Osimertinib, a 3rd-generation, CNS-active, oral EGFR-TKI, showed superior efficacy vs comparator EGFR-TKIs (erlotinib/gefitinib) in treatment-naïve EGFRm advanced NSCLC (median OS 38.6 vs 31.8 months; median PFS 18.9 vs 10.2 months). Gefitinib plus carboplatin/pemetrexed chemotherapy has shown improved ORR and PFS vs gefitinib alone. Combining osimertinib with platinum/pemetrexed may further improve patient outcomes.
The safety run-in to allow the opening of the phase III global FLAURA2 (NCT04035486) study was designed to assess safety and tolerability of osimertinib with platinum/pemetrexed chemotherapy. Thirty adults with confirmed EGFRm (ex19del/L858R) locally advanced/metastatic NSCLC, WHO PS 0/1, with no prior therapy for advanced disease, received osimertinib 80 mg QD, and either cisplatin 75 mg/m2 (n=15) or carboplatin AUC5 (n=15), plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for 4 cycles, then osimertinib 80 mg QD with pemetrexed 500 mg/m2 maintenance Q3W until discontinuation criteria were met (data cut-off [DCO] Feb 2020).
Median age was 61 years (range 45–84), 63% female, 73% Asian, 37% smoker, 67% ex19del/33% L858R. At DCO, 23 (77%) pts had completed 4 cycles of carboplatin/cisplatin chemotherapy. 27 (90%) pts had adverse events (AEs; Table). Two (7%) pts discontinued all study treatments due to AEs, including 1 ILD (CTCAE grade 2) and 1 fatal AE (haemoptysis) attributed to NSCLC, unrelated to treatment. Grade 3 / 4 CTCAE haematological toxicities were reported by 7 / 2 (23 / 7%) pts; the majority recovered by DCO. ∗1 pt also discontinued all study treatment due to fatal AE.†1 pt switched from cisplatin to carboplatin after 1 cycle; pt completed 4 cycles of platinum chemotherapy.
n (%) Osimertinib + carboplatin + pemetrexed (n=15) Osimertinib + cisplatin + pemetrexed (n=15) Total (N=30) Any AE 15 (100) 12 (80) 27 (90) Treatment-related AE 15 (100) 12 (80) 27 (90) CTCAE grade ≥3 3 (20) 8 (53) 11 (37) Serious AE 3 (20) 3 (20) 6 (20) Death 1 (7) 0 1 (3) Discontinuation of any study drug 4 (27) 3 (20) 7 (23) Discontinuation of osimertinib 1∗ (7) 0 1 (3) Discontinuation of carboplatin/cisplatin 2 (13) 2† (13) 4 (13) Discontinuation of pemetrexed 3 (20) 3 (20) 6 (20)
Osimertinib plus platinum/pemetrexed chemotherapy was generally well tolerated; no new safety signals were identified. No clear differences were observed between chemotherapy regimens. These results support further assessment of this combination in the FLAURA2 randomised study period (planned enrolment: 556; primary endpoint: PFS).
NCT04035486.
Alexandra Webster, MSc, from iMed Comms, an Ashfield Company, part of UDG Healthcare plc, who provided medical writing support funded by AstraZeneca.
AstraZeneca.
AstraZeneca.
D. Planchard: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Boehringer Ingelheim; Celgene; Eli Lilly; Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Pfizer; prIME Oncology; Honoraria (self), Advisory/Consultancy: Peer CME; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Daiichi Sankyo; Samsung. T.M. Kim: Honoraria (institution), Advisory/Consultancy: AstraZeneca; Boryung; Novartis; Regeneron; Roche/Genentech; Sanofi; Takeda; Voronoi; Research grant/Funding (self), outside this work: AstraZeneca-KHIDI. C.K. Lee: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Takeda. N. Yanagitani: Advisory/Consultancy: Chugai Pharmaceutical Co., Ltd. S. Powar: Full/Part-time employment: AstraZeneca. X. Huang: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. P. Howarth: Full/Part-time employment: AstraZeneca. P. Jänne: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca, Boehringer Ingelheim; Licensing/Royalties: LabCorp; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Acea Biosciences; Advisory/Consultancy: Ignyta; Shareholder/Stockholder/Stock options: Loxo Oncology, Gatekeeper Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (self): Eli Lilly pharmaceuticals; Advisory/Consultancy: Araxes pharmaceuticals; Advisory/Consultancy: SFJ Pharmarceuticals; Advisory/Consultancy: Voronoi; Advisory/Consultancy, Research grant/Funding (self): Daiichi Sankyo; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Takeda Oncology; Advisory/Consultancy: Mirati Therapeutics; Research grant/Funding (self): Astellas Pharmaceuticals; Research grant/Funding (self): Puma; Research grant/Funding (self): Revolution Medicines; Research grant/Funding (self): Takeda Oncology. K. Kobayashi: Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Bristol-Myers Squibb Japan; Speaker Bureau/Expert testimony: Ono Pharmaceutical; Speaker Bureau/Expert testimony: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Taiho Pharmaceutical Company. All other authors have declared no conflicts of interest.