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Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in Patients With Advanced Non–Small-Cell Lung Cancer and a Performance Status of 2

Rogerio Lilenbaum, Rita Axelrod, Sachdev Thomas, Afshin Dowlati, Leonard Seigel, Donald Albert, Karsten Witt, David Botkin

From the Mount Sinai Cancer Center, Miami Beach, FL; Thomas Jefferson University Hospital, Philadelphia, PA; Oncology/Hematology Associates of Central Illinois, IL; University Hospitals of Cleveland, Cleveland, OH; Holy Cross Hospital, Ft. Lauderdale, FL; OSI Pharmaceuticals, Boulder, CO; and Sharp Clinical Oncology Research, San Diego, CA

Corresponding author: Rogerio Lilenbaum, MD, Mount Sinai Cancer Center; 4306 Alton Road; Miami Beach, FL 33140; e-mail: rlilenbaum{at}aptiumoncology.com

	ABSTRACT

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Purpose A multicenter randomized phase II trial to evaluate two treatment strategies in the first-line management of advanced non–small-cell lung cancer (NSCLC) patients with a performance status (PS) of 2.

Patients and Methods Patients were assigned to erlotinib 150 mg orally daily until progression or to carboplatin (area under the curve [AUC] 6) and paclitaxel (200 mg/m² day 1 every 3 weeks) for up to four cycles. Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib. The primary end point was progression-free survival (PFS). Secondary end points were response, survival, quality of life (QOL), and a retrospective molecular correlation.

Results Fifty-two patients were randomly assigned to erlotinib and 51 to chemotherapy. Partial responses were 2% and 12%, respectively. Median PFS was 1.9 months in the erlotinib arm and 3.5 months in the chemotherapy arm (hazard ratio [HR] = 1.45; 95% CI, 0.98 to 2.15; P = .06). Median survival times were 6.5 and 9.7 months, respectively (HR = 1.73; 95% CI, 1.09 to 2.73; P = .018). Patients who crossed over to erlotinib had a median survival of 14.9 months. Sex, histology, skin rash, and smoking history predicted outcome with erlotinib. Rash and diarrhea were more common with erlotinib; emesis, alopecia, peripheral neuropathy, and fatigue were more common with chemotherapy. QOL was similar between the two arms. Molecular correlation was limited by available samples.

Conclusion Unselected patients with advanced NSCLC and PS 2 are best treated with combination chemotherapy as first-line therapy. Erlotinib may be considered in patients selected by clinical or molecular markers.

	INTRODUCTION

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Performance status (PS) is the most important predictor of outcome in advanced non–small-cell lung cancer (NSCLC). Patients with a PS of 2 tend to tolerate treatment poorly and have a significantly inferior survival compared with patients with a PS of 0 to 1.¹ As a result, PS 2 patients have been historically excluded from clinical trials, and scant evidence-based information is available to guide clinical practice.

A recent trial from the Cancer and Leukemia Group B (CALGB) randomly assigned 561 patients with advanced NSCLC, of whom 99 had a PS of 2, to combination versus single-agent chemotherapy.² The study showed a significant survival advantage for the combination of carboplatin and paclitaxel compared with paclitaxel alone in the subgroup of PS 2 patients. Although in the context of a subset analysis, these results suggest that combination chemotherapy may be of benefit in PS 2 patients.

Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR), a key regulator of cell growth.³ A large clinical trial compared erlotinib with placebo in previously treated patients with advanced NSCLC and showed significantly superior survival for erlotinib, which extended to the subgroup of patients with PS 2 and 3.⁴

On the basis of these observations, we conducted a randomized phase II trial to evaluate these two strategies in the first-line management of advanced NSCLC patients with PS 2. We also conducted a quality-of-life analysis and a retrospective correlation between molecular biomarkers and clinical outcome.

	PATIENTS AND METHODS

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Eligibility
Patients with cytologic or histologic confirmation of stage IIIB (malignant effusion) and IV NSCLC were required to have measurable or assessable disease and a PS of 2 by Eastern Cooperative Oncology Group (ECOG) criteria. Prior chemotherapy or prior EGFR inhibitor therapy was not allowed. Patients with locally advanced disease amenable to combined-modality therapy were not eligible. Prior radiation was allowed and toxicities had to be resolved before study entry. Patients with brain metastases were eligible if neurologically stable and no longer receiving corticosteroids after appropriate therapy. Adequate organ function was required. Patients with GI illness that may affect oral absorption, or any other serious medical condition that might impair their ability to receive protocol therapy, were not eligible. Patients with concurrent active malignancies, except in situ carcinoma of the cervix and basal cell carcinoma of the skin, were not eligible. Approval by the institutional review board at each participating institution was required. All patients signed informed consent.

