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

Abstract

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant nonsmall cell lung cancer (NSCLC), was approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in realworld practice. Medical records of patients who received afatinib for advanced EGFR-mutant NSCLC were retrospectively reviewed. In total, 128 patients were analyzed. Seventy-six patients received afatinib as the first-line setting and 52 as the re-challenge setting (i.e., after failure of prior first-generation TKI). There was no difference in patient characteristics, such as age, sex, and PS, between the first-line and the re-challenge settings. In the first-line setting, the median progression-free survival (PFS) was 17.8 months (95% confidence interval [CI] 13.7-21.5 months). The overall survival (OS) was 39.5 months (95% CI 34.4-not reached). The response rate (RR) was 64.4%. Subset analysis indicated that patients with dose reduction showed longer PFS than those without dose reduction (18.5 months versus 7.9 months) (P = 0.016). In the re-challenge setting, the median PFS was 8.0 months (95% CI 4.9-9.5 months). The RR was 25%. Most common adverse events leading to dose modification or treatment discontinuation included diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). In the real-world practice in Japan, afatinib showed comparable or better efficacy compared with that shown in previous clinical trials in both the first-line and the re-challenge settings.

Benefits and Limitations of Real-World Evidence: Lessons from EGFR Mutation-Positive Non-Small-Cell Lung Cancer

“…For example, in the Phase III LUX-Lung trials, diarrhea, rash/acne and stomatitis/mucositis were the most common treatment-related grade 3/4 AEs with first-line afatinib [56][57][58], and diarrhea, rash/acne and dry skin were most common in the Phase III FLAURA trial of first-line osimertinib [61]. The frequencies of these AEs have been broadly confirmed in several of the large, real-world studies described above, with no unexpected safety signals reported [21,38,[45][46][47].…”

Lower Starting Dose of Afatinib for the Treatment of Metastatic Lung Adenocarcinoma Harboring Exon 21 and Exon 19 Mutations

“…In two phase 3 clinical trials, Lux-Lung 3 and Lux-Lung 6, the median PFS among patients who harbored EGFR mutations and took 40 mg afatinib as their initial dose was 10.9 and 13.6 months, respectively. A real word practice study in Japan that enrolled 128 patients reported a median PFS of 17.8 months [20], while a phase 2 study which used a lower starting dose of 20 mg afatinib that increased in 10-mg increments up to 50 mg/day, reported a PFS of 15.2 months [19]. Another phase 2 study that enrolled 40 elderly patients had a shorter PFS of 12.9 months [22].…”

“…In terms of OS, the phase 3 Lux-Lung 3 and Lux-Lung 6 trials reported that the median OS was 31.4 and 33.3 months, respectively. Tanaka et al presented a real-world study of rst line afatinib in Japan, with a reported median OS of 39.5 months [20]. In the Giotag trial, all patients initially received 40 mg afatinib, followed by osimertinib if T790M acquired resistance was reported; the median OS was 41.3 months and the OS was as long as 45.7 months in patients with an exon 19 deletion [30].…”

“…In Liang et al, patients with signi cant pretreatment weight loss (>10.0% in 6 months) had a shorter median PFS, and patients with brain metastases had a poorer ECOG status and were associated with a shorter median PFS [31]. Tanaka et al also showed that patients with dose reduction had a signi cantly longer PFS than those without dose reduction in a real-world study (18.5 vs. 7.9 months, respectively; p=0.018) [20]. However, the average daily dose of <20 mg afatinib had a signi cantly shorter PFS compared with the other higher dose (p = 0.049) [32].…”

“…However, patients receiving afatinib treatment always have more ADRs compared with 1 st generation EGFR TKIs in patients with EGFR mutations, and 28 to 53.3% of patients receiving standard 40 mg afatinib daily had to discontinue or reduce their dose due to severe ADRs in the phase 3 Lux-Lung 3 and Lux-Lung 6 trials [13,14,18]. Real world data of 1 st line afatinib treatment showed that dose reduction occurred in 47.5 to 76.3% of cases [19,20]. Dose reductions were mainly due to ADRs and were more common in females, East Asian individuals and those with a low body-weight [21].…”