Brain metastases in oncogene-driven non-small cell lung cancer

Abstract

Molecular targeted therapies have significantly improved the treatment outcome of patients with non-small cell lung cancer (NSCLC) harboring driver gene mutations such as receptor (EGFR) or anaplastic lymphoma kinase (ALK). However, the brain is a frequent site of recurrence, and it significantly deteriorates the prognosis of these patients. Treatment strategies include surgical resection, whole-brain radiation therapy, stereotactic radiotherapy, and drug therapy depending on patient condition. First-generation EGFR/ALK tyrosine kinase inhibitors (TKI) demonstrates only limited efficacy for intracranial lesions probably because of low penetration through the blood-brain barrier (BBB). However, newly developed TKIs with improved penetration such as osimertinib for EGFR and alectinib, ceritinib, brigatinib, or lorlatinib for ALK have demonstrated significant intracranial activity that should contribute to improved overall survival. Whole-brain radiation therapy used to be a standard of care that confers alleviation of symptom and modest survival benefit. However, it potentially causes neurological and cognitive deficits as a chronic toxicity. With the prolonged survival owing to newer generation drugs, this toxicity is becoming more relevant. Stereotactic radiotherapy is considered when there are three or fewer lesions, and the lesions are <3 cm as local control of tumor is excellent, and neurotoxicity is less. In this review, we discuss the various aspects of brain metastases occurring in NSCLC patients with driver gene mutations. We also propose a treatment algorithm for these patients.

Keywords: Brain metastases; driver mutations; non-small cell lung cancer (NSCLC); targeted therapy.

Figure 1

Flow chart for management of brain metastasis in the oncogene-driven NCSLC. This flow chart is according to JLCS, ESMO, NCCN guidelines. Detection of T790M mutation is mandatory to use osimertinib in the case of EGFR mutation-positive NSCLC. ^#, Dexamethasone or equivalent corticosteroid is recommended for most patients with symptomatic brain metastasis; ^¶, Osimertinib as EGFR-TKI, alectinib, ceritinib and brigatinib as ALK-TKIs, is preferred; ^†, SRS is preferred when the total tumor volume is lower than 15 mL and the number of lesions is 10 or less; ^‡, Detection of T790M mutation is mandatory to use osimertinib in case of EGFR mutation-positive NSCLC. NSCLC, non-small cell lung cancer; JLCS, Japan Lung Cancer Society; ESMO, European Society of Medical Oncology; NCCN, National Comprehensive Cancer Network; EGFR, epidermal growth factor receptor; WBRT, whole brain radiation therapy; SRS/SRT, stereotactic radiosurgery/stereotactic radiotherapy; Gef, gefitinib; Erl, erlotinib; Afa, afatinib; Dac, dacomitinib; Osi, osimertinib; Cri, crizotinib; Ale, alectinib; Cer, ceritinib; Bri, brigatinib; Lor, lorlatinib.