Hiroyuki Yamaguchi1, Kazushige Wakuda2, Minoru Fukuda3, Hirotsugu Kenmotsu2, Hiroshi Mukae1, Kentaro Ito4, Kenji Chibana5, Kohji Inoue6, Satoru Miura7, Kentaro Tanaka8, Noriyuki Ebi9, Takayuki Suetsugu10, Taishi Harada11, Keisuke Kirita12, Toshihide Yokoyama13, Yuki Nakatani14, Kenichi Yoshimura15, Kazuhiko Nakagawa16, Nobuyuki Yamamoto17, Kenji Sugio18. 1. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 2. Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan. 3. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan. Electronic address: mifukuda258@nifty.com. 4. Department of Respiratory Medicine, Matsusaka Municipal Hospital Respiratory Center, Matsusaka, Japan. 5. Department of Respiratory Medicine, National Hospital Organization, Okinawa National Hospital, Ginowan, Japan. 6. Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan. 7. Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. 8. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 9. Department of Respiratory Medicine, Iizuka Hospital, Iizuka, Japan. 10. Department of Respiratory Medicine, Sendai Medical Association Hospital, Satsumasendai, Japan. 11. Department of Respiratory Medicine, Japan Community Health Care Organization (JCHO) Kyushu Hospital, Kitakyushu, Japan. 12. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 13. Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan. 14. Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan. 15. Future Medical Center, Hiroshima University Hospital, Hiroshima, Japan. 16. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan. 17. Internal Medicine III, Wakayama Medical University, Wakayama, Japan. 18. Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Lung Oncology Group in Kyushu (LOGiK), Fukuoka, Japan.
Abstract
OBJECTIVES: Osimertinib 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: This 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.
OBJECTIVES: Osimertinib 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: This 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.
Authors: A J Piper-Vallillo; Julia K Rotow; Jacqueline V Aredo; Khvaramze Shaverdashvili; Jia Luo; Jennifer W Carlisle; Hatim Husain; Alona Muzikansky; Rebecca S Heist; Deepa Rangachari; Suresh S Ramalingam; Heather A Wakelee; Helena A Yu; Lecia V Sequist; Joshua M Bauml; Joel W Neal; Zofia Piotrowska Journal: JTO Clin Res Rep Date: 2022-04-21