tbuckley/cabot-search huggingface dataset:
First-line (1L) systemic therapy in locally advanced/metastatic urothelial cancer (Ia/mUC): A living interactive systematic review and network meta-analysis.
Authors: Akshat Saxena, Irbaz Bin Riaz, Syed Arsalan Ahmed Naqvi, Arifa Bibi, Aneeta Channar, Nikita Tripathi, Muhammad Ali Khan, Ammad Raina, Kaneez Zahra Rubab Khakwani, Daniel S Childs, Alan Haruo Bryce, Parminder Singh
Journal: Journal of Clinical Oncology (2024)

e16579 Background: Recent results from EV 302 and CheckMate 901 have transformed the treatment landscape of untreated locally advanced/metastatic urothelial cancer (Ia/mUC). Here, we present the most up-to-date evidence of comparative efficacy and safety of first line (1L) treatment options in Ia/mUC with emphasis on Enfortumab vedotin (EV)-pembrolizumab (P) and gemcitabine (Gem)-cisplatin (Cis)-nivolumab (N). Methods: This living systematic review used the living interactive evidence (LIvE) synthesis framework. Full-text and abstract publications of phase II/III randomized clinical trials comparing 1L immunotherapy combined with chemotherapy (IO+C) or immunotherapy alone (IO) regimens with platinum-based chemotherapy (Plat) in Ia/mUC were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS) and treatment-related grade 3 or greater adverse events (≥G3 TRAE). Mixed treatment comparisons were made using network meta-analysis. P-scores were computed to assess relative treatment rankings. Results: A total of 5 trials (8 references) with 4,749 patients and 9 unique treatments were included. EV-P and Gem-Cis-N were ranked first and second in terms of OS and PFS improvement. EV-P improved OS compared to Gem-Cis-N (HR: 0.60; 0.45-0.81), Gem-Plat-atezolizumab(A) (0.55; 0.42-0.72), durvalumab(D)- tremelimumab(T) (0.55; 0.42-0.72), Gem-Plat-P (0.55; 0.42-0.72), P (0.51; 0.39-0.68), D (0.47; 0.36-0.63), A (0.48; 0.36-0.63) and Gem-Plat (0.47; 0.38-0.58). EV-P also improved PFS compared to Gem-Cis-N (0.63; 0.48-0.82), Gem-Plat-A (0.55; 0.43-0.69), D-T (0.42; 0.33-0.53), Gem-Plat-P (0.58; 0.45-0.74), P (0.34; 0.26-0.44), D (0.35; 0.27-0.44) and Gem-Plat (0.45; 0.38- 0.54). For ≥G3 TRAE, A was ranked first with the lowest adverse events compared to others. EV-P (rank 5) had significantly fewer events compared to Gem-Plat, Gem-Plat-A, Gem-Cis-N and Gem-Plat-P. Gem-Cis-N was ranked last with significantly greater events compared to A, P, D, D-T, Gem-Plat, EV-P, and Gem-Plat-A (Table with ranks [p-scores]). Conclusions: Current evidence suggests that patients with untreated la/mUC experience improved survival and slower disease progression with EV-P when compared to other contemporary options. Gem-Cis-N may be a reasonable alternative in patients who are cisplatin-eligible. Cost and access to these treatments are crucial and should be considered to facilitate shared decision making. [Table: see text]
Impact of β-adrenergic blockade on efficacy of immunotherapy in patients with metastatic clear cell renal cell carcinoma.
