Rebecca Kristeleit1, Irina Davidenko2, Vadim Shirinkin3, Fatima El-Khouly4, Igor Bondarenko5, Michael J Goodheart6, Vera Gorbunova7, Carol A Penning8, Jack G Shi8, Xiangdong Liu8, Robert C Newton8, Yufan Zhao8, Janet Maleski8, Lance Leopold8, Russell J Schilder9. 1. University College London (UCL) Cancer Institute, UCL, London, UK. Electronic address: r.kristeleit@ucl.ac.uk. 2. Clinical Oncological Dispensary #1, Healthcare Department of Krasnodar Region, Krasnodar, Russia. 3. Orenburg Regional Clinical Oncology Dispensary, Orenburg, Russia. 4. University College London (UCL) Cancer Institute, UCL, London, UK. 5. MI Dnipropetrovsk City Multidiscipline Clinical Hospital No. 4, SI Dnipropetrovsk Medical Academy under the MOH of Ukraine, Dnipropetrovsk, Ukraine. 6. University of Iowa Hospitals and Clinics, Iowa City, IA, USA. 7. N. N. Blokhin Russian Cancer Research, Center of RAMS, Moscow, Russia. 8. Incyte Corporation, Wilmington, DE, USA. 9. Thomas Jefferson University, Philadelphia, PA, USA.
Abstract
OBJECTIVE:Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.
RCT Entities:
OBJECTIVE:Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifenpatients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.
Authors: Kunle Odunsi; Feng Qian; Amit A Lugade; Han Yu; Melissa A Geller; Steven P Fling; Judith C Kaiser; Andreanne M Lacroix; Leonard D'Amico; Nirasha Ramchurren; Chihiro Morishima; Mary L Disis; Lucas Dennis; Patrick Danaher; Sarah Warren; Van Anh Nguyen; Sudharshan Ravi; Takemasa Tsuji; Spencer Rosario; Wenjuan Zha; Alan Hutson; Song Liu; Shashikant Lele; Emese Zsiros; A J Robert McGray; Jessie Chiello; Richard Koya; Thinle Chodon; Carl D Morrison; Vasanta Putluri; Nagireddy Putluri; Donald E Mager; Rudiyanto Gunawan; Martin A Cheever; Sebastiano Battaglia; Junko Matsuzaki Journal: Sci Transl Med Date: 2022-03-16 Impact factor: 19.319