The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response.
This was a phase I to II trial on the combination of pazopanib with interferon-alpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease.
Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of follow-up, 24 (72.7%) patients were still alive. CCL2, IL8, TNF-α, and PD-L1 were significantly overexpressed after treatment initiation, while TGF-β1 and CCL5 were significantly decreased. TNF-α, endoglin, and PD-L1 expression are correlated with the response after treatment initiation.
The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A.
Clinical genitourinary cancer. 2022 Mar 18 [Epub ahead of print]
Xavier García-Del-Muro, Ignacio Durán, Jose Luis Perez-Gracia, Miguel Ángel Climent, Begoña Mellado, Juan A Virizuela, Daniel E Castellano, Aranzazu González Del Alba, Iciar García Carbonero, Carlos Álvarez-Fernández, Jesús García-Donas, Marta Gil-Martin, Alvaro-González Hernández
Medical Oncology Department, Institut Català d'Oncología, IDIBELL, University Of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: ., Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain., Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain., Medical Oncology Department, Fundación Instituto Valenciano de Oncología, Valencia, Spain., Medical Oncology Department, Hospital Clínic Barcelona, Barcelona, Spain., Medical Oncology Department, Hospital Universitario Virgen de la Macarena, Sevilla, Spain., Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain., Medical Oncology Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain., Medical Oncology Department, Hospital Virgen de la Salud, Toledo, Spain., Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain., Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain., Medical Oncology Department, Institut Català d'Oncología, IDIBELL, University Of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain., Biochemical Department. Clínica Universitaria de Navarra, Pamplona, Spain.