Authors: Karl Semaan, Marc Eid, Eddy Saad, Wadih Issa, Renee Maria Saliby, Morgan Paul, Caiwei Zhong, Damla Gunenc, Noa Phillips, Rashad Nawfal, Marc Machaalani, Razane El Hajj Chehade, Emre Yekeduz, Chris Labaki, Talal El Zarif, Sylvan C. Baca, Wanling Xie, Bradley Alexander McGregor, Tian Zhang, Toni K. CHOUEIRI
Journal: Journal of Clinical Oncology (2024)

e16529 Background: Immunotherapy (IO) has become a cornerstone in the standard of care of patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC). Recent studies suggest concomitant beta-blockers (BB) use may improve the effectiveness of IO in melanoma by increasing CD8+ T cells tumor infiltration through β-adrenergic blockade. Herein, we assess the impact of BB on the clinical outcomes of pts with mccRCC treated with IO-based regimens in first-line (1L) settings. Methods: Real-world data from Dana-Farber Cancer Institute and the University of Texas Southwestern Medical Center were collected retrospectively. Pts with mccRCC who received 1L standard of care IO-based regimens, including dual-IO or IO in combination with vascular endothelial growth factor-targeted therapies (IO+VEGF-TT) were included. Pts receiving BB at the 1L initiation were classified as BB-treated pts, while pts who were not on BB at 1L initiation were labeled as BB-untreated pts. Time to treatment failure (TTF) and overall survival (OS) were compared between groups using a multivariable Cox regression adjusting for age at 1L start, body mass index (BMI), and IMDC risk group. Objective response rate (ORR; responders vs. non-responders/not evaluable) per RECIST 1.1 criteria was compared between groups using a Chi-Squared test. Results: Our cohort included 171 pts with mccRCC, 134 (78.4%) were male, and the median (Q1-Q3) age was 62 (56-68) years. A total of 55 deaths were observed. The median follow-up of pts was 28.1 months. At 1L treatment initiation, 52 (30.4%) pts were receiving BB. BB-treated pts (vs. those not) were older (65.1 vs 60.8; p=0.003) and had higher BMI (31.1 vs. 29; p=0.004) at 1L initiation. BB-treated pts (vs. those not) had comparable TTF (adjusted HR (aHR) = 1.0; 95% confidence interval (CI): 0.7-1.5; p=0.88) and comparable OS (aHR=1.1; 95%CI: 0.6-2.0; p=0.67). BB-treated pts (vs. those not) had a numerically increased ORR, but this difference was not statistically significant (31/52, 59.6% vs. 59/119, 49.6%; p=0.29). A sensitivity analysis within each of dual-IO (n=83, 48.5%) and IO+VEGF-TT (n=88, 51.5%) subgroups showed similar results (Table). Conclusions: This is the first effort to investigate the impact of β-adrenergic blockade on IO activity in pts with mccRCC. While previous data suggest concomitant BB use may enhance IO efficacy in pts with melanoma, our results show that the use of BB was not associated with better IO effectiveness in pts with mccRCC. Limitations of the study arise from its retrospective design. [Table: see text]
Clinical outcome differences based on gender in patients with advanced renal cell carcinoma (aRCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Yujin Choi, Rohit Vivek Goswamy, Mengting Wei, Yuan Liu, Ahmet Yildirim, Jacqueline T. Brown, Bassel Nazha, Dylan J. Martini, Caitlin Hartman, Greta Russler McClintock, Tony Zhuang, Haydn Kissick, Wayne B. Harris, Bradley Curtis Carthon, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2024)

e16542 Background: Current first-line therapy for aRCC involves ICIs, often administered with another ICI or tyrosine-kinase inhibitors (TKIs). While there has been some literature on the association between gender and clinical outcomes in patients with aRCC, some results are contradictory and thus the true association remains unknown. We explored the role of gender in the difference in clinical outcomes of patients undergoing therapies involving ICIs. Methods: We conducted a retrospective analysis on adult patients with advanced RCC treated with ICIs at Emory Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) was calculated from the date of treatment initiation to death and progression, respectively. Progression was determined by RECIST v1.1 or clinical progression. Clinical benefit (CB), including stable disease, partial response, and complete response, was determined by RECIST v.1.1. CB, OS, and PFS were used to identify the association between gender and clinical outcome through univariate (UVA) and multivariate (MVA) analyses. Results: Analysis was conducted on a total of 401 patients, consisting of 283 (70.6%) males and 118 (29.4%) females. Their median age was 66 (range = 18-95). Treatment plan involved 139 (34.6%) patients for single ICI therapy, 131 (32.6%) patients for ICI/ICI therapy, 108 (26.9%) patients for ICI/TKI therapy, 6 (1.5%) patients for ICI/ICI/TKI therapy, and 17 (4.23%) patients for therapy with ICI plus an experimental drug. CB, OS, and PFS all confirmed no difference in clinical outcomes of the patients based on gender in UVA and MVA. Female patients had hazard ratios (HR) close to 1 for both OS and PFS and odds ratios (OR) close to 1 for CB. Results from Kaplan-Meier (KM) plots also support the lack of difference in clinical outcomes between genders. The KM plot indicated similar OS and PFS for female and male patients, with the median OS for female and male patients being 36 and 28.2 months and the median PFS for female and male patients being 7.4 and 7.1 months, respectively. Conclusions: Patients treated with ICIs had similar clinical outcomes based on gender as indicated by insignificant differences in CB, OS, and PFS. However, prospective studies are still needed to validate such findings. [Table: see text]
Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.
