Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial

Myung Ju Ahn; Byoung Chul Cho; Xiaoling Ou; Andrew Walding; Angela W. Dymond; Song Ren; Mireille Cantarini; Pasi A. Jänne

doi:10.1016/j.jtho.2022.01.012

Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial

Myung Ju Ahn, Byoung Chul Cho, Xiaoling Ou, Andrew Walding, Angela W. Dymond, Song Ren, Mireille Cantarini, Pasi A. Jänne

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Introduction: EGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466). Methods: This open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated. Results: Before enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23–66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48–98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5–12.3). Conclusions: This study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.

Original language	English
Pages (from-to)	718-723
Number of pages	6
Journal	Journal of Thoracic Oncology
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.jtho.2022.01.012
Publication status	Published - 2022 May

Bibliographical note

Funding Information:
This study (NCT02143466) was funded by AstraZeneca (Cambridge, United Kingdom), the manufacturers of osimertinib and durvalumab. The sponsor designed the trial in collaboration with the investigators. Data were collected by the investigators and analyzed and interpreted jointly with the sponsor. The authors thank all the patients and their families and the staff and investigators at all of the study sites. The authors acknowledge Brandon Gufford (of Covance Clinical Research Unit Limited, Leeds, United Kingdom) and Karthick Vishwanathan (of AstraZeneca, Boston, MA) for their contributions to the pharmacokinetics analyses of this study and Geoff Oxnard (of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA) for his support during the early stages of this study. The authors acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare plc, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines ( http://www.ismpp.org/gpp3 ).

Funding Information:
This study (NCT02143466) was funded by AstraZeneca (Cambridge, United Kingdom), the manufacturers of osimertinib and durvalumab. The sponsor designed the trial in collaboration with the investigators. Data were collected by the investigators and analyzed and interpreted jointly with the sponsor. The authors thank all the patients and their families and the staff and investigators at all of the study sites. The authors acknowledge Brandon Gufford (of Covance Clinical Research Unit Limited, Leeds, United Kingdom) and Karthick Vishwanathan (of AstraZeneca, Boston, MA) for their contributions to the pharmacokinetics analyses of this study and Geoff Oxnard (of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA) for his support during the early stages of this study. The authors also acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines ( http://www.ismpp.org/gpp3).

Publisher Copyright:
© 2022 International Association for the Study of Lung Cancer

All Science Journal Classification (ASJC) codes

Oncology
Pulmonary and Respiratory Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtho.2022.01.012

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@article{5a9f4e8ff63e445daa41075a6e1fcf4b,

title = "Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial",

abstract = "Introduction: EGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466). Methods: This open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated. Results: Before enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23–66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48–98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5–12.3). Conclusions: This study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.",

author = "Ahn, {Myung Ju} and Cho, {Byoung Chul} and Xiaoling Ou and Andrew Walding and Dymond, {Angela W.} and Song Ren and Mireille Cantarini and J{\"a}nne, {Pasi A.}",

note = "Funding Information: This study (NCT02143466) was funded by AstraZeneca (Cambridge, United Kingdom), the manufacturers of osimertinib and durvalumab. The sponsor designed the trial in collaboration with the investigators. Data were collected by the investigators and analyzed and interpreted jointly with the sponsor. The authors thank all the patients and their families and the staff and investigators at all of the study sites. The authors acknowledge Brandon Gufford (of Covance Clinical Research Unit Limited, Leeds, United Kingdom) and Karthick Vishwanathan (of AstraZeneca, Boston, MA) for their contributions to the pharmacokinetics analyses of this study and Geoff Oxnard (of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA) for his support during the early stages of this study. The authors acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare plc, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines ( http://www.ismpp.org/gpp3 ). Funding Information: This study (NCT02143466) was funded by AstraZeneca (Cambridge, United Kingdom), the manufacturers of osimertinib and durvalumab. The sponsor designed the trial in collaboration with the investigators. Data were collected by the investigators and analyzed and interpreted jointly with the sponsor. The authors thank all the patients and their families and the staff and investigators at all of the study sites. The authors acknowledge Brandon Gufford (of Covance Clinical Research Unit Limited, Leeds, United Kingdom) and Karthick Vishwanathan (of AstraZeneca, Boston, MA) for their contributions to the pharmacokinetics analyses of this study and Geoff Oxnard (of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA) for his support during the early stages of this study. The authors also acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines ( http://www.ismpp.org/gpp3). Publisher Copyright: {\textcopyright} 2022 International Association for the Study of Lung Cancer",

year = "2022",

month = may,

doi = "10.1016/j.jtho.2022.01.012",

language = "English",

volume = "17",

pages = "718--723",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

number = "5",

}

TY - JOUR

T1 - Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC

T2 - A Phase 1b, Open-Label, Multicenter Trial

AU - Ahn, Myung Ju

AU - Cho, Byoung Chul

AU - Ou, Xiaoling

AU - Walding, Andrew

AU - Dymond, Angela W.

AU - Ren, Song

AU - Cantarini, Mireille

AU - Jänne, Pasi A.

N1 - Funding Information: This study (NCT02143466) was funded by AstraZeneca (Cambridge, United Kingdom), the manufacturers of osimertinib and durvalumab. The sponsor designed the trial in collaboration with the investigators. Data were collected by the investigators and analyzed and interpreted jointly with the sponsor. The authors thank all the patients and their families and the staff and investigators at all of the study sites. The authors acknowledge Brandon Gufford (of Covance Clinical Research Unit Limited, Leeds, United Kingdom) and Karthick Vishwanathan (of AstraZeneca, Boston, MA) for their contributions to the pharmacokinetics analyses of this study and Geoff Oxnard (of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA) for his support during the early stages of this study. The authors acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare plc, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines ( http://www.ismpp.org/gpp3 ). Funding Information: This study (NCT02143466) was funded by AstraZeneca (Cambridge, United Kingdom), the manufacturers of osimertinib and durvalumab. The sponsor designed the trial in collaboration with the investigators. Data were collected by the investigators and analyzed and interpreted jointly with the sponsor. The authors thank all the patients and their families and the staff and investigators at all of the study sites. The authors acknowledge Brandon Gufford (of Covance Clinical Research Unit Limited, Leeds, United Kingdom) and Karthick Vishwanathan (of AstraZeneca, Boston, MA) for their contributions to the pharmacokinetics analyses of this study and Geoff Oxnard (of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA) for his support during the early stages of this study. The authors also acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice guidelines ( http://www.ismpp.org/gpp3). Publisher Copyright: © 2022 International Association for the Study of Lung Cancer

PY - 2022/5

Y1 - 2022/5

N2 - Introduction: EGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466). Methods: This open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated. Results: Before enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23–66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48–98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5–12.3). Conclusions: This study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.

AB - Introduction: EGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466). Methods: This open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated. Results: Before enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23–66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48–98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5–12.3). Conclusions: This study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.

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Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial

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