Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

Helena A. Yu; Sarah B. Goldberg; Xiuning Le; Zofia Piotrowska; Jonathan W. Goldman; Adrianus J. De Langen; Isamu Okamoto; Byoung Chul Cho; Paul Smith; Ilhem Mensi; Helen Ambrose; Silvija Kraljevic; Julie Maidment; Juliann Chmielecki; Xiaocheng Li-Sucholeiki; Gail Doughton; Gargi Patel; Phil Jewsbury; Phil Szekeres; Jonathan W. Riess

doi:10.1016/j.cllc.2021.06.006

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

Helena A. Yu, Sarah B. Goldberg, Xiuning Le, Zofia Piotrowska, Jonathan W. Goldman, Adrianus J. De Langen, Isamu Okamoto, Byoung Chul Cho, Paul Smith, Ilhem Mensi, Helen Ambrose, Silvija Kraljevic, Julie Maidment, Juliann Chmielecki, Xiaocheng Li-Sucholeiki, Gail Doughton, Gargi Patel, Phil Jewsbury, Phil Szekeres, Jonathan W. Riess

Department of Internal Medicine

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

16 Citations (Scopus)

Abstract

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments. Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety. Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.

Original language	English
Pages (from-to)	601-606
Number of pages	6
Journal	Clinical Lung Cancer
Volume	22
Issue number	6
DOIs	https://doi.org/10.1016/j.cllc.2021.06.006
Publication status	Published - 2021 Nov

Bibliographical note

Funding Information:
The authors would like to thank the ORCHARD study team, the site staff and the patients involved in this study. The study (NCT03944772) was funded by AstraZeneca , Cambridge, United Kingdom, the manufacturer of osimertinib, savolitinib, durvalumab and gefitinib. The authors would like to acknowledge Eli Lilly and Company, the manufacturer of necitumumab and selpercatinib, and Roche, the manufacturer of alectinib. The authors would like to acknowledge Eleanor Thomas, BSc, and Alexandra Webster, MSc, of Ashfield MedComms, part of Ashfield Health for medical writing support that was funded by AstraZeneca, Cambridge, UK in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Funding Information:
The authors would like to thank the ORCHARD study team, the site staff and the patients involved in this study. The study (NCT03944772) was funded by AstraZeneca, Cambridge, United Kingdom, the manufacturer of osimertinib, savolitinib, durvalumab and gefitinib. The authors would like to acknowledge Eli Lilly and Company, the manufacturer of necitumumab and selpercatinib, and Roche, the manufacturer of alectinib. The authors would like to acknowledge Eleanor Thomas, BSc, and Alexandra Webster, MSc, of Ashfield MedComms, part of Ashfield Health for medical writing support that was funded by AstraZeneca, Cambridge, UK in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Publisher Copyright:
© 2021 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Oncology
Pulmonary and Respiratory Medicine
Cancer Research

UN SDGs

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

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Yu, H. A., Goldberg, S. B., Le, X., Piotrowska, Z., Goldman, J. W., De Langen, A. J., Okamoto, I., Cho, B. C., Smith, P., Mensi, I., Ambrose, H., Kraljevic, S., Maidment, J., Chmielecki, J., Li-Sucholeiki, X., Doughton, G., Patel, G., Jewsbury, P., Szekeres, P., & Riess, J. W. (2021). Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD). Clinical Lung Cancer, 22(6), 601-606. https://doi.org/10.1016/j.cllc.2021.06.006

@article{0e57226ff4f94b239e20cd4b45568a29,

title = "Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)",

abstract = "Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments. Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety. Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.",

author = "Yu, {Helena A.} and Goldberg, {Sarah B.} and Xiuning Le and Zofia Piotrowska and Goldman, {Jonathan W.} and {De Langen}, {Adrianus J.} and Isamu Okamoto and Cho, {Byoung Chul} and Paul Smith and Ilhem Mensi and Helen Ambrose and Silvija Kraljevic and Julie Maidment and Juliann Chmielecki and Xiaocheng Li-Sucholeiki and Gail Doughton and Gargi Patel and Phil Jewsbury and Phil Szekeres and Riess, {Jonathan W.}",

