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Combination Therapy With Gefitinib and Rofecoxib in Patients With Platinum-Pretreated Relapsed Non–Small-Cell Lung Cancer

Kenneth J. O'Byrne, Sarah Danson, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

From the St James's Hospital, Dublin, Ireland; Christie Hospital, Manchester; Beatson Oncology Centre, Glasgow, Scotland; AstraZeneca, Macclesfield, United Kingdom; and Vanderbilt-Ingram Cancer Center, Nashville, TN

Address reprint requests to Kenneth J. O'Byrne, MD, St James's Hospital, Dublin, Ireland; e-mail: kobyrne{at}stjames.ie

	ABSTRACT

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Purpose: In non–small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45).

Patients and Methods: Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33).

Results: Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea.

Conclusion: Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs.

	INTRODUCTION

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Five-year survival rates for patients with non–small-cell lung cancer (NSCLC) are 3% to 7% for stage IIIB, and less than 1% for stage IV disease.^1-3 Therapeutic options for relapsed NSCLC are limited. Molecular targeting approaches manipulating the biology of the disease may hold promise for the future.

The epidermal growth factor receptor (EGFR) plays a role in tumorigenesis, stimulating cell proliferation, inhibiting apoptotis, and promoting angiogenesis and metastasis.^4,5 EGFR overexpression is seen in NSCLC, linked with a poor prognosis, and is a target for anticancer therapy.⁶ When this study was designed, phase II study data showed that gefitinib, an orally active EGFR tyrosine kinase inhibitor (TKI), was well tolerated, with antitumor activity.^7,8

Cyclooxygenase-2 (COX-2) overexpression in NSCLC⁹ correlates with poor survival in early-stage disease.¹⁰ COX-2 promotes tumor invasion and angiogenesis through induction of prostaglandins and vascular endothelial growth factor (VEGF).^11,12 COX-2 inhibitors (COX-2Is) inhibit the proliferation and invasiveness of NSCLC in vitro and enhance the cytotoxicity of chemotherapeutic agents.^6,13 Selective COX-2Is are nonsteroidal anti-inflammatory drugs (NSAIDs). Phase II studies suggest that COX-2Is may enhance neoadjuvant and first-line chemotherapy in early-stage¹⁴ and advanced NSCLC¹⁵; however, this effect was not seen with second-line docetaxel therapy.^16,17

Although EGFR activation may induce COX-2 expression,^18,19 no relationship is seen between EGFR and COX-2 expression in NSCLC tumors.⁹ EGFR-TKIs and COX-2Is block different cancer signaling pathways. Therefore, their combination may be a useful anticancer strategy.^4,9 That gefitinib and the COX-2I celecoxib additively or synergistically inhibit head and neck squamous cell carcinoma growth in vitro, inducing G(1) arrest and apoptosis and suppression of endothelial capillary formation,²⁰ supports this contention and is consistent with other literature.^21,22 Collectively, these data provided a rationale for combining a COX-2I with gefitinib in NSCLC.

The safety and efficacy of gefitinib 250 mg/d in combination with the COX-2I rofecoxib (at three dose levels: 12.5, 25, or 50 mg/d) in advanced, pretreated NSCLC was investigated. The value of baseline serum proteomics analysis in predicting response to therapy was evaluated.

	PATIENTS AND METHODS

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Study Design
This was a three-center, single-arm, open-label, noncomparative trial. Patients (aged 18 years) with histologically/cytologically confirmed inoperable stage III or IV NSCLC and platinum-pretreated, relapsed disease were eligible. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) and a WHO performance status of 2 or lower was required.

Exclusion criteria included coexisting malignancies diagnosed within the last 5 years (except basal cell carcinoma or cervical cancer in situ); incomplete healing from previous surgery; unresolved chronic toxicity greater than National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 grade 2 from prior anticancer therapy; clinically active interstitial lung disease;severe or uncontrolled systemic disease; treatment with chemotherapy, hormone therapy, or immunotherapy within 21 days before enrollment; and pregnancy or current breastfeeding.

The primary objective was to evaluate the tolerability of gefitinib 250 mg/d in combination with rofecoxib 12.5, 25, or 50 mg/d. Secondary objectives were the efficacy of the combination in terms of objective response (complete response [CR] or partial response [PR]) and disease control (CR, PR, and stable disease [SD]) rates, time to tumor progression and overall survival, the pharmacokinetic effect of rofecoxib on gefitinib, and the role of serum proteomics in identifying patients benefiting from treatment. The trial was performed in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and appropriate regulatory requirements. Local ethics committee approval was obtained, and all patients provided written, informed consent.

