Elsevier

Clinical Lung Cancer

Volume 20, Issue 3, May 2019, Pages e274-e283
Clinical Lung Cancer

Original Study
Intracranial Responses to Afatinib at Different Doses in Patients With EGFR-mutated Non–small-cell Lung Carcinoma and Brain Metastases

https://doi.org/10.1016/j.cllc.2019.02.009Get rights and content

Abstract

Background

As the first-line treatment, afatinib is commonly used in patients with EGFR-mutated non–small-cell lung cancer (NSCLC). However, dose adjustments are frequently required. The optimal dose of afatinib for brain metastasis has seldom been investigated.

Patients and Methods

From May 2014 to March 2017, treatment-naive patients with advanced EGFR-mutated NSCLC and brain metastases at diagnosis who received afatinib therapy were retrospectively enrolled. Clinical data was reviewed and analyzed, including age, gender, performance status, smoking history, EGFR mutation status, initial doses of afatinib, average daily doses of afatinib, and best intracranial treatment responses.

Results

A total of 74 patients were included for analysis. The overall intracranial objective response rate (IORR) and intracranial disease control rate (IDCR) were 81.1% and 95.9%, respectively. For patients treated with afatinib alone (N = 45), no significant difference between an initial daily dose of 30 mg (N = 15) and 40 mg (N = 30) (30 mg vs. 40 mg, IORR: 86.7% vs. 80.0%; P = .581 and IDCR: 93.3% vs. 93.3%; P = 1.000, respectively). The IORRs were 75.0%, 91.7%, 80.0%, and 85.7% (P = .707), and the IDCRs were 93.8%, 100.0%, 90.0%, and 85.7% (P = .638) in patients with an average daily dose of 40 mg (N = 16), < 40 mg and > 30 mg (N = 12), 30 mg (N = 10), and < 30 mg and > 20 mg (N = 7), respectively. No significant differences in intracranial treatment responses between groups treated with afatinib alone or afatinib plus local treatments.

Conclusion

Dose reduction may not affect intracranial treatment responses to afatinib therapy, either alone or combined with local treatments, in patients with advanced EGFR-mutated NSCLC and brain metastases.

Introduction

Approximately 20% of patients with non–small-cell lung cancer (NSCLC) have brain metastases at diagnosis, which are often associated with neurological symptoms, poor quality of life, and worse prognoses.1 Whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and brain tumor resection are frequently used for the treatment of brain metastases; however, individual treatment strategies are required.2, 3

Patients with NSCLC harboring EGFR mutations are more likely to suffer from brain metastases compared with those without EGFR mutations.4, 5, 6 Among patients with NSCLC treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), those with brain metastases at diagnosis had significantly higher total medical costs.7 Previous studies demonstrated that first-generation EGFR-TKIs, including gefitinib and erlotinib, provided favorable intracranial responses in patients with EGFR-mutated NSCLC with brain metastases.8, 9, 10, 11, 12

In contrast, the effectiveness of afatinib, a second-generation EGFR-TKI, on brain metastasis in patients with NSCLC was less investigated. In 2 phase III trials using afatinib as the first-line treatment for EGFR-mutated NSCLC, subgroup analyses of patients with brain metastasis showed a systemic disease control rate of 89.3% and 95.0%.13 However, the intracranial response rates were not reported. Hoffknecht et al demonstrated a cerebral response rate of 35% and a central nervous system disease control rate of 66% in pretreated patients with EGFR-mutated NSCLC who received afatinib therapy.14

The initial dose of afatinib was 40 mg daily in phase III clinical trials, which was recommended as the starting dose by the European Medicines Agency.15, 16 In a real-world setting, 29.6% to 38.3% of patients with EGFR-mutated NSCLC treated with afatinib required dose adjustments owing to intolerable adverse events.17, 18 However, dose reduction may lead to an insufficient concentration of afatinib in the cerebrospinal fluid and may result in a low efficacy against brain metastases. Recently, Tan and his colleagues performed a retrospective study included 42 patients with EGFR-mutated NSCLC with brain metastases, and concluded that a starting dose of afatinib at 40 mg/day was associated with a better progression-free survival (PFS) compared with those who had a reduced starting dose of 30 mg/day.19 To examine intracranial responses to afatinib at different daily doses of afatinib in patients with EGFR-mutated NSCLC with brain metastases, this study and patient inclusion periods were extended from our previous study on the treatment effectiveness of afatinib at different average daily doses in patients with advanced lung adenocarcinoma.20

Section snippets

Patients

This multicenter retrospective study was conducted in 3 hospitals, including the National Taiwan University Hospital, the Far Eastern Memorial Hospital in northern Taiwan, and the E-Da Hospital in southern Taiwan. Treatment-naive patients with EGFR-mutated NSCLC and brain metastases at diagnosis who received afatinib as their first-line therapy between May 2014 and March 2017 were included retrospectively. The patient inclusion period is extended from our previous study20 to include more

Clinical Characteristics

From May 2014 to March 2017, 276 patients who had diagnosed advanced EGFR-mutated lung adenocarcinoma and received afatinib as the first-line therapy were enrolled in the 3 hospitals. Among them, 84 patients had brain metastases and were eligible for analysis (Figure 1). The demographic data is listed in Table 1. The median age of patients was 60.3 years. The majority of patients were females (67.9%), never-smokers (77.4%), and with an ECOG PS score of 0 to 1 (90.5%). The most common EGFR

Discussion

In this multicenter retrospective study, we reported the intracranial treatment responses to afatinib, alone or with local treatments, in patients with EGFR-mutated lung adenocarcinoma and brain metastases in Taiwan. The study showed comparable intracranial responses among the treatment groups at different daily doses. To the best of our knowledge, this is the first study on intracranial responses to afatinib at different daily doses as a first-line therapy against NSCLC.

The effectiveness of

Conclusion

In conclusion, dose reduction may not affect the intracranial responses to afatinib, either alone or in combination with local treatments, in patients with advanced EGFR-mutated NSCLC and brain metastases. Further prospective studies for validation are warranted.

Disclosure

Dr Chen reports payments from AstraZeneca, Roche, Novartis, Pfizer, Eli Lilly, Merck Sharp and Dohme, ONO Pharmaceutical, and Boehringer Ingelheim for lectures including service on speakers’ bureaus, as well as travel/accommodations/meeting expenses from Merck Sharp and Dohme, Chugai Pharmaceutical, Pfizer, and Boehringer Ingelheim. The remaining authors have stated that they have no conflicts of interest.

References (28)

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