP) kinase, and the vascular endothelial growth factor.6 In turn, cellular growth, invasive capacity, and tumor angiogenesis are enhanced. Preclinical data indicated that small molecules that competed with adenosine triphosphate for delivery of phosphate groups to critical tyrosine residues could block signal transduction through EGFR. Gefitinib [N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine] is a quinazoline compound with a molecular weight of 447. In vitro, this agent potently inhibited the EGFR tyrosine kinase in A431 vulvar squamous cell carcinoma (inhibitory concentration of 50%, 0.08 µM) and it possessed growth inhibitory properties in cell lines with lower levels of EGFR expression. Gefitinib demonstrated about 100-fold less activity against the HER-2 kinase than EGFR and little or no activity against serine threonine and other tyrosine kinases.7 In xenograft studies using EGFR-overexpressing A431 tumors in nude mice, growth inhibition was seen at low daily doses and objective regressions were seen at higher doses. Studies with several other tumors with variable degrees of EGFR expression (A549, CR10, DU145, HT29) showed similar growth inhibitory effects with long-term continuous dosing.8 Phase I trials of gefitinib given on an intermittent or daily schedule have studied doses between 50 and 1,000 mg.9–11 Dose-limiting toxicity (DLT) of diarrhea and fatigue were seen at levels above 600 mg and grade 1 to 2 acneiform rash on an erythematous base has been reproducibly noted as a dose-related toxicity. In the phase I trials, 100 patients with refractory NSCLC were treated and confirmed partial responses or improvement in evaluable indicator lesions were seen in 10 of these patients; responses were frequently accompanied by symptomatic relief. Subsequently, randomized international phase II trials confirmed gefitinib response rates of 9% to 18% after prior platinum or platinum and docetaxel therapy and linked objective response or disease stability with improvement in cancer-related symptoms.12,13 Encouraged by both single-agent activity and a favorable adverse event (AE) profile, we chose to explore preclinically whether gefitinib could enhance the effectiveness of chemotherapeutic agents active in NSCLC. We administered gefitinib with a variety of cytotoxic agents to human vulvar (A431) and several lung and prostate tumors.8 Gefitinib potentiated most cytotoxic agents in combination treatment of these tumors, irrespective of the degree of EGFR expression. The growth inhibitory action of cisplatin and carboplatin as single agents against A431, A549, LX-1, TSU-PR1, and PC-3 was increased several-fold when gefitinib was added, with partial regressions of A431 and PC-3 tumors. Although docetaxel and paclitaxel markedly inhibited the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3 as single agents, the addition of gefitinib resulted in partial or complete regressions in many cases. Our results indicated that potentiation of cytotoxic treatment by gefitinib did not require high levels of EGFR expression and that gefitinib should be studied with platinum- or taxane-containing regimens in NSCLC. Given the activity and tolerability of gefitinib in such advanced patient populations, the preclinical indication of additive effects of gefitinib with either carboplatin or paclitaxel (which is a widely used combination for the treatment of NSCLC),3,4 and the lack of overlapping toxicity of gefitinib with these agents, we undertook this pilot dose-escalation trial of these three agents in chemotherapy-naive patients with advanced NSCLC. In doing so, we sought to determine the safety of the combination and define the pharmacokinetic (PK) profile of the component agents when given together.
Eligibility Eligible patients had histologically or cytologically confirmed stage IIIB, IV, or recurrent NSCLC; had a World Health Organization performance status of 0 or 1; were  18 years of age; and provided written informed consent. Laboratory requirements for eligibility included neutrophil count 1.5 x 109/L, platelet count 100 x 109/L, serum bilirubin  1.25 times the upper limit of reference range (ULRR), ALT or AST 2.5 times the ULRR, and serum creatinine 1.25 times the ULRR. Patients with malignancy diagnosed within the past 5 years, prior chemotherapy for NSCLC, persistent hematuria or proteinuria (more than trace), active brain metastases (symptomatic or with progressive growth), or active facial dermatoses were excluded. Patients with any potentially visually threatening epithelial abnormality of the cornea and those receiving drugs with significant cytochrome P450 3A4 inhibitory effect were initially ineligible. However, after a review of phase I studies and a clinical pharmacologic study showing no clinically significant asymptomatic corneal abnormalities or any PK interaction between itraconazole and gefitinib, respectively, the protocol was amended to eliminate these restrictions.14
Patient Evaluation
Treatment Plan
DLT On the basis of the known toxicity profile of carboplatin, paclitaxel, and gefitinib alone, DLT was assessed after completion of 14 days of combination therapy (three drugs) and was defined as grade 3 to 4 thrombocytopenia or neutropenia lasting for more than 7 days; neutropenia of any duration associated with fever more than 38°C; grade 3 to 4 skin, CNS, cardiac, lung, hepatic, or renal toxicity; or grade 3 to 4 gastrointestinal toxicity that persisted more than 4 days despite antidiarrheal or antiemetic therapy. Ocular toxicities such as corneal punctate staining with symptoms, more than one quadrant of conjunctival hyperemia, or preclinical corneal changes of opacities or hyperemia were also defined as DLT. If zero or one DLT was observed in this initial cohort, six patients were to be enrolled at 500 mg daily for 2 of 8 weeks with an identical randomization schema. If two or three DLTs were observed, the given cohort was to be expanded to 12 patients. If four or more DLTs were noted in either the initial or expanded cohorts at a given dose level, that gefitinib dose was deemed to be in excess of the maximum-tolerated dose and accrual would proceed at a dose level of 250 or 150 mg if the level in question was 500 or 250 mg, respectively.
