Originally published as JCO Early Release 10.1200/JCO.2007.14.4824 on March 31 2008

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Phase III Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage III Non–Small-Cell Lung Cancer: SWOG S0023

Karen Kelly, Kari Chansky, Laurie E. Gaspar, Kathy S. Albain, James Jett, Yee C. Ung, Derick H.M. Lau, John J. Crowley, David R. Gandara

From the University of Kansas Medical Center, Kansas City, MO; Southwest Oncology Group Statistical Center, Seattle, WA; University of Colorado Health Sciences Center, Denver, CO; Loyola University School of Medicine, Maywood, IL; Mayo Clinic Rochester, Rochester, MN; University of California at Davis, Sacramento, CA; and Toronto-Sunnybrook Regional Cancer Center, Toronto, Ontario, Canada

Corresponding author: Karen Kelly, MD, University of Kansas Medical Center, 4030 Robinson Hall, Mail Stop 1027, 3901 Rainbow Blvd, Kansas City, KS 66160; e-mail: kkelly{at}kumc.edu

	ABSTRACT

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Purpose: Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non–small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease.

Patients and Methods: Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m² on days 1 and 8 plus etoposide 50 mg/m² on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m². Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease.

Results: Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo.

Conclusion: In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.

	INTRODUCTION

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In North America, the standard treatment for unresectable stage III non–small-cell lung cancer (NSCLC) is the concurrent administration of a platinum-based chemotherapy regimen with thoracic radiation.^1,2 In the Southwest Oncology Group (SWOG), the reference regimen for stage III disease consists of etoposide and cisplatin administered concurrently with thoracic radiation, followed by consolidation chemotherapy.^3,4 Other investigators have used induction chemotherapy followed by concurrent chemoradiotherapy.^5,6 At the present time, no single chemoradiotherapy regimen can be considered standard of care, but both local and distant control remain suboptimal, and the majority of patients continue to die from distant metastases.^2-6

In view of these findings, strategies to incorporate newly available molecularly targeted agents into chemoradiotherapy approaches are of high interest. Orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are theoretically attractive in this setting. EGFR is frequently overexpressed in NSCLC and correlates with a poor prognosis.^7-9 In vitro, EGFR inhibitors are reported to potentiate chemotherapy and radiation.^10-12 Moreover, these agents have proven to be clinically effective. In three phase I trials, a total of 100 previously treated NSCLC patients received gefitinib. Objective responses were observed in 10% of patients, and disease stabilization was achieved in an additional 13%.^13-15 Two randomized phase II trials in treated patients confirmed this efficacy with reported response rates ranging from 9% to 19%.^16,17 Despite these promising findings, when gefitinib and erlotinib were combined with concurrent chemotherapy in the first-line treatment of advanced-stage NSCLC in four large randomized trials, the combination proved to be no more effective than chemotherapy alone.^18-21 One possibility for this negative interaction relates to EGFR-TKI–induced G₁ cell cycle arrest.²² Nevertheless, the ability of gefitinib to produce both radiographic responses and disease stabilization in advanced refractory NSCLC, along with its oral route of administration and mild toxicity profile, made it ideal for evaluation in a long-term maintenance setting. Thus, we hypothesized that the introduction of gefitinib after maximum cytoreduction with chemoradiotherapy for stage III NSCLC would prolong progression-free survival (PFS) and extend overall survival (OS).

	PATIENTS AND METHODS

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Patient Eligibility
Adult patients with pathologically confirmed and inoperable stage IIIA or IIIB NSCLC were eligible to participate in this study. Patients with pleural or pericardial effusions or patients with multiple tumors within the lung were excluded. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 1; measurable or nonmeasurable disease; no prior systemic therapy, radiation therapy, or complete surgical resection; and adequate organ function. Patients with a forced expiratory volume in 1 second (FEV₁) of less than 2.0 L were eligible if they had a minimum FEV₁ of 800 mL in the contralateral lung.

The protocol was approved by institutional review boards at each site. All patients were informed of the investigational nature of the trial and provided written informed consent. SWOG and National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) patients were offered optional participation in S9925 (the Lung Cancer Specimen Repository).

Study Treatment
This trial was conducted in collaboration with the North Central Cancer Treatment Group and the NCIC-CTG. All patients received concurrent cisplatin and etoposide with thoracic radiation according to SWOG 9504. Cisplatin was administered at 50 mg/m² on days 1, 8, 29, and 36 with etoposide 50 mg/m² on days 1 to 5 and 29 to 33 and with concurrent thoracic radiation starting within 24 hours of chemotherapy. The initial field received 1.8 Gy/d for 5 weeks for a dose of 45 Gy. An additional radiation boost to gross disease with 2 Gy/d to 16 Gy was delivered without a break. The total radiation dose received was 61 Gy.

