In this retrospective analysis, we demonstrated clinical efficacy of afatinib in patients with EGFRm+ NSCLC consistent with large-scale randomized trials [12, 13], with worse outcome in patients with prior smoking histories. However, we did not identify the presence of BM as a negative prognostic factor, prompting us to further examine the patient characteristics and dosing profiles. Interestingly, we found that BM+ patients who commenced on afatinib 40 mg OD had better outcomes than those started on 30 mg OD (median PFS 5.3 vs 13.3 months, p = 0.041), and comparable to that of patients without BM (Fig. 2).

While first-line afatinib starting dose of 30 mg OD has been previously reported to have similar clinical efficacy as 40 mg OD and better tolerated in patients with EGFRm+ NSCLC [14], the effect of starting dose on BM has not been studied. In the post-hoc analyses of LUX-Lung 3 and 6 trials reported by Yang and colleagues [7], PFS of patients on afatinib reduced to 30 mg/day due to adverse events was found to be similar to those remaining on 40 mg/day. Although the authors concluded that dose adjustment of afatinib improved incidence of adverse events without compromising on therapeutic efficacy, such effect of afatinib dosing was not examined specifically in the subset of patients with brain metastases. Whereas in our study, we had demonstrated that significant effect of afatinib loading dose (40 mg vs 30 mg OD) 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 BM. To the best of our knowledge, this study is the first to demonstrate a difference on outcomes of BM+ patients with different starting doses of afatinib.

Conventionally, WBRT is considered the standard treatment for BM, especially for multiple and symptomatic BM. Although BM+ patients in the 40 mg group were more likely to have undergone WBRT prior to afatinib initiation as compared to the 30 mg group, it is noteworthy that starting dose remained significantly associated with PFS amongst patients who had WBRT before commencing afatinib, and also in multivariable analysis controlling for effect of WBRT. Moreover, patients who started on 40 mg tended to be less likely to progress intracranially than those on 30 mg dose, although not statistically significant due to small numbers. This effect was observed despite the frequency of dose reductions observed, and potentially represents how initial afatinib dose may impact on CNS control in these patients. This corroborates the findings of a competing risk analysis for progression of the LUX-Lung 3, 6, and 7 trials, that the hazard ratio for development of brain metastases as a site of progression was lower for afatinib compared to the control arms, providing another separate validation of the efficacy of afatinib as a brain-penetrant EGFR TKI [15].

The benefit of dose of afatinib on CNS metastases may be driven by the peak plasma concentrations attained, with initial phase I studies showing significant difference in C max (the maximum concentration of drug achieved after administration) when comparing 40 vs 30 mg [16]. In a small case series, Hochmair et al. reported in patients with multiple, symptomatic BM who declined WBRT, afatinib alone could achieve complete intracranial remission [17]. Two other studies also demonstrated effective CNS penetrance of afatinib – a Japanese one with cerebrospinal fluid (CSF) pharmacokinetic data with first-line afatinib treatment [18], and another German series demonstrating CNS activity in patients with BM progressing on first-generation TKIs [6]. Additional studies directed at overcoming CNS treatment failure include high-dose gefitinib and erlotinib given in a pulsatile manner, highlighting the importance of C max on intracranial responses [19, 20].