bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results from phase Ib/II neoadjuvant CG0070 and nivolumab (N) for cisplatin (C)-ineligible muscle invasive bladder cancer (MIBC).
Authors: Li Roger , Spiess Philippe E. , Sexton Wade J. , Gilbert Scott Michael , Poch Michael Adam , Pow-Sang Julio M. , Zhang Jingsong , Dhillon Jasreman , Thomas Kerry , Borjas Gustavo , Bala Juliet , Grandi Paola , Burke James , Mule James J , Conejo-Garcia Jose , Jain Rohit K. 
Published: June 2022

4574 Background: CG0070 is a replication-competent oncolytic adenovirus engineered to target RB deficient tumor cells and to express GM-CSF. CG0070 has previously demonstrated safety and efficacy against BCG-exposed high risk non-muscle invasive bladder cancer through tumor lysis and anti-tumor immune activation. We tested the safety and efficacy of CG0070 in combination with N as neoadjuvant therapy for MIBC in C-ineligible patients in this study (NCT04610671). Methods: C-ineligible pts with MIBC (cT2-4a, N≤1) were enrolled. Pts received 6 weekly intravesical CG0070 (1x1012vp) and 2 doses of N at wks 2 and 6, followed by radical cystectomy (RC). The primary objective is safety of CG0070+N as measured by CTCAEv5.0. Secondary objective is to assess pathologic response (PaR) (pT0N0). Exploratory objectives include the assessment of correlation between PaR with baseline 1) E2F expression; 2) immune infiltration; 3) PD-L1 expression; and 4) TLS expression. Results from a prespecified interim analysis following accrual of 15 patients is reported herein. Results: Between Nov 2020 and Jan 2022, 15 pts were enrolled with median age 75.5yrs, 73% male, 47% > cT2; 1 patient refused RC but was included in the ITT population. No DLTs were encountered. The overall rate of grade 3-4 AEs was 10/15 (75%), and the vast majority were related to RC (90%). Immune related AEs were seen in one pt, who had grade 2 autoimmune thyroiditis. There was no delay in time to RC and no unexpected surgical complications from treatment. PaR was observed in 6/13 (46%) evaluable pts, and an additional pt had negative post-treatment biopsy but refused RC. Conclusions: Neoadjuvant CG0070+N is safe and effective in C-ineligible pts with MIBC. This combination was well tolerated without any delays in RC and induced an overall response rate of 54%. Clinical trial information: NCT04610671. [Table: see text]
Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC).
Authors: Gupta Shilpa , Bellmunt Joaquim , Plimack Elizabeth R. , Sonpavde Guru P. , Grivas Petros , Apolo Andrea B. , Pal Sumanta K. , Siefker-Radtke Arlene O. , Flaig Thomas W. , Galsky Matt D. , Rosenberg Jonathan E. ,   Platinum-Ineligibility in Bladder Cancer Working Group
Published: June 2022

4577 Background: Treatment (tx) landscape has evolved significantly for cisplatin-ineligible mUC patients (pts). Carboplatin and gemcitabine followed by avelumab (Av) maintenance is the current preferred standard. Although pembrolizumab (P) and atezolizumab (At) were approved as 1L therapy for these pts in 2017, the FDA has now restricted the use of 1L P to “platinum ineligible” mUC pts. We previously suggested a consensus definition for “platinum-ineligible” pts with mUC (Gupta et al. ASCO GU 2019). We now updated the consensus definition for standard therapy and clinical trial eligibility in the current tx era. Methods: We surveyed 60 genitourinary medical oncologists in the US (similar cohort to 2019) using an online tool consisting of several clinical parameters used in our initial survey with additional questions related to current available tx options. Different age and creatinine thresholds in combination with ECOG PS along with other clinically relevant established criteria were analyzed. We compiled the responses to generate a consensus definition. Results: All 60 respondents provided 100% responses. Respondents (94%) reported using a carboplatin-based regimen followed by Av and 6% reported using carboplatin-based regimen followed by P for cisplatin-ineligible mUC pts. 17/60 (28.3%) and 29/60 (48.3%) checked PD-L1 status prior to using P or At respectively. Survey results for the most common responses are presented in the Table. Conclusions: Based on the survey, any mUC pt meeting one the following 5 parameters should be considered "platinum-ineligible”: ECOG PS > / = 3; Cr Cl < 30 ml/min; peripheral neuropathy > / =Grade 2; NYHA Heart Failure Class > 3; ECOG PS 2 AND Cr Cl < 30 ml/min. These criteria are proposed to guide treatment recommendations and standardization of eligibility criteria. [Table: see text]
Association of antibiotic therapy and treatment efficacy in urothelial cell carcinoma patients receiving immune checkpoint inhibitors.
Authors: Braun Avery , Deng Mengying , Handorf Elizabeth A. , Abbosh Philip 
Published: June 2022

