Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214

In the randomized, open-label, phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wk for four doses, then nivolumab 3 mg/kg every 2 wk) had superior efficacy over sunitinib (50 mg once daily, 4 wk on, 2 wk off) in patients with untreated International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk advanced renal cell carcinoma; the benefits were sustained through extended follow-up. To better characterize the association between outcomes and IMDC risk in CheckMate 214, we completed a post hoc analysis (n = 1051) of efficacy by the number of IMDC risk factors. The investigator-assessed objective response rate (ORR), overall survival (OS), and investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors v1.1 were evaluated. ORR with nivolumab plus ipilimumab was consistent across zero to six IMDC risk factors, whereas with sunitinib it decreased with increasing number of risk factors. Benefits of nivolumab plus ipilimumab over sunitinib in terms of ORR (40–44% vs 16–38%), OS (hazard ratio [HR] 0.50–0.72), and PFS (HR 0.44–0.86) were consistently observed in subgroups with one, two, three, or four to six IMDC risk factors (p < 0.05 for treatment × no. of risk factors interaction). These results demonstrate the benefit of first-line nivolumab plus ipilimumab over sunitinib across all intermediate-risk and poor-risk groups, regardless of the number of IMDC risk factors.Patient summaryThis report from the CheckMate 214 study describes a consistent efficacy benefit with first-line nivolumab plus ipilimumab over first-line sunitinib in all groups of patients with intermediate-risk or poor-risk advanced renal cell carcinoma, regardless of the number of risk factors they had before starting treatment. We conclude that there is a benefit of first-line treatment with nivolumab plus ipilimumab for all intermediate-risk patients, including those with one or two risk factors, and for all poor-risk patients, independent of the number of risk factors.     

Predictive impact of an early change in serum C-reactive protein levels in nivolumab therapy for metastatic renal cell carcinoma

ObjectiveTo investigate the predictive impact of a change in serum C-reactive protein (CRP) levels during the early phase of nivolumab therapy for metastatic renal cell carcinoma (mRCC).Patients and methodsSeventy mRCC patients treated with nivolumab after molecular-targeted therapy failure were retrospectively evaluated. Based on the CRP change, patients were classified as (1) normal: if pretreatment levels were <1 mg/dl; (2) normalized: if pretreatment levels were ≥1.0 mg/dl and nadir levels within the initial three months of nivolumab therapy declined to <1.0 mg/dl; and (3) non-normalized: if pretreatment levels were ≥1 mg/dl and nadir levels remained ≥1.0 mg/dl. The predictive association between the CRP change and progression-free survival (PFS) and overall survival (OS) after nivolumab initiation was evaluated.ResultsThe PFS was significantly lower in the non-normalized group (n = 25, 35.7%) than in the normal (n = 29, 41.4%) (median: 2.33 vs. 6.28 months, P = 0.0009) and normalized (n = 16, 22.9%) (2.33 vs. 8.38 months, P = 0.0006) groups, while no differences were observed between normal and normalized groups (P = 0.610). The OS was significantly lower in the non-normalized group than in the normal (8.02 months vs. not reached, P < 0.0001) and normalized groups (8.02 vs. 26.0 months, P = 0.0047); further, the OS of the normalized group was lower than that of the normal group (P = 0.0454). Multivariate analyses showed that the CRP change was an independent factor for PFS (P = 0.0025) and OS (P = 0.0009).ConclusionsThe CRP change during the early phase of nivolumab therapy was significantly associated with mRCC patient survival and may thus be used for outcome prediction.     

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk.Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.     

C-reactive protein and neutrophil-lymphocyte ratio are prognostic in metastatic clear-cell renal cell carcinoma patients treated with nivolumab