Authors: Junru Chen, Haoyang Liu, Qiyu Zhu, Chenhao Xu, Qiang Wei, Jiyan Liu, Zhenhua Liu, Pengfei Shen, Yige Bao, Peng Zhang, Banghua Liao, Jin Yao, Ni Chen, Kaijie Wu, Xiaodong Liu, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .
Neoadjuvant immunotherapy-driven bladder preservation for muscle-invasive bladder cancer: A multicenter, propensity score-matched cohort study.
Authors: Jiao Hu, ZHENYU Ou, Minfeng Chen, Jinhui Liu, Luzhe Yan, Jinbo Chen, Peihua Liu, Xiongbing Zu
Journal: Journal of Clinical Oncology (2024)

e16598 Background: The rise of neoadjuvant immunotherapy has brought neoadjuvant immunotherapy-driven bladder preservation (Neoimmu-CMT) into the spotlight, yet its application is hampered by a scarcity of robust clinical evidence. There are no comparative studies on the effectiveness of Neoimmu-CMT versus traditional trimodal therapy (TMT) or neoadjuvant chemotherapy-driven bladder preservation (NAC-CMT). To address this gap, our study (ChiCTR2300069303) aims to assess Neoimmu-CMT's viability and identify suitable candidates through a multicenter, propensity score-matched (PSM) analysis. Methods: The study included 163 patients from 14 hospitals, categorized into Neoimmu-CMT (n=97), TMT (n=30), and NAC-CMT (n=36) subgroups. PSM was utilized to mitigate baseline variability. Primary outcomes were disease-free survival (DFS), bladder-intact DFS (BI-DFS), and overall survival (OS). Univariate and multivariate Cox analyses were used to identify potential prognostic factors. Biomarker assessment comprised immunohistochemistry and single-cell RNA sequencing. Results: Post-PSM, Neoimmu-CMT significantly outperformed NAC-CMT in DFS (HR: 2.112, 95% CI: 1.247-3.576, P=0.005) and BI-DFS (HR: 2.329, 95% CI: 1.138-4.770, P=0.021), with a 2-year BI-DFS rate of 90.28% compared to NAC-CMT's 71.59%. However, Neoimmu-CMT and TMT showed no significant difference in DFS and BI-DFS, with Neoimmu-CMT marginally surpassing TMT in 2-year BI-DFS rates (86.42% vs. 80.89%). Clinical complete response to neoadjuvant treatment and lower clinical T stage were positive prognostic factors for Neoimmu-CMT. Interestingly, regardless of being combined with ADC (HR: 1.283, 95% CI: 0.224-7.359, P=0.780) or chemotherapy (HR: 0.769, 95% CI: 0.255-2.323, P=0.642), the DFS outcomes did not surpass those received with sole immunotherapy. Furthermore, conventional clinical parameters such as tumor-associated hydronephrosis, tumor number, and histology type did not emerge as significant predictors for bladder preservation outcomes. Biomarker analysis showed the tumor microenvironment immune phenotype closely relates to bladder preservation outcomes. Conclusions: Neoimmu-CMT is a promising bladder preservation strategy, comparable to TMT and superior to NAC-CMT. Its advancement could significantly broaden bladder preservation treatment options.
SOGUG-NEOWIN: A phase 2, open-label, multi-centre, multi-national interventional trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) whose tumours express FGFR gene alterations.