note = "Funding Information: The authors would like to thank the ORCHARD study team, the site staff and the patients involved in this study. The study (NCT03944772) was funded by AstraZeneca , Cambridge, United Kingdom, the manufacturer of osimertinib, savolitinib, durvalumab and gefitinib. The authors would like to acknowledge Eli Lilly and Company, the manufacturer of necitumumab and selpercatinib, and Roche, the manufacturer of alectinib. The authors would like to acknowledge Eleanor Thomas, BSc, and Alexandra Webster, MSc, of Ashfield MedComms, part of Ashfield Health for medical writing support that was funded by AstraZeneca, Cambridge, UK in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Funding Information: The authors would like to thank the ORCHARD study team, the site staff and the patients involved in this study. The study (NCT03944772) was funded by AstraZeneca, Cambridge, United Kingdom, the manufacturer of osimertinib, savolitinib, durvalumab and gefitinib. The authors would like to acknowledge Eli Lilly and Company, the manufacturer of necitumumab and selpercatinib, and Roche, the manufacturer of alectinib. The authors would like to acknowledge Eleanor Thomas, BSc, and Alexandra Webster, MSc, of Ashfield MedComms, part of Ashfield Health for medical writing support that was funded by AstraZeneca, Cambridge, UK in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = nov,

doi = "10.1016/j.cllc.2021.06.006",

language = "English",

volume = "22",

pages = "601--606",

journal = "Clinical Lung Cancer",

issn = "1525-7304",

publisher = "Elsevier",

number = "6",

}

Yu, HA, Goldberg, SB, Le, X, Piotrowska, Z, Goldman, JW, De Langen, AJ, Okamoto, I, Cho, BC, Smith, P, Mensi, I, Ambrose, H, Kraljevic, S, Maidment, J, Chmielecki, J, Li-Sucholeiki, X, Doughton, G, Patel, G, Jewsbury, P, Szekeres, P & Riess, JW 2021, 'Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)', Clinical Lung Cancer, vol. 22, no. 6, pp. 601-606. https://doi.org/10.1016/j.cllc.2021.06.006

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD). / Yu, Helena A.; Goldberg, Sarah B.; Le, Xiuning et al.

In: Clinical Lung Cancer, Vol. 22, No. 6, 11.2021, p. 601-606.

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

TY - JOUR

T1 - Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

AU - Yu, Helena A.

AU - Goldberg, Sarah B.

AU - Le, Xiuning

AU - Piotrowska, Zofia

AU - Goldman, Jonathan W.

AU - De Langen, Adrianus J.

AU - Okamoto, Isamu

AU - Cho, Byoung Chul

AU - Smith, Paul

AU - Mensi, Ilhem

AU - Ambrose, Helen

AU - Kraljevic, Silvija

AU - Maidment, Julie

AU - Chmielecki, Juliann

AU - Li-Sucholeiki, Xiaocheng

AU - Doughton, Gail

AU - Patel, Gargi

AU - Jewsbury, Phil

AU - Szekeres, Phil

AU - Riess, Jonathan W.

N1 - Funding Information: The authors would like to thank the ORCHARD study team, the site staff and the patients involved in this study. The study (NCT03944772) was funded by AstraZeneca , Cambridge, United Kingdom, the manufacturer of osimertinib, savolitinib, durvalumab and gefitinib. The authors would like to acknowledge Eli Lilly and Company, the manufacturer of necitumumab and selpercatinib, and Roche, the manufacturer of alectinib. The authors would like to acknowledge Eleanor Thomas, BSc, and Alexandra Webster, MSc, of Ashfield MedComms, part of Ashfield Health for medical writing support that was funded by AstraZeneca, Cambridge, UK in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Funding Information: The authors would like to thank the ORCHARD study team, the site staff and the patients involved in this study. The study (NCT03944772) was funded by AstraZeneca, Cambridge, United Kingdom, the manufacturer of osimertinib, savolitinib, durvalumab and gefitinib. The authors would like to acknowledge Eli Lilly and Company, the manufacturer of necitumumab and selpercatinib, and Roche, the manufacturer of alectinib. The authors would like to acknowledge Eleanor Thomas, BSc, and Alexandra Webster, MSc, of Ashfield MedComms, part of Ashfield Health for medical writing support that was funded by AstraZeneca, Cambridge, UK in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/11

Y1 - 2021/11

N2 - Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments. Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety. Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.

AB - Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments. Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety. Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.

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Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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