Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study

Fiona Blackhall; Kevin Jao; Laurent Greillier; Byoung Chul Cho; Konstantin Penkov; Noemi Reguart; Margarita Majem; Kristiaan Nackaerts; Konstantinos Syrigos; Karin Hansen; Wolfgang Schuette; Jeremy Cetnar; Federico Cappuzzo; Isamu Okamoto; Mustafa Erman; Seppo W. Langer; Terufumi Kato; Harry Groen; Zhaowen Sun; Yan Luo; Poonam Tanwani; Laura Caffrey; Philip Komarnitsky; Niels Reinmuth

doi:10.1016/j.jtho.2021.02.009

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study

Fiona Blackhall, Kevin Jao, Laurent Greillier, Byoung Chul Cho, Konstantin Penkov, Noemi Reguart, Margarita Majem, Kristiaan Nackaerts, Konstantinos Syrigos, Karin Hansen, Wolfgang Schuette, Jeremy Cetnar, Federico Cappuzzo, Isamu Okamoto, Mustafa Erman, Seppo W. Langer, Terufumi Kato, Harry Groen, Zhaowen Sun, Yan LuoPoonam Tanwani, Laura Caffrey, Philip Komarnitsky, Niels Reinmuth

Department of Internal Medicine

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

Abstract

Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m²) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6–7.3) in the Rova-T arm and 8.6 months (7.7–10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17–1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.

Original language	English
Journal	Journal of Thoracic Oncology
DOIs	https://doi.org/10.1016/j.jtho.2021.02.009
Publication status	Accepted/In press - 2021

Bibliographical note

Funding Information:
This study was funded by AbbVie, Inc., which also participated in the study design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. The authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Swati Ghatpande, PhD and Allison Cherry, PhD of Bio Connections, and funded by AbbVie, Inc. Dr. Blackhall contributed to the study conceptualization and resources and the writing of the manuscript. Dr. Jao contributed to the writing and review of the manuscript. Drs. Greillier and Erman contributed to the study investigation and resources, and the writing and review of the manuscript. Dr. Nackaerts contributed to the study visualization and resources and the writing and review of the manuscript. Dr. Sun contributed to the formal analysis, data curation, and writing and review of the manuscript. Drs. Luo and Komarnitsky contributed to the study supervision and the writing and review of the manuscript. Ms. Tanwani and Caffrey contributed to the study resources, data curation, and review of the manuscript. The remaining authors contributed to the study resources and the writing and review of the manuscript. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. Rovalpituzumab tesirine (Rova-T) has been developed by AbbVie, Inc. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), and other information (e.g. protocols and clinical study reports) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided after review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.h. Disclosures: Dr. Blackhall reports participating on advisory boards of AbbVie, AstraZeneca, Roche, Boehringer Ingelheim, Novartis, Pfizer, Celgene, Regeneron, and Amgen. Dr. Jao reports serving on the advisory boards of AbbVie, Roche, AstraZeneca, and Merck. Dr. Greillier reports participating on the advisory boards of AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche. Dr. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence Corp.; serves as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Janssen, Medpacto, and Blueprint Medicines; has stock ownership at TheraCanVac Inc., Gencurix Inc., Bridgebio therapeutics, KANAPH Therapeutic Inc., Cyrus therapeutics, and Interpark Bio Convergence Corp.; serves on the scientific advisory boards of KANAPH Therapeutics Inc., Brigebio Therapeutics, Cyrus Therapeutics, and Guardant Health; serves as a member of the board of directors of Gencurix Inc. and Interpark Bio Convergence Corp; received royalty from Champions Oncology; and is the founder of DAAN Biotherapeutics. Dr. Penkov reports receiving honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, H3B, Janssen, Merck Sharp & Dohme, Mylan, Nektar, Pfizer, Polyphor, Prestige, Regeneron, Roche, Takeda, and Tanvex. Dr. Reguart reports receiving research grants from Pfizer and Novartis; and served in the consulting, advisory, and speaker activities for Merck, Roche, AstraZeneca, Pfizer, Amgen, Novartis, Eli Lilly, Takeda, and Boehringer Ingelheim. Dr. Majem reports receiving grants and personal fees from Bristol-Myers Squibb; personal fees and nonfinancial support from Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Roche; personal fees from Kyowa Kyrin; and personal fees from Pierre Fabre and Novartis outside the submitted work. Dr. Nackaerts reports participating in advisory boards for AbbVie, Boehringer Ingelheim, Novartis, Pfizer, and Roche. Dr. Schuette reports receiving sponsorship from and served a consulting or advisory role with Roche, Eli Lilly, Amgen, and Merck. Dr. Cappuzzo reports serving in an advisory role for and received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Bayer, Pfizer, Roche, Pharmamar, and Takeda. Dr. Okamoto reports receiving grants from AbbVie, Astellas Pharma, and Boehringer Ingelheim during the conduct of the study; and grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Merck Sharp & Dohme Oncology, and Novartis; and personal fees from Pfizer outside the submitted work. Dr. Erman reports receiving honoraria and consulting fees from Pfizer, AstraZeneca, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Boehringer Ingelheim, Roche, and Nobel. Dr. Langer reports receiving a research grant from AbbVie, and participated in the advisory boards of Merck, Roche, AstraZeneca, and Pfizer. Dr. Kato reports receiving grants from AbbVie during the conduct of the study; grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Ono, Pfizer, and Taiho; received personal fees from Boehringer Ingelheim, Daiichi-Sankyo, F. Hoffman?La Roche, Nippon Kayaku, Nitto Denko, Shionogi, Sumitomo Dainippon, and Takeda; and grants from Astellas, Kyorin, Kyowa-Kirin, and Regeneron outside the submitted work. Dr. Groen reports to have participated on advisory boards of AbbVie. Dr. Reinmuth reports receiving honoraria for speaker activities and participation in advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. Dr. Sun, Dr. Luo, Ms. Tanwani, Ms. Caffrey, and Dr. Komarnitsky are employees of AbbVie and hold AbbVie stock. The remaining authors declare no conflict of interest.

