Does dose reduction of afatinib affect treatment outcomes of patients with EGFR-mutant metastatic non-small cell lung cancer in real-world clinical practice?

Abstract

Background: Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear.

Methods: This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1^st January 2015 to 31^st December 2020 were analyzed.

Results: Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had EGFR exon 19 deletion and 23.3% had EGFR exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months.

Conclusions: Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with EGFR-mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.

Keywords: Adenocarcinoma; resource-limited settings; survival; treatment outcome; tyrosine kinase inhibitors (TKIs).

Figure 1

Flowchart of patients who met the inclusion and exclusion criteria for the study population. EGFRm+ NSCLC, epidermal growth factor receptor mutated non-small cell lung cancer; TTF, time to treatment failure.

Figure 2

Kaplan-Meier plot for time-to-treatment failure of patients on first-line afatinib. CI, confidence interval.

Figure 3

Kaplan-Meier curves for time-to-treatment failure for patients who received afatinib 40 mg once daily and those who received afatinib less than 40 mg once daily. CI, confidence interval; HR, hazard ratio.

Figure 4

Kaplan-Meier plot for overall survival of patients on first-line afatinib. CI, confidence interval.

Figure 5

Kaplan-Meier curves for time-to-treatment failure of patients on second-line osimertinib and that of patients treated with chemotherapy. CI, confidence interval; HR, hazard ratio; tx, treatment.