Treatment Plan
Patients enrolled from all participating institutions were randomly assigned to treatment with erlotinib 150 mg orally once daily until progression, or to the combination of carboplatin at an area under the curve (AUC) of 6 and paclitaxel at a dose of 200 mg/m², both administered IV on day 1 every 21 days for up to four cycles. Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib provided that they still met the initial eligibility criteria. Patients who progressed after erlotinib were treated at their physicians’ discretion. Random assignment was performed by an independent provider not involved in the study. Patient random assignment was stratified by center, stage (IIIB v IV) and age ( 70 v > 70 years).

Toxicity was assessed every cycle using the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 3.0. Dose modifications for erlotinib included one reduction to 100 mg for grade 3 or greater diarrhea and/or grade 2 or greater skin rash. For chemotherapy, the first dose reduction was to carboplatin AUC 5 and paclitaxel 175 mg/m²; the second to AUC 4 and 150 mg/m², respectively. Further reductions were not allowed. Administration of growth factors was permitted at investigators’ discretion, but was not a substitute for appropriate dose reductions. The need for palliative radiation was considered as indicative of progression, and such patients were discontinued from the study. Response was assessed by imaging studies every two cycles and evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).⁵

Quality of Life and Molecular Correlation
Health-related quality of life (HRQL) was assessed using the self-administered European Organisation for Research and Treatment of Cancer (EORTC) lung-specific questionnaire (QLQ-LC13), which includes lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related adverse effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication.⁶ Patients completed the questionnaire before receiving the first dose of treatment, on day 1 of each subsequent 21-day cycle, and at end of study.

Data regarding molecular predictors of benefit from EGFR inhibitors became available during the conduct of the trial,⁷ which was then amended to allow collection of tumor samples whenever available.

Statistical Analysis
The primary objective was to estimate the efficacy of erlotinib and standard chemotherapy in the PS 2 patient population. The primary end point was median PFS, defined as the time from random assignment until the first day of progression or until death in the absence of progression. For either arm of the study, if the median PFS was less than 2 months, the treatment would be considered ineffective. If the median PFS was at least 3.5 months, the treatment would be worthy of further evaluation. Using a one-sided test at the 5% level of significance, 51 patients were needed in each arm to have 90% power to detect the specified difference in each arm.

Additional end points included response rate, overall survival (OS), toxicities, and quality of life. OS was calculated as the time from random assignment until the date of death resulting from any cause. If a patient was known not to have died, survival was excluded at the last known alive date. All patients who received at least one dose of erlotinib or standard chemotherapy were considered assessable for PFS, OS, and safety. Since patients who experienced failure with chemotherapy were allowed to cross over to erlotinib although no formal crossover was assigned in the erlotinib arm, a separate survival analysis for these patients was performed. Patients who received at least 21 days of erlotinib or one cycle of standard chemotherapy and had disease reassessed were considered assessable for response. Median time to event and 95% CIs were estimated from the Kaplan-Meier curves. Cox regression analyses were used to estimate hazard ratios. A log-rank test was used for exploratory testing of time-to-event outcomes.

Adverse events were based on the investigator's attribution of causality. All patients who filled out at least the baseline and one subsequent questionnaire were considered assessable for the HRQL analysis. The EORTC QLQ-LC13 questionnaire was scored according to the Scoring Manual.⁶ For each treatment arm, baseline scores were summarized using descriptive statistics, and changes from baseline for each of the 10 symptom scores were calculated for each 21-day cycle. Changes were categorized as "improved" (10% or greater improvement from baseline at any time), "worsened" (10% or greater worsening from baseline at any time), or "stable." For patients who signed the optional informed consent, tumor tissue samples were analyzed for EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number by fluorescent in situ hybridization (FISH), and EGFR and Kras gene mutations. These results were correlated with PFS and OS using Cox regression analyses.

	RESULTS

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Baseline Characteristics
A total of 103 patients at 14 study sites were randomly assigned between May 2002 and March 2004 to erlotinib (n = 52) or chemotherapy (n = 51). There were no major differences between the two arms in baseline characteristics (Table 1). Eighty-six percent of patients had stage IV disease, and 46% were 70 years of age or older. There were slightly more females (56% v 45%) and adenocarcinoma with bronchoalveolar features (17% v 6%) in the erlotinib arm. However, there were more patients with nonadenocarcinoma histology in the erlotinib arm (50% v 38%). Smoking history was not different between the arms.

View larger version (48K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram. AUC, area under the curve.

