bluuebunny/crossref_metadata_2025_split huggingface dataset:
DUTRENEO Trial: A randomized phase II trial of DUrvalumab and TREmelimumab versus chemotherapy as a NEOadjuvant approach to muscle-invasive urothelial bladder cancer (MIBC) patients (pts) prospectively selected by an interferon (INF)-gamma immune signature.
Authors: Grande Enrique , Guerrero Félix , Puente Javier , Galante Isabel , Duran Ignacio , Dominguez Mario , Alonso Gordoa Teresa , Burgos Javier , Font Albert , Pinto Alvaro , Alvarez-Maestro Mario , Reig Oscar , Maroto José , Garcia del Muro Xavier , Galvan Patricia , Garcia Juan Fernando , Malats Nuria , Prat Aleix , Real Francisco X. , Castellano Daniel 
Published: May 2020

5012 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]
Phase II study of nivolumab and ipilimumab for advanced rare genitourinary cancers.
Authors: McGregor Bradley Alexander , Campbell Matthew T , Xie Wanling , Farah Subrina , Bilen Mehmet Asim , Sonpavde Guru , Kilbridge Kerry L. , Choudhury Atish Dipankar , Mortazavi Amir , Shah Amishi Yogesh , Venkatesan Aradhana M. , Bubley Glenn , Siefker-Radtke Arlene O. , McKay Rana R. , Choueiri Toni K. 
Published: May 2020

5018 Background: Patients with rare genitourinary malignancies (Bladder cancer of variant histologies (BCVH), adrenal tumors, chemotherapy refractory germ cell tumors (CRGCT), penile carcinoma and prostate cancer of variant histology (PCVH)) have poor outcomes. Nivolumab and ipilimumab has demonstrated safety and efficacy in genitourinary malignancies. In this multicenter, single arm, multi-cohort phase II trial we evaluated the efficacy of nivolumab and ipilimumab in pts with advanced rare genitourinary cancers (NCT 03333616). Herein, we report the results of the fully accrued BCVH, adrenal and other cohorts. Methods: Eligible pts had a metastatic rare genitourinary malignancy, ECOG performance status of 0-2 and no prior immune checkpoint inhibitor exposure; aside from CRGCT pts could be treatment naïve. Eligible pts received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses with continued nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 56 pts were enrolled at 6 institutions between 4/2018 and 7/2019 in 3 cohorts: BCVH (N = 19), adrenal tumors (n = 18) and other tumors (n = 19). Median follow-up was 9.9 (range < 1~21) months. 28(50%) pts received all 4 doses of nivolumab and ipilimumab. 25 pts received nivolumab maintenance at a median of 4 (range 1-18) cycles. ORR in entire cohort was 16% (n = 9: 2 CR 7 PR, Table); 67% of responders (6/9) maintained response greater than 9 months. Median PFS was 2.8 (2.7-5.2) months. 22 pts (39%) developed treatment-related ≥ grade 3 toxicity; 23% required high dose steroids (≥40 mg prednisone or equivalent) and 15 (27%) pts discontinued treatment due to an AE. Grade 5 toxicity occurred in 3 pts; 1 death was treatment related. Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of pts with rare GU malignancies, especially in BCVH. Biomarkers are being evaluated and an additional cohort exploring the activity in genitourinary tumors with neuroendocrine differentiation is ongoing. This combination warrants further investigation in these pts with substantial unmet needs. Clinical trial information: NCT 03333616 . [Table: see text]
A phase Ib trial of neoadjuvant/adjuvant durvalumab +/- tremelimumab in locally advanced renal cell carcinoma (RCC).
Authors: Ornstein Moshe Chaim , Zabell Joseph , Wood Laura S. , Hobbs Brian , Devonshire Sarah , Martin Allison , Allman Kimberly D. , Rao Arpit , Gilligan Timothy D. , Campbell Steven , Krishnamurthi Venkatesh , Rini Brian I. 
Published: May 2020

