Fiona Blackhall1, Kevin Jao2, Laurent Greillier3, Byoung Chul Cho4, Konstantin Penkov5, Noemi Reguart6, Margarita Majem7, Kristiaan Nackaerts8, Konstantinos Syrigos9, Karin Hansen10, Wolfgang Schuette11, Jeremy Cetnar12, Federico Cappuzzo13, Isamu Okamoto14, Mustafa Erman15, Seppo W Langer16, Terufumi Kato17, Harry Groen18, Zhaowen Sun19, Yan Luo19, Poonam Tanwani19, Laura Caffrey19, Philip Komarnitsky19, Niels Reinmuth20. 1. University of Manchester and Christie NHS Foundation Trust, Manchester, United Kingdom. Electronic address: Fiona.Blackhall@christie.nhs.uk. 2. Hopital du Sacre Coeur Montreal, Montreal, Canada. 3. Aix-Marseille University, APHM, INSERM, CNRS, CRCM, Marseille, France. 4. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 5. Private Medical Institution Euromedservice, St. Petersburg, Pushkin, Russian Federation. 6. Hospital Clinic de Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) Barcelona, Spain. 7. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 8. KU Leuven, University Hospital Leuven, Leuven, Belgium. 9. National & Kapodistrian University of Athens, Athens, Greece. 10. Odense Universitets Hospital, Odense, Denmark. 11. Krankenhaus Martha-Maria Halle-Doelau Halle, Germany. 12. Oregon Health & Science University, Portland, Oregon, USA. 13. Istituto Nazionale Tumori IRCCS Regina Elena, Roma, Italy. 14. Kyushu University Hospital, Fukuoka, Japan. 15. Hacettepe University, Cancer Institute, Ankara, Turkey. 16. Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. 17. Kanagawa Cancer Center, Yokohama, Japan. 18. University of Groningen and University Medical Center Groningen, Groningen, Netherlands. 19. AbbVie, Inc, North Chicago, Ilinois, USA. 20. Asklepios Fachkliniken München-Gauting, Gauting, Germany.
Abstract
INTRODUCTION:Delta-like protein 3 (DLL3), an atypical Notch ligand, is expressed in small cell lung cancer (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 via a protease-cleavable linker. 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: TAHOE was an open-label, 2:1 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 2 cycles, with 2 additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on Days 1-5 of a 21-day cycle. The primary endpoint was overall survival (OS). RESULTS: Patients randomized to Rova-T (n=296) and topotecan (n=148) were included in efficacy analyses. The median age was 64 years, and 77% had extensive disease at initial diagnosis. Median OS (95% CI) 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% CI: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued due to 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 showed an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. Significant unmet therapeutic need remains in this population.
RCT Entities:
INTRODUCTION:Delta-like protein 3 (DLL3), an atypical Notch ligand, is expressed in small cell lung cancer (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 via a protease-cleavable linker. 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: TAHOE was an open-label, 2:1 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 2 cycles, with 2 additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on Days 1-5 of a 21-day cycle. The primary endpoint was overall survival (OS). RESULTS:Patients randomized to Rova-T (n=296) and topotecan (n=148) were included in efficacy analyses. The median age was 64 years, and 77% had extensive disease at initial diagnosis. Median OS (95% CI) 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% CI: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued due to 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 showed an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. Significant unmet therapeutic need remains in this population.
Authors: Joshua A Korsen; Julia A Gutierrez; Kathryn M Tully; Lukas M Carter; Zachary V Samuels; Samantha Khitrov; John T Poirier; Charles M Rudin; Yu Chen; Michael J Morris; Lisa Bodei; Nagavarakishore Pillarsetty; Jason S Lewis Journal: Proc Natl Acad Sci U S A Date: 2022-06-27 Impact factor: 12.779
Authors: Melissa Frizziero; Elaine Kilgour; Kathryn L Simpson; Dominic G Rothwell; David A Moore; Kristopher K Frese; Melanie Galvin; Angela Lamarca; Richard A Hubner; Juan W Valle; Mairéad G McNamara; Caroline Dive Journal: Clin Cancer Res Date: 2022-05-13 Impact factor: 13.801
Authors: Kathryn M Tully; Salomon Tendler; Lukas M Carter; Sai Kiran Sharma; Zachary V Samuels; Komal Mandleywala; Joshua A Korsen; Avelyn Mae Delos Reyes; Alessandra Piersigilli; William D Travis; Triparna Sen; Nagavarakishore Pillarsetty; John T Poirier; Charles M Rudin; Jason S Lewis Journal: Clin Cancer Res Date: 2022-04-01 Impact factor: 13.801