Patients
From July 2012 to March 2014, 371 patients were enrolled and 322 patients were treated with ≥1 afatinib dose (Fig. 1). Common reasons for discontinuation were disease progression (53.4%) and EAP completion (28.3%). After the EAP was stopped, patients were transitioned to commercial product, if appropriate. Baseline demographic characteristics were generally representative of NSCLC patients with EGFR mutations (Table 1); most (82.9%) had common EGFR mutations (Del19/L858R). T790M mutation or exon 20 insertion was present in 25 (7.8%) and 22 (6.8%) patients, respectively; 23/25 patients with T790M mutations also had other EGFR mutations. The mean age was 64.6 years, and most patients were female (68.6%), white (73.6%), and had an ECOG PS of 0 or 1 (87.0%). Most patients received prior therapy, with 87.3% of patients previously exposed to a TKI (primarily erlotinib), 67.1% to systemic chemotherapy, and 8.7% to another anticancer therapy. Afatinib was first-line therapy for 23 (7.1%) patients, second-line therapy for 85 (26.4%) patients, third-line therapy for 71 (22.0%) patients, and later-line therapy for 143 (44.4%) patients. A total of 86 (26.7%) patients had brain metastases present at screening.
Table 1 Demographic Data (Treated Set)
Exposure
Median treatment duration was 86 days (maximum, 393 days). Nearly half of the patients (48.1%) received afatinib for ≥90 days. Dose reductions occurred in 100 (31.1%) patients, with 98 patients reduced from 40 to 30 mg (including 30 patients subsequently reduced to 20 mg) and two patients reduced from 40 to 20 mg.
Safety
Most patients (96.3%) experienced an AE, with 89.4% experiencing ≥1 drug-related AE (Table 2). Serious AEs occurred in 33.9% of patients, with 7.8% considered related to afatinib. Treatment discontinuation due to AEs was reported for 12.1% of patients; 5.3% discontinued due to afatinib-related AEs.
Table 2 AE Overall Summary (Treated Set)
The most common drug-related AEs were diarrhea (77.0%) and rash (36.0%); the majority were grade 1 or 2. Afatinib-related grade 3 AEs occurred in 18.0% of patients, including diarrhea (9.9%); rash (1.9%); dehydration (1.6%); stomatitis, mucosal inflammation, and fatigue (each 1.2%); and acute renal failure (0.9%). Grade 4 afatinib-related AEs occurred in 4 (1.2%) patients (peripheral edema, multi-organ failure, dehydration, and acute renal failure; n = 1 each), but only one required discontinuation (peripheral edema).
The majority of afatinib-related serious AEs were grade 3, with diarrhea (n = 9), dehydration (n = 6), and acute renal failure (n = 3) the most common. Disease progression was responsible for most fatal events; no fatal event was considered related to afatinib.
Supportive care measures were implemented for 66.8% of patients with diarrhea and 33.9% with rash. Dose reductions occurred in 31.1% of patients: 16.8% due to diarrhea, and 3.7% due to rash. With dose reduction and treatment, few patients discontinued because of diarrhea (1.6%) or rash (0.3%).
Efficacy
While no efficacy objectives were prespecified, data were collected and analyzed where possible. Afatinib demonstrated antitumor activity in this heavily pretreated population in which 44.4% of patients had received ≥3 prior therapies. The population included patients with common and non-sensitizing EGFR mutations. Overall, 69.9% of patients achieved disease control (Table 3). Although subgroup comparisons must be interpreted cautiously due to small sample sizes and patient heterogeneity, TKI-naïve patients generally experienced better efficacy versus TKI-exposed patients. Most responses (89.1%) were observed within the first 16 weeks from start of treatment, and median duration of tumor response (4.1 months) was similar for TKI-naïve and TKI-exposed patients. Although many patients (28.3%) transitioned to commercial drug and were not fully documented until disease progression, median PFS was 3.6 months and was longer among TKI-naïve patients. Due to early censoring, OS data were immature.
Table 3 Efficacy End Points (Treated Set)