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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2350-2357 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2280 Erlotinib for Advanced Non–Small-Cell Lung Cancer in the Elderly: An Analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21
From the Princess Margaret Hospital/University Health Network, University of Toronto, Toronto; National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston, Ontario, Canada; and OSI Pharmaceuticals Inc, Boulder, CO Corresponding author: Paul Wheatley-Price, MBChB, MRCP, Department of Medical Oncology, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, M5G 2M9 Canada; e-mail: paul.wheatley-price{at}uhn.on.ca
Purpose National Cancer Institute of Canada Clinical Trials Group Study BR.21 established erlotinib as a standard of care in patients with non–small-cell lung cancer (NSCLC) after failure of first- or second-line chemotherapy. The current study analyzes the influence of age on outcomes in BR.21.
Patients and Methods BR.21 was a double-blind phase III trial that randomly assigned 731 patients to erlotinib 150 mg daily or placebo. End points included progression-free survival and overall survival (OS), response, quality of life (QOL), drug exposure, and toxicity, which are analyzed in this retrospective study by the following two age groups: Results There were 163 elderly patients (112 on erlotinib, 51 on placebo) and 568 young patients (376 on erlotinib, 192 on placebo). There was no significant difference between age groups randomly assigned to erlotinib or placebo in progression-free survival (elderly: 3.0 v 2.1 months; hazard ratio [HR] = 0.63; 95% CI, 0.44 to 0.90; P = .009; young: 2.1 v 1.8 months; HR = 0.64; 95% CI, 0.53 to 0.76; P < .0001; interaction, P = .77) or OS (elderly: 7.6 v 5.0 months; HR = 0.92; 95% CI, 0.64 to 1.34; P = .67; young: 6.4 v 4.7 months; HR = 0.73; 95% CI, 0.61 to 0.89; P = .0014; interaction, P = .31). Response rates were similar between age groups. Elderly patients, compared with young patients, had significantly more overall and severe (grade 3 and 4) toxicity (35% v 18%; P < .001), were more likely to discontinue treatment as a result of treatment-related toxicity (12% v 3%; P < .0001), and had lower relative dose-intensity (64% v 82% received > 90% planned dose; P < .001). Conclusion Elderly patients treated with erlotinib gain similar survival and QOL benefits as younger patients but experience greater toxicity.
Lung cancer is the most common cause of cancer death worldwide. In the United States, there were estimated to be 213,000 new cases and 160,000 deaths in 2007.1 The risk of developing lung cancer increases with age, with probabilities of 1.09% (one in 92), 2.61% (one in 38), and 6.76% (one in 15) in men in the age groups 40 to 59 years, 60 to 69 years, and 70+ years, respectively; similar increments are seen in women, with probabilities of 0.85% (one in 117), 1.84% (one in 54), and 4.52% (one in 22) in the same age groups, respectively.1 The median age at diagnosis is now 70 years, having climbed from 64 years or older in the 1970s.2 Death rates continue to climb among women aged 65 years or older, although in men over 60 years of age, the death rate peaked in the 1980s.3 Most patients with non–small-cell lung cancer (NSCLC) have incurable disease at diagnosis, with only approximately 15% presenting with localized disease, a rate that does not significantly vary when stratified by age.4 The elderly have been consistently under-represented in clinical trials, where only 25% to 32% of participants are over the age of 65 years compared with 61% to 63% of all patients diagnosed with cancer.5,6
Treatment for advanced disease is palliative in nature. In patients with a good performance status, first-line treatment with platinum-based combination chemotherapy leads to improved overall survival (OS) and improvement in symptoms.7-9 However, in elderly patients, single-agent therapy is used more frequently based largely on the results of an Italian phase III trial that demonstrated a significant survival benefit of single-agent vinorelbine over best supportive care in patients Retrospective analyses of trials not restricted to elderly patients have generally demonstrated that the elderly have similar response rates to chemotherapy as younger patients and also similar survival benefits. Most studies also have shown that older patients are more likely to stop treatment as a result of toxicity, although objectively, these studies have reported either little or no increase in toxicity in elderly subgroups.14-21 Some investigators evaluating chemotherapy in the elderly have suggested that performance status and comorbidity index are probably more important prognostic markers than age alone, suggesting that biologic rather than chronologic age may be more predictive of outcome and tolerance to treatment.18,21
For patients who experience progression after first-line treatment, second-line cytotoxic chemotherapy with either docetaxel or pemetrexed may prolong survival.22,23 A retrospective analysis that compared elderly patients ( Erlotinib (OSI Pharmaceuticals, Melville, NY) targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21 study randomly assigned patients who had experienced failure with first- or second-line chemotherapy to erlotinib or placebo in a two to one ratio. Treatment with erlotinib resulted in a significant survival benefit over placebo (hazard ratio [HR] = 0.70; P < .001).25 The median age was 62 years (range, 34 to 87 years) in the erlotinib arm and 59 years (range, 32 to 89 years) in the placebo arm. Because no randomized studies have been reported to document the efficacy and tolerance of elderly patients treated with EGFR inhibitors, we performed this retrospective analysis of patients treated in the BR.21 study.