Four to eight weeks after completion of radiation, patients without progressive disease by Response Evaluation Criteria in Solid Tumors were reregistered to receive three cycles of docetaxel 75 mg/m² on day 1 every 21 days.²³ Patients unable to complete the planned three cycles as a result of toxicity could proceed to random assignment.

Three to six weeks after the last dose of docetaxel, patients were again restaged, reregistered, and randomly assigned to receive gefitinib 500 mg or placebo orally, once a day for 5 years or until disease progression or intolerable toxicity. In May 2003, results from two phase II dose-finding trials of gefitinib in previously treated advanced NSCLC patients revealed similar efficacy between the 250 and 500 mg/d doses but more toxicity with the 500 mg/d dose.^16,17 Therefore, S0023 was amended to the 250 mg/d dose. Patients receiving the 500 mg/d dose were switched to the lower dose.

Treatment Modifications
This study used the National Cancer Institute Common Toxicity Criteria version 2.0 for toxicity and adverse event reporting. During concurrent chemoradiotherapy, cisplatin was omitted on day 8 or 36 for grade 4 neutropenia, febrile neutropenia, grade 4 esophagitis, or grade 2 renal toxicity. On day 29, cisplatin and etoposide were delayed 1 week for an absolute neutrophil count of less than 1,500/µL, a platelet count less than 100,000/µL, or grade 3 nonhematologic toxicity. If febrile neutropenia occurred during the previous cycle, etoposide was reduced to 4 days. Cisplatin was reduced or omitted if the serum creatinine was 1.7 to 2 mg/100 mL. A break in radiation was allowed only for severe esophagitis requiring parenteral alimentation and/or grade 4 neutropenia.

Patients who developed febrile neutropenia, grade 4 thrombocytopenia, or grade 3 or 4 neutropenia during docetaxel consolidation required a dose reduction to 60 mg/m². Growth factors were allowed at this time.

The administration of gefitinib or placebo could be interrupted for a maximum of 2 weeks for grade 3 or 4 skin rash and/or diarrhea or intolerable toxicity. Patients with new onset of pulmonary symptoms or worsening dyspnea, cough, or fever required temporary discontinuation of gefitinib or placebo and immediate evaluation for interstitial pneumonitis.

Study Evaluation and Follow-Up
Prestudy evaluation included a complete medical history and physical examination including performance status, laboratory analysis, pulmonary function tests, ECG, and a brain scan. Baseline computed tomography scans of the chest and abdomen were required 4 weeks before study entry. Response assessment occurred at the end of chemoradiotherapy and docetaxel. Patients receiving maintenance therapy were evaluated every 3 months. During chemoradiotherapy, weekly CBCs were obtained. CBC, chemistries, history, physical, and toxicity evaluation were required before each cycle of chemotherapy. Patients receiving gefitinib or placebo were observed with a history and physical examination, blood work, and toxicity evaluation every 4 weeks for the first 12 weeks and then every 3 months. Patients could be removed from the study for unacceptable toxicity, disease progression, development of an intercurrent, non–cancer-related illness that prevented study continuation, or patient refusal. Patients off all therapy were observed every 6 months for 5 years and then annually thereafter for 10 years.

Statistical Methods
We hypothesized that gefitinib would produce a 33% increase in median survival time over the expected median survival time of 21 months for the control arm. The sample size for the randomized comparison was 672 patients with a power of 0.89 using a one-sided 2.5% level log-rank test. Given the results of SWOG 9504, we anticipated that 20% of patients would not proceed to the random assignment because of progressive disease or toxicity. The planned accrual target was 840 patients. Kaplan-Meier survival curves were generated to describe OS and PFS from the time of random assignment, and survival comparisons were performed via stratified Cox proportional hazards analysis. Stratification factors at the time of initial registration were stage (IIIA v IIIB), measurable versus nonmeasurable disease, and histologic/cytologic subtype (squamous v nonsquamous). Comparisons of toxicity rates used a standard ² test.

