A phase II study of afatinib treatment for elderly patients with previously untreated advanced non-small-cell lung cancer harboring EGFR mutations

Highlights

• This is the first study of first-line afatinib in EGFR mutated elderly patients.

• First-line afatinib of 30 mg/day is highly effective in this population.

• First-line afatinib of 30 mg/day has acceptable toxicity in this population.

• First-line afatinib could be a treatment option in this population.

Abstract

Objective

The efficacy and safety of afatinib in elderly patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have not been evaluated. This study aimed to assess the efficacy and safety of afatinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations.

Materials and Methods

We prospectively assessed the clinical effects of afatinib as a first-line treatment for elderly (age ≥70 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially administered afatinib (30 mg/day).

Results

Between May 2014 and August 2017, 40 patients (13 men, 27 women) with adenocarcinoma were included in our analysis. The median age was 77 years (range, 70–85 years). The dose was reduced in 19 patients. The objective overall response and disease control rates were 72.5% and 100%, respectively, and the median progression-free survival and overall survival were 12.9 months and not reached, respectively. Common adverse events (AEs) included diarrhea, rash/acne, and anemia. Major grade 3 or higher toxicities included diarrhea (12.5%), mucositis (7.5%), and pneumonitis (7.5%). Afatinib treatment was discontinued in 8 patients owing to AEs of elevated amylase (n = 1), liver dysfunction (n = 1), rash/acne (n = 1), nail change (n = 1), anorexia (n = 2), pneumonitis (n = 2), and diarrhea (n = 2). Two patients died due to treatment-related pneumonitis.

Conclusions

This is the first study that verified the efficacy and feasibility of first-line chemotherapy with afatinib at 30 mg/day in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. First-line afatinib of 30 mg/day could be a treatment option in this patient population.

Introduction

The number of elderly people with advanced lung cancer is increasing globally owing to the aging population and advances in cancer therapy [1]. More than 50% of patients diagnosed with lung cancer are aged >65 years, which is the lower limit for defining “elderly” in epidemiologic researches [2]. Non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer among both the elderly [3] and the adults. Although platinum-combination regimens including newer agents are the standard first-line chemotherapy for most patients with advanced NSCLC, their use in elderly patients remains controversial [4]. The main reasons for withholding standard platinum-combination regimens in elderly patients include age-related organ function impairment, the presence of potentially complicating comorbid conditions, and patients’ potentially lower tolerance to toxicity from combination chemotherapy compared to younger patients. However, the European Society for Medical Oncology Clinical Practice Guidelines prefer platinum-based chemotherapy for elderly patients with advanced NSCLC who have an Easter Cooperative Oncology Group performance status (ECOG-PS) of 0–1 and adequate organ function, whereas a single-agent approach is recommended for elderly unfit or comorbid patients because they are more likely to experience treatment-related adverse events (AEs) [5]. Gemcitabine and vinorelbine are the most frequently studied agents among all platinum drugs. In a Japanese trial comparing docetaxel and vinorelbine, no significant difference between the two agents was observed despite a trend toward longer survival with docetaxel monotherapy [6].

Previous clinical studies have shown the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, erlotinib, and afatinib as first-line chemotherapy for patients with EGFR-mutated NSCLC [[7], [8], [9], [10], [11], [12]]. As cancer therapy for elderly patients with NSCLC harboring sensitive EGFR mutations, first-line gefitinib and erlotinib treatment also showed a high response rate (RR) and prolonged survival [[13], [14], [15], [16], [17], [18], [19], [20], [21]].

Afatinib is a second-generation EGFR-TKI orally administered as an irreversible inhibitor of the ErbB family of tyrosine kinases [22]. Recently, two phase III studies have compared platinum-containing chemotherapy to afatinib in a first-line setting and demonstrated that afatinib can improve progression-free survival (PFS) in patients harboring sensitive EGFR mutations [12]. Moreover, the LUX-Lung 7 trial has reported that afatinib might offer improved PFS compared with gefitinib [23]. However, these prospective studies were not able to elucidate the clinical benefit of afatinib for the treatment of elderly patients harboring sensitive EGFR mutations; thus, it remains unclear whether afatinib is suitable for the treatment of such patients.

Previous clinical studies have used a standard initial dose of 40 mg daily of afatinib; however, although prolonged PFS was achieved, they have also reported high rates of severe AEs including grade 3–4 diarrhea, skin rash, and paronychia [[24], [25], [26]]. In clinical practice, the development of moderate to severe AEs often leads to discontinuation of treatment or a dose reduction, and some patients even refuse re-administration.

Dose reductions in 53.3% (122/229) and 28.0% (67/239) of the patients using 40 mg of afatinib daily were reported in the LUX-Lung 3 and LUX-Lung 6 trials, respectively [24,25]. A subgroup analyses of these trials showed that reducing the dose to 30 mg daily decreased the incidence of AEs with a similar median PFS [12,24,25,27]. A previous study reported that an initial afatinib dose of 30 mg daily yielded similar response and PFS with that of an initial dose of 40 mg daily [28]. The standard afatinib dose of 40 mg seems to be inappropriate for elderly patients because it yields severe AEs such as diarrhea and skin eruption. However, afatinib as second-generation EGFR-TKI is more beneficial and effective than first-generation EGFR-TKIs. A reduced afatinib dose of 30 mg as initial therapy is presumed to yield similar clinical benefits while being tolerable for elderly patients. Based on these information, we conducted a prospective phase II study to investigate the efficacy and safety of afatinib for elderly patients with advanced NSCLC harboring sensitive EGFR mutations.