Publisher Copyright:
© 2021 International Association for the Study of Lung Cancer

All Science Journal Classification (ASJC) codes

Oncology
Pulmonary and Respiratory Medicine

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Blackhall, F., Jao, K., Greillier, L., Cho, B. C., Penkov, K., Reguart, N., Majem, M., Nackaerts, K., Syrigos, K., Hansen, K., Schuette, W., Cetnar, J., Cappuzzo, F., Okamoto, I., Erman, M., Langer, S. W., Kato, T., Groen, H., Sun, Z., ... Reinmuth, N. (Accepted/In press). Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study. Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2021.02.009

Blackhall, Fiona ; Jao, Kevin ; Greillier, Laurent ; Cho, Byoung Chul ; Penkov, Konstantin ; Reguart, Noemi ; Majem, Margarita ; Nackaerts, Kristiaan ; Syrigos, Konstantinos ; Hansen, Karin ; Schuette, Wolfgang ; Cetnar, Jeremy ; Cappuzzo, Federico ; Okamoto, Isamu ; Erman, Mustafa ; Langer, Seppo W. ; Kato, Terufumi ; Groen, Harry ; Sun, Zhaowen ; Luo, Yan ; Tanwani, Poonam ; Caffrey, Laura ; Komarnitsky, Philip ; Reinmuth, Niels. / Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC : Results From the Phase 3 TAHOE Study. In: Journal of Thoracic Oncology. 2021.