Authors: Syed A. Hussain, Yohann Loriot, Guillermo de Velasco, Andrea Necchi
Journal: Journal of Clinical Oncology (2024)

TPS4623 Background: The standard treatment for nonmetastatic MIBC is neoadjuvant cisplatin-based therapy followed by radical cystectomy (RC). However, many patients are ineligible for cisplatin. Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for metastatic urothelial cancer (mUC), including for cisplatin-ineligible patients. Based on these results, ICIs are being explored as neoadjuvant treatment in resectable UC with preliminary data suggesting antitumour activity. ERDA is a Fibroblast Growth Factor Receptor (FGFR) inhibitor, which has shown efficacy in advanced UC with select FGFR2/3 mutations/fusions. ERDA plus cetrelimab demonstrated clinically meaningful activity in patients with newly diagnosed FGFR-altered mUC in the phase 2 NORSE trial. We hypothesize that ERDA plus cetrelimab will improve the pathological complete response (pCR) rate in patients with FGFR+ MIBC who are candidates for RC and are ineligible for or refuse neoadjuvant cisplatin-based therapy. Methods: SOGUG-NEOWIN is a prospective, non-comparative, open label, multicentre, international trial to assess the efficacy of 9 or 12 weeks of neoadjuvant ERDA (cohort 1) or the combination of cetrelimab and ERDA (cohort 2) in patients with MIBC (cT2-Ta N0/1 M0) and FGFR alterations. Key eligibility criteria include ECOG PS 0-1; pure or predominant UC histology; decline or ineligible for cisplatin-based chemotherapy as defined by one of the following criteria: impaired renal function (GFR &lt; 60 mL/min), ≥ grade 2 hearing loss, or ≥ grade 2 peripheral neuropathy; patients are considered fit for cystectomy; no prior FGFR-targeted or anti-PD-(L)1 therapy; no prior systemic therapy, radiation or surgery (except TURBT or biopsies) for bladder cancer; prior BCG was allowed if completed ≥ 6 weeks before initiation of study treatment; no current retinopathy. A total of 45 patients will be allocated to each cohort by a centralized system. Co-primary endpoints are pCR rate and percentage of pathological downstaging response (&lt;ypT2). Secondary endpoints include event-free survival, overall survival, overall response rate, safety, tolerability, and delay to surgery. Biomarkers of response and resistance will be assessed using baseline archival tissues, blood and urine. Quality of life (QoL) will be assessed using FACT-Bl and EQ-5D-5L. Tumour response assessment via PET-MRI will be performed in a subset of patients. The trial is approved in 4 countries. The first patient was included on 31-Jan-2024. This trial would be the first to systematically address whether ERDA ± cetrelimab improves pCR in patients with FGFR-positive MIBC. (EudraCT 2022-002586-15). Clinical trial information: 2022-002586-15.
Efficacy and safety of neoadjuvant therapy with disitamab vedotin plus toripalimab in treating muscle invasive urothelial bladder cancer followed by selective bladder-preserving or radical cystectomy.
Authors: ZHENYU Ou, Jiao Hu, Minfeng Chen, Yangle Li, Xiongbing Zu
Journal: Journal of Clinical Oncology (2024)

e16590 Background: Neoadjuvant cisplatin-based chemotherapy remains the standard systemic therapy for cisplatin-eligible patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). However, its application is constrained due to suboptimal efficacy and considerable safety concerns. The combination of immunotherapy with antibody-drug conjugates is being actively explored as an innovative approach to neoadjuvant therapy for MIBC. Disitamab vedotin (DV) has demonstrated encouraging outcomes in HER2-positive locally advanced or metastatic urothelial carcinoma. Thereby our study aimed to assess the effectiveness and safety of DV combined with toripalimab (PD-1 inhibitor) as neoadjuvant therapy in patients with HER2-expressing MIBC followed by either selective bladder preservation or RC. Methods: This retrospective, single-arm study included patients with histopathologically diagnosed MIBC (T2-4N0-1M0). The regimens comprised DV at a dose of 2.0 mg/kg and toripalimab at 3.0 mg/kg, both delivered intravenously biweekly. Following the neoadjuvant