Change in platelet count as a prognostic indicator for response to primary tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma.

OBJECTIVE: To evaluate change in platelet count as an indicator of response to primary tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: We conducted a multicentre retrospective analysis of patients with mRCC undergoing primary TKI therapy from May 2005 to August 2014. Change in platelet count was defined as post-treatment platelet count after the first cycle of treatment minus the pretreatment platelet count. Response Evaluation Criteria in Solid Tumours were used to define partial response (PR), stable disease (SD) and progressive disease (PD). Analysis was conducted between subgroups with stable/increased (+ΔPlt) and decreased (-ΔPlt) counts. The primary outcome was overall survival (OS), determined using Kaplan-Meier analysis. Multivariable analysis was conducted for risk factors associated with PD. RESULTS: A total of 115 patients with mRCC were analysed, of whom 19 (16.6%) had a +ΔPlt and 96 (83%) a -ΔPlt. More patients with a +ΔPlt had a Karnofsky score <80 (42.1 vs 14.6%; P = 0.005) and >2 metastatic sites (78.9 vs 51%; P = 0.041). More patients with +ΔPlt than with -ΔPlt had PD (89.4 vs 19.1%; P < 0.001) and more of those with -ΔPlt than with +ΔPlt had SD/PR (80.9 vs 10.6%; P < 0.001). Multivariable analysis showed that +ΔPlt (odds ratio [OR] 5.36, P < 0.001), Karnofsky score < 80 (OR 2.96, P = 0.002) and >2 metastatic sites at presentation (OR 1.87, P = 0.013) were risk factors for PD. Kaplan-Meier analysis showed a lower 5-year OS in patients with +ΔPlt than in those with -ΔPlt (23 vs 53%; P < 0.0001). +ΔPlt had a sensitivity of 48.6%, a specificity of 97.4%, a positive predictive value of 89.5% and a negative predictive value of 80.9% for PD. CONCLUSIONS: Patients with a -ΔPlt were more likely to respond to TKI therapy and had longer OS. +ΔPlt above baseline had a high specificity for PD after primary TKI. Further investigation is required to determine the utility of ΔPlt.

Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor-Based Immunotherapy.

Purpose: Tumor mutational burden detected by tissue next-generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response.Experimental Design: We assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived ctDNA NGS testing (54-70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), progression-free survival (PFS), and overall survival (OS) were assessed based on total and VUS alterations.Results: Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD ≥6 months/PR/CR 45% versus 15%, respectively; P = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 vs. <6). Statistically significant OS improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders versus nonresponders with VUS >3 had a median PFS of 23 versus 2.3 months (P = 0.0004).Conclusions: Given the association of alteration number on liquid biopsy and checkpoint inhibitor-based immunotherapy outcomes, further investigation of hypermutated ctDNA as a predictive biomarker is warranted. Clin Cancer Res; 23(19); 5729-36. ©2017 AACR.