@article{cb9e249dbb3840f08fca8175364aa4c1,

title = "Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study",

abstract = "Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6–7.3) in the Rova-T arm and 8.6 months (7.7–10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17–1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.",

author = "Fiona Blackhall and Kevin Jao and Laurent Greillier and Cho, {Byoung Chul} and Konstantin Penkov and Noemi Reguart and Margarita Majem and Kristiaan Nackaerts and Konstantinos Syrigos and Karin Hansen and Wolfgang Schuette and Jeremy Cetnar and Federico Cappuzzo and Isamu Okamoto and Mustafa Erman and Langer, {Seppo W.} and Terufumi Kato and Harry Groen and Zhaowen Sun and Yan Luo and Poonam Tanwani and Laura Caffrey and Philip Komarnitsky and Niels Reinmuth",

note = "Funding Information: This study was funded by AbbVie, Inc., which also participated in the study design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. The authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Swati Ghatpande, PhD and Allison Cherry, PhD of Bio Connections, and funded by AbbVie, Inc. Dr. Blackhall contributed to the study conceptualization and resources and the writing of the manuscript. Dr. Jao contributed to the writing and review of the manuscript. Drs. Greillier and Erman contributed to the study investigation and resources, and the writing and review of the manuscript. Dr. Nackaerts contributed to the study visualization and resources and the writing and review of the manuscript. Dr. Sun contributed to the formal analysis, data curation, and writing and review of the manuscript. Drs. Luo and Komarnitsky contributed to the study supervision and the writing and review of the manuscript. Ms. Tanwani and Caffrey contributed to the study resources, data curation, and review of the manuscript. The remaining authors contributed to the study resources and the writing and review of the manuscript. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. Rovalpituzumab tesirine (Rova-T) has been developed by AbbVie, Inc. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), and other information (e.g. protocols and clinical study reports) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided after review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.h. Disclosures: Dr. Blackhall reports participating on advisory boards of AbbVie, AstraZeneca, Roche, Boehringer Ingelheim, Novartis, Pfizer, Celgene, Regeneron, and Amgen. Dr. Jao reports serving on the advisory boards of AbbVie, Roche, AstraZeneca, and Merck. Dr. Greillier reports participating on the advisory boards of AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche. Dr. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence Corp.; serves as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Janssen, Medpacto, and Blueprint Medicines; has stock ownership at TheraCanVac Inc., Gencurix Inc., Bridgebio therapeutics, KANAPH Therapeutic Inc., Cyrus therapeutics, and Interpark Bio Convergence Corp.; serves on the scientific advisory boards of KANAPH Therapeutics Inc., Brigebio Therapeutics, Cyrus Therapeutics, and Guardant Health; serves as a member of the board of directors of Gencurix Inc. and Interpark Bio Convergence Corp; received royalty from Champions Oncology; and is the founder of DAAN Biotherapeutics. Dr. Penkov reports receiving honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, H3B, Janssen, Merck Sharp & Dohme, Mylan, Nektar, Pfizer, Polyphor, Prestige, Regeneron, Roche, Takeda, and Tanvex. Dr. Reguart reports receiving research grants from Pfizer and Novartis; and served in the consulting, advisory, and speaker activities for Merck, Roche, AstraZeneca, Pfizer, Amgen, Novartis, Eli Lilly, Takeda, and Boehringer Ingelheim. Dr. Majem reports receiving grants and personal fees from Bristol-Myers Squibb; personal fees and nonfinancial support from Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Roche; personal fees from Kyowa Kyrin; and personal fees from Pierre Fabre and Novartis outside the submitted work. Dr. Nackaerts reports participating in advisory boards for AbbVie, Boehringer Ingelheim, Novartis, Pfizer, and Roche. Dr. Schuette reports receiving sponsorship from and served a consulting or advisory role with Roche, Eli Lilly, Amgen, and Merck. Dr. Cappuzzo reports serving in an advisory role for and received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Bayer, Pfizer, Roche, Pharmamar, and Takeda. Dr. Okamoto reports receiving grants from AbbVie, Astellas Pharma, and Boehringer Ingelheim during the conduct of the study; and grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Merck Sharp & Dohme Oncology, and Novartis; and personal fees from Pfizer outside the submitted work. Dr. Erman reports receiving honoraria and consulting fees from Pfizer, AstraZeneca, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Boehringer Ingelheim, Roche, and Nobel. Dr. Langer reports receiving a research grant from AbbVie, and participated in the advisory boards of Merck, Roche, AstraZeneca, and Pfizer. Dr. Kato reports receiving grants from AbbVie during the conduct of the study; grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Ono, Pfizer, and Taiho; received personal fees from Boehringer Ingelheim, Daiichi-Sankyo, F. Hoffman?La Roche, Nippon Kayaku, Nitto Denko, Shionogi, Sumitomo Dainippon, and Takeda; and grants from Astellas, Kyorin, Kyowa-Kirin, and Regeneron outside the submitted work. Dr. Groen reports to have participated on advisory boards of AbbVie. Dr. Reinmuth reports receiving honoraria for speaker activities and participation in advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. Dr. Sun, Dr. Luo, Ms. Tanwani, Ms. Caffrey, and Dr. Komarnitsky are employees of AbbVie and hold AbbVie stock. The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2021 International Association for the Study of Lung Cancer",