ObjectiveTo evaluate the impact of markers of systemic inflammation such as C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) on outcomes of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with nivolumab.Patients and methodsWe retrospectively evaluated m-ccRCC patients treated with nivolumab and collected known prognostic factors and survival data. We used Kaplan-Meier survival analysis and cox proportional hazards regression analysis to study prognostic factors for overall survival (OS) and progression-free survival (PFS) since start of nivolumab. Harrell's C-index was used to evaluate the models.ResultsWe included 113 patients. Median OS and PFS after initiation of nivolumab was 15 (interquartile range 7–28) and 4 months (interquartile range 3–11), respectively.Elevated baseline CRP was associated with worse OS (HR per 25 mg/l 1.35, 95% CI 1.16–1.52, P < 0.001) and PFS (HR per 25 mg/l 1.19, 95% CI 1.08–1.35, P = 0.001), independent from the international metastatic renal cell carcinoma database consortium (IMDC) prognostic criteria, increasing the model's C-index from 0.72 to 0.77 for OS and 0.59 to 0.62 for PFS.Elevated NLR was associated with worse OS (HR 1.10, 95% CI 1.04–1.17, P = 0.002) and PFS (HR 1.06, 95% CI 1.01–1.11, P = 0.03) independent from the other IMDC prognostic criteria. The model's C-index decreased from 0.72 to 0.70 for OS and increased from 0.59 to 0.60 for PFS.ConclusionsElevated baseline CRP and NLR predict worse OS and PFS on nivolumab in m-ccRCC patients. Including baseline CRP in the IMDC prognostic model improves its discriminatory power to predict OS and PFS since start of nivolumab.     

The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort

BackgroundTyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN).ObjectiveTo assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting.MethodsOverall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS).ResultsOverall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib (66%), followed by Sorafenib (20%) and Pazopanib (10%). After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis.ConclusionThe role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.     

PAK1 expression determines poor prognosis and immune evasion in metastatic renal cell carcinoma patients

BackgroundPrevious studies have shown the prognostic value of PAK1 expression in different tumor patients, including nonmetastatic renal cell carcinoma. In this study, we explored the prognostic and drug predictive value of PAK1 expression in metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs).Materials and MethodsWe retrospectively enrolled 138 mRCC patients treated with TKIs from a single institution from 2005 to 2014. Analyses were based on 111 patients who met our inclusion criteria. The validation set enrolled 538 RCC patients from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma cohort (TCGA KIRC) between 1998 and 2013 in North America. PAK1 expression was assessed by immunohistochemistry (IHC) on tissue microarrays.ResultsHigh PAK1 expression was associated with short overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.008). Multivariate analyses further indicated that PAK1 expression was an independent prognostic factor for OS (hazard ratio 3.301 [95% confidence interval 2.579–10.899], P < 0.001) and PFS (hazard ratio 3.108 [95% confidence interval 1.795–5.381], P < 0.001). Subgroup analyses suggested that PAK1 was more significant in patients with the intermediate risk group of Heng risk criteria (OS, P = 0.004). Of note, patients treated with Sunitinib showed improved outcome in the low PAK1 subgroup (OS, P = 0.002; PFS, P = 0.013). Finally, relationship was found between PAK1 expression and natural killer cell-mediated cytotoxicity according to gene profile investigation.ConclusionsHigh PAK1 expression predicted dismal prognosis in mRCC patients treated with TKIs. Besides, PAK1 was a potential predictor for TKIs treatments.     

A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy

BackgroundCytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy.ObjectiveTo evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy.Materials and methodsA multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality.ResultsThe study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2–79.8) compared to the ST alone group (19.1 months IQR 12.8–23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS.ConclusionsCN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.     

Association between prior nephrectomy and efficacy of immune checkpoint inhibitor therapy in metastatic renal cell carcinoma - A systematic review and meta-analysis

BackgroundImmune checkpoint-inhibitor (ICI)-based therapy is the standard of care for first-line treatment of metastatic renal cell carcinoma (mRCC). It is unclear whether prior removal of the primary tumor influences the efficacy of these treatments. We performed a systematic review and meta-analysis of studies of first-line ICI in mRCC to determine whether the efficacy of ICI-therapy, compared to sunitinib, is altered based on receipt of prior nephrectomy.MethodsWe systematically reviewed studies indexed in MEDLINE (PubMed), Embase, and Scopus and conference abstracts from relevant medical societies as of August 2020 to identify randomized clinical trials assessing first-line immunotherapy-based regimes in mRCC. Studies were included if overall survival (OS) and progression-free survival (PFS) outcomes were reported with data stratified by nephrectomy status. We pooled hazard ratios (HRs) stratified by nephrectomy status and performed random effects meta-analysis to assess the null hypothesis of no difference in the survival advantage of immunotherapy-based regimes based on nephrectomy status, while accounting for study level correlations.ResultsAmong 6 randomized clinical trials involving 5,121 patients, 3,968 (77%) had undergone prior nephrectomy. We found an overall survival benefit for immunotherapy-based regimes, compared to sunitinib, among both patients who had undergone nephrectomy (HR 0.75, 95% CI 0.63 –0.88) and those who had not (HR 0.74, 95% CI 0.59 –0.92), without evidence of difference based on nephrectomy history (P = 0.70; I² = 36%). Results assessing PFS were similar (P = 0.45, I² = 0%).ConclusionsThese clinical data suggest that prior nephrectomy does not affect the efficacy of ICI-based regimens in mRCC relative to sunitinib.     