5021 Background: Effective neoadjuvant and adjuvant therapies are lacking in locally advanced RCC. Given robust activity of checkpoint inhibitors in mRCC, a phase Ib trial of perioperative Durvalumab (D) +/- Tremelimumab (T) in locally advanced RCC was conducted (NCT02762006). Methods: Pts with radiographic evidence of high risk localized RCC (clinical stage T2b-4 and/or N1, M0 disease), adequate performance status, and adequate laboratory values were eligible. Primary objective was safety and feasibility of neoadjuvant/adjuvant D +/- T. Results: Twenty-nine pts were enrolled. Cohorts, regimens, and immune-related adverse events (irAE) are detailed in the table. In total, 79% male, median age 61 (range, 42-84), 8%/88%/4% clinical T2/T3/T4, 27% positive clinical lymph nodes (LN+), and median time from neoadjuvant dose to surgery was 7 days. On surgical pathology: 5%/14%/77%/5% pathologic T1/T2/T3/T4, and 13% LN+. Median time from treatment to first grade (Gr) >3 irAE or any Gr irAE requiring corticosteroids was 99 days (range, 32-207). There were no treatment-related delays to nephrectomy or surgical complications. Although not meeting the protocol-defined MTD, given higher than expected irAEs, the study was suspended. Conclusions: Perioperative durvalumab in locally advanced RCC appears safe. The addition of tremelimumab is associated with higher rates of toxicity. Updated toxicity will be presented. Clinical trial information: NCT02762006 . [Table: see text]
Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy.
Authors: Petrylak Daniel Peter , Tagawa Scott T. , Jain Rohit K. , Bupathi Manojkumar , Balar Arjun Vasant , Rezazadeh Arash , George Saby , Palmbos Phillip Lee , Nordquist Luke T. , Davis Nancy B. , Vogelzang Nicholas J. , Ramamurthy Chethan , Sternberg Cora N. , Loriot Yohann , Agarwal Neeraj , Hong Quan , Gladden Allison , Kanwal Charu , Goswami Trishna , Grivas Petros 
Published: May 2020

5027 Background: SG is an antibody-drug conjugate consisting of a humanized monoclonal anti–Trop-2 antibody coupled to the cytotoxic agent, SN-38, via a unique hydrolyzable linker. The epithelial cell surface antigen, Trop-2, demonstrates greater expression between UC vs normal tissue, and is a promising target. In a phase 1/2 basket study (IMMU-132-01), SG showed an overall response rate (ORR) of 31% and manageable toxicity in 45 pts with mUC who had a median of 2 (range 1–6) prior therapy lines (Tagawa 2019 ASCO GU). Recent interim results for cohort 1 of the TROPHY-U-01 study in 35 pts with mUC who progressed on platinum and CPI therapy demonstrated an ORR of 29% in pts with a median of 3 prior treatment lines (range 2–6) (Tagawa 2019 ESMO). The most common grade ≥3 treatment-related AE (TRAE) was neutropenia. Methods: TROPHY-U-01 (NCT03547973) is a global, open-label, phase 2 trial evaluating the antitumor activity of SG (10 mg/kg, days 1 and 8 of 21-day cycles) in pts with advanced UC with measurable disease and ECOG PS 0 or 1. Cohort 2 includes platinum-ineligible pts who progressed after CPI therapy in the first-line metastatic setting. The primary objective is ORR evaluated with RECISTv1.1 by central review. Secondary objectives include progression-free survival, overall survival, and duration of response. Results: 18 pts with baseline tumor assessment (50% male; median age 79 y [range 57–87], 67% visceral metastases; 28% liver metastases) received a median of 2 (range 1–5) prior therapies. At a median follow-up of 6 months, ORR was 28% (5/18) with 4 confirmed PRs, and 1 PR pending confirmation. The majority of pts (61% [11/18]) had target lesion reduction. The safety profile was consistent with prior reports. Key grade ≥3 TRAEs were neutropenia (39%), fatigue (33%), diarrhea (28%), leukopenia (22%), anemia (17%), and febrile neutropenia (11%). No events of interstitial lung disease, ocular toxicities, or grade > 2 neuropathy were reported. There were no treatment-related deaths. Conclusions: In cisplatin-ineligible pts, the ORR for currently approved first-line CPI treatments is ~23–29% (Balar 2017 Lancet; Vuky 2018 ASCO). These preliminary data with SG show a manageable safety profile with an encouraging ORR of 28% and support the development of SG in platinum-ineligible pts with mUC who have progressed after CPI therapy. Clinical trial information: NCT03547973 .
Association of molecular subtypes with pathologic response in a phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy (NAC) for localized, muscle-invasive bladder cancer (SWOG S1314; NCT02177695).
Authors: Lerner Seth P. , McConkey David James , Tangen Catherine , Meeks Joshua J , Flaig Thomas W. , Hua Xing , Daneshmand Siamak , Alva Ajjai Shivaram , Lucia M. Scott , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Choi Woonyoung , Bangs Richard Carlton , Gustafson Daniel , Thompson Ian Murchie 
Published: May 2020