year = "2021",

doi = "10.1016/j.jtho.2021.02.009",

language = "English",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

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

}

Blackhall, F, Jao, K, Greillier, L, Cho, BC, Penkov, K, Reguart, N, Majem, M, Nackaerts, K, Syrigos, K, Hansen, K, Schuette, W, Cetnar, J, Cappuzzo, F, Okamoto, I, Erman, M, Langer, SW, Kato, T, Groen, H, Sun, Z, Luo, Y, Tanwani, P, Caffrey, L, Komarnitsky, P & Reinmuth, N 2021, 'Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study', Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2021.02.009

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC : Results From the Phase 3 TAHOE Study. / Blackhall, Fiona; Jao, Kevin; Greillier, Laurent; Cho, Byoung Chul; Penkov, Konstantin; Reguart, Noemi; Majem, Margarita; Nackaerts, Kristiaan; Syrigos, Konstantinos; Hansen, Karin; Schuette, Wolfgang; Cetnar, Jeremy; Cappuzzo, Federico; Okamoto, Isamu; Erman, Mustafa; Langer, Seppo W.; Kato, Terufumi; Groen, Harry; Sun, Zhaowen; Luo, Yan; Tanwani, Poonam; Caffrey, Laura; Komarnitsky, Philip; Reinmuth, Niels.

In: Journal of Thoracic Oncology, 2021.

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

TY - JOUR

T1 - Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC

T2 - Results From the Phase 3 TAHOE Study

AU - Blackhall, Fiona

AU - Jao, Kevin

AU - Greillier, Laurent

AU - Cho, Byoung Chul

AU - Penkov, Konstantin

AU - Reguart, Noemi

AU - Majem, Margarita

AU - Nackaerts, Kristiaan

AU - Syrigos, Konstantinos

AU - Hansen, Karin

AU - Schuette, Wolfgang

AU - Cetnar, Jeremy

AU - Cappuzzo, Federico

AU - Okamoto, Isamu

AU - Erman, Mustafa

AU - Langer, Seppo W.