Efficacy and safety of anti-vascular endothelial growth factor therapies in older patients for first line treatment of metastatic renal cell carcinoma

Backgroundimmunotherapy became the first line treatment of metastatic renal cell carcinoma (mRCC). Nevertheless, a better understanding of the specificities of targeted therapies (TT) in the elderly population could be helpful in order to improve the management of mRCC in this population. The aim of this retrospective study was to assess efficacy and safety of sunitinib and sorafenib used as first-line TT in 70 years older patients compared to younger patients.MethodsData were retrospectively collected for all consecutive mRCC patients receiving first line TT treatment by sunitinib or sorafenib for mRCC from January 2006 to November 2017. Patients were divided into two groups according to the age using a cut-off at 70 years old. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared using log-rank test.ResultsIn total, 147 patients were included; 94 (63.9%) were <70 and 53 (36.1%) were 70 years old or more. First line TT used was sunitinib in 123 (83.7%) patients or sorafenib in 24 (16.3%) patients. Median PFS was 8 months for elderly patients vs. 6 in younger group (P=0.68). Median OS were 26 vs. 36 months (P=0.08). Severe induced toxicity was more frequent among elderly patients: 34 (64.2%) vs. 46 patients (48.9%) (P=0.07). Rate of treatment discontinuation due to toxicity was 22 patients (23.4%) in younger group vs. 28 patients (52.8%) in the elderly group (P=0.0005). Results were similar in the 2 groups regarding the type of toxicities.ConclusionsOur results suggest similar efficacy of anti-vascular endothelial growth factor (VEGF) agents as first-line treatment for mRCC among younger and older patients with an age cut-off of 70 years. Safety results suggest that these drugs can be safely used for older patients with a need of caution regarding toxicity prevention.     

Albumin levels predict prognosis in advanced renal cell carcinoma treated with tyrosine kinase inhibitors: a systematic review and meta-analysis

PurposeWith the development of therapy and prognostic criteria for metastatic Renal Cell Carcinoma (mRCC), the prognostic value of serum albumin level has remained in dispute. The aim of this meta-analysis was to evaluate the role of pre-treatment albumin in predicting the prognosis of mRCC patients in the era of tyrosine kinase inhibitor (TKI) treatments.MethodsThe qualitative and quantitative synthesis was conducted of studies retrieved from PubMed, Embase, and Cochrane library from inception of these databases to July 19, 2020. The hazard ratio (HR) and its 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS) were extracted from studies comparing different levels of pre-treatment serum albumin (as a dichotomous or continuous variable) in mRCC patients treated with TKI agents.ResultsWithin 5,638 primitive records, 16 were eligible and 14 had adequate data for quantitative analysis (N = 2,863 participants). Random-effects meta-analysis showed that lower albumin was related to poorer OS (dichotomous: HR = 2.01, 95% CI: 1.64-2.46, P < 0.001, I² = 28.8%; continuous: HR =0.93, 95% CI: 0.86-1.00, P = 0.040, I² = 67.5%) and PFS (dichotomous: HR = 1.45, 95% CI: 1.04-2.01, P = 0.029, I² = 57.4%; continuous: HR = 0.89, 95% CI: 0.80-0.98, P = 0.023, I² = 93.3%).ConclusionLower pre-treatment serum albumin level is an independent adverse predictor of prognosis of mRCC patients receiving TKI therapy.RegistrationPROSPERO ID: CRD42020196802 Sep. 2^nd, 2020     

Efficacy of nivolumab plus ipilimumab as first-line therapy for primary tumors in patients with renal cell carcinoma

ObjectivesWith the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors.Methods and materialsWe retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP.ResultsThe median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1–6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%–60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391).ConclusionsSignificant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints.     

Preoperative apolipoprotein B/A1 ratio is an independent prognostic factor in metastatic renal cell carcinoma

Objectives

We aimed to explore the prognostic value of preoperative apolipoprotein B/apolipoprotein A1 (Apo B/A1) ratio in metastatic renal cell carcinoma (mRCC).