4578 Background: The content of gut microbiome has been linked to the effectiveness of immune checkpoint inhibitory (ICI) therapy in various cancer types. Antibiotic therapy (ABT) induces significant alterations in gut microbiota; however, only a limited number of single-institutional studies have examined the impact of ABT on ICI treatment. Utilizing a national database, we sought to provide ‘real world outcomes’ by investigating the association between ABT and ICI on overall survival (OS) and real-world progression free survival (rwPFS) in advanced urothelial carcinoma (aUC). Methods: We used the electronic health record (EHR)-derived de-identified FlatIron Health (FIH) database after Institutional Review Board approval was obtained, and included a waiver of informed consent to select 1491 subjects with aUC who received ICI therapy. Patient characteristics were described and compared between those with known ABT use and without known ABT use (in the 3 months pre/post ICI initiation), using ANOVA and Chi-square tests. rwPFS and OS were calculated from date of initiation of ICI to date of real-world progression/date of death. 3-month landmark Kaplan Meier methods and log-rank tests were used to estimate and compare rwPFS and OS between patients with-ABT and without-ABT, as well as patients with ABT use pre-ICI initiation, post-ICI initiation, and no known ABT use. Cox proportional models were used to investigate the association between rwPFS, OS, and antibiotic use, adjusting for patient characteristics. Results: In patients who received ICI, we included 407 patients who received ABT and 1084 who did not. Those who received ABT were younger (p < 0.001), more likely Caucasian (p = 0.046) and insured by Medicare (p < 0.001). rwPFS (median: 9.0 vs 10.0 months; p = 0.41) and OS (median: 14.0 vs 16.0 months; p = 0.073) were not significantly different between the with or without ABT subgroups. We included 101, 182, and 715 patients who received ABT prior to ICI, after ICI initiation, or did not receive ABT. When assessing timing of ABT, there was a significant difference in OS amongst pre-ICI initiation ABT, post-ICI initiation ABT and no known ABT groups (median: 17.0 vs 10.9 vs 16.0; p = 0.005). However, rwPFS (median: 10.1 vs 7.5 vs 10.0 months; p = 0.22) was not statistically different. Multivariable analysis identified no antibiotic use as a significant predictor of improved OS (HR 0.733, CI 0.598-0.898; p = 0.003). Other factors associated with OS were male gender (HR 1.158, Cl 1.005-1.335; p = 0.043) and receipt of extirpative surgery (HR 0.785, Cl 0.684-0.900; p < 0.001). Conclusions: This study identifies a potential negative association of ABT and OS, particularly after starting ICI. These results support the relevance of the gut microbiome on the efficacy of ICI treatment, may guide future efforts to improve the efficacy of ICI, and emphasize the importance of antibiotic stewardship.
Biomarkers of response to neoadjuvant atezolizumab with gemcitabine and cisplatin in muscle-invasive bladder cancer.
Authors: Lattanzi Michael , Solovyov Alexander , Lihm Jayon , Quinlan Colleen , Whiting Karissa , Li Hao , Al-Ahmadie Hikmat A. , Teo Min Yuen , Aggen David Henry , Ostrovnaya Irina , Regazzi Ashley Marie , Jihad Marwah , Bajorin Dean F. , Balar Arjun Vasant , Mortazavi Amir , Merghoub Taha , Iyer Gopa , Rosenberg Jonathan E. , Greenbaum Benjamin , Funt Samuel Aaron 
Published: June 2022