PK Studies
The minimum trough concentration (Cmin) for gefitinib was defined as the concentration in the predose sample collected on the sampling day when administered alone or as the concentration in the 24-hour sample collected on the sampling day after administration in combination with the chemotherapy. Maximum trough concentration (Cmax) for free carboplatin and paclitaxel was defined as the concentration determined at the end of the infusion period. The area under the concentration-time curve from 0 to 24 hours (AUC0–24) for gefitinib and paclitaxel and AUC0– Plasma concentrations of gefitinib were analyzed as previously described.16 Gefitinib was found to be stable after four freeze-thaw cycles, for up to 24 hours at room temperature in plasma, and for up to 12 months when stored frozen in plasma at -20°C. Paclitaxel plasma concentrations were analyzed by a high-performance liquid chromatography method with ultraviolet spectrometry detection. The assay was linear up to 2.5 µg/mL with no significant interference from endogenous material and with a limit of quantification of 0.02 µg/mL. During this trial, the precision across the assay range was 2.69% to 7.33%, with an accuracy of 92% to 105%. Paclitaxel was found to be stable after three freeze-thaw cycles, for up to 24 hours at room temperature in plasma, and for up to 3 months when stored frozen in plasma at -20°C. Free carboplatin concentrations in plasma ultrafiltrate were analyzed by a high-performance liquid chromatography method with tandem mass spectrometry detection. The assay was linear up to 5 µg/mL with no significant interference from endogenous material and with a limit of quantification of 0.05 µg/mL. During this trial, the precision across the assay range was 2.41% to 6.35% with an accuracy of 101% to 104%. Carboplatin was found to be stable after four freeze-thaw cycles, for up to 28 hours at room temperature in plasma, and for up to 4 months when stored frozen in plasma at -70°C.
Study Agents
Twenty-five patients provided informed consent, were believed to meet eligibility criteria, and were randomly assigned to receive treatment. However, before initiation of therapy one patient developed symptomatic brain metastases. After treatment another patient was found to have melanoma and not NSCLC and thus was rendered ineligible. Results are reported for each of the 24 patients who received treatment (including the melanoma patient). Two patients withdrew from the study. Baseline characteristics are displayed in Table 1  .
DLT None of the nine patients who received 250 mg of gefitinib intermittently with chemotherapy experienced a DLT. One of six patients who received chemotherapy with 500 mg of intermittent gefitinib experienced a DLT event with grade 3 rash. On the continuous gefitinib schedule, one of nine patients experienced a DLT with grade 4 neutropenia lasting more than 7 days. There were three deaths during the study or within 30 days of study completion. One was unequivocally believed to be the result of progressive disease and occurred after the first treatment cycle. A second death occurred because of septic shock during the first treatment cycle with chemotherapy and gefitinib. We believed that this death was consistent with chemotherapy-related sepsis and as such did not consider it to be a DLT event. Arguably, because a role of gefitinib could not be entirely excluded, this death might have been more appropriately classified as a DLT but would not have affected accrual or conduct of the trial. A third death, caused by severe pneumonia in the setting of advanced intraparenchymal lung metastases, was believed unlikely to be caused by gefitinib therapy and occurred after the fifth cycle of chemotherapy. Both of the latter two patients were receiving 500 mg of gefitinib on the continuous schedule and also had National Cancer Institute common toxicity criteria grade 3 or 4 neutropenia at the time of their deaths. No autopsy was obtained on the patient who died as a result of pneumonia.