therapy, patients achieving a complete response (CR) or downstaged to non-MIBC were given the choice of either RC or opting for bladder-sparing. Patients not meeting the criteria underwent RC. The primary endpoint was the complete clinical response (cCR) rate. Secondary endpoints included bladder intact disease-free survival (BI-DFS), pathological downstaging (pDS) rate, and safety. Furthermore, we investigated the correlation between cCR and HER2 expression levels. Results: This study enrolled 47 patients between June27, 2022, and October 20, 2023. The median age was 66.0 years, with male representation at 85.1%. Baseline molecular profiling revealed varying levels of HER2 expression: HER2 IHC 3+ (17.0%), HER2 IHC 2+ (48.9%), and HER2 IHC 1+ (34.0%). The median number of treatment cycles administered was 4 ( 3.0-9.0). Remarkably, out of 47 patients, 29 achieved cCR (61.7%). This cCR rate positively correlated with the levels of HER2 expression. Additionally, 37 of the 47 patients achieved pDS (78.7%). Post neoadjuvant therapy, 30 patients opted for bladder-preserving and the rest underwent RC. Over a median follow-up period of 8.0 months (3.0-14.0), the median BI-DFS was not reached, with a 1-year BI-DFS rate of 100%. The most common TRAEs of any grade included anorexia (68.1%), peripheral sensory neuropathy (66.0%), and fatigue (61.7%). Grade 3 or worse TRAEs occurred in 25% of patients, primarily involving anemia, elevated ALT, and fatigue. Conclusions: The combination of DV and Toripalimab as neoadjuvant therapy demonstrated notable efficacy and a manageable safety profile in patients with HER2-expressing MIBC followed by either selective bladder preservation or RC.
Effectiveness of adjuvant immunotherapy in muscle-invasive urothelial cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Isadora Mamede Mendes da Silva, Caroliny Silva, Ana Caroline Fonseca Alves, João Pedro Oliveira, Melissa Maia, Caio Dabbous de Liz, Audrey Cabral Ferreira de Oliveira
Journal: Journal of Clinical Oncology (2024)

e16599 Background: Neoadjuvant platinum-based chemotherapy followed by radical surgery is the established treatment for muscle-invasive urothelial cancer (MIUC). However, over 50% of patients face lethal metastatic recurrence, and adjuvant chemotherapy's efficacy lacks consensus for high-risk cases, with others encountering eligibility issues. Recent breakthroughs highlight adjuvant pembrolizumab's significant enhancement of disease-free survival. In response, a meta-analysis was conducted to assess immunotherapy's effectiveness in managing high-risk MIUC. Methods: A systematic search across PubMed, Embase, Cochrane, ClinicalTrials.gov, and ASCO GU abstracts identified randomized controlled trials (RCTs) comparing adjuvant PD-1 and PD-L1 inhibitors against control (placebo or observation) for MIUC. Key outcomes included disease-free survival (DFS), grade 3 or higher adverse events (AE), and overall survival (OS). Heterogeneity was assessed using I 2 statistics, employing a random-effects model for analysis. Statistical analyses utilized R software version 4.3.2. Results: In a cohort of 2,220 patients from three RCTs, 1,113 (50.14%) received immunotherapy. Immunotherapy significantly improved DFS (HR 0.73; 95% CI 0.59-0.90; p &lt; 0.01), particularly in lower tract tumors (HR 0.71; 95% CI 0.56-0.91; p &lt; 0.01). No significant DFS improvement was observed in the upper tract subgroup (HR 1.21; 95% CI 0.87-1.68; p = 0.25) (p-interaction = 0.01). Further analyses showed no significant subgroup differences in PDL1+/- (p-interaction = 0.85) and previous neoadjuvant chemotherapy use (p-interaction = 0.12). However, immunotherapy exhibited a higher incidence of grade ≥ 3 AE (RR 1.47; 95% CI 1.13-1.91; p &lt; 0.01). No differences in OS were found (HR 0.94; 95% CI 0.80-1.11; p = 0.46). Conclusions: Adjuvant PD-1 and PD-L1 inhibitors significantly enhance MIUC disease-free survival, irrespective of PD-L1 status. However, this benefit comes with an increased risk of grade 3 or higher adverse events. These results offer compelling evidence supporting immunotherapy as a valuable adjuvant treatment option for high-risk MIUC patients.