BR.21 Design The National Cancer Institute of Canada Clinical Trials Group maintains the trial database where all analyses were performed. Full protocol details, eligibility criteria, and study results have been reported previously.25 Participating institutions received approval from their institutional ethics review boards, and all patients provided written informed consent. BR.21 had no upper age limit for inclusion in the trial, and patients with a performance status of 0 to 3 were eligible. Responses were assessed with the use of the Response Evaluation Criteria in Solid Tumors.26 Laboratory results, adverse events, and other symptoms were graded using the National Cancer Institute Common Toxicity Criteria (version 2.0). Treatment was with erlotinib 150 mg daily or placebo. Patients were to be treated until progression of disease, intolerability of study medication, or patient choice to come off study. For grade 2 diarrhea, loperamide was recommended without reduction in the dose of erlotinib. For grade 3 diarrhea, the study treatment was withheld until the diarrhea was grade 1 or less, and then erlotinib at a dose of 100 mg daily was started. For grade 1 or 2 rash, treatment modification was not recommended. For grade 3 rash, treatment was withheld, the rash was treated symptomatically, and erlotinib at a dose of 100 mg daily was restarted when the rash was grade 1 or less.
Definitions and Data Sets All randomly assigned patients were included in efficacy and quality of life (QOL) analyses, whereas all patients who received at least one dose of erlotinib or placebo were included in the toxicity and exposure analyses. For toxicity analyses, only patients treated with erlotinib are presented.
QOL
Dose-Intensity and Exposure
Statistical Methods
Patients In total, 731 patients were randomly assigned to erlotinib (n = 488) or placebo (n = 243), of whom 727 patients received protocol treatment (erlotinib, n = 485; placebo, n = 242). At study entry, 162 patients (22%) were elderly (112 randomly assigned to erlotinib). In the younger age group, 373 patients received erlotinib. There were no statistically significant demographic differences between the young and the elderly groups (Table 1), except that the elderly were less likely to have received prior platinum-based chemotherapy (P < .0001) and were more likely to be receiving erlotinib as second-line treatment (P = .08) For patients who received one line of treatment before erlotinib, 22% of the elderly received single-agent therapy compared with less than 1% of the young.
Efficacy Eight percent of elderly erlotinib patients had an objective response, and 70% had a best response of stable disease compared with 9% and 59% of young patients, but these differences were not significant (Table 2). The median duration of response was 39 weeks for the elderly (95% CI, 24 to 48 weeks) and 34 weeks for the young (95% CI, 25 to 49 weeks). There was no significant difference in survival between elderly and young patients randomly assigned to placebo (HR = 0.81; 95% CI, 0.57 to 1.14; P = .22) or to erlotinib (HR = 1.02; 95% CI, 0.81 to 1.30; P = .85; Figs 1A and 1B).
The treatment effect was not significantly different between elderly and young patients (interaction, P = .31). For elderly patients, median survival time was 7.6 months for patients receiving erlotinib compared with 5.0 months for patients receiving placebo (HR = 0.92; 95% CI, 0.64 to 1.34; P = .67), and for young patients, the median survival times were 6.4 months compared with 4.7 months (HR = 0.73; 95% CI, 0.61 to 0.89; P = .0014; Figs 1C and 1D). Progression-free survival was significantly improved in both the elderly and young populations with erlotinib compared with placebo (elderly: 3.0 v 2.1 months; P = .009; young: 2.1 v 1.8 months; P < .0001; interaction, P = .77; Figs 1E to 1H). After progression on BR.21, 18% of elderly patients received further chemotherapy or EGFR inhibitor compared with 24% of young patients (Table 2).
Treatment Delivery and DI
Toxicity Thirty-five percent of the elderly group experienced severe toxicity (  grade 3) compared with 18% of the younger group (P < .001; Table 4). The elderly were more likely than the younger group to have grade 3 rash, fatigue, stomatitis, or dehydration, as well as any grade of anorexia (26% v 16%; P = .03) and fatigue (22% v 14%; P = .04). Fatal drug-related toxicities were unusual and occurred in only five patients (two young patients and three elderly patients). There were no statistically significant differences in all-cause fatal adverse events or in hospitalization rates between the age groups.