Toxicity
Treatment-related grade 3 or 4 adverse events in the erlotinib arm were noted in 23% and 2% of patients, respectively (Table 2). Grade 3 events included diarrhea in three patients (6%) and skin rash in four patients (8%). One patient had grade 3 anemia and grade 3 thrombocytopenia, and one patient had transient grade 3 elevation of liver enzymes. Grade 4 and 5 events included one patient each with pulmonary embolism and lung infiltration, respectively.

View this table: [in this window] [in a new window]   Table 2. Common Treatment-Related Adverse Events (incidence 10% in either arm)

Efficacy
Objective partial responses were observed in two of 52 patients in the erlotinib arm (4%), and in six of 51 patients (12%) in the chemotherapy arm (Table 3). The two responders in the erlotinib arm were females and never smokers. In the chemotherapy arm, responses did not seem correlated with either sex or smoking status. Of the 29 patients who crossed over to erlotinib, three (10%) had a response: one complete response in a female with a mutation-positive tumor, and two patients (including one never smoker) with a partial response for whom no molecular data were available. In the erlotinib arm, 23 patients (44%) progressed in the first assessment after the first two cycles, whereas 20% of patients treated with chemotherapy had progressive disease after the first two cycles. Best response could not be determined in 15% and 25% of patients in the erlotinib and the chemotherapy arm, respectively, primarily because of lack of confirmation of tumor response by RECIST.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier plots. (A) Erlotinib-treated patients had shorter progression-free survival (PFS; median, 1.91 months) compared with patients treated with chemotherapy (median, 3.52 months; hazard ratio [HR] = 1.45; 95% CI, 0.98 to 2.15). (B) Median survival times were shorter in the erlotinib-treated group (6.6 months) compared with the chemotherapy group (9.7 months; HR = 1.73; 95% CI, 1.09 to 2.73); median survival was 14.9 months for the 29 patients who crossed over to erlotinib. PC, paclitaxel + carboplatin.

Tumor samples were obtained from 22 of 52 patients in the erlotinib arm and 16 of 51 patients in the chemotherapy arm, although not all were appropriate for analysis. In the erlotinib arm, 13 of 19 assessable tumors (74%) stained positive for EGFR by IHC, seven (37%) of 19 had EGFR gene amplification or high polysomy by FISH, and none harbored EGFR mutations. In the chemotherapy arm, the corresponding figures were 11 (79%) of 14, seven (54%) of 13, and five (50%) of 10 (Table 5). Kras mutations were detected in three (23%) of 13 patients in the erlotinib arm, whereas none were found in the chemotherapy arm.

	DISCUSSION

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To the best of our knowledge, this is the first trial to provide information about the efficacy and safety of first-line treatment with erlotinib in a controlled population of PS 2patients with advanced NSCLC. Selection or "enrichment" based on clinical or molecular markers was not part of the eligibility criteria.

Our results showed a superior response rate and PFS for patients treated with up-front combination chemotherapy. Although the study was not adequately powered, the difference in PFS between patients treated with chemotherapy versus erlotinib was clinically meaningful and nearly reached statistical significance. Further, median survival of patients treated with chemotherapy was superior to that of those who received up-front erlotinib. However, median survival was partially confounded by the crossover option from chemotherapy to erlotinib. The median survival for patients who crossed over to erlotinib after chemotherapy was 14 months. Although this may represent, at least in part, a selection bias inherent to second-line therapy, the magnitude of the survival difference favors a positive impact of salvage erlotinib on outcome.

The subgroup analyses identified sex and histology as predictors of outcome, with females having a better PFS on erlotinib and squamous cell carcinoma patients having a better PFS when treated with chemotherapy. The PFS was also substantially better for patients who developed moderate to severe skin rash on erlotinib compared with those who had mild or no rash, but was still not better than chemotherapy. Lastly, patients who had never smoked had a better outcome with erlotinib. These predictive factors are consistent with prior studies of EGFR tyrosine kinase inhibitors.⁸ Although these findings are helpful in identifying patients who tend to benefit the most from erlotinib, our subset analysis was based on small numbers of patients and cannot be used to guide decisions regarding the use of chemotherapy versus an EGFR inhibitor in the first-line management of patients with PS 2.

Both treatments were well tolerated. Rash and diarrhea were the only frequent toxicities seen in the erlotinib arm. One death resulting from interstitial lung disease was observed. Although rare in the white population, this is a known complication of erlotinib, with poor response to treatment and high fatality rates.⁹ Toxicity in the chemotherapy arm was more severe compared with the erlotinib arm and required dose modification in 31% of patients. Furthermore, two patients died as a result of febrile neutropenia, highlighting the need for aggressive supportive care when treating PS 2 patients with combination chemotherapy.

