Effects of dose modifications on safety and efficacy of dacomitinib for EGFR-mutant non-small-cell lung cancer

In patients with EGFR mutation-positive advanced NSCLC, first-line dacomitinib significantly improved PFS, OS, DoR, and time to treatment failure vs gefitinib [3,4]. Stepwise dose reduction from 45 mg to 15 mg once daily (QD) maintained PFS and OS benefits while decreasing the incidence and severity of treatment-related AEs.

Dacomitinib is an investigational, second-generation, irreversible EGFR TKI [5]. The multinational, randomised, phase 3 ARCHER 1050 trial investigated its safety and efficacy. Eligible patients were treatment-naïve, had EGFR activating mutation, no CNS metastases, and ECOG performance status of 0 or 1. A total of 452 patients were randomised to dacomitinib (45 mg QD) or gefitinib (250 mg QD) in 28-day cycles. Randomisation was stratified by race (Japanese, Chinese, other East-Asian, or non-Asian) and EGFR mutation type (Ex19del or L858R). Protocol-defined dose reduction parameters and study endpoints have been previously described [3]. The investigators evaluated reasons for dose reductions, and their effects on the incidence and severity of AEs and key efficacy endpoints (PFS, OS, ORR). The data cut-off date for OS was February 2017. It was July 2019 for other endpoints.

Approximately two-thirds (n=50; 66.1%) of patients had dose reductions; 87 (38.3% of the overall population) went to 30 mg QD as the lowest dose. The lowest dose for 63 patients (27.8% of the overall population) was 15 mg QD. All patients had an initial dose reduction to 30 mg QD. Median time to dose reduction for patients with the lowest dose of 30 mg QD was 13 weeks. Among patients whose dose was reduced to 15 mg QD, median time to the first dose reduction to 30 mg was 8 weeks. The subsequent median time for the reduction to 15 mg QD was 12 weeks. The most common reason for dose reductions were skin toxicities, with dermatitis acneiform the leading AE. It was followed by diarrhoea, paronychia, and stomatitis. The incidence and severity of AEs decreased after dose reduction. Grade ≥3 diarrhoea fell from 11.3% to 4.0%. Dermatitis acneiform dropped from 15.3% to 6.17%, stomatitis from 3.35% to 2.7%, and paronychia from 7.3% to 4.7%.