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In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum–pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum–pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum–pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67–1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8) for osimertinib and platinum–pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16–0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum–pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum–pemetrexed arm. In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum–pemetrexed, which possibly reflects the high crossover rate of patients from platinum–pemetrexed to osimertinib. ClinicalTrials.gov NCT02151981 ; https://clinicaltrials.gov/ct2/show/NCT02151981. • Median OS with osimertinib was 26.8 months versus 22.5 months with platinum–pemetrexed (HR 0.87, 95% CI 0.67–1.12; P = 0.277). • The lack of a significant survival benefit could reflect high percentage (73%) of platinum–pemetrexed to osimertinib crossover. • Analysis of OS adjusted for crossover showed an HR of 0.54 (95% CI 0.18–1.60). • Among patients receiving subsequent anticancer therapy, platinum chemotherapy was the most common after osimertinib (65%). • Grade ≥3 (possibly treatment-related) adverse events were observed less frequently with osimertinib (9% versus 34% with platinum–pemetrexed). [ABSTRACT FROM AUTHOR]

Background In AURA3 (NCT02151981), osimertinib, a 3rd-generation EGFR-TKI, significantly prolonged progressionfree survival (PFS) and improved response rate vs plt-pem in pts with centrally confirmed EGFR T790M advanced NSCLC and progression on a prior EGFR-TKI. Here we report mature OS data. Methods Adult pts were randomised 2:1 to receive oral osimertinib (80 mg once daily) or intravenous pem (500 mg per m2 of body surface area) + carboplatin (target area under the curve 5)/cisplatin (75 mg per m2), every 3 weeks, ≤6 cycles. Treatment beyond progression (RECIST 1.1) was allowed if clinical benefit continued. Pts receiving plt-pem could cross over to osimertinib on disease progression. Asymptomatic CNS metastases were allowed. Primary endpoint was investigator-assessed PFS. OS and safety are reported as secondary endpoints. Data cut-off (DCO): 15 March 2019. Results In total, 419 pts were randomised (osimertinib, n = 279; plt-pem, n = 140); 99 pts (71%) crossed over to osimertinib from plt-pem. At DCO, 188 pts (67%) in the osimertinib arm vs 93 pts (66%) in the plt-pem arm had died, including 66/99 (67%) crossover pts; median OS 26.8 mo (95% confidence interval [CI] 23.5, 31.5) vs 22.5 mo (95% CI 20.2, 28.8) respectively, hazard ratio (HR) 0.87 (95% CI 0.67, 1.12; p = 0.277); survival rate at 24 mo was 55% vs 43% and at 36 mo was 37% vs 30%. Time to first subsequent treatment showed a large, clinically meaningful numerical advantage towards osimertinib, HR 0.21 (95% CI 0.16, 0.28; p < 0.001); time to second subsequent treatment, HR 0.87 (95% CI 0.69, 1.11; p = 0.263). In both arms, 99% pts had any adverse event (AE). Any AE grade ≥3 causally related to study treatment was 9% vs 34% for osimertinib and plt-pem respectively. Most common AEs were diarrhoea, 44% (grade ≥3, 1%), and nausea, 49% (grade ≥3, 4%), with osimertinib and plt-pem respectively. Conclusions A numerical advantage in OS was observed for pts receiving osimertinib vs plt-pem, with the majority of pts in the plt-pem arm having crossed over to osimertinib. The safety profile of osimertinib remains consistent with previous findings. Clinical trial identification NCT02151981. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, who provided medical writing support funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. T.S.K. Mok: Honoraria (self): ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, Hengrui Therapeutics Inc. Ignyt; Advisory / Consultancy: ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, geneDecode Co. Ltd. (un; Leadership role: AstraZeneca PLC, Hutchison Chi-Med; Research grant / Funding (institution): AstraZeneca, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, XCovery; Shareholder / Stockholder / Stock options: Shareholder: Hutchison Chi-Med, Sanomics Ltd. Stock option: Clearbridge Biomedics (now Biolidics Ltd.), Loxo-Oncology, OrigiMed Co. Ltd. Virtus Medical Group; Full / Part-time employment: The Chinese University of Hong Kong; Officer / Board of Directors: Remunerated: AstraZeneca PLC, Hutchison Chi-Med Non-remunerated: American Society of Clinical Oncology (ASCO) Asian Thoracic Oncology Research Group (ATORG) Chinese Lung Cancer Research Foundation Limited (CLCRF) Chinese Society of Clinical Oncology (CS. J-Y. Han: Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, Lilly; Research grant / Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. M-J. Ahn: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Merck, Sharp & Dohme, Ono Pharmaceutical, Lilly, Roche; Advisory / Consultancy: Alpha Pharmaceutical, Takeda. S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. S-W. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. F.A. Shepherd: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: AstraZeneca. J. Laskin: Research grant / Funding (institution): AstraZeneca, Roche, Boehringer Ingelheim, Pfizer; Honoraria (self): AstraZeneca, Roche, Pfizer. H. Akamatsu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Honoraria (institution): Chugai; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution): Boehringer Ingelheim. W-C. Su: Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. M. Sebastian: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Roche, Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Boehringer Ingelheim, Celgene, Takeda, Bristol-Myers Squibb, MSD; Honoraria (self), Advisory / Consultancy: Lilly. H. Mann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Miranda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. G. Laus: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Papadimitrakopoulou: Honoraria (self): F Hoffman-La Roche; Advisory / Consultancy: Nektar Therapeutics, AstraZeneca Pharmaceuticals, Arrys Therapeutics, Merck&Co, LOXO Oncology, Araxes Pharma, F.Hoffman-LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly &Co, Novartis Pharmaceuticals Corp. Takeda ; Research grant / Funding (institution): Eli Lilly &Co, Novartis, Merck, AstraZeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]