Higher afatinib starting dose, better PFS in NSCLC patients with brain metastases
Patients with advanced non-small-cell lung cancer (NSCLC) and brain metastases demonstrated better progression-free survival (PFS) when initiating the oral EGFR* TKI** afatinib at a higher rather than a lower dose, according to a retrospective study from Singapore.
This single-centre study conducted at the National Cancer Centre Singapore looked at data of 125 patients with advanced or stage 4 EGFR+ NSCLC (median age at diagnosis 62 years, 51.2 percent male, 80 percent Chinese), of whom 62 patients initiated afatinib at a dose of 40 mg once/day, 61 at a dose of 30 mg once/day, and one at 20 mg once/day between January 2012 and February 2017. At a median follow up of 13.8 months, response rate was 70.4 percent and median afatinib treatment duration 8.7 months, with an 11.9-month median PFS.
Forty-two patients had brain metastases at baseline, with patients on the 40 mg once/day afatinib dose more likely to have undergone whole brain radiotherapy (WBRT) for symptomatic brain metastases before starting afatinib than those on 30 mg once/day (82.4 percent vs 48.0 percent; p=0.024).
Patients with brain metastases who initiated afatinib at a dose of 40 mg once/day (n=17) demonstrated superior PFS compared with those who initiated afatinib at a dose of 30 mg once/day (n=25; 13.3 vs 5.3 months, hazard ratio [HR], 0.39, 95 percent confidence interval [CI], 0.15–0.99; p=0.041). [BMC Cancer 2018;18:1198]
However, a 40 mg once/day dose conferred no additional PFS benefit for patients with NSCLC without brain metastases (HR, 0.95, 95 percent CI, 0.44–2.04; p=0.898 vs 30 mg once/day).
Furthermore, median PFS was comparable between patients with and without brain metastases who started afatinib at 40 mg once/day (13.3 vs 15.0 months, HR, 0.79, 95 percent CI, 0.34–1.80; p=0.558).
Previous research has suggested similar PFS outcomes between patients with advanced lung adenocarcinoma initiating afatinib at a dose of 30 or 40 mg once/day, with a lower incidence of adverse drug reactions among those starting with the lower dose, [BMC Pharmacol Toxicol 2017;18:82] while other studies revealed similar PFS among patients who reduced their dose from 40 to 30 mg once/day and those with no dose reductions. [Ann Oncol 2016;27:2103-2110]
“[I]n our study, we had demonstrated that significant effect of afatinib loading dose [40 vs 30 mg once/day] on PFS was present only in patients with baseline brain metastases, and not amongst those without brain metastases prior to afatinib initiation – a provocative finding suggesting afatinib dose effect on brain metastases,” said the researchers.
Among patients with brain metastases, the 40 mg once/day dose was associated with PFS benefit even after factoring in effect of WBRT, with a reduction in the risk of intracranial disease progression in this group, though the latter results were not significant due to the small number of patients, they said.
“This effect … potentially represents how initial afatinib dose may impact on central nervous system [CNS] control in these patients,” they added.
The difference in peak plasma concentrations or Cmax – which previous studies have shown significantly differed between 40 and 30 mg doses – may explain the dose-response benefit on CNS metastases conferred by afatinib, they said. “This has significant implications on future studies in oncogene-driven NSCLC, where CNS metastases are a common reason for treatment failure and optimal CNS control remains an unmet need.”
“Future prospective studies exploring alternative TKI dosing schedules such as intermittent dosing with 40 mg once/day, so as to maintain Cmax while circumventing toxicities from continuous dosing of afatinib, are warranted to specifically address the impact of drug exposure on durability of CNS disease control,” they concluded.