Abstract
ObjectivesOsimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. MethodsThe OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA. ResultsThe median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%–79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively. ConclusionsThis study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
Highlights
Patients with NSCLC whose tumors harbor activating EGFR mutations exhibit a higher incidence of central nervous system (CNS) metastasis than those whose tumors are free from such mutations.[1,2,3] radiotherapy (RT), such as whole-brain RT (WBRT) and stereotactic RT (SRT), is the standard treatment for CNS metastasis, it can delay the start of systemic chemotherapy, and WBRT carries a risk of cognitive dysfunction.[4,5]Osimertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI), which selectively inhibits both the T790M mutation, which is a major cause of acquired resistance to EGFR TKIs, and EGFR TKI-sensitizing mutations.[6]
Osimertinib for RT-Naive CNS Metastasis From T790MD NSCLC 3 the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion
Radiotherapy (RT), such as whole-brain RT (WBRT) and stereotactic RT (SRT), is the standard treatment for CNS metastasis, it can delay the start of systemic chemotherapy, and WBRT carries a risk of cognitive dysfunction.[4,5]
Summary
Patients with NSCLC whose tumors harbor activating EGFR mutations exhibit a higher incidence of central nervous system (CNS) metastasis than those whose tumors are free from such mutations.[1,2,3] radiotherapy (RT), such as whole-brain RT (WBRT) and stereotactic RT (SRT), is the standard treatment for CNS metastasis, it can delay the start of systemic chemotherapy, and WBRT carries a risk of cognitive dysfunction.[4,5]Osimertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI), which selectively inhibits both the T790M mutation, which is a major cause of acquired resistance to EGFR TKIs, and EGFR TKI-sensitizing mutations.[6]. Osimertinib is expected to be effective in patients with CNS metastasis because it displayed greater penetration into the brain than rociletinib, gefitinib, or afatinib in a preclinical model.[9] In a study in which pooled data from two phase 2 trials of osimertinib as a treatment for EGFR T790M mutation-positive NSCLC (AURA extension and AURA2) were analyzed, the frequency of confirmed CNS responses to osimertinib was found to be 54% in 50 patients with measurable CNS metastasis, including 19 patients with brain metastasis who had already been treated with RT within the past 6 months.[10] in a subgroup analysis of the AURA3 trial, the CNS response rate of osimertinib among patients who had been treated with RT within the 6 months before randomization was 70%.11 In these two subgroup analyses, the true antitumor effects of osimertinib alone were unclear because the studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of RT. These patients were mainly treated with the first-generation EGFR TKI erlotinib between 2008 and 2014, and the efficacy of osimertinib against CNS metastasis in patients who have not received RT remains unclear
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