AU - Kato, Terufumi

AU - Groen, Harry

AU - Sun, Zhaowen

AU - Luo, Yan

AU - Tanwani, Poonam

AU - Caffrey, Laura

AU - Komarnitsky, Philip

AU - Reinmuth, Niels

N1 - Funding Information: This study was funded by AbbVie, Inc., which also participated in the study design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. The authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Swati Ghatpande, PhD and Allison Cherry, PhD of Bio Connections, and funded by AbbVie, Inc. Dr. Blackhall contributed to the study conceptualization and resources and the writing of the manuscript. Dr. Jao contributed to the writing and review of the manuscript. Drs. Greillier and Erman contributed to the study investigation and resources, and the writing and review of the manuscript. Dr. Nackaerts contributed to the study visualization and resources and the writing and review of the manuscript. Dr. Sun contributed to the formal analysis, data curation, and writing and review of the manuscript. Drs. Luo and Komarnitsky contributed to the study supervision and the writing and review of the manuscript. Ms. Tanwani and Caffrey contributed to the study resources, data curation, and review of the manuscript. The remaining authors contributed to the study resources and the writing and review of the manuscript. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. Rovalpituzumab tesirine (Rova-T) has been developed by AbbVie, Inc. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), and other information (e.g. protocols and clinical study reports) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided after review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.h. Disclosures: Dr. Blackhall reports participating on advisory boards of AbbVie, AstraZeneca, Roche, Boehringer Ingelheim, Novartis, Pfizer, Celgene, Regeneron, and Amgen. Dr. Jao reports serving on the advisory boards of AbbVie, Roche, AstraZeneca, and Merck. Dr. Greillier reports participating on the advisory boards of AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche. Dr. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence Corp.; serves as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Janssen, Medpacto, and Blueprint Medicines; has stock ownership at TheraCanVac Inc., Gencurix Inc., Bridgebio therapeutics, KANAPH Therapeutic Inc., Cyrus therapeutics, and Interpark Bio Convergence Corp.; serves on the scientific advisory boards of KANAPH Therapeutics Inc., Brigebio Therapeutics, Cyrus Therapeutics, and Guardant Health; serves as a member of the board of directors of Gencurix Inc. and Interpark Bio Convergence Corp; received royalty from Champions Oncology; and is the founder of DAAN Biotherapeutics. Dr. Penkov reports receiving honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, H3B, Janssen, Merck Sharp & Dohme, Mylan, Nektar, Pfizer, Polyphor, Prestige, Regeneron, Roche, Takeda, and Tanvex. Dr. Reguart reports receiving research grants from Pfizer and Novartis; and served in the consulting, advisory, and speaker activities for Merck, Roche, AstraZeneca, Pfizer, Amgen, Novartis, Eli Lilly, Takeda, and Boehringer Ingelheim. Dr. Majem reports receiving grants and personal fees from Bristol-Myers Squibb; personal fees and nonfinancial support from Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Roche; personal fees from Kyowa Kyrin; and personal fees from Pierre Fabre and Novartis outside the submitted work. Dr. Nackaerts reports participating in advisory boards for AbbVie, Boehringer Ingelheim, Novartis, Pfizer, and Roche. Dr. Schuette reports receiving sponsorship from and served a consulting or advisory role with Roche, Eli Lilly, Amgen, and Merck. Dr. Cappuzzo reports serving in an advisory role for and received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Bayer, Pfizer, Roche, Pharmamar, and Takeda. Dr. Okamoto reports receiving grants from AbbVie, Astellas Pharma, and Boehringer Ingelheim during the conduct of the study; and grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Merck Sharp & Dohme Oncology, and Novartis; and personal fees from Pfizer outside the submitted work. Dr. Erman reports receiving honoraria and consulting fees from Pfizer, AstraZeneca, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Boehringer Ingelheim, Roche, and Nobel. Dr. Langer reports receiving a research grant from AbbVie, and participated in the advisory boards of Merck, Roche, AstraZeneca, and Pfizer. Dr. Kato reports receiving grants from AbbVie during the conduct of the study; grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Ono, Pfizer, and Taiho; received personal fees from Boehringer Ingelheim, Daiichi-Sankyo, F. Hoffman?La Roche, Nippon Kayaku, Nitto Denko, Shionogi, Sumitomo Dainippon, and Takeda; and grants from Astellas, Kyorin, Kyowa-Kirin, and Regeneron outside the submitted work. Dr. Groen reports to have participated on advisory boards of AbbVie. Dr. Reinmuth reports receiving honoraria for speaker activities and participation in advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. Dr. Sun, Dr. Luo, Ms. Tanwani, Ms. Caffrey, and Dr. Komarnitsky are employees of AbbVie and hold AbbVie stock. The remaining authors declare no conflict of interest. Publisher Copyright: © 2021 International Association for the Study of Lung Cancer

PY - 2021

Y1 - 2021

N2 - Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6–7.3) in the Rova-T arm and 8.6 months (7.7–10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17–1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.

AB - Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6–7.3) in the Rova-T arm and 8.6 months (7.7–10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17–1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.

UR - http://www.scopus.com/inward/record.url?scp=85103071607&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85103071607&partnerID=8YFLogxK

U2 - 10.1016/j.jtho.2021.02.009

DO - 10.1016/j.jtho.2021.02.009

M3 - Article

C2 - 33607312

AN - SCOPUS:85103071607

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

ER -

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study

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