A phase I study of afatinib for patients aged 75 or older with advanced non-small cell lung cancer harboring EGFR mutations

Abstract

This phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose of afatinib for phase II trial in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or older with advanced NSCLC harboring EGFR mutations were enrolled. The doses of afatinib, which were given once daily, were planned as follows: level 1, 20 mg/day; level 2, 30 mg/day; level 3, 40 mg/day. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic, persistent grade > 2 diarrhea for > 2 days despite concomitant medications or grade 3 non-hematologic toxicity. DLT was evaluated during day 1–28. Fifteen patients were enrolled. Patient characteristics were: male/female 3/12; median age 79 (range 75–87); PS 0/1, 2/13. Six patients have been treated at levels 1 and 3, and three patients at level 2. At level 1, one of six patients experienced grade 3 rush, grade 3 anorexia, and grade 3 infection as DLTs. At level 2, none of three patients experienced a DLT. At level 3, two patients developed grade 3 diarrhea, one of whom also experienced grade 3 anorexia. Most frequent adverse events of any grade were diarrhea, paronychia, rush, and nausea. Most patients at level 2 and 3 required dose reduction in 3 months. MTD was defined as 40 mg/day, and recommended dose for phase II study in elderly patients was 30 mg/day.

Real-world study of afatinib in first-line or re-challenge settings for patients with EGFR mutant non-small cell lung cancer

“…Preferably, the patients with dose reduction showed even longer PFS than those without dose reduction. In our study, interstitial lung disease was observed in 5.7%, which was similar to the numbers in previous reports [21].…”

“…Moreover, we previously reported the phase I trial of afatinib for elderly patients (75 ≤). Although dose reduction rate of afatinib was high, the response rate was as high as 73.3% and PFS was 22 months (95% CI 13.1-not reached) [21].…”

A Phase II Study of First-line Afatinib For Patients Aged ≥ 75 Years With EGFR Mutation-positive Advanced Non-small Cell Lung Cancer: North East Japan Study Group Trial NEJ027

“…Clinical activity of afatinib with respect to response and other e cacy outcomes (PFS and OS) was encouraging, consistent with other studies in elderly Japanese patients treated with afatinib in the same setting. 19,20 E cacy outcomes were also similar in patients with EGFR Del19-and L858R-postive tumours, as reported previously. 20 The safety pro le of afatinib was as expected from EGFR TKI treatment in elderly Japanese patients, 13,20,23 and was manageable with dose reductions.…”

“…In this study, we examined elderly patients aged ≥ 75 years (median [range] 77.5 [75-91] years); this has been identi ed previously as a relevant cut-off when considering the age at which more effective and tolerable therapies compared with chemotherapy are needed. 16,22 Baseline patient and disease characteristics were largely similar to those reported in two previous investigations of afatinib in 16 However, the frequency of patients with Del19-positive disease (61%) was slightly higher than reported in elderly patients in the other two Japanese studies (20% to 55%), 19,20 and in the LUX-Lung 7 subanalysis (37%). 16 Most patients (84%) in the current study had comorbidities, the most common being hypertension, and more than one third (34%) had baseline brain metastases.…”

“…16 In addition to evidence from the LUX-Lung studies, a phase I trial including treatment at the approved dose of 40 mg, and a phase II trial employing afatinib 30 mg support the feasibility of rst-line afatinib as a treatment option in elderly Japanese patients with EGFR mutation-positive NSCLC. 19,20 The aim of the current study was to further investigate the antitumour activity and safety pro le of daily afatinib (40 mg) in previously untreated Japanese patients aged ≥ 75 years, with EGFR mutation-positive NSCLC.…”