4584 Background: We previously reported the clinical outcomes of a positive multi-center phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) plus atezolizumab (A) in patients with muscle-invasive bladder cancer (Funt, et al. JCO 2022). In this and another trial of neoadjuvant GC with pembrolizumab (Rose et al, JCO 2021), PD-L1 positivity by immunohistochemistry was not predictive of non–muscle-invasive downstaging ( < pT2N0). Therefore, we investigated other pre-treatment tissue-based genomic and gene expression biomarkers of response and resistance. Methods: 36 pts had pre-treatment tissue available for genomic analysis. We performed targeted hybridization capture DNA sequencing using the CLIA-certified MSK-IMPACT platform and whole transcriptome RNA sequencing. We examined genomic and gene expression biomarkers which have been previously investigated in the context of neoadjuvant cisplatin-based chemotherapy or anti-PD-1/L1 immunotherapy for MIBC, including tumor mutation burden (TMB), a DNA damage response (DDR) 9-gene panel (NCT03609216) associated with response to neoadjuvant chemotherapy, and an 8-gene cytotoxic T cell transcriptional signature associated with response to neoadjuvant A (tGE8; Powles et al, Nature Medicine 2019). We also evaluated TGF-β pathway activation, which was associated with resistance to A in pts with metastatic BC (Mariathasan et al, Nature 2018). Putative biomarkers were assessed for correlation with < pT2N0, the trial’s primary endpoint. Results: DNA was available from all 36 pts, and RNA met quality control metrics for 29 pts. TMB was significantly higher in pts with < pT2N0 (median 16 mut/Mb, IQR 12-25) versus ≥ pT2N0 (median 10 mut/ Mb, IQR 8-10; p < 0.01). A single patient had a TMB > 200 Mut/Mb with a POLE hotspot mutation and achieved pT0N0; TMB was still significantly higher in responders after omission of this patient (p < 0.01). Nine of 25 pts (36%) with < pT2N0 had a deleterious DDR mutation versus 1 of 10 pts (10%) with ≥ pT2N0 (p = 0.13). While tGE8 was significantly increased in patients with < pT2N0 compared to those without (p = 0.01), TGF-β pathway activation was not increased in pts with ≥ pT2N0 (p = 0.99). Conclusions: TMB and the tGE8 cytotoxic T cell transcriptional signature were associated with response to combination GC+A in muscle-invasive bladder cancer. More detailed molecular analyses will be reported. Clinical trial information: NCT02989584.
Results for patients with muscle-invasive bladder cancer (MIBC) in the CheckMate 274 trial.
Authors: Witjes Alfred , Bajorin Dean F. , Galsky Matt D. , Gschwend Jürgen E. , Tomita Yoshihiko , Lebret Thierry , Pérez-Valderrama Begoña , Bamias Aristotelis , Collette Sandra , Zhang Joshua , Nasroulah Federico , Shariat Shahrokh F. 
Published: June 2022

4585 Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]
Quantifying the absolute benefit of neoadjuvant chemotherapy followed by definitive therapy in patients with muscle-invasive bladder cancer: A systematic review and meta-analysis.
Authors: Ikram Waleed , Naqvi Syed Arsalan Ahmed , Raina Ammad , Fatima Ezza , Siddiqi Rabbia , Islam Mahnoor , Asghar Noureen , Khakwani Kaneez Zahra Rubab , Khan Ahsan Masood , Hussain Syed A. , Bryce Alan Haruo , Riaz Irbaz Bin , Singh Parminder 
Published: June 2022