The study consisted of two phases: dose-finding and efficacy. Eligible patients entered the dose-finding phase of the study and received gefitinib 250 mg/d for 7 days. On day 8, rofecoxib was added to gefitinib 250 mg/d in three cohorts at three different dose levels: 12.5 mg/d (dose level 1), 25 mg/d (dose level 2), and 50 mg/d (dose level 3). Combination treatment continued until day 28, when tolerability assessments were performed. The maximum-tolerated dose (MTD) of rofecoxib was defined as the dose immediately preceding that at which more than one in six patients experienced grade 3/4 nonhematologic toxicity (dose-limiting toxicity [DLT]). If more than one in six patients in a dose level experienced DLT, either, in the case of dose level 1, the trial was to be stopped with no expansion of an MTD cohort or, in the cases of dose levels 2 and 3, the rofecoxib dose was reduced to the previous dose level. However, if toxicity was grade 2 or lower, patients entered the next cohort. In the subsequent efficacy phase, patients received gefitinib 250 mg/d and rofecoxib at its MTD (up to 50 mg/d) until disease progression or unacceptable toxicity.

Tolerability
Adverse events (AEs) and their causality and severity using NCI-CTC criteria were recorded. Grade 3/4 toxicity was managed by dose interruption (up to 14 days) of gefitinib and/or rofecoxib. Repeat dose interruptions were allowed to manage toxicity. If management was insufficient for gefitinib-related toxicity, patients were withdrawn. If management was insufficient for rofecoxib, dose reduction to the lower dose level was permitted. Any patient receiving rofecoxib 12.5 mg/d who experienced unacceptable toxicity had rofecoxib discontinued but continued gefitinib if gaining clinical benefit.

Efficacy
Patients underwent computer tomography scans every 2 months to determine RECIST response. CR was defined as the disappearance of all target lesions, PR at least a 30% decrease in the sum of the longest diameter of target lesions, progressive disease (PD) at least a 20% increase in the sum of the longest diameter of target lesions, and SD neither sufficient shrinkage to qualify for PR nor increase to qualify for PD. Objective responses (CR or PR) were confirmed 4 or more weeks after the criteria for response were first met. Disease control rate was defined as CR plus PR plus SD. Progression-free survival was determined from date of enrollment to date of disease progression (PD) or death. Overall survival was determined from date of enrollment until death or the last date the patient was recorded alive.

Pharmacokinetics
Blood samples (5 mL) were taken (a) at predose on day 7 and after 1, 3, 7, and 24 hours after administration of gefitinib 250 mg/d, and (b) predose on day 28 and after 1, 3, 7, and 24 hours after administration of gefitinib and rofecoxib combination therapy to evaluate the pharmacokinetic effect of rofecoxib by comparison of the area under the plasma concentration-time curve during the dosing interval (AUC_0-) and minimum plasma concentration (C_min) of gefitinib alone (day 7) and when given with rofecoxib (day 28). After immediate centrifugation (10 minutes at 1,000 x g), plasma samples were stored at –20°C. Samples were analyzed by high-performance liquid chromatography with tandem mass spectrometry at a central laboratory (AstraZeneca, Alderley Park, United Kingdom).

Matrix-Assisted Laser Desorption/Ionization–Proteomic Profiling of Serum Samples
Serum samples obtained from patients before gefitinib and rofecoxib treatment were stored at –80°C until analysis. Each sample was thawed on ice and diluted to 10% in H₂O, and 1 µL was mixed with the same amount of matrix (50% acetonitrile, 0.1% trifluoroacetic acid, 35 mg/mL sinnapinic acid) on a gold plate. Protein expression profiles were analyzed with a Voyager STR matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometer (PerSeptive Biosystems, Framingham, MA). Each spectrum was the average of two spectra (each the result of 250 laser shots randomly acquired over a serum spot). Spectra were internally calibrated with peaks of hemoglobin-ß and apolipoprotein C-1 (APOC-1). The baseline of each spectrum was corrected using Data Explorer software (Applied Biosystems, Foster City, CA). Signals in 2,000 to 20,000 M/Z were considered, binned, and normalized as previously reported.²³

Statistical Analysis
A cohort size of six patients was considered sufficient to detect DLTs during the dose-finding phase of the study. During the efficacy phase, a sample size of 33 patients was considered sufficient to give at least 80% probability of rejecting a baseline response rate of 5% with an exact 5% one-sided significance test when the true response is at the clinically relevant rate of 20%.

The intention-to-treat (ITT) population, comprising all patients enrolled who received medication, was used to analyze efficacy parameters. Tumor response rate was summarized by proportion and 90% CIs. Progression-free and overall survival were summarized using the Kaplan-Meier method, along with the appropriate 95% CIs.