5028 Background: Cisplatin-based NAC is recommended for patients with MIBC prior to radical cystectomy (RC) but the majority will not have a pathologic response. To identify responders the COXEN gene expression model with chemotherapy-specific scores (for DD-MVAC and GC) was developed and in a prospective rPII clinical trial (SWOG S1314) the GC score was associated with path downstaging in the pooled arms. We investigated RNA based molecular subtypes as additional predictive biomarkers for response to NAC in patients treated in S1314. Methods: Eligibility required cT2-T4a N0 M0, predominant urothelial, > 5 mm tumor, cisplatin eligible, and plan for RC and PLND. 237 patients were randomized between 4 cycles of ddMVAC and GC. Based on Affymetrix transcriptomic data used to assign COXEN scores, we determined subtypes using 3 classifiers: TCGA (k=5), Consensus (k=6), and MD Anderson (MDA; k=3). Primary objective was to assess subtype association with pathologic response to NAC in the pooled arms and to determine any association with COXEN. TCGA and Consensus classifiers were collapsed into 3 groups for ROC analyses. We tested whether each classifier contributed additional predictive power when added to a model based on pre-defined stratification factors (PS 0 vs. 1; T2 vs. T3, T4a). Results: 161 patients had adequate tissue and gene expression results, received at least 3 of 4 cycles of NAC and had pT-N response based on RC. Covariates were 78% PS=0, 89% T2, 84% male, median age 65, 51% randomized to ddMVAC, 49% GC with 33% pT0 and 52% downstaging. Although the TCGA 3 group classifier (Basal-Squamous (BS)/Neuronal, Luminal, Luminal infiltrated) and GC Coxen score yielded the largest AUCs (0.607, 0.610) for pT0 response, neither reached statistical significance (p=0.20, p=0.22). For downstaging (<pT2), the 3 category Consensus classifier (BS/NE-like, Luminal, Stroma-rich) significantly increased the AUC from 0.568 (strat factors alone) to 0.620 (p=0.044). The MDA classifier AUC was 0.640 and the GC Coxen score AUC was 0.626, but neither were significant (p=0.076, p=0.14. The MVAC Coxen score did not improve the AUC beyond the stratification factors. Conclusions: The Consensus classifier, which is based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging when added to clinical stage and PS. With additional followup, we will assess the association of COXEN scores and subtypes with overall survival. Clinical trial information: NCT02177695 .
Pathological response rates and quality of life outcomes of neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle-invasive transitional cell carcinoma of the urinary bladder.
Authors: Challapalli Amarnath , Masson Susan , White Paul , Dailami Narges , Pearson Sylvia , Rowe Edward , Koupparis Anthony , Oxley Jon , Ash-Miles Janice , Bravo Alicia , Foulstone Emily , Persad Raj , Bahl Amit 
Published: May 2020

5030 Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy, safety and tolerability of cisplatin cabazitaxel combination in this patient group. Methods: A phase 2 single arm trial (Simon 2 stage), to recruit at least 26 evaluable patients was designed with 80% power to detect the primary endpoint, objective response rate (ORR) of > 35%. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging), measured by pathologic staging (T2 or greater at diagnosis, to T1 or less at radical cystectomy). Treatment was with Cisplatin 70mg/m2 and Cabazitaxel 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. Quality of Life (QoL) data were collected at baseline, prior to each cycle of chemotherapy and at 3-5 weeks after 4th cycle of chemotherapy using EQ-5D and EORTC QLQ-C30, BLM30 questionnaires. Results: Objective response was seen in 15 out of 26 evaluable patients, 57.7% and over a third of patients achieved pCR (9/26; 34.6%). 78% (21/27) of patients completed all cycles of treatment, with only 6.7% of the reported adverse events (AEs) being graded 3 or 4. There were 6 treatment related SAEs reported but no SUSARs. In patients who achieved objective response the median progression free (PFS) and overall survival (OS) were not reached (median follow up: 41.5m). In contrast, median PFS (7.2m) and OS (16.9m) were significantly worse (p = 0.001) in patients who did not respond. Response rates for EORTC QLQ-C30, BLM 30 and EQ5D questionnaires was 70.4, 70.4 & 63% respectively, at end of treatment. There was no significant difference in EORTC QLQ C30 summary, global health scores and EQ5D score with treatment. There was a significant decline in mean QLQ C30 domain scores after 1st cycle compared to baseline, but no further deterioration with subsequent cycles of chemotherapy. Conclusions: Cabazitaxel with cisplatin as NAC of MIBC can be considered a safe, well-tolerated and effective regimen with higher pCR rate of 34.6%. This compares favorably to that with Cisplatin/Gemcitabine (23-26%). Minimal changes in Global Health & EQ5D observed during NAC further demonstrates the excellent tolerability of this regimen and to our knowledge are the first data regarding QoL in NAC in MIBC. These results warrant further evaluation in a larger phase 3 study. Clinical trial information: 2011 004090 82 .
Comparative effectiveness of second-line (2L) single-agent atezolizumab (A), nivolumab (N), and pembrolizumab (P) in patients (Pts) with locally advanced or metastatic urothelial cancer (aUC) who progressed on platinum-based systemic chemotherapy (plat-chemo): Results from a real-world dataset.
Authors: Swami Umang , Haaland Ben , Maughan Benjamin Louis , Nussenzveig Roberto , Esther John , Kessel Adam , Pal Sumanta K. , Grivas Petros , Agarwal Neeraj 
Published: May 2020

