Erlotinib treatment after platinum-based therapy in elderly patients with non-small-cell lung cancer in routine clinical practice – results from the ElderTac study

Lung cancer is the leading cause of cancer deaths worldwide [1]; about 85% of cases are diagnosed as non-small-cell lung cancer (NSCLC) [2]. The median age of NSCLC patients is 70 years and the disease is usually diagnosed in advanced stages, when curative surgery is no longer feasible [3]. In metastasized disease, first-line chemotherapy is often not successful and the 5-year survival rate is only 4.2% [3]. NSCLC is histologically classified into the major subtypes adenocarcinoma (~ 40%) [4, 5], squamous cell carcinoma (~ 30–40%) [6‐9] and large cell carcinoma (~ 5–10%) [9]. Survival has improved for all subtypes in recent years, but the extent of improvement has been higher for adenocarcinoma than squamous tumors [10]. Recurring mutations have been reported in genes coding for epidermal growth factor receptors (EGFR) in 10–40% of adenocarcinomas [11‐13], but these mutations are rare in squamous tumors [14]. EGFR mutations can lead to constitutive activation of anti-apoptotic and proliferation signaling pathways, which promote cancer progression [15].

EGFR tyrosine kinase inhibitors (TKI) are the preferred first-line treatment for advanced NSCLC with EGFR mutations [16, 17], and the EGFR-TKI erlotinib (Roche Pharma, Tarceva®, Basel, Switzerland) is also approved in Europe for treatment of patients with EGFR wild-type tumors after failure of at least one prior chemotherapy regimen [18].

Treating NSCLC is challenging because of the advanced age of patients. As EGFR-TKI avoid the systemic side effects of traditional chemotherapy they might be more suitable for treating elderly patients [19]. A large phase-3 trial with erlotinib including 586 younger and 163 elderly patients demonstrated a similar survival and quality of life (QoL) in both age groups, although a somewhat higher toxicity in the elderly was observed [20]. Clinical studies examining the elderly population are limited and often firm conclusions cannot be drawn [21, 22]. In this study (ElderTac: erlotinib in routine clinical practice in elderly patients with NSCLC), we examined the effectiveness and tolerability of erlotinib in elderly NSCLC patients with progressive disease on ≥1 platinum-based chemotherapy in Germany.

Few data regarding targeted cancer therapy in pretreated elderly NSCLC patients exist. Available study results in elderly patients with advanced NSCLC treated with erlotinib are summarized in Table 4.

In most studies, patients received erlotinib as first-line treatment [27‐29] or the treatment line was not defined [30, 31]. Four studies included exclusively Asian patients [27, 31‐33], who are known to have a better outcome with EGFR-TKI treatment compared to Caucasian patients [34]. In the phase-3 trial BR.21, involving 731 patients after progression on ≥1 platinum-based chemotherapy, erlotinib demonstrated prolonged survival [26] and improved QoL compared to placebo [35]. A retrospective subgroup analysis revealed that older (≥70 years) and younger patients had the same survival and QoL benefit, with a somewhat greater toxicity in the elderly [20]. However, the elderly population receiving erlotinib in that study (n = 112) [20] was small and a retrospective design involves a greater risk for bias compared with a prospective design.

The ElderTac study was designed to examine the effectiveness and tolerability of erlotinib as a second−/third-line treatment for advanced NSCLC in elderly patients in real life. In accordance with previous findings, females treated with erlotinib lived longer than males [36, 37]. The effectiveness of erlotinib in ElderTac was comparable with that in the BR.21 trial in which median OS/PFS durations of 7.6/3.0 months were observed in elderly patients receiving second- or third-line treatment with erlotinib [20]. Likewise, symptom control – as a surrogate for QoL – was improved in our population, confirming the results of the BR.21 trial [20, 26]. Maintenance of QoL is particularly important in patients with advanced disease receiving second- or third-line treatment. A recent clinical trial demonstrated a similar efficacy for erlotinib and chemotherapy as a second-line treatment for advanced NSCLC in unselected patients and the authors suggested that second-line treatment should be given on patient preference and individual toxicity-risk profiles [24]. However, this recommendation was based on a patient population with a median age of 59 years [24]. In our study, the median age was 72 years and a quarter of patients had an ECOG PS ≥2. Therefore, we have demonstrated that patients with a low performance status, who are not eligible for further chemotherapy, can still benefit from erlotinib. The tolerability of erlotinib in our study was consistent with previous clinical findings in elderly and non-elderly populations, with a tolerable toxicity profile and rash and diarrhea being the most frequently reported AEs [20, 26‐28, 30, 38]. No new safety signals were observed. Erlotinib therefore represents a potential palliative treatment for elderly patients with advanced NSCLC.