Efficacy and safety of immunological checkpoint inhibitors combined with anti-angiogenic drugs in first-line treatment of metastatic renal cell carcinoma: a systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) have shown promising results for the second-line treatment of metastatic renal cell carcinoma (mRCC). Several randomized controlled trials have so far also evaluated the efficacy of ICIs for first-line treatment of mRCC. In this study, we conducted a meta-analysis of relevant studies to further clarify the efficacy and safety of ICIs combined with anti-angiogenic drugs for the treatment of mRCC.MethodsWe searched the PubMed, Embase, and Cochrane libraries for RCT trials of ICIs combined with anti-angiogenic drugs for first-line treatment of mRCC published before November 20, 2019. A meta-analysis was conducted based on methodological recommendations by the Cochrane Collaboration.ResultsFour articles with a total of 2,967 patients met the inclusion criteria. Our meta-analysis revealed that progression-free survival (PFS) and objective response rate (ORR) were significantly improved in the experimental group while there was no significant difference in overall survival (OS) (HR 0.75, 95% CI: 0.67–0.84; HR 1.43, 95% CI: 1.07–1.91; HR 0.74, 95% CI: 0.53–1.03). After stratification for PD-L1 expression, OS, PFS, and ORR of PD-L1 positive patients were significantly increased in the experimental group (HR 0.74, 95% CI: 0.56–0.96; HR 1.66, 95% CI: 1.11–2.49; HR 0.65, 95% CI: 0.57–0.75).ConclusionsImmunological checkpoint inhibitors combined with anti-angiogenic drugs as a first-line treatment for mRCC improve PFS and ORR. This effect is more pronounced in PD-L1 positive patients, where ICIs also improve OS. ICIs do not increase the incidence of adverse events.     

Characterization of outcomes in patients with advanced genitourinary malignancies treated with immune checkpoint inhibitors

PurposeSeveral immune checkpoint inhibitors (ICIs) are FDA approved for treatment of genitourinary (GU) malignancies. We aim to determine demographic and clinicopathologic characteristics that significantly affect clinical outcomes in patients with advanced stage GU malignancies treated with ICIs.Materials and methodsWe performed a single-center, consecutive, retrospective cohort analysis on patients with metastatic or unresectable GU malignancies who were treated with ICIs at the University of Michigan. Immune-related adverse events (irAEs), putative immune-mediated allergies, and overall response rates (ORR) were assessed. Comorbidity index scores were calculated. Survival analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS), stratifying and controlling for a variety of clinicopathologic baseline factors including site of metastases.ResultsA total of 160 patients were identified with advanced renal cell carcinoma (RCC) or urothelial carcinoma. Median PFS and OS were 5.0 and 23.6 months for RCC, and 2.8 and 9.6 months for urothelial carcinoma, respectively. Patients who experienced increased frequency and higher grade irAEs had better ICI treatment response (P < 0.0001). Presence of liver metastases was associated with poor response to ICI therapy (P = 0.001). Multivariable modeling demonstrates that patients with urothelial carcinoma and liver metastases had statistically worse PFS and OS compared to patients with RCC or other sites of metastases, respectively.ConclusionGreater frequency and higher grades of irAEs are associated with better treatment response in patients with RCC and urothelial malignancy receiving ICI therapy. The presence of liver metastases denotes a negative predictive marker for immunotherapy efficacy.SummaryImmune checkpoint inhibitors (ICI) are increasingly used to treat genitourinary (GU) malignancies. However, clinical data regarding patients with advanced-stage GU malignancies treated with ICI is lacking. Thus, we performed a single-center, retrospective cohort study on patients with metastatic and unresectable renal cell carcinoma (RCC) and urothelial carcinoma who were treated with ICIs at the University of Michigan to provide demographic and clinicopathologic data regarding this population. We specifically focused on immune-related adverse events (irAEs), immune-mediated allergies, and the associated overall response rates (ORR). To better assess performance status, we calculated comorbidity scores for all patients. Finally, survival analyses for progression-free survival (PFS) and overall survival (OS) were performed using Kaplan-Meier analysis and Cox proportional hazards modeling, stratifying and controlling for clinicopathologic baseline factors, including sites of metastases, in our multivariable analysis. A total of 160 patients were identified with advanced RCC or urothelial carcinoma. We found decreased PFS (2.8 vs. 5.0 months) and decreased OS (9.8 vs. 23.6 months) for urothelial carcinoma compared to RCC patients. We noted that patients who experienced increased frequency and higher grades of irAEs had better treatment ORR with ICI therapy (P ≤ 0.0001). The presence of liver metastases was associated with worse ORR (P = 0.001), PFS (P = 0.0014), and OS (P = 0.0028) compared to other sites of metastases including lymph node, lung, and CNS/bone. The poor PFS and OS associated with urothelial carcinoma and liver metastases were preserved in our multivariable modeling after controlling for pertinent clinical factors. We conclude that greater frequency and higher grades of irAEs are associated with better treatment response in GU malignancy patients receiving ICI, a finding that is consistent with published studies in other cancers. The presence of liver metastases represents a significantly poor predictive marker in GU malignancy treated with ICI. Our findings contribute to the growing body of literature that seeks to understand the clinicopathologic variables and outcomes associated with ICI therapy.     

