Sumanta K Pal1, Andres Forero-Torres2, John A Thompson3, John C Morris4, Saurabh Chhabra5, Christopher J Hoimes6, Nicholas J Vogelzang7, Thomas Boyd8, Paulo G Bergerot1, Jacob J Adashek1, Hong Li9, Xuesong Yu9, Elaina M Gartner9, Anne-Sophie Carret9, David C Smith10. 1. Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California. 2. Division of Hematology/Clinical Oncology, University of Alabama at Birmingham, Birmingham, Alabama. 3. Seattle Cancer Care Alliance/University of Washington, Seattle, Washington. 4. University of Cincinnati Cancer Institute, Cincinnati, Ohio. 5. Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. 6. University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio. 7. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada. 8. North Star Lodge Cancer Care Center, Yakima Valley Memorial Hospital, Yakima, Washington. 9. Seattle Genetics, Inc, Seattle, Washington. 10. University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Abstract
BACKGROUND: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC. METHODS: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response. RESULTS: The maximum tolerated dose was determined to be 30 μg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential. CONCLUSIONS: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.
BACKGROUND: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC. METHODS: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response. RESULTS: The maximum tolerated dose was determined to be 30 μg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential. CONCLUSIONS: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.
Authors: Jacob J Adashek; Joshua J Breunig; Edwin Posadas; Neil A Bhowmick; Leigh Ellis; Stephen J Freedland; Hyung Kim; Robert Figlin; Jun Gong Journal: Drugs Date: 2022-02-17 Impact factor: 9.546
Authors: David A Braun; Ziad Bakouny; Laure Hirsch; Ronan Flippot; Eliezer M Van Allen; Catherine J Wu; Toni K Choueiri Journal: Nat Rev Clin Oncol Date: 2021-01-12 Impact factor: 66.675
Authors: Aleksandar Obradovic; Nivedita Chowdhury; Scott M Haake; Casey Ager; Vinson Wang; Lukas Vlahos; Xinzheng V Guo; David H Aggen; W Kimryn Rathmell; Eric Jonasch; Joyce E Johnson; Marc Roth; Kathryn E Beckermann; Brian I Rini; James McKiernan; Andrea Califano; Charles G Drake Journal: Cell Date: 2021-05-20 Impact factor: 66.850
Authors: Tal Flieswasser; Astrid Van den Eynde; Jonas Van Audenaerde; Jorrit De Waele; Filip Lardon; Carsten Riether; Hans de Haard; Evelien Smits; Patrick Pauwels; Julie Jacobs Journal: J Exp Clin Cancer Res Date: 2022-01-06