Antiangiogenic tyrosine kinase inhibitors and immunotherapy as first-line treatment for metastatic renal cell carcinoma: is there an increased risk of hypothyroidism?
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ABSTRACT:
SUBMITTER: Roviello G
PROVIDER: S-EPMC8273868 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The change in renal function induced by first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma remains unclear.One hundred and thirty-four patients were evaluated. Sunitinib (SU) and sorafenib (SO) were administered to 91 (67.9%) and 43 (32.1%) patients, respectively. The change in estimated glomerular filtration rate (?eGFR) was calculated as [(eGFR at each time point - pre-treatment eGFR)/pre-treatment eGFR] × 100. ?eGFR was compared between SU- and SO users using a mixed-effects model for repeated measures data with two or greater. Additionally, predictors for ?eGFR ? -10% at 6 months after therapy initiation were evaluated using multivariate logistic regression analysis.Throughout the 24 months after therapy initiation, ?eGFR was negatively greater in SU users, compared with that in SO users (P < 0.0001). In SU users, renal dysfunction was observed regardless of pre-treatment chronic kidney disease (CKD) status, whereas the magnitude of renal dysfunction was milder in SO users. In SO users without pre-treatment CKD, renal function did not significantly deteriorate. Moreover, ?eGFR ? -10% was more frequently observed in SU users after 3 months (P = 0.0121) and 6 months (P = 0.0009). Finally, SU usage was an independent predictor for ?eGFR ? -10% at 6 months (odds ratio 8.87, P = 0.0053), along with pre-treatment hypertension (odds ratio 4.69, P = 00072).Deterioration of renal function was stronger with SU than SO. During SU therapy, renal function should be monitored and pre-treatment kidney function should be taken into consideration for therapy selection.
| S-EPMC5896698 | biostudies-literature
Project description:PURPOSE:To investigate whether black race is an independent predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC). METHODS:We performed a retrospective 2-cohort (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] and trial-database) study of patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Unmatched (UM) and matched (M) analyses accounting for imbalances in region, year of treatment, age, and sex between races were performed. Cox models adjusting for histology, number of metastatic sites, nephrectomy, and IMDC risk compared time to treatment failure (TTF; IMDC cohort), progression-free survival (PFS; trial-database cohort), and OS. RESULTS:The IMDC cohort included 73 black versus 3,381 (UM) and 1,236 (M) white patients. The trial-database cohort included 21 black versus 1,040 (UM) and 431 (M) white patients. Median OS for black versus white patients was 18.5 versus 25.8 months in the IMDC group and 21.0 versus 25.6 months in the trial-database group. Differences in OS were not significant in multivariable analysis in the IMDC group (hazard ratio [HR]M, 1.0; 95% CI, 0.7 to 1.5; HRUM, 1.1; 95% CI, 0.8 to 1.4) and trial-database (HRM, 1.5; 95% CI, 0.8 to 2.7; HRUM, 1.4; 95% CI, 0.8 to 2.6) cohorts. TTF for black patients was shorter in the UM IMDC cohort (HRUM, 1.4; 95% CI, 1.1 to 1.8; P = .003), but not in the M analysis. PFS was shorter for black patients in both analyses in the trial-database cohort (HRM, 2.3; 95% CI, 1.4 to 3.9; P = .002; HRUM, 2.3; 95% CI, 1.4 to 3.9; P = .002). CONCLUSION:Black patients had more IMDC risk factors and worse outcomes with TKIs versus white patients. Race was not an independent predictor of OS. Strategies to understand biologic determinants of outcomes for minority patients are needed to optimize care.
| S-EPMC7055470 | biostudies-literature
Project description:ObjectiveThe purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor (TKI) as the first-line therapy for patients with metastatic renal cell carcinoma (mRCC) in terms of overall survival (OS), progression-free survival (PFS), and rates of discontinuation and adverse effects during the treatment period.MethodsThis is a retrospective, nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017. We focused on patients at either "favorable" or "intermediate" risk according to the International mRCC Database Consortium criteria, and they were followed up (median 335 days). Finally, a total of 1409 patients were selected as the study population. We generated a Cox proportional hazard model adjusted for covariates, and the different therapy schemes were statistically tested in terms of OS as well as PFS. In addition, frequencies of discontinuation and adverse events were compared among the therapy schemes.ResultsOf the primary patterns of treatment sequences (24 sequences), "sunitinib-pazopanib" and "sunitinib-everolimus-immunotherapy" showed the most beneficial results in both OS and PFS with significantly lower hazards than "sunitinib", which is the most commonly treated agent in Korea. Considering that the "TKI-TKI" structure showed relatively higher discontinuation rates with higher adverse effects, the overall beneficial sequence would be "sunitinib-everolimus-immunotherapy".ConclusionAmong several sequential therapy starting with TKIs, "sunitinib-everolimus- immunotherapy" was found to be the best scheme for mRCC patients with "favorable" or "intermediate" risks.
| S-EPMC11318389 | biostudies-literature
Project description:The treatment landscape of metastatic renal cell carcinoma (mRCC) has been transformed with the advent of antiangiogenics, notably tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR), and immune checkpoint inhibitors (ICIs). Both treatment options have improved outcomes of patients and modified the natural history of mRCC. Clinical investigations have focused on evaluating combination regimens containing ICIs and VEGFR-directed TKIs. Namely, the combinations of axitinib plus pembrolizumab (KEYNOTE-426) and axitinib plus avelumab (JAVELIN RENAL 101) have shown improved outcomes compared with sunitinib in treatment-naïve patients with mRCC. In this review, we discuss the clinical data of single-agent TKIs and ICIs in mRCC and the rationale for the combination ICIs and TKIs based on preclinical and clinical evidence. We also explore the current challenges for regimen selection and development of predictive biomarkers.
| S-EPMC7081462 | biostudies-literature
Project description:The introduction of targeted therapy a decade ago revolutionized the treatment of metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR). Currently recommended first-line treatments in Canada include sunitinib, pazopanib, and temsirolimus. With the heterogeneity of mRCC disease, the choice of treatment is driven largely by prognostic factors.
| S-EPMC5215299 | biostudies-other
Project description:Purpose: To investigate the effect of bone metastasis (BM) on survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKI) by performing propensity-score matching (PSM) analysis. Materials & Methods: We retrospectively reviewed 1,151 patients with mRCC who were treated with first-line TKI from December 2006 to September 2016. After excluding 135 patients, 1,016 patients with mRCC were finally analyzed. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. After 1:1 PSM analysis, survival outcomes were compared between patients with BM (n=237) and without BM (n=237). Multivariate Cox regression analysis was used to determine predictors of survival. Results: Among 1,016 total patients, 27.5% (n=279) had BM. Before PSM, patients with BM had worse OS outcomes than those without BM. Even after PSM, OS was significantly poorer in patients with BM compared to those without BM. Of note, the presence of BM was identified as an independent predictor of OS (HR=1.36), in addition to prior nephrectomy, sarcomatoid differentiation, and IMDC risk group. However, there were no differences in PFS according to the presence of BM after PSM. In the subgroup analysis, only intermediate IMDC risk group showed significant differences in OS according to the presence of BM. Conclusion: Based on PSM analysis, the presence of BM negatively affected OS outcomes in patients with mRCC treated with first-line TKI, particularly in the IMDC intermediate risk group.
| S-EPMC7646162 | biostudies-literature
Project description:IntroductionThis network meta-analysis aims to deliver an up-to-date, comprehensive efficacy and toxicity comparison of the approved first-line tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) in order to provide support for evidence-based treatment decisions. Previous NMAs of first-line mRCC treatments either predate the approval of all the first-line TKIs currently available or do not include evaluation of safety data for all treatments.MethodsWe performed a systematic literature review and network meta-analysis of phase II/III randomised controlled trials (RCTs) assessing approved first-line TKI therapies for mRCC. A random effects model with a frequentist approach was computed for progression-free survival (PFS) data and for the proportion of patients experiencing a maximum of grade 3 or 4 adverse events (AEs).ResultsThe network meta-analysis of PFS demonstrated no significant differences between cabozantinib and either sunitinib (50 mg 4/2), pazopanib or tivozanib. The network meta-analysis indicated that in terms of grade 3 and 4 AEs, tivozanib had the most favourable safety profile and was associated with significantly less risk of toxicity than the other TKIs.ConclusionThese network meta-analysis data demonstrate that cabozantinib, sunitinib, pazopanib and tivozanib do not significantly differ in their efficacy, but tivozanib is associated with a more favourable safety profile in terms of grade 3 or 4 toxicities. Consequently, the relative toxicity of these first-line TKIs may play a more significant role than efficacy comparisons in treatment decisions and in planning future RCTs.
| S-EPMC7004428 | biostudies-literature
Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. PATIENTS AND METHODS:This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used. RESULTS:Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. CONCLUSIONS:In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.
| S-EPMC7537491 | biostudies-literature
Project description:Since 2005, an abundance of targeted agents has been approved for the treatment of metastatic renal cell carcinoma (mRCC), without any specification as to what may be the most optimal first-line and second-line sequence. Hence, our objective was to critically examine the evidence supporting the use of first-line and second-line agents in the management of mRCC. Our review suggests that in first line, sunitinib and pazopanib represent treatment options for patients with favorable or intermediate-risk features and clear cell histology. Unfortunately, the Phase III trial cannot conclusively prove the noninferiority of pazopanib relative to sunitinib. Hence, the use of sunitinib as first-line standard of care remains justified. Pazopanib represents an option for specific patients in whom sunitinib might not be tolerated. In patients with poor-risk features, temsirolimus represents the only option supported with level 1 evidence. Less optimal alternatives include sunitinib and bevacizumab combined with interferon, based on the minimal inclusion of poor-risk patients in pivotal Phase III studies of these two molecules. In patients with non-clear cell mRCC, the use of temsirolimus is supported by Phase III data, unlike for any other molecule. In second line, the options consist of everolimus and axitinib. However, the axitinib data are substantially more robust given the inclusion of more patients considered as true second-line, and validly justify the choice of axitinib over everolimus. Nonetheless, the Phase III trial of everolimus may be considered as level 1 evidence for use as third-line or subsequent lines of therapy.
| S-EPMC4219683 | biostudies-literature
Project description:Approximately 20?30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment.
| S-EPMC6162741 | biostudies-literature