title: Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab.
abstract: Purpose:A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.Experimental Design:A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC).Results:A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n= 20) and other sarcomas (n= 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively.Conclusions:Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy.Clin Cancer Res; 23(12); 2972-80. ©2016 AACR.
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. dangelos@mskcc.org.|Weill Cornell Medical College, New York, New York.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: D'Angelo
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Shoushtari
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Mary Louise
authors.initials: ML
authors.lastname: Keohan
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Gounder
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Loo
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leigh
authors.initials: L
authors.lastname: Gaffney
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lee
authors.initials: L
authors.lastname: Schneider
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zarine
authors.initials: Z
authors.lastname: Patel
authors.affiliation: Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Joseph Patrick
authors.initials: JP
authors.lastname: Erinjeri
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bluth
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ana
authors.initials: A
authors.lastname: Sjoberg
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
authors.forename: Howard
authors.initials: H
authors.lastname: Streicher
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, Rockville, Maryland.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.affiliation: Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Cristina
authors.initials: C
authors.lastname: Antonescu
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
authors.affiliation: Columbia University Medical Center, New York, New York.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
mesh_terms: D000328:Adult; D000368:Aged; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D000069439:Dasatinib / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004357:Drug Synergism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D000074324:Ipilimumab / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib