CNS metastases (mets) are common in pts with EGFRm advanced NSCLC. Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. Preclinical studies have shown CNS penetration of osimertinib, and clinical data from Ph II and III trials showed CNS activity in pts with T790M-positive advanced NSCLC.
The Ph III FLAURA study (NCT02296125) compared osimertinib vs SoC EGFR-TKI in previously untreated pts with EGFRm advanced NSCLC. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg qd po). Neurologically stable pts with CNS mets were allowed, provided definitive treatment/steroids were completed for ≥2 weeks. A prespecified subgroup analysis investigated CNS activity in pts with CNS mets present on baseline brain scan, as assessed by blinded independent central neuroradiology review (BICR). Endpoints included CNS progression-free survival by RECIST v1.1, CNS objective response rate and duration of CNS response. The CNS full analysis set (cFAS) included pts with ≥1 measurable and/or non-measurable CNS lesion present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) included only pts with ≥1 measurable CNS lesion.
As of 12 June 2017, 128/556 pts (23%) were included in the cFAS (osimertinib: 61, SoC, 67). Baseline characteristics were balanced across treatment arms (osimertinib/SoC): female 62/61%; Asian, 66/55%, prior brain radiotherapy, 25/24%. Efficacy in the cFAS and cEFR are shown in the table:Table: LBA5
|CNS efficacy endpoints, cFAS||Osimertinib||SoC|
|n = 61||n = 67|
|CNS PFS events, including death, total pts (% maturity)||18||30|
|Median CNS PFS, months* (95% confidence interval)||NR (16.5, NC)||13.9 (8.3, NC)|
|CNS PFS HR† (95% confidence interval)||0.48 (0.26, 0.86); p = 0.014#|
|Confirmed CNS ORR, n (%) [95% confidence interval]||35 (57) [44, 70]||27 (40) [29, 53]|
|Odds Ratio†† (95% confidence interval)||2.0 (1.0, 4.1); p = 0.053|
|Median CNS DoR, months (95% confidence interval)||NR (11.9, NC)||14.4 (8.3, 18.7)|
|CNS efficacy endpoints, cEFR||Osimertinib n = 22||SoC n = 19|
|Confirmed CNS ORR, n (%) [95% confidence interval]||17 (77) [55, 92]||12 (63) [38, 84]|
|Odds Ratio†† (95% confidence interval)||2.0 (0.5, 8.2); p = 0.322|
|Median CNS DoR, months (95% confidence interval)||NR (8.5, NC)||18.7 (4.2, 18.7)|
DoR, duration of response; HR, hazard ratio; NR, not reached; ORR, objective response rate; PFS, progression-free survival*
Median PFS with 95% confidence intervals calculated from a Cox proportional Hazard model.
†A HR 1 favours osimertinib.#
Nominally statistically significant.
In patients with documented CNS mets by neuroradiology BICR, osimertinib had superior CNS PFS compared to SoC, with a benefit similar to that reported in the overall group of patients. CNS response rate was higher and more durable with osimertinib.
Clinical trial identification
Legal entity responsible for the study
J. Vansteenkiste: Personal fees (lectures and consulting) for AstraZeneca. B.C. Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST; Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly. S. Bohnet: advisory board membership. N. Nogami: Dr. Nogami reports other from AstraZeneca, other from Chugai Pharmaceutical Co., Ltd., other from Pfizer Japan Inc., other from Eli Lilly Japan K.K., other from Ono Pharmaceutical Co., LTD., other from Taiho Pharmaceutical Co., Ltd, outside the submitted work. I. Okamoto: Grants and personal fees from AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, and Pfizer Japan, R. Hodge: Employee and shareholder of AstraZeneca, conducts analysis of osimertinib data at AstraZeneca in addition to the submitted work. A. McKeown: Employee and shareholder: AstraZeneca. A.P. Brown: Employee and stock owner of AstraZeneca. Y. Rukazaencov: Full salaried employee of AstraZeneca and holds shares in AstraZeneca. S. Ramalingam: Advisory boards for Amgen, Astra Zeneca, Abbvie, BMS, Lilly, Celgene, Genentech, and Novartis, outside the submitted work. All other authors have declared no conflicts of interest.