Quality of life was not significantly different between the two treatments. Because of higher response rates, improvement in disease-related symptoms tended to be more pronounced in patients treated with chemotherapy. However, in the same group, arthralgias and neuropathy had a more negative impact in quality of life. Overall, quality of life tended to improve rather than worsen on either treatment.

The molecular analysis was an ad hoc addition to the study. Because of the small number of tumor samples, proper correlation with outcome was not possible. One consistent trend was that patients whose tumors were negative for EGFR expression by IHC had a substantially lower PFS and median OS with erlotinib than with chemotherapy, whereas the difference in patients whose tumors were positive was of much smaller magnitude. This observation is similar to prior molecular analyses,^10,11 but whether it is on its own sufficient to guide therapy, particularly in our patient population, remains controversial.

In summary, unselected patients with advanced NSCLC and PS 2 are best treated with up-front chemotherapy. Patients selected on the basis of clinical and/or molecular markers may fare better than unselected patients when treated with erlotinib. Patients treated with chemotherapy followed by erlotinib had the best outcome. Additional studies are needed to evaluate the best strategy to incorporate molecular targeted agents in the treatment of PS 2 patients.

	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: Donald Albert, OSI Pharmaceuticals (C); Karsten Witt, OSI Pharmaceuticals (C) Consultant or Advisory Role: Rogerio Lilenbaum, Genentech (U) Stock Ownership: Karsten Witt, OSI Pharmaceuticals Honoraria: Afshin Dowlati, Genentech, Eli-Lilly Research Funding: Rogerio Lilenbaum, Genentech; Afshin Dowlati, Celgene, GlaxoSmithKline, Genetech, OSI Pharmaceuticals; Leonard Seigel, OSI Pharmaceuticals Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Rogerio Lilenbaum, Donald Albert, Karsten Witt

Provision of study materials or patients: Rogerio Lilenbaum, Rita Axelrod, Sachdev Thomas, Afshin Dowlati, Leonard Seigel, David Botkin

Collection and assembly of data: Sachdev Thomas, Afshin Dowlati, Donald Albert, Karsten Witt, David Botkin

Data analysis and interpretation: Rogerio Lilenbaum, Rita Axelrod, Afshin Dowlati, Donald Albert, Karsten Witt

Manuscript writing: Rogerio Lilenbaum, Rita Axelrod, Afshin Dowlati, Donald Albert, Karsten Witt

Final approval of manuscript: Rogerio Lilenbaum, Sachdev Thomas, Afshin Dowlati, Leonard Seigel, Donald Albert, Karsten Witt, David Botkin

	NOTES

 
Supported by OSI Pharmaceuticals Inc, Melville, NY.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Lilenbaum R: Treatment of advanced non-small-cell lung cancer in special populations. Oncology (Williston Park) 18:1321-1325, 2004[Medline]

2. Lilenbaum RC, Herndon JE II, List MA, et al: Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 23:190-196, 2005[Abstract/Free Full Text]

3. Jänne PA, Engelman JA, Johnson BE: Epidermal growth factor receptor in non-small cell lung cancer: Implications for treatment and tumor biology. J Clin Oncol 23:3227-3234, 2005[Abstract/Free Full Text]

4. Shepherd FA, Pereira JR, Ciuleanu T, et al: Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353:123-132, 2005[Abstract/Free Full Text]

5. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

6. Fayers PM, Aaronson NK, Bjordal K, et al: The EORTC QLQ-C30 Scoring Manual (ed 3). Brussels, Belgium, European Organisation for Research and Treatment of Cancer, 2001

7. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer patients to gefitinib. N Engl J Med 350:2129-2139, 2004[Abstract/Free Full Text]

8. Shah NT, Kris MG, Pao W, et al: Practical management of patients with non-small cell lung cancer treated with gefitinib. J Clin Oncol 23:165-174, 2005[Abstract/Free Full Text]

9. Yoneda KY, Hardin KA, Gandara DR, et al: Interstitial Lung Disease associated with epidermal growth factor receptor tyrosine kinase inhibitor therapy in non-small cell lung carcinoma. Clin Lung Cancer 8:S31–S35, 2006 (suppl)[Medline]

10. Tsao MS, Sakurada A, Cutz J, et al: Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005[Abstract/Free Full Text]

11. Bunn PA Jr, Dziadziuszko R, Varella-Garcia M, et al: Biological markers for non-small cell lung cancer patient selection for epidermal growth factor receptor tyrosine kinase inhibitor therapy. Clin Cancer Res 12:3652-3656, 2006[Free Full Text]

Submitted June 29, 2007; accepted October 24, 2007.

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