Mind Your Elders: Therapeutic Implications of Epidermal Growth Factor Receptor Inhibition in Older Patients With Advanced Non–Small-Cell Lung Cancer

Abstract

Elderly patients with advanced non–small-cell lung cancer (NSCLC) constitute a special therapeutic challenge. Historically, they have been underrepresented in clinical trials, often out of bias or misperception rather than true ineligibility. In addition, the elderly are more likely to have logistical challenges or comorbidities, including renal and hepatic dysfunction, as well as cardiopulmonary disorders and impaired marrow reserve, which limit their opportunities to participate in clinical trials. “Minding our elders” in this context has two distinct meanings: taking care of older individuals to the best of our ability; listening and appreciating the unique insights and expectations of older patients, particularly when it comes to their care and prognosis. The optimal approach toward elderly patients with NSCLC combines both concepts. The automatic initiation of standard platinum-based therapy in the elderly may not necessarily be appropriate, particularly in individuals with significant comorbidities or in fit patients who have therapeutic expectations that differ from their younger counterparts. The frequent failure to apply standard therapy— or any therapy at all to the elderly—is equally inappropriate, particularly if older patients are medically fit and willing to accept toxicities of treatment. Advanced age does not automatically connote compromised performance status or inability to tolerate appropriate therapy. While most US medical oncologists will administer platinum-based combinations to younger individuals with advanced NSCLC, the therapeutic paradigms employed in older individuals are divergent, even in clinicians who share the same practice. In this issue of the Journal of Clinical Oncology, Jackman et al have succinctly summarized the results of a Boston-based consortium trial evaluating the role of erlotinib in treatment-naive, otherwise fit elderly individuals with advanced NSCLC. This is the first elderly-specific trial to specifically assess the role of epidermal growth factor receptor tyrosine kinase inhibition (EGFR TKI) in NSCLC; and it remains one of the relatively few trials to evaluate EGFR TKI in treatment-naive patients. Based on a landmark phase III trial in the secondand third-line setting in advanced NSCLC, in which erlotinib yielded a greater than 40% improvement in 1-year survival compared with placebo control, this agent is the first EGFR inhibitor to be approved in solid tumor oncology. The therapeutic advantage of erlotinib was realized despite the “unselected” nature of the patients enrolled onto that trial, none of whom were picked on the basis of EGFR expression or absence or presence of EGFR mutation. Despite a response rate of only 10% with single-agent erlotinib, Jackman et al noted a median progression-free survival rate of 3.5 months and, more impressively, a median overall survival of nearly 11 months. The latter is encouraging in this setting, particularly for a single agent that does not yield the toxicity typically seen with chemotherapy. The study met its primary end point: median survival exceeded a pre-established target of 37 weeks. In addition, the 1and 2-year survival rates rival results observed in E4599, which established a therapeutic advantage for bevacizumab in combination with chemotherapy compared with standard chemotherapy alone in a more tightly defined population. Treatment with erlotinib, as summarized by Jackman et al, was reasonably well-tolerated, although there was one putative treatment-related death from interstitial lung disease. The authors properly conclude that this approach needs to be investigated further, ideally in a more targeted population. Based on the results available, these conclusions are unimpeachable. However, before we embrace the empiric use of EGFR TKI prematurely, it is probably best to temper our enthusiasm. In a broader population of patients with good performance status and advanced NSCLC treated with standard platinum doublets, the median survival in cooperative group trials typically ranges between 8 and 10 months, not much less than that observed in this effort. In addition, some degree of inherent selection bias is likely. It is quite possible that the patients enrolled on the Jackman et al trial were in better shape and more functional than age-equivalent patients who rejected treatment, received standard chemotherapy instead, or were treated elsewhere. In addition, 90% were performance status (PS) 0 to 1, and 50% were women. In advanced NSCLC trials, women typically fare better than men, and the higher-than-usual percentage seen in this study may have a favorably influenced outcome. We have very little data regarding baseline comorbidities, quality of life (QoL), and instrumental activities of daily living (IADL), although analyses of the latter are promised. Gridelli et al have shown that baseline QoL and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 7 MARCH 1 2007