Based on the mode of action, erlotinib is a more effective treatment for EGFR-mutated tumors. As expected, patients with an activating EGFR mutation had the greatest benefit from erlotinib treatment, in agreement with previous findings [28, 39]. Nonetheless, consistent with the results of two phase-3 trials [40], our response rates show that EGFR wild-type patients can also benefit from erlotinib treatment. A systematic review of the literature and metaanalysis revealed a significant improvement in OS with erlotinib versus other management options in patients with EGFR wild-type tumors [41]. In contrast, in the TAILOR and DELTA studies, chemotherapy with docetaxel was more effective than erlotinib for second- or third-line treatment of EGFR wild-type patients [42, 43]. However, the populations in TAILOR and DELTA are hardly comparable to the ElderTac population: Patients in TAILOR and DELTA were about six or five years younger and 92.7% or 96.0% of patients had an ECOG PS ≤1, respectively, compared to only 71.2% in ElderTac [42, 43]. Additionally, clinical parameters between the study cohorts in TAILOR were not balanced, as its original concept was not a comparison between erlotinib and docetaxel [42]. In the DELTA study, the subgroup analysis in the unselected population revealed no PFS benefit for docetaxel over erlotinib in patients ≥70 years of age [43], demonstrating that age is an important factor for the treatment decision.

Interestingly, erlotinib-treated patients with squamous tumors tended to live longer than patients with non-squamous EGFR wild-type carcinoma, which contradicts previous findings that the prognosis of adenocarcinoma patients is generally better than that of patients with squamous tumors [10]. The finding is unexpected considering the very low EGFR mutation rate in squamous tumors but may be explained by EGFR gene amplifications frequently found in these tumors [44, 45]. In a phase-4 trial in 1093 patients with metastastic squamous NSCLC, 95% of patients had tumors expressing detectable EGFR and 38% of tumors had a high EGFR expression as confirmed by immunohistochemistry [46]. The LUX-Lung 8 study revealed that the ErbB family blocker afatinib was superior to erlotinib in the treatment of squamous NSCLC [47]. However, the study exclusively included fit patients with an ECOG PS ≤1, and a statistically significant OS benefit for afatinib over erlotinib was only apparent in the subgroup of patients < 65 years of age (HR 0.68, 95% CI 0.55–0.85) but not in patients ≥65 years (HR 0.95, 95% CI 0.76–1.19) [47]. In contrast, our results demonstrate a benefit of erlotinib treatment in older patients (≥65 years) with squamous carcinoma, including unfit patients with an ECOG > 1. A recent case report of a 65-year-old man with EGFR-wildtype squamous lung cancer who had an unexpected prolonged response to third-line erlotinib confirms our results [48]. Because genomic alterations have not been comprehensively characterized in squamous tumors, no molecular-targeted therapies have been developed for this NSCLC type so far [45]. Meanwhile, immune checkpoint inhibitors are established first- and/or second-line treatments for NSCLC including squamous tumors [49‐52], so that EGFR-TKI will likely move to further therapy lines in patients with squamous EGFR wild-type tumors.

A further unexpected result was that older patients with non-squamous EGFR wild-type carcinoma (≥75 years) tended to live longer than their younger counterparts. This finding is confirmed by results from a Japanese study with gefitinib in which an age < 75 years was an independent negative factor affecting PFS after EGFR-TKI therapy in patients with advanced NSCLC [53].

Most limitations of our study relate to the nature of a non-interventional trial, especially the lack of a control group and the open-label design. The low rate of EGFR mutation testing hampered the comparison of erlotinib effectiveness in a larger group of patients with or without EGFR mutations. It, however, reflects the clinical routine in Germany at the time the study was performed, with EGFR mutation analysis being done in less than 50% of NSCLC patients [54]. The high rate of treatment discontinuations due to the severely ill patient population might have had an influence on data analysis and interpretation. Furthermore, the results of post-hoc analyses have to be interpreted with caution. Nevertheless, our observational study generated invaluable results for real-life treatment decisions.