Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Abstract

Background: We investigated acute adverse events in patients with brain metastases (BMs) of anaplastic lymphoma kinase-rearranged (ALKr) non-small cell lung cancer (NSCLC) treated with both cranial radiotherapy and tyrosine kinase inhibitors (TKIs) of ALK. Patients and Methods: Acute AEs were retrospectively investigated in patients with BMs of ALKr-NSCLC who received both wholebrain radiotherapy (WBRT) and ALK-TKI. For comparison, they were also assessed in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC and wild-type with neither ALK rearrangement nor EGFR mutation treated with WBRT. Results: Two ALKr cases were consequently eligible. Grade 3 otitis media unexpectedly occurred in both cases, while there was one case out of 11 and one case out of 18 of grade 2 otitis media among the EGFR-mutated cases and wildtype cases (p=0.013), respectively. Conclusion: Concurrent treatment with WBRT and ALK-TKI may be associated with acute severe ear toxicity in patients with BMs of ALKr-NSCLC. Anaplastic lymphoma kinase gene rearrangement (ALKr) is a significant driver of gene mutation for novel moleculartargeted therapy in lung cancer, and is identified in about 2-7% of non-small cell lung cancer (NSCLC) cases (1). The predominant histological subtype in ALKr NSCLC is adenocarcinoma, and ALKr is rarely seen in other histological subtypes, including small-cell lung cancer. In addition, unlike mutation of epidermal growth factor receptor (EGFR), which differs in humans according to race, there is no race-related difference in the frequency of ALKr. With regard to the prognostic significance of ALKr, some investigations have reported ALKr itself to be a favorable prognostic factor (2). The existence of brain metastases (BMs) is a major factor leading to poor survival outcome in NSCLC, with the median survival of patients with BMs ranging from 3 to 14.8 months according to diagnosis-specific graded prognostic assessment (3). The incidence of BMs from ALKr NSCLC ranges from approximately 25% to 35%; it is greater than that for those with wild-type NSCLC, and slightly higher or equivalent to that of NSCLC with EGFR mutation (4). BMs seem to be more commonly detected at initial diagnosis in those with ALKr NSCLC compared with those with wildtype NSCLC. Many previous clinical trials reported that multi-targeted receptor tyrosine kinase inhibitors (TKIs) of ALK, such as crizotinib, alectinib and ceritinib, achieved better local control of BMs and intracranial progression-free survival (IPFS) in ALKr NSCLC (5-7). Crizotinib, a first-generation ALK-TKI, was associated with a median IPFS of 7 months in patients with BMs that was previously untreated in the analysis of PROFILE 1005 and 1007 (8). After the experience of progression with a single ALK-TKI, it is promising to consider sequential therapy with multiple ALK-TKI (9-12). Regardless of the efficacy of ALK-TKI for BMs, it is concerning that many patients invariably develop progression of intracranial disease. Therefore, radiotherapy such as whole-brain radioth...

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“…For ALK TKIs, there is currently minimal evidence for or against their combined use with irradiation; one retrospective study of ALKr NSCLC patients suggested an increase in ototoxicity with combined ALK TKIs and WBRT (87). For WBRT (where the globes receive radiation dose), care may need to be exerted because of potential overlapping ocular toxicity with crizotinib (83).…”