QOL QOL benefits were similar in elderly and young patients, with age x treatment interaction P = .26, .44, and .44 for cough, dyspnea, and pain, respectively (Table 5). Elderly erlotinib patients, compared with younger patients, had a significantly longer time to deterioration for cough (7.4 v 3.2 months; P = .04) and dyspnea (8.0 v 2.8 months; P = .07) but not for pain (2.9 v 2.8 months; P = .47). Younger erlotinib patients, compared with elderly patients, had significantly improved time to deterioration in dyspnea (4.6 v 3.1 months; P = .04) and pain (2.8 v 1.9 months; P = .01) but not cough (4.9 v 3.9 months; P = .20).
Given the median age of patients presenting with NSCLC, the impact of age on outcomes including efficacy, toxicity, and QOL is an important consideration. Some retrospective analyses of patients treated with combination chemotherapy have shown that the elderly report slightly more toxicity,19,20 although the Eastern Cooperative Oncology Group 1594 study of four different platinum-based chemotherapy regimens in NSCLC in the first-line setting showed no significant difference in toxicity between the younger than 70 years age group and the 70 to 80 years age group.16 It seems that elderly patients and their physicians are less willing to accept even mild toxicity, and this leads to more frequent dose reduction and discontinuation in the elderly compared with younger patients. This seems to be the case even when cure is the goal, as in limited-stage small-cell lung cancer30 and in the adjuvant setting after complete resection of NSCLC.31 However, there is little information available on the impact of age on outcomes after treatment in the second-line or third-line setting for NSCLC, either with chemotherapy or EGFR inhibitors.
Current options for second- or third-line treatment of NSCLC are limited, with docetaxel, pemetrexed, and erlotinib being the only agents supported by level 1 evidence.22,23,25 Interestingly, although only 15% of patients were aged The BR.21 study established erlotinib as the standard of care for NSCLC patients who have experienced treatment failure with standard chemotherapy for advanced disease based on a significant survival benefit and improved QOL.25,29 In this retrospective analysis of BR.21, we demonstrate that there is no significant difference in benefit (survival, response, and QOL) between elderly and young patients. Although the HR for survival was numerically lower in the elderly, the test of interaction was not significant. Lack of interaction by age is further supported by the similar and statistically significant progression-free survival improvement seen in both young and elderly patients. Single-agent chemotherapy is considered the standard of care for most elderly patients, and as expected, elderly patients in BR.21 were significantly less likely to have received a platinum-containing regimen. Although not a statistically significant difference, the elderly were slightly more likely to receive erlotinib in the second-line rather than third-line setting. It is noted that, as for most trials, the eligibility criteria for BR.21 would have excluded patients with moderate to severe comorbidity irrespective of age, although unusually for a trial in NSCLC, patients with Eastern Cooperative Oncology Group performance status of both 2 and 3 were eligible to participate.
Although, to our knowledge, this is the first analysis of a placebo-controlled study demonstrating the benefit of an EGFR inhibitor in an elderly population in the second- and third-line settings, data are available from smaller studies to support these conclusions. A 59-patient single-arm study of gefitinib in previously treated patients with NSCLC reported a response rate of 3% in the elderly (> 70 years) or unfit ( A recent phase II study by Jackman et al28 reported the efficacy of erlotinib as first-line treatment in 80 patients greater than 70 years of age. Their 10% partial response rate is similar to the 9% response rate seen in our trial, even though in BR.21 all patients had received prior chemotherapy. Another phase II study of first-line erlotinib in 53 previously untreated patients of unselected age (median age, 60 years; range, 30 to 80 years) showed a response rate of 23% and a median OS of 12.8 months.34 In our analyses, elderly patients were more likely to report grade 3 or greater toxicity, particularly rash, fatigue, stomatitis, or dehydration. However, this incidence of severe toxicity was relatively low, with rash being the most commonly reported toxicity (16%). Despite higher rates of severe toxicities, these did not result in statistically different hospitalization rates between age groups (P = .91). In keeping with this excess of toxicity, the elderly required more dose modifications and were more likely to discontinue therapy as a result of toxicity, resulting in a lower exposure to erlotinib. It is interesting to speculate that pharmacogenomic or pharmacodynamic differences in the elderly may explain similar benefits despite lower exposure. Erlotinib is primarily metabolized by the cytochrome P450 enzymes CYP3A4, CYP3A5, and CYP1A1.35,36 Activity of these enzymes may be affected by age, with reduced activity seen in some elderly populations.37,38 Although not explored in our study, such investigations may be informative in the future.
