Initial Low-Dose Dacomitinib for First-Line Treatment of Patients with EGFR Exon 21-Mutated Non-Small-Cell Lung Cancer

Background: Dacomitinib has demonstrated superior efficacy compared with first-generation tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) exon 21-mutated non-small-cell lung cancer (NSCLC). However, the standard 45 mg dose often leads to a high incidence of grade 3 and 4 toxicities, limiting its clinical application. This study aimed to evaluate the preliminary efficacy and safety of a proactive low-dose dacomitinib strategy as first-line treatment. Methods: This retrospective cohort study analyzed data from 31 patients with EGFR exon 21-mutated advanced NSCLC consecutively enrolled between August 2019 and April 2023, who initiated dacomitinib at 15 or 30 mg/d. A comparative cohort of 35 patients receiving first-generation EGFR-TKIs was also included. Initial dose selection was based on clinical judgment regarding patient age, comorbidities, and performance status. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline. Results: The objective response rate (ORR) in the low-dose dacomitinib group was 67.7%, higher than that observed in the first-generation EGFR-TKI group ( P = .009). Subgroup analysis showed ORRs of 75% and 60% in the 15 mg and 30 mg cohorts, respectively ( P = .389). The median progression-free survival (PFS) in the low-dose dacomitinib group was 14.2 months (95% confidence interval [CI] = 12.4-15.9 months). Compared with first-generation EGFR-TKIs, low-dose dacomitinib was associated with significantly prolonged PFS (HR = 0.43, 95% CI = 0.25-0.72; P = .001). No significant difference in PFS was observed between the 15 mg and 30 mg groups (HR = 0.81, 95% CI = 0.37-1.76; P = .594). While grade 1 and 2 toxicities were common, the 15 mg group exhibited a significantly lower incidence of grade 3 and 4 rash compared with the 30 mg group (0% vs 33.3%). Conclusions: Initial low-dose dacomitinib demonstrated promising efficacy with an improved safety profile in patients with EGFR exon 21-mutated NSCLC. These findings support the feasibility of a dose-optimization strategy, although further prospective studies are warranted.