Enfortumab vedotin (EV) is an antibody–drug conjugate approved alone and in combination with pembrolizumab for advanced urothelial cancer (UC). EV-related-cutaneous-events (EVCEs) are common and ...rarely life-threatening. Black patients are frequently under-represented in oncology trials, and dermatologic conditions may vary with race.
Therefore, this retrospective analysis investigated differences in EVCE frequency between Black and White patients in an urban cohort (Johns Hopkins JH) and a US-based, nationwide electronic health record (EHR)-derived deidentified database (Flatiron Health FH) with sub-group analysis of those who had received prior pembrolizumab.
The study included 12 Black patients in the JH Cohort (17.1%) and 24 Black patients in the FH Cohort (7.6%). In both cohorts, the frequency of EVCEs among Black patients was higher compared to White patients (JH: 66.7% vs. 33.3%; FH: 25.0% vs. 15.8%), though not statistically significant. In the larger FH Cohort EVCEs were significantly more common among Black compared to White patients treated with prior pembrolizumab (Odds Ratio OR: 4.76 95%CI: 1.42, 15.95) and recent pembrolizumab (within 90 days of EV initiation) (OR 9.00 95%CI: 1.94, 41.66).
This hypothesis-generating retrospective study, comprising the largest population of EV-treated Black patients reported to date, emphasizes the importance of attentiveness to EVCEs among Black patients, particularly with receipt of pembrolizumab.
This retrospective study compared the frequency of enfortumab vedotin (EV) - related cutaneous events (EVCEs) between Black and White patients in 2 real-world cohorts. EVCEs were more common among Black patients who had received prior pembrolizumab, suggesting that further study of these events in this population, frequently under-represented in oncology trials, is warranted.
Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after ...platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial cancer. Despite this ample target, clinical benefit is not achieved by all patients, and mechanisms of treatment resistance are undescribed. Herein we summarize what is known to date regarding coorelative findings and subgroup analysis and EV response, including novel biopsy data in patients with tumor progression post EV.
The ideal number of neoadjuvant chemotherapy (NAC) cycles for muscle-invasive bladder cancer is uncertain with 3 to 4 representing the standard of care (SOC). We compared ypT0 rates and survival ...between patients receiving 4 versus 3 cycles of NAC with evaluation of chemotherapy-related toxicity for correlation with tumor chemosensitivity and pathological response.
Patients receiving NAC followed by radical cystectomy for cT2-4N0M0 urothelial carcinoma from 2 institutions were included. Primary study groups included 4 cisplatin-based NAC cycles, 3 cisplatin-based NAC cycles, and nonSOC NAC (1-2 cycles or noncisplatin-based) to compare ypT0/≤ypT1 rates and survival. A cohort of patients not receiving NAC was included for pathological reference.
Of 693 total patients, 318 (45.9%) received NAC. ypT0 and ≤ypT1 rates were 42/157 (26.8%) and 86/157 (54.8%) for 4 cycles, 38/114 (33.3%) and 71/114 (62.3%) for 3 cycles, and 6/47 (12.8%) and 13/47 (27.7%) for nonSOC (p=0.03 and p <0.01, respectively). Pathological response appeared higher among patients receiving 3 cycles due to toxicity (ypT0: 29/77 37.7%; ≤ypT1: 51/77 66.2%) but did not reach statistical significance. Toxicities leading to treatment modifications were thrombocytopenia (32.1%), neutropenia (27.2%), renal insufficiency (22.2%), and constitutional symptoms (18.5%). NonSOC patients had lower Kaplan-Meier survival (cT2-cT4N0M0: log-rank p=0.07; cT2N0M0: log-rank p=0.02). There were no statistically significant differences in survival between 4 and 3 cycles (HR 1.00 95% CI 0.57-1.74, p=0.99).
Patients completing 3 cycles of cisplatin-based NAC have similar pathologic response and short-term survival compared to 4 cycles. Further evaluation of patients experiencing toxicity as a potential marker of tumor chemosensitivity is needed.
Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of refractory advanced urothelial cancer. Cutaneous toxicity is well described but has not been correlated with ...response. In this retrospective single-center study, data from patients treated with more than one dose of EV between December 2017 and June 2022 were analyzed. Of 56 patients with a median age of 69 yr, 41 (73.2%) were male and 27 (48.2%) had any-grade skin toxicity. For all 51 patients evaluable by physician-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the response rate was 41.2%. For those with cutaneous toxicity, the response rate was 57.7%; for those without cutaneous toxicity, it was 24.0% (p = 0.0145). All three patients with complete response experienced cutaneous toxicity, and two of these responses remain durable 5 and 24 mo off EV. The median starting weight and body mass index (BMI) were, respectively, 80.86 kg and 26.53 kg/m2 among patients with cutaneous toxicity, and 69.37 kg and 23.29 kg/m2 in patients without (p = 0.0129 and 0.0014, respectively). In this small dataset, EV-related cutaneous toxicity was more common in patients with higher weight and BMI at baseline, and was associated with disease response. Confirmation in prospective trials may confirm this association and lead to an important clinical biomarker of response.
