G Goss1, C-M Tsai2, F A Shepherd3, M-J Ahn4, L Bazhenova5, L Crinò6, F de Marinis7, E Felip8, A Morabito9, R Hodge10, M Cantarini11, M Johnson12, T Mitsudomi13, P A Jänne14, J C-H Yang15. 1. Division of Medical Oncology, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada. Electronic address: ggoss@toh.on.ca. 2. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. 3. Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada. 4. Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 5. Division of Hematology and Oncology, UC San Diego Health, Moores Cancer Center, La Jolla, USA. 6. Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia. 7. Thoracic Oncology Division, European Institute of Oncology, Milan, Italy. 8. Oncology Department, Vall D'Hebron Institute of Oncology, Barcelona, Spain. 9. Thoracic Medical Oncology, Istituto Nazionale Tumori, Fondazione "G. Pascale" - IRCCS, Naples, Italy. 10. Biometrics and Information Sciences, AstraZeneca, Cambridge, UK. 11. Early Phase Clinical, AstraZeneca, Macclesfield, UK. 12. Quantitative Clinical Pharmacology, AstraZeneca, Cambridge, UK. 13. Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. 14. Department of Adult Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, USA. 15. Department of Oncology, National Taiwan University Hospital, Taiwan.
Abstract
Background: Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods: Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results: Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions: Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number: NCT01802632; NCT02094261.
Background: Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods: Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results: Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions: Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number: NCT01802632; NCT02094261.
Authors: Minjee Kim; Janice K Laramy; Afroz S Mohammad; Surabhi Talele; James Fisher; Jann N Sarkaria; William F Elmquist Journal: Drug Metab Dispos Date: 2019-01-31 Impact factor: 3.922