We investigated the characteristics and outcomes of patients with muscle invasive bladder cancer treated with transurethral resection plus chemotherapy alone in a large observational cohort ...reflecting the continuum of practice settings in the United States.
In the National Cancer Database from 2004 to 2015 we identified 1,538 patients treated with transurethral resection plus multi-agent chemotherapy as definitive treatment of cT2-T4aN0M0 urothelial carcinoma of the bladder. For comparison purposes we included in study 17,866 patients treated with radical cystectomy with or without perioperative chemotherapy. Baseline characteristics were compared between the 2 groups by multivariable logistic regression. Treatment outcomes were assessed using Kaplan-Meier analysis and a Cox regression model.
On multivariate analysis several variables, including patient demography (older age, African American race, prior malignancy and lack of insurance), tumor characteristics (higher cT stage) and facility type (nonacademic facilities and lower radical cystectomy volume) were associated with a higher probability of transurethral resection plus chemotherapy for muscle invasive bladder cancer compared to the standard of care. Two and 5-year survival rates in all patients treated with transurethral resection plus chemotherapy were 49.0% and 32.9%, and in patients with cT2 disease the rates were 52.6% and 36.2%, respectively.
This large population level cohort of unselected patients shows that long-term survival can be achieved in a subset of patients treated with transurethral resection plus chemotherapy alone for muscle invasive bladder cancer. However, the best candidates for this approach remain to be defined. Ongoing clinical trials are now being launched to evaluate the ability of biomarkers to accurately select patients who could be treated with this bladder sparing strategy.
We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary ...(GU) malignances.
Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).
Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.
CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic ...urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown.
To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors.
We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated.
From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI −0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively.
Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes.
In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.
Restricted mean survival time estimates may be used to benchmark survival outcomes and inform future trial design.Programmed death-1 and programmed death ligand-1 blockade in patients with platinum-resistant metastatic urothelial cancer yield comparable survival outcomes.
The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical ...cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ.
KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.
Between April 12, 2016, and June 17, 2021, 132 patients (104 79% men and 28 21% women) who had received a median of ten (IQR 9–15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6–27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4–59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9–51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three 2% patients) and diarrhoea (in two 2%). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients 2%) was most common. No treatment-related deaths occurred.
Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial.
Merck Sharp & Dohme.
The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce ...quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies.
Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy.
MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.
Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of ...individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.
Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.
From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (
= 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months;
< 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (
= 0.045). PD-L1
CTCs on-therapy were associated with worse OS (
< 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category.
Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1
CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
PURPOSE Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal ...cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208 ). RESULTS The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI).
...A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability.
Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months 95% confidence interval (CI), 3.7-33.5, median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS.
CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.
•PET/MRI combines the benefits of Magnetic resonance imaging with functional imaging.•PET/MRI can detect metastatic bladder cancer lesions not seen on CT.•PET/MRI may be an option for patients that ...cannot receive contrast.•PET/MRI may lead to improved treatment planning and monitoring for bladder cancer.
Metastatic bladder cancer is an aggressive disease that can often be difficult to diagnose and stage with conventional cross-sectional imaging. The primary objective of this study was to determine the clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/MRI for surveillance and restaging of patients with muscle-invasive, locally advanced, and metastatic bladder cancer compared to conventional imaging methods.
This retrospective study enrolled patients with muscle-invasive, locally advanced and metastatic bladder cancer in a single institute evaluated with 18F-FDG PET/MRI. All patients also underwent conventional imaging with CT. Additional imaging may also have included 18F-FDG PET/CT (18F-FDG PET), or sodium fluoride (NaF) PET/CT in some patients. Images were reviewed by a diagnostic radiologist/nuclear medicine physician. Number of lesions and sites of disease were captured and compared between 18F-FDG PET/MRI and conventional imaging. Lesions were confirmed by sequential imaging or lesion biopsy. All patients were followed for survival.
Fifteen patients (4 for surveillance; 11 for restaging) underwent 34 18F-FDG PET/MRI scans. Each patient received a corresponding conventional CT around the time of the 18F-FDG PET/MRI (median 6 days). The 15 patients (11 male; 4 female) had a median age of 61.5 years (range 37–73) and histologies of urothelial carcinoma (n = 13) and small-cell carcinoma of the bladder (n = 2) diagnosed as stage 4 (n = 13), stage 3 (n = 1), or stage 2 (n = 1). 18F-FDG PET/MRI detected 82 metastatic malignant lesions involving lymph nodes (n = 22), liver (n = 10), lung (n = 34), soft tissue (n = 12), adrenal glands (n = 1), prostate (n = 1), and bone (n = 2) with a resultant advantage of 36% for lesion visibility in comparison with CT. Serial imaging or biopsy confirmed these lesions as malignant.
18F-FDG PET/MRI can detect metastatic lesions which cannot be identified on conventional CT, and this can allow for better treatment planning and improved disease monitoring during therapy.
Abstract Our group has previously reported that the majority of human melanomas (> 60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug ...currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo . Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.
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