	RESULTS

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Patient Characteristics
SWOG 0023 was activated in June 2001 and closed prematurely on April 15, 2005 on the recommendation of an unplanned interim analysis that was prompted by the failure of gefitinib to improve survival in the Iressa Survival Evaluation in Lung Cancer (ISEL) trial.²⁴ Accrual to the three phases of this trial is shown in Figure 1. At the time of study closure, 620 (74%) of the planned 840 patients had been registered to the initial chemoradiotherapy treatment. Of these patients, 49 (7.9%) were ineligible. Incorrect stage was the primary reason for ineligibility (57% of patients); additional reasons included inadequate FEV₁ (12%), inadequate pathology (10%), and other reasons (21%). Of 571 eligible patients, 503 completed concurrent therapy as planned, and 429 proceeded to consolidation. Sixty-eight patients did not complete chemoradiotherapy as a result of adverse events (n = 22), progressive disease (n = 11), death (n = 7), refusal (n = 7), other reasons (n = 16), or unknown reasons (n = 5). Sixty-four patients dropped out of study after completion of the first step as a result of disease progression on restaging (n = 33), death (n = 6), refusal (n = 5), other reasons (n = 15), or unknown reasons (n = 5). Ten other patients proceeded but were ineligible for reasons unrelated to disease progression.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study schema with accrual and completion. NSCLC, non–small-cell lung cancer; CDDP, cisplatin; VP-16, etoposide; CR, complete response; PR, partial response.

Patient characteristics for all patients and the two randomly assigned cohorts are listed in Table 1. There was a higher proportion of nonwhite participants randomly assigned to the placebo arm compared with the gefitinib arm (14% v 3%, respectively; P = .003), but only 22 nonwhite patients were randomly assigned in total. Otherwise, there were no other significant differences in baseline characteristics between the randomly assigned groups.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival for patients receiving gefitinib or placebo.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival for patients receiving gefitinib or placebo.

Treatment Delivery
Fifty-two percent of patients on the gefitinib arm discontinued treatment within the first 6 months compared with 44% of patients on the placebo arm (P = .23). Discontinuation was primarily a result of disease progression on both arms.

	DISCUSSION

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In this randomized, placebo-controlled trial in unresectable stage III NSCLC, gefitinib maintenance therapy failed to show a survival advantage. In fact, although the patient sample size was smaller than planned because of premature closure, patients receiving gefitinib had unexpectedly inferior survival, with a median survival time of 23 months compared with 35 months for patients receiving placebo(P = .013). Decreased survival did not seem to be a result of toxicity, with only a 2% toxicity death rate reported. Instead, the most common cause of death was lung cancer. This finding does not seem to be a result of differences in baseline patient characteristics in the two arms or significant treatment interactions. Although an imbalance in additional patient characteristics not captured in this study, such as smoking history, is possible, this factor by itself is unlikely to explain the negative results with gefitinib. Smoking status is a significant predictor of response and survival after treatment with EGFR-TKIs. In the two randomized trials of gefitinib (ISEL) or erlotinib (BR.21) versus placebo in previously treated NSCLC patients, never-smoking populations had a significant survival benefit compared with the placebo groups.^24,25 This favorable result in the ISEL study was demonstrated despite lack of an OS benefit with gefitinib. However, the inverse relationship, a negative impact of EGFR-TKIs in smoking patients, was not demonstrated. In fact, in BR.21, a survival benefit with erlotinib was also demonstrated for ever-smokers (currently smoking or with a prior history of smoking) and even for male ever-smokers with squamous histology (HR 0.66; P = .016).²⁶

Similarly, an imbalance in tumor-related molecular characteristics could be present in our study, but it is difficult to understand how such an imbalance would result in a negative survival impact. It is well recognized that patients with tumors characterized by an activated EGFR pathway related to EGFR mutations, increased gene copy number, and/or high protein expression show favorable response and survival when treated with EGFR-TKIs compared with placebo. Retrospective analyses on a subset of patients with available tumor tissue in ISEL and BR.21 demonstrate both the prognostic and predictive value of abnormal EGFR expression.^27,28 Interestingly, in ISEL, patients receiving gefitinib who had low tumor protein expression had a numerically inferior survival of 4.2 months compared with 5.5 months for patients with high protein expression; the interaction P value was significant (P = .049). The possibility of an imbalance in K-ras mutations, a marker of resistance to EGFR inhibitors, must also be considered.²⁹ In S0023, we prospectively collected archival tumor, genomic DNA, and plasma samples from consenting patients. Analysis for EGFR pathway markers and associated abnormalities such as K-ras mutations are underway and may assist in explaining the results in this patient population unselected for EGFR-TKI sensitivity.

It should also be recognized that poststudy treatments were not collected in this study. Therefore, an imbalance in subsequent therapies between the arms may have influenced the survival outcome.

