Melissa L Johnson1, Zanete Zvirbule2, Konstantin Laktionov3, Aslaug Helland4, Byoung Chul Cho5, Vanesa Gutierrez6, Benoît Colinet7, Herve Lena8, Martin Wolf9, Maya Gottfried10, Isamu Okamoto11, Cor van der Leest12, Patricia Rich13, Jen-Yu Hung14, Christina Appenzeller15, Sun Zhaowen16, David Maag16, Yan Luo16, Caroline Nickner16, Alena Vajikova16, Philip Komarnitsky16, Jair Bar17. 1. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee, USA. Electronic address: Melissa.johnson@sarahcannon.com. 2. Riga East University Hospital, Riga, Latvia. 3. Federal State Budgetary Institution "N.N.Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation (N.N. Blokhin NMRCO), Moscow, Russian Federation. 4. Oslo University Hospital, The Norwegian Radium Hospital and University of Oslo, Oslo, Norway. 5. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 6. Hospital Regional Universitario de Malaga, Malaga, Spain. 7. Grand Hôpital de Charleroi, Charleroi, Belgium. 8. Hospital de Pontchaillou, Centre Hospitalier Universitaire, Rennes, France and INSERM U 1242, Université Rennes 1, Rennes, France. 9. Klinikum Kassel Hospital, Kassel, Germany. 10. Meir Medical Center, Kfar Saba, Israel. 11. Kyushu University Hospital, Fukuoka, , Japan. 12. Amphia Ziekenhuis, Breda, Netherlands. 13. Cancer Treatment Centers of America, Newnan, Georgia USA. 14. Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan. 15. Kantonsspital St. Gallen, St. Gallen, Switzerland. 16. AbbVie, Inc, North Chicago, IL USA. 17. Sheba Medical Center, Ramat Gan, Israel, and Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel.
Abstract
INTRODUCTION:Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting delta-like protein 3 (DLL3), an atypical Notch ligand expressed in small cell lung cancer (SCLC) tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive stage (ES) SCLC after platinum-based chemotherapy. METHODS: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression following 4 cycles of platinum-based front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (q6wk, omitted every third cycle). Primary efficacy endpoints were progression-free survival (PFS) assessed by the Central Radiographic Assessment Committee (CRAC) and overall survival (OS) in DLL3-high patients. RESULTS:Median age of all randomized patients (N=748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the DLL3-high subset, the hazard ratio (HR) for OS was 1.07 (95% CI: 0.84-1.36) favoring placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 months, HR=0.48; P<0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%). CONCLUSIONS: Due to the lack of survival benefit in the Rova-T arm, the study did not meet its primary endpoint and was terminated early. As a result, CRAC assessment of PFS was not performed. The frequency of Grade ≥3 and drug-related toxicities were higher with Rova-T vs placebo. Rova-T was associated with unique toxicities such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the ES SCLC population.
RCT Entities:
INTRODUCTION:Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting delta-like protein 3 (DLL3), an atypical Notch ligand expressed in small cell lung cancer (SCLC) tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive stage (ES) SCLC after platinum-based chemotherapy. METHODS:MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression following 4 cycles of platinum-based front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (q6wk, omitted every third cycle). Primary efficacy endpoints were progression-free survival (PFS) assessed by the Central Radiographic Assessment Committee (CRAC) and overall survival (OS) in DLL3-high patients. RESULTS: Median age of all randomized patients (N=748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the DLL3-high subset, the hazard ratio (HR) for OS was 1.07 (95% CI: 0.84-1.36) favoring placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 months, HR=0.48; P<0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%). CONCLUSIONS: Due to the lack of survival benefit in the Rova-T arm, the study did not meet its primary endpoint and was terminated early. As a result, CRAC assessment of PFS was not performed. The frequency of Grade ≥3 and drug-related toxicities were higher with Rova-T vs placebo. Rova-T was associated with unique toxicities such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the ES SCLC 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: 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