5032 Background: Five PD-1/L1 inhibitors (PDi) are approved for 2L therapy (Rx) for aUC after progression on plat-chemo, but none compared with each other in randomized trials. Here, we assessed comparative effectiveness of 2L PDi in real-world setting. Methods: Pt level data of Pts with aUC were extracted from Flatiron Health EHR-derived de-identified database. Inclusion criteria: 1L Rx with plat-chemo; receipt of single agent PDi in 2L; initiation of 2L PDi 6 mos before data-cut off. Exclusion criteria: >90 days from diagnosis to date of next visit to ensure active engagement of Pts with data providing site; initiation of 2L after 7/31/2016 to ensure uptake of PDi for aUC. OS was compared from the date of initiation of 2L Rx. Comparative effectiveness was examined by Cox proportional hazards model, stratified by treatment propensity score. Each Pts’ propensity of receiving each 2L PDi was modeled via a random forest based on Pt and disease characteristics potentially driving Rx selection for a PDi (gender, smoking status, race/ethnicity, relapsed vs de novo disease, time between 1L & 2L Rx, cis vs carboplatin in 1L; year of Rx with PDi & following characteristics before 2L Rx: ECOG, Hb, age, ICD codes for liver or CNS mets, albumin & PD-L1 status when available). Results: 703 Pts with aUC who initiated 2L Rx between 8/1/2016 to 10/31/2019 were eligible. 2L Rx were A (n=322), N (n=127) & P (n=254). Durvalumab & avelumab were excluded due to low utilization in this dataset. Median follow up from 2L initiation was 4.8 mos. Median OS (mos; 95% CI) with A (6.4 mos; 5-8.7), N (8 mos; 6.3-11.3) and P (8.5 mos; 6.1-11.6) were similar (propensity stratified log rank p=0.19; simple log-rank p=0.34). Over time proportion of Pts receiving 2L A decreased, P increased & N increased then decreased (p<0.001). Propensity stratified comparative effectiveness estimates are below. Conclusions: In this real-world cohort of Pts with aUC, OS with 2L Rx with A, N, & P were similar on both univariate and propensity stratified analyses. These results agree with prior trial level meta-analysis (PMID 31200951). Strength of this analysis includes large Pt level data from a real world cohort. Limitations include retrospective nature of this study. [Table: see text]
Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Results of an open-label phase II clinical study Polaris-03.
Authors: Sheng Xinan , Chen Haige , Hu Bin , Yao Xudong , Liu Ziling , Yao Xin , Guo Hongqian , Hu Yi , Ji Zhigang , Luo Hong , Shi Benkang , Liu Jiyan , WU Jin , Zhou Fangjian , He Zhisong , Fan Jinhai , Huang Yiran , Guo Jun 
Published: May 2020

5040 Background: Patients with advanced metastatic urothelial carcinoma (UC) who experience disease progression after standard therapy have limited treatment options. Phase I study of toripalimab in subjects with heavily pretreated metastatic UC had demonstrated an acceptable safety profile and promising clinical activity. Here we report the safety and efficacy result of toripalimab in a phase II clinical study (POLARIS-03) in Chinese patients with metastatic urothelial carcinoma. (Clinical trial ID: NCT03113266). Methods: Metastatic UC Patients receive toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response is assessed every 8 weeks. Tumor PD-L1 expression and other biomarkers will be evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 204 patients were screened and the study enrollment was completed with 151 patients enrolled from 15 participating centers. The median age was 62 years and 66% were male. 87% patients had visceral metastasis. By the cut-off date of Jan 6, 2020, 92.1% (139/151) patients experienced treatment related adverse event (TRAE) and grade 3 and above TRAE occurred in 35.8% (54/151) patients. Most common TRAE included anemia, triglycerides increased, proteinuria, fatigue, and hyperglycemia. Treatment discontinuation due to a TRAE occurred in 6 (4.0%) patients, while dose delay due to a TRAE occurred in 23 (15.2%) patients. Three patients with major protocol deviations were excluded from efficacy analysis. Among 148 patients assessed by IRC per RECISTv1.1, 2 CR, 36 PR, and 30 SD were observed for an ORR of 25.7% and a DCR of 45.9%. The median DOR was 15.7 months. The median PFS was 1.9 months, and the median OS was estimated 20.8 months. PD-L1 expression results were obtained from 141 patients. PD-L1+ patients (n=46) had significant better ORR than PD-L1- patients (n=95), 41.3% versus 16.8% ( p<0.01). Conclusions: Toripalimab has demonstrated encouraging clinical activity in chemo-refractory UC patients with a manageable safety profile. Patients will be continuously monitored for safety and overall survival. Clinical trial information: NCT03113266 .