Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for first-line treatment of advanced NSCLC with sensitizing EGFR mutations [1, 2]. Despite high response rates of 60–70%, treatment failure inevitably ensues after a median duration of 10–18 months, regardless of choice of TKI. Although the emergence of genomic alterations commonly accounts for secondary resistance to EGFR TKI, CNS failure is often attributed to inadequate penetration into the CNS – regarded as a ‘sanctuary’ site. Indeed, the lifetime risk of brain metastases (BM) is more than 30% of patients in EGFR mutant NSCLC, and where present, has traditionally been associated with poorer survival [3‐5].

Although intracranial efficacy of first-line EGFR TKIs has not been established in prospective large-scale studies, clinical observations from trials support intracranial activity with afatinib – a second-generation, irreversible pan-human epidermal growth factor receptor (HER) inhibitor. In a combined post-hoc analysis on patients with asymptomatic baseline BM from the LUX-lung 3 and LUX-lung 6 studies, afatinib significantly improved the objective response rate (RR) and progression-free survival (PFS) compared to chemotherapy [3, 6]. However, due to potent EGFR wild-type inhibition, afatinib is associated with increased skin and gastrointestinal toxicities, resulting in dose reductions reported in up to 53.3 and 28% patients in the randomized LUX-Lung 3 and 6 trials respectively [7]. The potential impact of dose reductions with afatinib on CNS disease control also remains poorly characterized.

We performed a retrospective study to evaluate the clinicopathological factors affecting survival outcomes of patients with EGFRm+ NSCLC treated with first-line afatinib, specifically examining the impact of starting dose in patients with or without BM at diagnosis.

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].

The main limitations of the current study include the small sample size and retrospective nature of the study, challenging the ability to draw definitive conclusions particularly with regards to afatinib dose effect on patterns of disease progression in BM+ patients. Notwithstanding this, our findings highlight the potential importance of C_max in control of brain metastases. 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. A phase 1b study recently demonstrated the feasibility and tolerability of high-dose intermittent (HDI) afatinib (3 days every 14 days) achieving high plasma concentrations of afatinib, but focused on heavily pretreated advanced T790 M+ NSCLC [21]. Albeit modest activity (7.7%) with HDI afatinib, this may be a potential strategy for patients with CNS metastases. To this end, we have initiated a prospective dose-finding study of continuous (40 mg OD) vs. intermittent high-dose (HDI) afatinib (160 mg × 3 days every 2 weeks) on CNS metastases and leptomeningeal disease in patients with advanced refractory EGFRm+ NSCLC (NCT03711422) to address control of CNS metastases. In this prospective study we will also be assessing the plasma and CSF drug ratios from the 2 different dosing schedules to determine pharmacokinetic efficacy of HDI afatinib on CNS control. Future prospective studies exploring alternative TKI dosing schedules such as intermittent dosing with 40 mg OD, so as to maintain C_max while circumventing toxicities from continuous dosing of afatinib, are warranted to specifically address the impact of drug exposure on durability of CNS disease control.

We demonstrated that in advanced EGFR-mutant NSCLC patients with brain metastases, starting dose of afatinib at 40 mg/day led to better clinical outcomes compared to those who had reduced starting dose of 30 mg/day, possibly due to effects of a higher C_max on CNS control. These results also lend support to the CNS activity from afatinib. Moving forward, further elucidation and validation of afatinib dose effect specifically on BM control with concomitant plasma C_max testing in a larger prospective study will certainly be crucial.