receiving sunitinib subsequently crossed over to the combination and achieved an overall response rates of 28%. These outcomes suggest encouraging activity for the combination of atezolizumab + bevacizumab in both the first- and second-line setting for patients with metastatic RCC.4 Multikinase inhibitor and everolimus. CM082A small phase I study tested the combination of CM082, a novel oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination with other therapies, everolimus in patients with metastatic renal cell carcinoma. At 200mg dose level, partial responses were noted in 5/14 (36%) patients, with a disease control rate of 71%. The median PFS was noted to be 5.7 months in this cohort. Toxicities were manageable, as well, warranting further investigation of this novel agent and combination.5 Pazopanib and pembrolizumab. Chowdhury et al reported the results of a small phase I/II study evaluating the combination of pazopanib and pembrolizumab. Overall, 35 patients were tested with combinations of pemborlizumab 2mg/kg and pazopanib at 600mg or 800mg; one cohort was treated with a sequential strategy of single-agent pazopanib followed by the combination. The study found that 80-90% of the patients in each cohort experienced grade 3 or 4 toxicities, especially hepatotoxicity, severely limiting the utility of this novel combination. 6 Synergistic Effects With Radiation, Check Point Inhibitors In addition to combinations of systemic therapies, preclinical data suggests that there are synergistic effects between radiation therapy and check point inhibitors. Lin and colleagues sought to explore the immunomodulatory activity of radiation therapy alone or in combination with pembrolizumab in solid tumors, including renal cell cancer. Twelve RCC patients who had progressed after first-line therapy received radiation therapy (8Gy x 1 or 4Gy x 5) followed by pembrolizumab or 1 dose pembrolizumab followed by radiation therapy then were given another dose of pemproliumab. Pre- and post- radiation tumor biopsies were obtained to evaluate PD-L1 expression and flow cytometry was performed before, during, and after treatment to assess immune markers. Grade 3 adverse effects experienced included fatigue, nausea, hyperglycemia, lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets). Five patients had stable disease of 18 to 45 weeks and 4 patients had progression within 9 weeks. Preliminary flow cytometry findings showed consistently higher numbers of monocytes in non-responders compared to responders. CD4+, CD8+ and NK cells and other markers are also being analyzed. Overall, these results suggest that the combination of radiation therapy with pembrolizumab is tolerable while exhibiting clinical worth. Additionally, the adverse effect profile was not dramatically different when compared 54 Kidney Cancer Journal to single agent pembrolizumab.7 Encouraging Progress on Biomarkers Finding clinically useful biomarkers in RCC has been a thorn in the side of researchers for decades now, still with no suitable candidates finding their way into standard daily practice. But a few studies presented do try to make some headway in this area. A study presented by Escuider sought to validate the 16-gene Recurrence Score in 212 patients with high-risk stage III disease from S-TRAC trial. Primary tissue from these patients was analyzed and it was found that time to recurrence and disease-free survival in patients receiving sunitinib or placebo were significantly predicted using the Recurrence Score. No significant interaction was reported between treatment and the Recurrence Score. The results further support the value of the Recurrence Score, which can be used to identify high-risk patients who may benefit from adjuvant treatment. Further studies to determine the predictive value of the score are necessary before it can be clinically used to select patients for adjuvant therapies. 8 In the pursuit of reliable biomarkers in metastatic RCC patients, Arafat and colleagues reported on the development and clinical validation of predictive circulating tumor cell (CTC) biomarkers that will be assessed in the OMNIVORE trial. Findings show that CTC frequency and PDL1/HLA expression are lower in nivolumab responders versus patients with early progression. High but variable HLA expression suggests resistance mechanisms are variable. CTCs were found in 26 out of 27 patients using the RCC-specific CA IX antibody. Staining with CAXII and PAX8 confirmed CTC were of renal origin. The findings report the identification of clear cell RCC circulating tumor cells using CAIX, CAXII and PAX8 as confirmatory markers. The authors plan to further study the usefulness of these biomarkers in the phase II OMNIVORE trial, which examines ipilumimab efficacy in patients with stable or progressive disease on nivolumab alone.9 Adjuvant Therapy: New Results From PROTECT Of course, an effective adjuvant therapy for RCC has been an elusive holy grail sought after almost as much as a reliable biomarker. Results of a randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy, called the PROTECT study, were presented. This large study included 1538 subjects with locally advanced RCC post-nephrectomy who were randomized to receive pazopanib vs placebo for 1 year following surgery. The dose of pazopanib had to be decreased from 800 mg to 600 mg to improve tolerability, and the primary endpoint of the study was changed to disease-free survival in 1135 patients. In the intent-to-treat population with the 800-mg dose a 31% reduced risk of recurrence was reported and in the much larger group of patients treated with 600mg a 20% reduction in risk of recurrence was noted; however, the primary endpoint was not met with pazopanib 600 mg. Treatment was discontinued frequently due to transaminitis. 10
20291GA
To see the actual publication please follow the link above