The weighted flexible compound covariate method (WFCCM)²⁴ was used to verify whether the proteomic patterns could be used to classify serum samples into two classes according to response to treatment as follows: (a) [CR and PR] versus [SD and PD] or (b) [CR, PR, and SD] versus PD. The agglomerative hierarchical clustering algorithm was also applied to define the pattern among the significant discriminators in this cohort.

	RESULTS

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Patients
A total of 45 patients were recruited to the study (Table 1), with the first patient enrolled in June 2002. Adenocarcinoma and squamous cell carcinoma (SCC) were the most common primary tumors, accounting for 42% and 38% of patients, respectively. Of these, 21 had received carboplatin and 23 cisplatin regimens combined with vinblastin/mitomycin (n = 11), ifosfamide/mitomycin (n = 7), vinorelbine (n = 3), docetaxel (n = 12), or gemcitabine (n = 11). Fourteen patients received second-line chemotherapy, eight with docetaxel. One patient recruited had not received platinum-based therapy and was subsequently withdrawn from the study.

MTD
During the dose-finding stage, no patient in any of the cohorts experienced grade 3/4 nonhematologic toxicity; therefore, the MTD for rofecoxib was not defined. For this study, dose level 3 (rofecoxib 50 mg/d) was assumed to be the MTD and subsequently expanded to 33 patients for safety and efficacy assessment.

Tolerability
Thirty-one (69%) of 45 patients experienced treatment-related AEs, most of which were mild/moderate. Grade 1/2 rash and diarrhea in 14 (31.1%) and 14 (31.1%) patients, respectively, were the most common gefitinib-related AEs (Fig 1). Rofecoxib-related AEs included grade 1/2 dyspepsia (6.7%) and abdominal pain (6.7%).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment-related adverse events occurring in at least 5% of patients and categorized by causality. Grade 3 only. Includes rash follicular; rash not otherwise specified (NOS); dermatitis acneiform; rash pustular. Includes diarrhea NOS; loose stools. Includes abdominal pain NOS; abdominal pain upper. G, grade.

In eight patients, treatment-related AEs led to treatment interruptions: one in dose level 2 (gefitinib); seven in dose level 3 (gefitinib in two patients, rofecoxib in one, and both drugs in four). One patient in dose level 1 experienced grade 1 renal impairment attributed to rofecoxib; rofecoxib was withdrawn and gefitinib continued. One patient experienced grade 4 dyspnea attributed to gefitinib, which was withdrawn.

Efficacy
Of 42 patients assessable according to RECIST criteria, two (4.8%; 95% CI, 0.6% to 16.2%) responded to treatment (one male, one female) and 13 patients had SD (11 male, two female), giving a 35.7% disease control rate (95% CI, 21.6% to 52.0%). The male patient with the CR (duration of response, 197 days) had SCC and a 48 pack-year history of cigarette consumption, and also smoked cigars and a pipe. The female patient with the PR (duration of response, 190 days) had adenocarcinoma and was an ex-smoker. A third patient, a nonsmoker with adenocarcinoma, was considered by the investigator to have a PR not measurable by RECIST criteria because of the diffuse nature of the response (Fig 2). Overall, smoking history was available for 41 of these patients. Four of 16 current smokers (25%; one CR; three SD), nine of 20 ex-smokers (45%; one PR, eight SD), and two of five never-smokers (40%; one PR, one SD) had disease control for at least 4 months.

View larger version (47K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. The (A) pre- and (B) post-treatment chest x-rays and soft tissue computed tomography images of the patient whose response was difficult to measure by Response Evaluation Criteria in Solid Tumors criteria are shown. There is clearly a greater than 50% resolution of the tumor mass. In all, of the 42 patients with measurable disease at baseline, there were three patients with objective tumor responses, 12 with stable disease, and 27 with disease progression.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. (A) Time to disease progression and (B) overall survival in the intention-to-treat population. Circles represent censored observations.

0-

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. The impact of rofecoxib on gefitinib pharmacokinetics 24 hours post-treatment in each patient cohort was studied. Mean area under the plasma concentration-time curve during the dosing interval (AUC0-) did not differ significantly for gefitinib alone compared with gefitinib in combination with rofecoxib 12.5, 25, or 50 mg.

View larger version (37K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Agglomerative hierarchical clustering of matrix-assisted laser desorption/ionization-time of flight mass spectroscopy signals of (A) responders (n = 3) versus stable disease (SD)/progressive disease (PD; n = 31) and (B) disease control (n = 14) versus PD (n = 20) is shown with significant differential expression of (a) 55 and (b) 90 signals, respectively.

