Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases

Abstract

BackgroundAfatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control.MethodsWe performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models.ResultsOut of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3–19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15–0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34–1.80).ConclusionIn patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.

Real-world experience of first-line afatinib in patients with EGFR-mutant advanced NSCLC: a multicenter observational study

“…Similar beneficial response was not seen in such patients treated with first-generation EGFR -TKIs [27]. Contrary to the findings by Tan et al [22], the present study did not find a significantly shorter mPFS among patients with symptomatic brain metastases receiving first-line afatinib [22]. This favorable outcome could be explained by the uniform afatinib starting dose of 40 mg once daily and the comprehensive brain surgery or radiotherapy approach in the present study cohort.…”

“…The former study included 14 patients who achieved a partial response or at least 6 months of stable disease when on first-line afatinib while the latter study only involved patients with ECOG 0–2 which could have contributed to the longer mPFS. Similar to the present study, Liang et al [21], Tan et al [22] Kim et al [26] and Tanaka et al [24] also consistently highlighted a longer mPFS and better ORR in patients with tumors harboring exon 19 deletion treated with first-line afatinib compared to those with exon 21 L858R point mutation. In patients with complex or rare EGFR mutations treated with first-line afatinib, the present study and another three real-world studies reported a modest mPFS and ORR [21, 22, 27].…”

“…Similar to the present study, Liang et al [21], Tan et al [22] Kim et al [26] and Tanaka et al [24] also consistently highlighted a longer mPFS and better ORR in patients with tumors harboring exon 19 deletion treated with first-line afatinib compared to those with exon 21 L858R point mutation. In patients with complex or rare EGFR mutations treated with first-line afatinib, the present study and another three real-world studies reported a modest mPFS and ORR [21, 22, 27]. Similar beneficial response was not seen in such patients treated with first-generation EGFR -TKIs [27].…”

Efficacy and safety of afatinib in a Chinese population with advanced lung adenocarcinoma with sensitive EGFR mutations

“…However, Tan et al revealed that among patients with advanced EGFR mutant NSCLC with brain metastasis, the initiation of 40 mg afatinib once daily was associated with improved PFS compared to 30 mg once daily. 23 We did not observe this outcome, which may result from our relatively small sample of patients with baseline brain metastasis treated with 30 mg afatinib.…”

<p>Effect of Dose Adjustments on the Safety and Efficacy of Afatinib in Chinese Patients with <em>EGFR</em>-Mutated Non-Small Cell Lung Cancer Who Participated in the LUX-Lung Clinical Trial Program</p>

“…In a retrospective study of 125 patients who received treatment with afatinib at an Asian cancer treatment center, the median PFS was longer in patients with brain metastases who started treatment with afatinib 40 mg/day (n=17) than in 25 patients who initiated 30 mg/day. 28 Pharmacokinetic analysis of patients in LL3 found that afatinib trough plasma concentrations were higher on day 22 in patients who subsequently had a reduction in dose from 40 mg/day to 30 mg/day due to TRAEs than in those who remained on 40 mg/day. Subsequently, on day 43, afatinib trough plasma concentrations in the patients now on 30 mg/day were similar to those in patients who had remained on 40 mg/day.…”