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

9 Citations (Scopus)

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
Pages (from-to)	1547-1558
Number of pages	12
Journal	Journal of Thoracic Oncology
Volume	16
Issue number	9
DOIs	https://doi.org/10.1016/j.jtho.2021.02.009
Publication status	Published - 2021 Sep

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.

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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10.1016/j.jtho.2021.02.009

Cite this

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. (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, 16(9), 1547-1558. 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 ; Vol. 16, No. 9. pp. 1547-1558.

@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. Publisher Copyright: {\textcopyright} 2021 International Association for the Study of Lung Cancer",

year = "2021",

month = sep,

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

language = "English",

volume = "16",

pages = "1547--1558",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

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

number = "9",

}

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, vol. 16, no. 9, pp. 1547-1558. 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, Vol. 16, No. 9, 09.2021, p. 1547-1558.

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

PY - 2021/9

Y1 - 2021/9

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.

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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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