Sumanta Kumar Pal1, Dewan Md Sakib Hossain2, Qifang Zhang2, Paul Henry Frankel3, Jeremy O Jones4, Courtney Carmichael5, Christopher Ruel3, Clayton Lau6, Marcin Kortylewski2. 1. Department of Medical Oncology and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. Electronic address: spal@coh.org. 2. Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. 3. Department of Biostatistics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. 4. Department of Molecular Pharmacology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. 5. Department of Medical Oncology and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. 6. Department of Urology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
Abstract
PURPOSE: Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood. MATERIALS AND METHODS: Study eligibility was limited to patients with 2 prior lines of therapy, including at least 1 vascular endothelial growth factor directed therapy, as well as ECOG performance status 0 to 2 and clear cell histology. Patients received pazopanib 800 mg daily. A Simon minmax 2-stage design was used with 80% power to determine an encouraging 23% overall response rate (10% type I error). Immunological profiles were assessed monthly on a Luminex® platform using the Human Cytokine 30-Plex Cytokine Immunoassay (Invitrogen™). RESULTS: A total of 28 patients with a median age of 63 years (range 45 to 86) were enrolled in study. Of the patients 12 (43%) had a confirmed complete (1) or partial (11) response. In the cohort median progression-free survival was 16.5 months (95% CI 14.7-not reached). The most common grade 3/4 toxicities were hypertension (46% of cases) and proteinuria (14%). At 6 and 12 months responders had lower levels of HGF, VEGF, IL-6 and 8, and soluble IL-2R (each p <0.05). Nonresponders also showed increased numbers of myeloid-derived suppressor cells at each interval. Phenotypic and functional studies confirmed that the myeloid-derived suppressor cells were granulocytic. CONCLUSIONS: Progression-free survival and the overall response rate associated with third line pazopanib were encouraging. Immunological profile differences between responders and nonresponders suggest that the mechanism of pazopanib resistance is at least partly related to the generation of systemic tumor immune tolerance.
PURPOSE:Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood. MATERIALS AND METHODS: Study eligibility was limited to patients with 2 prior lines of therapy, including at least 1 vascular endothelial growth factor directed therapy, as well as ECOG performance status 0 to 2 and clear cell histology. Patients received pazopanib 800 mg daily. A Simon minmax 2-stage design was used with 80% power to determine an encouraging 23% overall response rate (10% type I error). Immunological profiles were assessed monthly on a Luminex® platform using the Human Cytokine 30-Plex Cytokine Immunoassay (Invitrogen™). RESULTS: A total of 28 patients with a median age of 63 years (range 45 to 86) were enrolled in study. Of the patients 12 (43%) had a confirmed complete (1) or partial (11) response. In the cohort median progression-free survival was 16.5 months (95% CI 14.7-not reached). The most common grade 3/4 toxicities were hypertension (46% of cases) and proteinuria (14%). At 6 and 12 months responders had lower levels of HGF, VEGF, IL-6 and 8, and soluble IL-2R (each p <0.05). Nonresponders also showed increased numbers of myeloid-derived suppressor cells at each interval. Phenotypic and functional studies confirmed that the myeloid-derived suppressor cells were granulocytic. CONCLUSIONS: Progression-free survival and the overall response rate associated with third line pazopanib were encouraging. Immunological profile differences between responders and nonresponders suggest that the mechanism of pazopanib resistance is at least partly related to the generation of systemic tumor immune tolerance.
Authors: Dewan M S Hossain; Sumanta K Pal; Dayson Moreira; Priyanka Duttagupta; Qifang Zhang; Haejung Won; Jeremy Jones; Massimo D'Apuzzo; Stephen Forman; Marcin Kortylewski Journal: Clin Cancer Res Date: 2015-05-12 Impact factor: 12.531
Authors: Michela Roberto; Maria Bassanelli; Elsa Iannicelli; Silvana Giacinti; Chiara D'Antonio; Anna Maria Aschelter; Paolo Marchetti Journal: Case Rep Oncol Med Date: 2015-12-20