We evaluated patients with urothelial cancer who were treated at our institution with enfortumab vedotin (EV). We found that patients who experienced the common side effect of any type of skin toxicity, such as rash or itching, were more likely to have improvement in their cancer from EV treatment than those who did not experience skin toxicity. Patients with higher weight and body mass index when starting EV tended to have more skin toxicity. We conclude that presence of skin toxicity might help doctors make decisions about how to manage the care of patients with EV in the future.
Background
Inhibition of the programmed cell death protein 1 (PD‐1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight ...the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid‐derived suppressor cells (MDSCs) and improve T‐cell activation.
Methods
The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum‐Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE‐ST‐005) was a randomized phase 2 trial evaluating the PD‐1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum‐refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression‐free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells.
Results
Seventy‐five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response CR) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment.
Conclusions
Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on‐treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T‐cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue‐based immune cell infiltration.
In this randomized phase 2 study of metastatic urothelial cancer, a combination of pembrolizumab and a Bruton tyrosine kinase inhibitor (acalabrutinib) does not improve clinical outcomes in comparison with pembrolizumab alone. Comprehensive flow cytometry is used to evaluate circulating immune cells during treatment.
On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and ...atezolizumab anti-programmed cell death ligand 1 (PD-L1) together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy.
We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors.
Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients' plasma was associated with short survival.
No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.
Abstract Purpose The purpose of the study was to characterize the contemporary trends in lymphadenectomy for the treatment of upper tract urothelial carcinoma in a population-based cohort and to ...determine if number of lymph nodes removed and tumor location are predictors of cancer-specific survival in patients undergoing nephroureterectomy. Materials and methods Individuals with upper tract urothelial carcinoma undergoing nephroureterectomy in the Surveillance, Epidemiology, and End Results program from 2004 to 2012 were identified. Linear regression was used to assess trends in lymphadenectomy. Patients were stratified based on nodal status, quartiles of nodes removed, and tumor location. Kaplan-Meier analysis, log-rank tests, and Cox proportional hazards models were used to compare cancer-specific survival and overall survival among groups. Results In the cohort, 25% (721/2,862) of all patients and 27% (566/2,079) of grade 3/4 patients underwent lymphadenectomy. The percentage of patients undergoing lymphadenectomy increased from 20% (60/295) in 2004 to 33% (106/320) in 2012 ( P = 0.02). Patients with the highest quartile of lymph nodes removed had improved the 5-year cancer-specific survival of 78% (95% CI: 69%–85%) compared to the second quartile (60%; 95% CI: 51%–67%; P = 0.003) and the third quartile (60%; 95% CI: 51%–68%; P = 0.002) of nodes removed. This trend held for node-negative and node-positive patients. In multivariable modeling, a lower number of lymph nodes dissected (hazard ratio = 0.94, 95% CI: 0.91–0.98) and ureteral tumors (hazard ratio = 1.29, 95% CI: 1.07–1.56) were predictors of worse cancer-specific survival. Conclusions In patients with upper tract urothelial carcinoma undergoing nephroureterectomy, rates of lymphadenectomy have increased from 2004 to 2012 in the United States. In this contemporary cohort, an increase in the number of nodes removed and renal pelvis tumors are associated with improved cancer-specific survival, which highlights the importance of intentional lymph node dissection with adequate lymph node yield in these patients.
Abstract Tremendous advances in our understanding of the tumor immunology and molecular biology of urothelial carcinoma (UC) have led to the recent approval of immunotherapy as a novel option for ...patients with UC with advanced disease. Despite the promising data of novel immune checkpoint inhibitors, only a small subset of patients with UC achieves durable remissions. Because an optimal antitumor response requires coordination of multiple immune, tumor, and microenvironment effector cells, novel approaches targeting distinct mechanisms of action likely in combination are needed. In addition, discovery of reliable immune biomarkers, understanding of mechanisms of resistance, and novel clinical trial designs are warranted for maximum benefit of UC immunotherapy.
Background
The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein ...CREBBP and/or E1A binding protein p300 EP300 histone acetyltransferase genes in a single‐arm, open‐label phase 2 study.
Methods
Eligible patients with platinum‐treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week TIW escalating to 90 mg TIW) in 28‐day cycles in a 3‐stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.
Results
Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent‐to‐treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% 1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose‐normalized maximum serum concentration Cmax after TIW dosing of 0.2 ng/mL/mg).
Conclusions
To the authors’ knowledge, the current study represents the first clinical trial using genomic‐based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.
After the genomic‐based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, single‐agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinum‐refractory disease.
PDF
