Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in ...RCC.
Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed.
Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; P<0.05).
RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.
Immunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses ...after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy.
The Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This
analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS.
Overall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 - 10.1), while mPFS was 7.0 months (95% CI: 5.7 - 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months;
< 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%;
= 0.075) and disease control rate (61.3% vs 55.5%;
= 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59).
We found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.
Abstract
Background
Severe immune-related Adverse Events (irAEs) develop in 10–27% of patients treated with Immune-Oncology (IO) Powles (Lancet 391:748–757, 2018); Galsky (Lancet 395:1547–1557, ...2020); Haanen (Ann Oncol 28:119–142, 2017). The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs.
Methods
We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3–G4 toxicities have been included as control group.
Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3–4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago).
Results
18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6–2.1), mPFS was 7.4 months (95% CI 3.16–11.6) and mOS was 15.5 months (5.1–25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5–5.6), mPFS was 4.6 months (95% CI 3.5–5.6) and mOS was 19.6 months (95% CI 15.1–24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0–5.9) and mOS was 19.6 months (95% CI 15.1–24.0).
Conclusions
ICIs seem to maintain efficacy even after early interruption due to severe irAE.
Purpose of Review
The aim of this review is to sum up the state of the art of urachal carcinoma (UC) in order to easily guide clinicians.
Recent Findings
UC is a rare and aggressive disease with ...consequent few data about diagnosis and treatment. Dates are mainly based on retrospective trial and case reports with limited prospective trial. Clinical presentation is not specific, often with urinary symptoms. Diagnosis is mainly based on CT scan and MRI, useful to evaluate local invasion and nodal status and to detect the presence of distant metastases. Therefore, biopsy is needed to obtain histological confirmation. Surgery is the gold standard for localized disease, while different chemotherapy schemes have been used in metastatic setting.
Summary
Novel findings based on mutational analysis of the tumor include the use of biological treatment, such as cetuximab, and immunotherapy, such as atezolizumab, with satisfactory responses, suggesting that personalized treatment could be the most suitable option for UC.
Abstract
Background
Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma ...(mccRCC).
Methods
Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings.
Results
A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004).
Conclusions
The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.
Background:
Immune checkpoint inhibitors (ICIs) are currently the standard of care for metastatic urothelial cancer (mUC) after the failure of previous platinum-based chemotherapy. The choice of ...further therapy after ICI progression is a new challenge, and scarce data support it. We aimed to examine the outcomes of mUC patients after progression to ICI, especially when receiving chemotherapy.
Methods:
Data were retrospectively collected from clinical records of mUC patients whose disease progressed to anti-programmed death 1 (PD-1)or programmed death ligand 1 (PD-L1) therapy at 14 Italian centers. Patients were grouped according to ICI therapy setting into SALVAGE (ie, ICI delivered ⩾ second-line therapy after platinum-based chemotherapy) and NAÏVE (ie, first-line therapy) groups. Progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared among subgroups. Cox regression assessed the effect of treatments after progression to ICI on OS. Objective response rate (ORR) was calculated as the sum of partial and complete radiologic responses.
Results:
The study population consisted of 201 mUC patients who progressed after ICI: 59 in the NAÏVE cohort and 142 in the SALVAGE cohort. Overall, 52 patients received chemotherapy after ICI progression (25.9%), 20 (9.9%) received ICI beyond progression, 115 (57.2%) received best supportive care only, and 14 (7.0%) received investigational drugs. Objective response rate to chemotherapy in the post-ICI setting was 23.1% (28.0% in the NAÏVE group and 18.5% in the SALVAGE group). Median PFS and OS to chemotherapy after ICI-PD was 5 months (95% confidence interval CI: 3-11) and 13 months (95% CI: 7-NA) for the NAÏVE group; 3 months (95% CI: 2-NA) and 9 months (95% CI: 6-NA) for the SALVAGE group, respectively. Overall survival from ICI initiation was 17 months for patients receiving chemotherapy (hazard ratio HR = 0.09, p < 0.001), versus 8 months for patients receiving ICI beyond progression (HR = 0.13, p < 0.001), and 2 months for patients who did not receive further active treatment (p < 0.001).
Conclusions:
Chemotherapy administered after ICI progression for mUC patients is advisable irrespective of the treatment line.
Clear cell renal carcinoma (ccRCC) can occur in young people and could be associated with an aggressive behavior. While for the first-line treatment in metastatic disease, there is an agreement to ...rely on an immunotherapy (IO)-based combination regimen, no standard second-line regimens exist. Generally, tyrosine kinase inhibitors (TKIs) are employed, even in sequence, although no trials have demonstrated yet the best succession. Herein, we present the case of a 39-year-old male, with a very aggressive ccRCC with somatic
mutation and distant metastases at diagnosis. He was treated with four different lines of therapies, including TKIs, with progressive multiple tumor deposits. Lenvatinib alone as the fifth line was able to induce a remarkable and prolonged tumor shrinkage with manageable toxicities.
Abstract
Objective
Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this ...study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials.
Methods
Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan–Meier curves, log-rank test and multivariable Cox’s models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose.
Results
Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium’s good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium’s favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged.
Conclusions
In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium’s favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium’s good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.
The PAMERIT study retrospectively confirmed first-line pazopanibas active, efficacious, safe and cost-effective in the real-worldmRCC patients, particularly in IMDC good prognosis patients.
Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, ...elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care.
Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received ≥1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0.
A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported.
The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.
Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous histological group which is 20-25% of those with renal cell carcinoma (RCC). Patients with nccRCC have limited therapeutic ...options due to their exclusion from phase III randomized trials. The aim of the present study was to investigate the effectiveness and tolerability of pembrolizumabaxitinib combination in chromophobe and papillary metastatic RCC (mRCC) patients enrolled in the I-RARE (Italian Registry on rAre genitor-uRinary nEoplasms) observational ongoing study (Meet-URO 23). Baseline characteristics, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) and toxicities were retrospectively and prospectively collected from nccRCC patients treated in 14 Italian referral centers adhering to the Meet-Uro group, from December 2020 to April 2022. Only patients with chromophobe and papillary histology were considered eligible for the present pre-specified analysis. There were 32 eligible patients who received pembrolizumab-axitinib as first-line treatment, of whom 13 (40%) had chromophobe histology and 19 (60%) were classified as papillary RCC. The DCR was 78.1% whereas ORR was 43.7% (11 patients achieved stable disease and 14 patients obtained partial response: 9/19 papillary, 5/13 chromophobe). Six patients (18.7%) were primary refractory. Median PFS was 10.8 months (95%CI 1.7-11.5). Eleven patients (34.3%) interrupted the full treatment due to immune-related adverse events (irAEs): G3 hepatitis (n = 5), G3 hypophisitis (n = 1), G3 diarrhea (n = 1), G3 pancreatitis (n = 1), G3 asthenia (n = 1). Twelve patients (37.5%) temporarily interrupted axitinib only due to persistent G2 hand-foot syndrome or G2 hypertension. Pembrolizumab-axitinib combination could be an active and feasible first-line treatment option for patients with papillary or chromophobe mRCC.
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