A phase II study of afatinib treatment for elderly patients with previously untreated advanced non-small-cell lung cancer harboring EGFR mutations
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.
Section snippets
Patient selection
This multicenter phase II study was conducted at ten Japanese institutions. The principal eligibility criteria were (1) chemotherapy-naive patients with NSCLC harboring sensitive mutations of EGFR (exon 19 deletion or L858R point mutation in exon 21), but those with a resistant T790 M mutation were excluded; (2) age 70 years or older with an ECOG-PS of 0–2; (3) histologically or cytologically confirmed NSCLC; (4) stage IIIB to IV or postoperative relapsed NSCLC; (5) presence of a measurable
Patient characteristics
Between May 2014 and August 2017, a total of 40 patients were enrolled and received afatinib at a dose of 30 mg/day. The patient characteristics are listed in Table 1. Forty patients (13 men, 27 women) with a median age of 77 years (range, 70–85 years) were included in this study. Thirty-one patients (77.5%) were never smokers. Thirty-nine patients (97.5%) had a PS of 0–1, and 1 had a PS of 2. A total of 34 patients (85%) were at stage IV, and 6 (15%) had postoperative recurrence. The
Discussion
This is the first study targeting elderly patients harboring sensitive EGFR mutation for afatinib treatment. We found that first-line afatinib of 30 mg/day provided a high RR and extended the survival time in elderly NSCLC patients harboring EGFR mutations.
We defined elderly patients as those who were aged 70 years and older. Many studies and subgroup analyses were performed by considering elderly patients as those aged 70 years or older, particularly in Western countries. A previous study
Conclusions
Our results suggest that first-line afatinib of 30 mg/day is highly effective and has acceptable toxicity in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. Thus, first-line afatinib of 30 mg/day could be a treatment option in this patient population.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
KK has received research grants and a speaker honorarium from Boehringer Ingelheim Company. All other authors declare no conflicts of interest.
Acknowledgements
We thank Drs. Satoshi Wasamoto, Nobuyo Tamiya, Norihito Hida, Reiko Sakurai, Masakiyo Yatomi, Akihiro Ono, Akihiro Yoshii, Miwa Morikawa, Maiko Kadowaki, and Sakae Fujimoto for their assistance in preparing this manuscript.
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2022, Journal of Geriatric OncologyCitation Excerpt :Toxicity, however, was greater than that described in fitter populations, with 59% of patients having grade ≥ 3 toxicity, most commonly diarrhea [39]. Two Japanese trials that treated patients aged ≥70 years with afatinib showed significant efficacy, including a mOS of 35.2 months [40,41]. Toxicity of afatinib, however, can be substantial, particularly diarrhea, skin/nail toxicity, and stomatitis.I In one study, dose reductions due to AEs occurred in 78.9% of patients, with 21.1% eventually discontinuing treatment [40].