	DISCUSSION

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In the recent ISEL placebo-controlled trial, gefitinib improved time to treatment failure (P = .0006) and objective response (8.0% v 1.3%; P < .0001) compared with placebo. Disease control was achieved in 39.7% of patients,²⁵ similar to that seen in the IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL) randomized phase II studies.^7,8 However, the overall survival with gefitinib 250 mg/d monotherapy failed to reach statistical significance (P = .087).²⁵ In a similar setting, the EGFR-TKI erlotinib improved survival.³¹ In the present study, 35.7% of patients (12 male and three female patients) achieved disease control, with an objective tumor response seen in three patients (7.1%; one male and two female). These findings suggest that rofecoxib combined with gefitinib is not superior to single-agent gefitinib in platinum-pretreated NSCLC. Pharmacokinetic analyses indicate that rofecoxib (up to 50 mg/d) does not affect exposure to gefitinib (250 mg/d). Therefore, the results cannot be attributed to a detrimental effect of rofecoxib on gefitinib metabolism.

Certain clinicopathological features—female sex, nonsmoker status, bronchioalveolar cell carcinoma and adenocarcinomas, and Asian origin—predict an increased likelihood of response to gefitinib therapy.^32-34 In keeping with this, two of three responders were female with adenocarcinomas, one a nonsmoker and the other an ex-smoker. In contrast, the patient with a CR had a squamous cell carcinoma and was a current smoker. This observation, confirmed in other studies, indicates that clinicopathologic parameters alone are insufficient to identify those patients likely to benefit from EGFR-TKIs.^25,31 NSCLC tumors with EGFR tyrosine kinase domain mutations are more sensitive to gefitinib.^34,35 Fluorescence in situ hybridization–detected increased EGFR gene copy number may also be predictive for a gefitinib treatment effect.³⁶ Unfortunately, in our patients, the EGFR gene mutational or copy number status of the responding tumors is unknown.

A number of recent studies have reported EGFR TKI/COX-2I combinations in NSCLC. An interim analysis investigating gefitinib 250 mg/d and the COX-2I celecoxib 400 mg twice daily in 10 platinum-refractory NSCLC patients demonstrated a PR in two patients (20%) and SD in three (30%).³⁷ In a further phase II study, 31 chemotherapy-naïve patients treated with gefitinib and celecoxib 400 mg/d gave a response rate of 16.1%. Median duration of response, progression-free survival, and overall survival were 5.7, 2.8, and 7.2 months, respectively. Finally, a dose-finding study combining celecoxib with erlotinib in 22 patients with advanced NSCLC demonstrated an objective response rate of 33% and disease control rate of 57%. The optimal biologic dose of celecoxib, based on maximal decrease in urinary prostaglandin E-M was celecoxib 600 mg twice daily.^38,39 These studies provide encouragement that in selected patients, identified on the basis of clinical and biochemical predictive factors, cotargeting EGFR and COX-2 may be an effective strategy.

Proteomic analysis, evaluating changes in the expression of a broad range of proteins to a given drug or stimulus, may identify patients likely to benefit from targeted therapies. The results from this study led to subsequent work on pretreatment serum samples from EGFR-TKI–treated patient cohorts. The MALDI-spectra obtained are reproducible within and between institutions. An algorithm developed to predict benefit was validated in subsequent cohorts and is being tested in prospective studies.^40,41

In conclusion, rofecoxib combined with gefitinib is well tolerated but does not appear more active than gefitinib alone. Further evaluation of baseline serum proteomics to identify patients likely to benefit from therapy is justified.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Nick Botwood, AstraZeneca Leadership: Nick Botwood, AstraZeneca Consultant: David Carbone, AstraZeneca; Malcolm Ranson, AstraZeneca Stock: Nick Botwood, AstraZeneca Honoraria: David Carbone, AstraZeneca; Malcolm Ranson, AstraZeneca; Kenneth J. O'Byrne, AstraZeneca Research Funds: Kenneth J. O'Byrne, Funds, AstraZeneca Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Kenneth J. O'Byrne, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

Financial support: Kenneth J. O'Byrne, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

Administrative support: Kenneth J. O'Byrne, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

Provision of study materials or patients: Kenneth J. O'Byrne, Sarah Danson, David Dunlop, David Carbone, Malcolm Ranson

Collection and assembly of data: Kenneth J. O'Byrne, Sarah Danson, David Dunlop, Fumiko Taguchi, David Carbone, Malcolm Ranson

Data analysis and interpretation: Kenneth J. O'Byrne, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

Manuscript writing: Kenneth J. O'Byrne, Sarah Danson, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

Final approval of manuscript: Kenneth J. O'Byrne, Sarah Danson, David Dunlop, Nick Botwood, Fumiko Taguchi, David Carbone, Malcolm Ranson

	ACKNOWLEDGMENTS

 
We thank Maxine Holland, Complete Medical Communications, for medical writing support funded by AstraZeneca.

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted October 26, 2006; accepted April 24, 2007.

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