Gefitinib has now been compared with docetaxel in the second-line setting in one randomized phase II and two randomized phase III trials.39-41 These studies all demonstrated similar activity and efficacy but an improved toxicity profile in the gefitinib arms. In a preplanned subgroup analysis of the phase III Iressa Non–Small-Cell Lung Cancer Trial Evaluating Response and Survival Against Taxotere in 1,466 patients, of whom approximately 35% were In BR.21, response to erlotinib correlated with EGFR protein expression, presence of EGFR mutations, and EGFR gene copy number,42,43 whereas EGFR copy number and a never-smoking history were predictive of a differential survival benefit. In the Jackman et al28 study, EGFR mutation was associated with disease control. Currently, there is no clear evidence of EGFR expression changing with age in lung cancer, although there is a report of increasing EGFR expression with age in patients with glioblastoma multiforme.44 We feel that the numbers of elderly patients with EGFR protein, gene copy, and mutation status results from BR.21 are too small to justify subgroup analyses and correlation with outcome, although it should be noted that, in this small cohort, EGFR protein expression was present in 68% of the elderly tested versus 46% of the young (P = .03). In conclusion, this analysis demonstrates that the benefit of erlotinib as second- or third-line therapy in NSCLC is not restricted to younger patients, although careful management of older patients is appropriate given their higher incidence of severe toxicity.
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: Gary M. Clark, OSI Pharmaceuticals (C) Consultant or Advisory Role: Frances A. Shepherd, AstraZeneca Advisory Board (C), Roche Advisory Board (C) Stock Ownership: Frances A. Shepherd, AstraZeneca Honoraria: Frances A. Shepherd, AstraZeneca, Roche Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Lesley Seymour, Frances A. Shepherd Financial support: Gary M. Clark Administrative support: Frances A. Shepherd Provision of study materials or patients: Frances A. Shepherd Collection and assembly of data: Keyue Ding, Lesley Seymour, Gary M. Clark, Frances A. Shepherd Data analysis and interpretation: Paul Wheatley-Price, Keyue Ding, Lesley Seymour, Gary M. Clark, Frances A. Shepherd Manuscript writing: Paul Wheatley-Price, Lesley Seymour, Frances A. Shepherd Final approval of manuscript: Paul Wheatley-Price, Keyue Ding, Lesley Seymour, Gary M. Clark, Frances A. Shepherd
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007 2. Hayat MJ, Howlader N, Reichman ME, et al: Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12:20-37, 2007 3. Wingo PA, Cardinez CJ, Landis SH, et al: Long-term trends in cancer mortality in the United States, 1930-1998. Cancer 97:3133-3275, 2003[CrossRef][Medline] 4. National Cancer Institute: SEER stage distribution by race, sex and age group for lung and bronchus cancer: SEER 9 Registries for 1988-2003. http://seer.cancer.gov/faststats/sites.php?site=Lung+and+Bronchus+Cancer&stat=Survival 5. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999 6. Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 years of age or older in cancer clinical trials. 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Niho S, Ichinose Y, Tamura T, et al: Results of a randomized phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non–small-cell lung cancer who failed one or two chemotherapy regimens. J Clin Oncol 25:307s, 2007 (suppl, abstr LBA7509) 42. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 43. Shepherd FA, Ding K, Sakurada A, et al: Updated molecular analyses of exons 19 and 21 of the epidermal growth factor receptor (EGFR) gene and codons 12 and 13 of the KRAS gene in non-small cell lung cancer (NSCLC) patients treated with erlotinib in National Cancer Institute of Cancer. J Clin Oncol 25:402s, 2007 (suppl; abstr 7571) 44. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests or Fisher's exact tests were used to assess associations between categoric variables; analysis of variance was used to compare continuous variables between age groups; Kaplan-Meier curves were used to estimate the distributions of time-to-event outcomes (OS and time to deterioration of lung cancer symptoms as assessed by QOL scores); and Cox regression models were used to correlate the age groups, other baseline factors, and study treatment to the time-to-event outcomes. To test the interaction of treatment with age group, proportional hazards models were used with their interaction term included. All reported P values are from two-sided tests unless otherwise specified. Statistical analyses were carried out using SAS (SAS Institute, Cary, NC). 
70 years and performance status > 2).