Impact of modified Glasgow prognostic score on predicting prognosis and modification of risk model for patients with metastatic renal cell carcinoma treated with first line tyrosine kinase inhibitor

Introduction and ObjectivesIntermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria is thought to consist of patients with different prognoses. This study investigated the impact of a pretreated modified Glasgow prognostic score (mGPS), which is defined on the basis of the pretreated serum albumin and C-reactive protein level, on predicting the prognosis of patients with metastatic renal cell carcinoma (mRCC) and its usefulness for the re-stratification of patients into a more improved risk model.Materials and MethodsOne hundred ninety-six mRCC patients treated with first-line tyrosine kinase inhibitor (TKI) were retrospectively investigated. All patients were classified into either a high-mGPS or a low-mGPS group on the basis of mGPS score upon starting systemic therapy, the overall survival (OS) and cancer specific survival (CSS) rates in each group were compared. We use decision curve analysis and calculate C-index based on OS and CSS to compare IMDC+mGPS model and IMDC model.ResultsThe categories of favorable, intermediate, and poor risk groups in the IMDC model were assessed in 32, 113, and 51 cases, respectively. The low- and high-mGPS groups consisted of 149 and 47 cases. The median OS in the high- and low-mGPS groups were 38.4 months and 5.6 months, and their median CSSs were 41.0 months and 5.6 months, respectively (P < 0.0001). Multivariate analysis showed that a high mGPS, multiple metastatic organs, and hypercalcemia were independent predictive factors for a worse OS (P = 0.0260). Next, we divided the intermediate risk group into two subgroups using the mGPS score. The OS and CSS for the high-mGPS subgroup were significantly worse than those for the low-mGPS one (P = 0.0024, median OS: 21.0 months and 33.7 months, P = 0.0007, median CSS: 21.0 months and 39.8 months), and there was no significant difference in OS between the high-mGPS subgroup in the intermediate risk group and poor risk group (P = 0.2250). The value of C-index based on OS at IMDC and IMDC+mGPS model were 0.6771 and 0.6967, and those based on CSS were 0.6850 and 0.7080, respectively. In decision curve analysis to evaluate the clinical net benefit using the IMDC+mGPS model compared to the IMDC model, there was no significant difference between the two groups.ConclusionmGPS is useful for establishing a more improved prognostic model that is able to stratify mRCC patients treated with first-line TKI.     

External validation of the REMARCC model for the selection of cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma: A multicenter retrospective study

ObjectivesThis study aims to evaluate the utility of the scoring system of the Registry for Metastatic Renal Cell Carcinoma (REMARCC) model on the overall survival (OS) of patients undergoing cytoreductive nephrectomy (CN).MethodsA total of 278 patients with primary metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019 were identified. The c-index and net benefit between the REMARCC score were compared with the International mRCC Database Consortium (IMDC) score in patients with CN (CN group, n = 146). The effect of the REMARCC score on OS was compared between the CN group and patients without CN (non-CN group, n = 132) using Cox regression analysis under the propensity score-based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances.ResultsOf the 146 patients with CN, the c-index of the REMARCC model (0.60) was higher than the IMDC model (0.54). The decision curve analysis showed the advantage of REMARCC model predicting OS compared with the IMDC model. OS was significantly longer in the REMARCC low-score (0–2) than that in the high-score (3–6) among the patients with CN. IPTW-adjusted Cox regression analyses showed that OS was significantly longer in the CN group than that in the non-CN group among the patients with REMARCC low-score but was not significantly different between the groups among the patients with REMARCC high-score.ConclusionsThe REMARCC score may be active for selecting the CN candidate in patients treated with TKIs.     

PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: Multicenter validation in patients from the Chinese Prostate Cancer Consortium

ObjectiveDocetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China. We have previously shown that time to nadir (TTN) of prostate-specific antigen (PSA) is an important prognostic factor in patients from a single center in Northwestern China. In this study, we performed a multicenter validation of the prognostic role of TTN in additional Chinese patients with mCRPC receiving docetaxel treatment.Materials and methodsThe data were gathered from 170 eligible Chinese patients who received docetaxel chemotherapy from January 2007 to October 2018 in 11 Chinese Prostate Cancer Consortium member hospitals in China. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS) and progression-free survival (PFS).ResultsPatients with a TTN ≥ 15 weeks had a longer OS and PFS compared to those with a TTN < 15 weeks (43 vs. 15 months, P < 0.001; 24 vs. 6 months, P < 0.001, respectively). In addition, Patients with a TTN ≥ 15 weeks and PSA nadir <4.55ng/ml were associated with longer OS than others (HR 0.093, 95% CI 0.044-0.188, P < 0.001; HR 4.002, 95% CI 1.890–8.856, P = 0.001, respectively) and TTN, PSA nadir, PSA baseline (optimal threshold 56.07 ng/ml), and PSA reduction (optimal threshold 50%) were associated with PFS (HR 0.238, 95% CI 0.149–0.382, P < 0.001; HR 1.676, 95% CI 1.033–2.722, P = 0.037; HR 1.770, 95% CI 1.134–2.763, P = 0.012; HR 0.573, 95% CI 0.428–0.756, P < 0.001; respectively). Furthermore, patients with a PSA nadir <4.55 ng/ml had longer OS and PFS compared to other patients when TTN was ≥15 weeks.ConclusionIn this multicenter validation study, TTN and PSA nadir remain important prognostic markers in predicting therapeutic outcomes in Chinese men who receive chemotherapy for mCRPC.     

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: A registry-based analysis

ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.     

Development of novel ACN (albumin,C-reactive protein and neutrophil-to-lymphocyte ratio) prognostication model for patients with metastatic renal cell carcinoma receiving first-line molecular-targeted therapy

PurposeThe objective of this study was to develop a novel prognostication model in patients with treatment-naïve metastatic renal cell carcinoma (mRCC).MethodsThis study included 325 consecutive mRCC patients receiving first-line molecular-targeted therapy at 4 institutions. Potential parameters associated with overall survival (OS) in these patients were investigated to develop a novel stratification model.ResultsMedian OS of the 325 patients was 38 months. A multivariable analysis of several factors identified independent predictors associated with unfavorable OS as follows: no previous nephrectomy, Karnofsky performance status <80%, albumin (Alb) ≤3.5 g/dl, C-reactive protein (CRP) >0.5 mg/dl and neutrophil-to-lymphocyte ratio (NLR) >3. Of these 5 independent OS predictors, 3 numeric factors were used to develop the ACN (Alb, CRP, and NLR) model by dividing patients into 3 groups according to the positive numbers of these 3 numeric risk factors. Median OS durations were 63, 37, and 11 months in the favorable (n = 105, 32.3%, without risk factors), intermediate (n = 88, 27.1%, with a single risk factor), and poor (n = 132, 40.6%, with multiple risk factors) risk groups, respectively. The ACN model as a prognostication tool was shown to be superior to the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models by both the concordance index and decision curve analysis.ConclusionsThe ACN model could stratify the prognostic risk of mRCC patients receiving first-line targeted therapy more accurately than the MSKCC and IMDC models.     

Posttherapeutic skeletal muscle mass recovery predicts favorable prognosis in patients with advanced urothelial carcinoma receiving first-line platinum-based chemotherapy

Objectives

Sarcopenia, decreased skeletal muscle mass (SMM), is an adverse prognostic factor in patients with advanced urothelial carcinoma (aUC). Given that SMM is variable depending on disease and patient conditions, changes in SMM over the course of treatments may be also prognostic. We investigated the prognostic role of posttherapeutic SMM recovery (PSR) in patients with aUC receiving first-line platinum-based chemotherapy.