Drug Delivery and Toxicity
There were no apparent differences in toxicity or tolerability across doses with the possible exception of increased diarrhea and acne in patients receiving 500 mg of gefitinib either continuously or intermittently. Table 3 lists Coding Symbols for Thesaurus of Adverse Reaction Terms data on AEs occurring in cycles 1 and 2 of therapy for both parts 1 and 2 of the study. Diarrhea, rash, acne, and dry skin, which are known toxicities of gefitinib, seem to be more common in those cycles in part 1 in which individuals received this agent. Grade 3 AEs occurring in cycles 1 and 2 when gefitinib was given, as opposed to during cycles without gefitinib, included grade 3 leukopenia (one patient at 250 mg and two patients at 500 mg), grade 3 diarrhea (one patient at 250 mg), grade 3 rash (one patient at 500 mg), grade 3 prolongation of the internationalized normalized ratio (one patient at 250 mg), and one episode each of grade 3 arthralgia, myalgia, and vocal cord paralysis (each at 250 mg daily). Conversely, one episode each of grade 3 nausea, vomiting, and leukopenia occurred in the cycles when chemotherapy was given without gefitinib. Thus, no novel or unexpected worsening of known toxicities of carboplatin, paclitaxel, or gefitinib is indicated in this side-by-side comparison.
PK Data Of the 15 patients who participated in part 1 of the trial, 10 and nine patients were assessable for analysis of free carboplatin and paclitaxel PK parameters, respectively, and 12 patients were assessable for gefitinib PK. There seems to be no significant PK effect of steady-state (ss) levels of either dose of gefitinib on free carboplatin, as measured by AUC(0–20) or Cmax, or paclitaxel. However, the geometric mean AUC24ss and Cminss values of gefitinib in the presence of chemotherapy were higher for both levels studied. For the 250-mg dose level, the geometric mean AUC24ss and Cminss were 56% and 85% higher, respectively, and for the 500-mg dose level, the geometric mean AUC24ss and Cminss were 30% and 33% higher, respectively, in the presence of chemotherapy. Plasma PK parameters for gefitinib alone and in combination with chemotherapy are listed in Table 4 .
Response and Survival Five confirmed partial responses were observed in 24 treated patients (major objective response rate, 21%; 95% confidence interval [CI], 9 to 40). The median duration of response was 5 months. Of the other 19 patients, two had an unconfirmed partial response; nine had stable disease; three had progression as best response; three had no subsequent tumor measurementsbecause they had been withdrawn as a result of progression of disease (n = 1), sepsis (n = 1), and trial ineligibility (n = 1, melanoma); and two did not have measurable disease at baseline per RECIST guidelines.15 One of the documented responders was a woman with brain and widespread pulmonary and bony metastases who had a near-complete radiographic response at day 56, received six cycles of combination therapy, and continued receiving gefitinib without progression for more than 20 months. The only evidence of residual disease was a solitary focus of increased uptake in the right pleura visualized on positron emission tomographic scan. One of the two patients not assessable for response by RECIST guidelines was a woman with bilateral pulmonary nodules who had a complete or near-complete regression that lasted for more than 20 months (ongoing at completion of the trial). Nine patients had stable disease or unconfirmed partial response as best response, with the median duration of 2 months (range, 0 to 6 months) from time of first observation. No differences were apparent on the basis of schedule, dose, or sequence of gefitinib in the small patient cohorts. The median survival for the 24 patients was 8 months. One- and 2-year survivals were 39% and 22%, respectively.
