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

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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

Authors: 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

Citation: JOURNAL OF THORACIC ONCOLOGY, Vol.16(9) : 1547-1558, 2021-09

Journal Title: JOURNAL OF THORACIC ONCOLOGY

ISSN: 1556-0864

Issue Date: 2021-09

MeSH: Adult ; Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols / therapeutic use ; Benzodiazepinones ; Humans ; Immunoconjugates* / therapeutic use ; Intracellular Signaling Peptides and Proteins ; Lung Neoplasms* / drug therapy ; Membrane Proteins ; Middle Aged ; Small Cell Lung Carcinoma* / drug therapy ; Topotecan / therapeutic use

Keywords: Delta-like protein 3 ; Rovalpituzumab tesirine ; Small cell lung cancer ; Topotecan

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.