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      A phase III, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer

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          Abstract

          Background

          ASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor.

          Patients and methods

          This global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile.

          Results

          Patients ( n = 530) were randomized 1 : 1 to receive ASP8273 ( n = 267) or erlotinib/gefitinib ( n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6–11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8–NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 ( P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4–39.0) versus 47.9% (95% CI 41.7–54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib.

          Conclusions

          First-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib.

          ClinicalTrial.gov number

          NCT02588261.

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          Most cited references 15

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          Lung cancer.

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            AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.

            First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. ©2014 American Association for Cancer Research.
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              Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

              Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC).
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                Author and article information

                Journal
                Ann Oncol
                Ann. Oncol
                annonc
                Annals of Oncology
                Oxford University Press
                0923-7534
                1569-8041
                July 2019
                09 May 2019
                09 May 2019
                : 30
                : 7 , Targeting the PI3-kinase pathway in triple-negative breast cancer
                : 1127-1133
                Affiliations
                [1 ]The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore and The Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas, USA
                [2 ]Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
                [3 ]Departments of Oncology
                [4 ]Biostatistics, Astellas Pharma US, Inc., Northbrook
                [5 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, USA
                Author notes
                Correspondence to: Dr Ronan J. Kelly, Director of Oncology at the Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, USA. Tel: +1-214-820-2881; E-mail: Ronan.Kelly@ 123456BSWHealth.org
                Article
                mdz128
                10.1093/annonc/mdz128
                6736319
                31070709
                © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Counts
                Pages: 7
                Product
                Funding
                Funded by: Astellas Pharma 10.13039/501100004948
                Funded by: Inc.
                Funded by: Astellas 10.13039/100004324
                Funded by: Bristol-Myers Squibb 10.13039/100002491
                Funded by: Eli Lilly
                Funded by: AstraZeneca 10.13039/100004325
                Funded by: Novartis 10.13039/100004336
                Funded by: Gritstone Oncology
                Funded by: Astellas 10.13039/100004324
                Funded by: Genentech 10.13039/100004328
                Funded by: Xcovery
                Funded by: Merck 10.13039/100004334
                Categories
                Original Articles
                Thoracic Tumors

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