4594 Background: Cisplatin based neoadjuvant chemotherapy (NAC) followed by definitive therapy improves survival in patients with muscle invasive bladder cancer (MIBC). However, the clinical benefit of NAC might vary with the choice of definitive therapy. Therefore, we assessed the absolute benefit of NAC followed by radical cystectomy or radical radiotherapy separately using the totality of evidence. Methods: MEDLINE and EMBASE were systematically searched to identify randomized trials assessing cisplatin based neoadjuvant chemotherapy followed by either radical cystectomy or definitive radiotherapy in patients with MIBC. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). Treatment effects were expressed as hazard ratios (HR) with 95% confidence interval (CI). Incidence rate ratios were calculated to estimate time to event outcomes for trials not reporting HR. A random-effects DerSimonian-Laird meta-analysis was conducted. Absolute effects were then obtained using baseline risks from the control arm of RCTs. Results: Of 4887 studies identified, 13 trials with 2529 patients were included in this meta-analysis. Most trials included patients with T2-4 and N0 patients and only 3 trials included patients with node positive disease. Total of 180 (47%) DFS events were observed with NAC+RC compared to 213 (56%) events in RC alone (HR: 0.72; 95% CI: 0.59-0.89) and 346 (58%) OS events were observed with NAC+ RC compared to 385 (52%) events in RC alone (HR: 0.80; 95% CI: 0.69-0.92). Total of 186 (70%) DFS events were observed with NAC + radiotherapy compared to 205 (71%) events in radiotherapy alone (HR: 0.91; 95% CI: 0.74-1.12) and 263 (58%) OS events were observed with NAC+ radiotherapy compared to 294 (61%) events in radiotherapy alone (HR:0.93; 95% CI: 0.79-1.08). Conclusions: The choice of definitive therapy after cisplatin-based NAC impacts survival in patients with MIBC. RC after NAC improved DFS (114 fewer events per 1000 events) and OS (76 fewer per 1000 events) whereas radiotherapy after NAC showed no survival benefit. [Table: see text]
Influence of darolutamide on cabazitaxel systemic exposure.
Authors: Buck Stefan , Guchelaar Niels A.D. , de Bruijn Peter , Moghaddam-Helmantel Inge M. Ghobadi , De Hoop Esther Oomen , Westgeest Hans M. , Hamberg Paul , Mathijssen-van Stein Danielle , Lolkema Martijn P. , Koolen Stijn L.W. , De Wit Ronald , Mathijssen Ron H.J. 
Published: June 2022

5038 Background: Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signalling inhibitor (ARSI) enzalutamide improves cabazitaxel efficacy. However, we have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent. Methods: We investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m2 Q3W) on day 1 and received concomitant darolutamide (600 mg b.i.d.) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, we measured cabazitaxel systemic exposure via Area Under the Curve from 0 to 24 hours (AUC0-24h). Results: Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC0-24h: -4%; 95%CI -19 – +13%; p = 0.58). Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC0-24h: +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study (Table). Conclusions: From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients. Our findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer. Clinical trial information: NL8611. [Table: see text]
Adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: 8-year follow-up of the randomized ASTRRA trial.
Authors: Baek Soo Yeon , Noh Woo Chul , Ahn Sei-Hyun , Kim Hyun-Ah , Ryu Jai Min , Kim Seung Il , Lee Eun-Gyeong , Im Seock-Ah , Jung Yongsik , Park Min Ho , Park Kyong Hwa , Kang Su Hwan , Jeong Joon , Park Eunhwa , Kim Sung Yong , Lee Min Hyuk , Kim Lee Su , Lim Woosung , Kim Seonok , Kim Hee Jeong 
Published: June 2022