Our trial was undertaken to assess the safety of gefitinib given either intermittently (part 1, sequence A or B) or continuously (part 2) with standard doses of carboplatin and paclitaxel, to determine whether the addition of gefitinib to these agents resulted in changes in their clearance or metabolism, and to assess whether these chemotherapeutic agents affected gefitinib steady-state. We found no evidence of novel or worsened toxicities related to the combination as compared with those of the component drugs, and only one episode of DLT was observed during the first combined treatment cycle. For example, diarrhea, rash, dry skin, and acne were more common in cycles in which gefitinib was added to chemotherapy. However, the frequency and severity of these toxicities did not seem to be increased versus those of gefitinib monotherapy given at the same doses.12,13 Moreover, gefitinib did not seem to compromise the number of cycles of chemotherapy given (median, 3.5 cycles). The range of three to four cycles is consistent with drug delivery of the carboplatin and paclitaxel combination in recent phase III trials.4 The observation that the intermittent 250-mg dose was associated with a greater median number of cycles delivered than either the 500-mg intermittent or continuous schedule is intriguing but requires validation in larger studies. On the basis of predetermined criteria in the protocol, both doses of gefitinib were believed to be suitable for further study with the carboplatin and paclitaxel combination. Because both paclitaxel and gefitinib (in vitro) are metabolized, at least in part, by cytochrome P-450 isoform 3A4, we sought to explore whether coadministration could result in significant effects on the exposure to paclitaxel or the steady-state of gefitinib or both.14,17 Because carboplatin is excreted unchanged by the kidneys, an interaction with gefitinib was not anticipated and was not observed. In this study, there was no evidence of any effect of gefitinib on the exposure to paclitaxel. In a small number of patient samples there was an increased AUC24ss and Cminss of gefitinib with coadministration of paclitaxel and carboplatin. Conceivably, this also could have been related to the known three-fold intrapatient range of gefitinib bioavailability. Regardless, no clinical sequelae of either increased parameter were apparent. Although assessment of antitumor activity was not a primary objective of this trial, durable responses were seen. Some patients seemed to garner benefit from continuation of gefitinib alone after completion of a variable number of cycles of combination cytotoxic chemotherapy. The relatively small number of patients treated precludes any comparison of dose or schedule effects. Although the activity of this regimen compares favorably to results of recent phase III studies, such a comparison is ill advised given the inherent differences in populations under study. Conversely, these results are comparable to, but not superior to, those of other phase II trials conducted at our institutions in the last several years.18 Unfortunately, because of the small number of patients studied, the multiplicity of cohorts, and the limited availability of tumor tissue for study, no correlative studies were believed likely to be of benefit in elucidating the molecular profile of a responding patient. The safety of this combination, lack of new or enhanced toxicities with the addition of gefitinib to carboplatin and paclitaxel, and preclinical and clinical activity of gefitinib warranted additional testing of this agent in advanced NSCLC. Parallel, placebo-controlled, randomized phase III international trials of carboplatin plus paclitaxel or cisplatin plus gemcitabine with or without gefitinib completed accrual in mid-2001. Recently, data from these Iressa NSCLC Trial Assessing Combination Therapy (INTACT) 1 and 2 studies showed that the addition of gefitinib, 250 or 500 mg, to either of the two cytotoxic doublets failed to improve response rate, survival, or quality of life.19,20 Future studies will need to identify the molecular profile of responding patients, standardize definitions for EGFR expression and overexpression, and validate antibodies that measure the phosphorylated (basally activated) form of EGFR, which is one of several possible surrogates for pathway activation in patients. It is hoped that the integration of this unique agent into practice will herald an era in which targeted therapy improves outcome and lessens treatment-related morbidity for NSCLC patients.
Supported in part by AstraZeneca, Wilmington, DE. L.M.K., V.A.M., A.S., D.C., P.K., and B.P. have received honoraria from AstraZeneca. Presented in part at the thirty-seventh annual meeting of the American Society of Clinical Oncology, May 12–15, 2001, San Francisco, CA.
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9. Ranson M, Hammond L, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240–2250, 2002 10. Negoro S, Nakagawa K, Fukuoka M, et al: Final results of a phase I intermittent dose-escalation trial of ZD1839 (‘Iressa’) in Japanese patients with various solid tumours. Proc Am Soc Clin Oncol: 324a, 2001
11. Herbst R, Maddox A-M, Rothenberg M, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815–3825, 2002 12. Kris M, Natale R, Herbst R, et al: A phase II trial of ZD1839 (‘Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol: 2002 (abstr 1166) 13. Fukuoka M, Yano S, Giaccone G, et al: Final results from a phase II trial of ZD1839 (Iressa) for patients with advanced non-small cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol: 2002 (abstr 1188) 14. Swaisland H, Laight A, Stafford L, et al: Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in normal volunteers. Clin Pharmacokinet 40:297–306, 2001[CrossRef][Medline]
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19. Johnson DH, Herbst R, Giaccone G, et al: ZD1839 (‘Iressa’) in combination with paclitaxel and carboplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC): Results from a phase III clinical trial (INTACT 2). Ann Oncol 13:127–128, 2002
20. Giaccone G, Johnson D, Manegold C, et al: A phase III clinical trial of ZD1839 (‘Iressa’) in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (INTACT 1). Ann Oncol 13:2–3, 2002 Submitted December 2, 2002; accepted March 17, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
for carboplatin were calculated using the linear trapezoidal rule. 