Finally, S0023 was designed to deliver gefitinib after completion of chemoradiotherapy and consolidation therapy, thus avoiding a potentially negative interaction with chemotherapy; the inferior survival observed in the gefitinib arm raises the possibility of a deleterious effect. Gefitinib or erlotinib was administered as maintenance therapy in all four randomized trials in advanced disease comparing chemotherapy plus a TKI with chemotherapy alone.^18-21 Although no benefit with concurrent EGFR-TKI was seen in response rate, PFS, or OS, landmark analyses of INTACT 2 and TRIBUTE favored patients receiving single-agent TKI maintenance therapy after completion of chemotherapy.^18,20 Our study differed in that radiation therapy was used, raising a hypothetical concern that radiation alters EGFR signaling and confers gefitinib resistance. Two additional studies, one closed and one ongoing, may shed further light on this issue. BR.19, an NCIC-CTG randomized phase III trial of gefitinib or placebo as adjuvant therapy in pathologic stage IB to IIIA NSCLC, is closed, with 503 of the planned 1,160 patients enrolled. An ongoing randomized trial, RADIANT, is evaluating maintenance erlotinib versus placebo in resected patients selected to benefit by high EGFR gene copy number and/or positive protein expression.

As expected, gefitinib was well tolerated in this trial, with grade 3 rash and diarrhea occurring in 7% of patients and grade 3 or 4 pneumonitis occurring in 3%. Likewise, the core regimen of chemoradiotherapy followed by docetaxel consolidation produced a toxicity profile similar to that of the prior SWOG phase II study, S9504.³⁰ Although the random assignment scheme after consolidation therapy does not allow direct comparison of the S0023 results with those of the predecessor phase II study, S9504, the median survival time of 19 months and 2-year survival rate of 40% are favorable. The role of consolidation docetaxel after cisplatin/etoposide and thoracic radiation has also been evaluated by the Hoosier Oncology Group. The median survival time for the 73 patients who received docetaxel was 23 months compared with 24 months for the observation arm (P = .94), suggesting no benefit for consolidation docetaxel in this study.³¹ However, the survival time in S0023 compares favorably with those obtained in other larger phase III cooperative group studies.^2,5

In conclusion, gefitinib resulted in inferior survival compared with placebo when delivered as maintenance therapy in this trial. Although the reasons for this result remain unclear, routine use of maintenance EGFR-TKIs in stage III disease outside of a clinical trial should be avoided.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Karen Kelly, Sanofi-Aventis (C), AstraZeneca (C); Kathy S. Albain, AstraZeneca (C), Sanofi-Aventis (C), Genetech (C); David R. Gandara, Sanofi-Aventis (C), AstraZeneca (C), Bristol-Myers Squibb Co (C) Stock Ownership: None Honoraria: Kathy S. Albain, AstraZeneca, Sanofi-Aventis, Genetech; David R. Gandara, Pfizer Inc Research Funding: Karen Kelly, Sanofi-Aventis; Kathy S. Albain, Genetech; David R. Gandara, Bristol-Myers Squibb Co, Lilly Oncology Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Karen Kelly, Kari Chansky, Laurie E. Gaspar, Kathy S. Albain, John J. Crowley, David R. Gandara

Provision of study materials or patients: Karen Kelly, Laurie E. Gaspar, Kathy S. Albain, James Jett, Yee C. Ung, Derick H.M. Lau, David R. Gandara

Collection and assembly of data: Karen Kelly, Kari Chansky, John J. Crowley

Data analysis and interpretation: Karen Kelly, Kari Chansky, Kathy S. Albain, John J. Crowley, David R. Gandara

Manuscript writing: Karen Kelly, Kari Chansky, James Jett, Yee C. Ung, John J. Crowley, David R. Gandara

Final approval of manuscript: Karen Kelly, Kari Chansky, Laurie E. Gaspar, Kathy S. Albain, James Jett, Yee C. Ung, Derick H.M. Lau, John J. Crowley, David R. Gandara

	NOTES

 
published online ahead of print at www.jco.org on March 31, 2008.

Supported in part by AstraZeneca and Sanofi-aventis and the following National Cancer Institute, Department of Health and Human Services, Public Health Service Cooperative Agreement Grants No.: CA38926, CA32102, CA46441, CA35431, CA37663, CA46282, CA35261, CA14028, CA35119, CA45377, CA35178, CA45450, CA42777, CA67575, CA20319, CA04919, CA35090, CA46368, CA35176, CA45808, CA45560, CA35192, CA52654, CA63844, CA35281, CA45807, CA35128, CA35262, CA63845, CA74647, CA86780, CA63850, CA13612, CA45461, CA63848, CA11083, CA58882, and CA74811.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

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

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Submitted October 10, 2007; accepted December 6, 2007.

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