506 Background: Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial, at 63 months median follow-up, showed that the addition of 2 years of ovarian function suppression (OFS) to Tamoxifen (TAM) significantly improved disease-free survival (DFS) compared with TAM alone in patients with hormone receptor–positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. We report updated long-term outcomes from ASTRRA trial with 106.4 months median follow-up. Methods: This study is a post-trial follow-up of the ASTRRA trial, which randomly assigned 1,298 patients with breast cancer in a 1:1 ratio to receive TAM only (n = 647) or TAM + OFS (n = 635). The primary endpoint was DFS and secondary endpoint was overall survival (OS). We used Kaplan-Meier estimates for time to event endpoints and hazard ratios (HR) with 95% confidence interval (CI) from Cox-regression model. Results: At 106.4 months of median follow-up, there continues to be a statistically significant reduction in DFS event rate in favor of the TAM+OFS group. The estimated 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (HR 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between two groups. The estimated 8-year OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). The results of DFS and OS between the two groups defined from the time of random assignment to the time of events were also similar. Conclusions: These data demonstrate consistent survival advantages of adding OFS 2 years to TAM treatment over time, with the long-term follow-up reported to date. This study finding suggest that adding OFS to TAM should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. Longer follow-up is needed to fully evaluate the OS benefit.
Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: Meta-analysis of individual participant data from randomized trials.
Authors: Vale Claire Louise , Fisher David , Godolphin Peter , Rydzewska Larysa H , Boher Jean-Marie , Burdett Sarah , Chen Yu-Hui , Gravis Gwenaelle , James Nicholas D. , Liu Glenn , Murphy Laura , Parmar Mahesh K. B. , Rogozinska Ewelina , Sfumato Patrick , Sweeney Christopher , Sydes Matthew R. , Tombal Bertrand F. , White Ian R , Tierney Jayne F. ,   The STOPCAP M1 Collaboration
Published: June 2022

5070 Background: Adding docetaxel to androgen deprivation therapy(ADT) improves survival in metastatic, hormone-sensitive prostate cancer (mHSPC), but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaborationconducted a meta-analysis of individual participant data (IPD) from relevant trials. Methods: Methods were included in a registered protocol ( CRD42019140591 ). Updated IPD from the GETUG-15, CHAARTED and STAMPEDE trials were harmonised and checked. The main outcomes were overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS). Overall pooled effects were estimated using intention-to-treat, 2-stage, fixed-effect meta-analysis, adjusted for age, PSA, Gleason sum score, performance status, and timing of metastatic disease (missing covariate values imputed), with 1-stage and random-effects sensitivity analyses. We assessed subgroup effects using 2-stage, fixed-effect meta-analysis of within-trial interactions, adjusted for the same covariates. We based these on PFS to maximise power, and OS whenever interactions were found. To explore multiple subgroup interactions, and to derive subgroup-specific absolute treatment effects, we used 1-stage, flexible parametric modelling and standardisation. Results: We obtained IPD for all 2261 men randomised, with median FU of 6 years (all patients). There were clear relative benefits of docetaxel on OS (HR = 0.79, 95% CI 0.70 to 0.88, p<0.0001), PFS (HR = 0.70, 95% CI 0.63 to 0.77, p<0.0001) and FFS (HR = 0.64, 95% CI 0.58 to 0.71, p<0.0001). With evidence of non-proportional hazards, we also estimated 5-year absolute differences: OS 10% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%). The relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR = 0.60, 95% CI 0.52 to 0.68; low volume HR = 0.78, 95% CI 0.64 to 0.94), and timing of metastatic disease (interaction p=0.077; synchronous HR = 0.67, 95% CI 0.60 to 0.75; metachronous HR = 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease (Table). Conclusions: This IPD meta-analysis provides the most detailed assessment of the effects of docetaxel for mHSPC, and suggests that men with low volume, metachronous disease should be managed differently to those with other types of metastatic disease. [Table: see text]