bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular biomarker analysis and survival in patients (pts) with advanced urothelial cancer (UC) previously treated with chemotherapy.
Authors: Szabados Bernadett , Rebelatto Marlon , Barker Craig , Milner Alvin , Lewis Arthur , Stokes Michael , Zajac Magda , Powles Thomas , Shire Norah J 
Published: May 2019

4529 Background: The biomarkers PD-L1, FOXP3, and CD8 have been explored in pts with advanced UC who progressed after platinum-based chemotherapy (CTx). However, their relevance earlier in the disease process is less well understood. Methods: The Phase 2/3 LaMB study (NCT00949455) compared maintenance lapatinib vs placebo after first-line (1L) platinum-based CTx in pts with HER1/HER2-overexpressing stage IV advanced UC. Pre-CTx archival samples from this study were retrospectively analyzed and included both randomized and screen failure pts. PD-L1 expression was assessed (VENTANA SP263 Assay) and categorized as high (≥25% of tumor cells [TC] and/or immune cells [IC]) or low/negative ( < 25% TC and IC). Overall survival (OS) and progression-free survival (PFS) were estimated via Kaplan-Meier method; results were stratified by PD-L1 expression. The exploratory biomarkers CD8 and FOXP3 were also analyzed. The prognostic significance of the biomarkers was explored by multivariable Cox proportional hazards models and a bootstrap method for model selection. Results: Of 446 pts (232 randomized; 214 screened), 243 (54.5%) were assessed for PD-L1 expression, with 61 (25.1%) PD-L1 high and 158 (65.0%) PD-L1 low/negative. In PD-L1 high and low/negative pts, respectively, median OS (95% CI) was 12.0 (9.4–19.7) vs 12.5 months (10.4–15.5); median PFS (95% CI) was 6.5 (3.5–8.8) vs 5.0 months (4.3–6.3). PD-L1 expression was not associated with OS or PFS in univariate analysis or in a multivariate model for OS (hazard ratio [HR] for PD-L1 high vs low/negative 1.4 [95% CI, 0.8–2.3]). In a multivariate model for PFS, PD-L1 expression improved accuracy of the model by 23% and was a significant variable (HR, 2.1 [95% CI, 1.2–3.5]). Results of analyses of CD8 and FOXP3 will also be reported. Conclusions: Overall, these data suggest a lack of association between PD-L1 expression and survival in pts receiving 1L platinum-based CTx. Mechanisms underlying the potential association of PD-L1 expression with PFS remain unclear. CD8 and FoxP3 exploratory analyses may help to elucidate these results. Clinical trial information: NCT00949455.
Adenocarcinoma (ACB), urothelial carcinoma (UCB) and squamous cell carcinoma (SCCB) of the bladder: A Comprehensive Genomic Profiling (CGP) Study.
Authors: Jacob Joseph , Bratslavsky Gennady , Shapiro Oleg , Liu Nick , Ferry Elizabeth Kate , Basnet Alina , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ramkissoon Shakti , Severson Eric Allan , Ali Siraj Mahamed , Chung Jon , Schrock Alexa Betzig , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Miller Vincent A. , Necchi Andrea , Ross Jeffrey S. 
Published: May 2019

4533 Background: We performed a CGP to compare the genomic alterations (GA) in ABC, UBC and SCCB. Methods: 143 cases of ACB, 2,142 cases of UCB and 83 cases of SCCB were subjected to CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: ABC patients were younger and more often female than UBC and SCCB (P < 0.0001). UBC and SCCB had a higher GA/tumor than ABC (P = 0.01). Un-targetable GA were similar in all 3 groups involving TP53 and KRAS. APC GA were more frequent in ABC whereas TERT, CDKN2A/B and DNA-repair genes ( ARID1A and KDM6A) more frequently altered in UBC and SCCB. Targetable MTOR pathway GA ( PIK3CA, TSC1, PTEN) were more frequent in UBC and SCCB as were targetable kinase alterations ( FGFR3 and ERBB2). The UBC and SCCB had a significantly higher TMB than ABC (P < 0.0001) including mean TMB and TMB > 20 mut/Mb (P < 0.0001). CD274 (PD-L1) was amplified more frequently in SCCB than ACB or UBC (P < 0.0001). MSI high status was very uncommon in all tumor types. Conclusions: Deep sequencing reveals that ABC features a widely different genomic profile from UBC and SCCB. UBC has the highest frequencies of targetable kinase GA and high TMB. SCCB has the highest frequencies of IO efficacy predicting biomarkers including mean TMB and PD-L1 amp. Nonetheless, ABC does feature potential kinase targets such as FGFR3 and ERBB2. [Table: see text]
Squamous-cell carcinoma variant histology (SCC-VH) in muscle-invasive bladder cancer (MIBC): A comprehensive clinical, genomic, and therapeutic assessment from multiple datasets.
Authors: Bandini Marco , Pederzoli Filippo , Madison Russell , Briganti Alberto , Plimack Elizabeth R. , Ross Jeffrey S. , Niegisch Guenter , Yu Evan Y. , Bamias Aristotelis , Agarwal Neeraj , Sridhar Srikala S. , Rosenberg Jonathan E. , Bellmunt Joaquim , Galsky Matt D. , Gallina Andrea , Salonia Andrea , Montorsi Francesco , Ali Siraj Mahamed , Chung Jon , Necchi Andrea 
Published: May 2019

4535 Background: Pure or predominant SCC-VH is not uncommon in MIBC. Nevertheless, very few data are available about the efficacy of neoadjuvant chemotherapy (NAC). Here, we examined the outcomes after NAC, explored novel therapeutic targets, and propose new results in these patients (pts) by integrating multiple datasets. Methods: Within RISC and San Raffaele databases (1990-2018), we identified 2858 MIBC pts with urothelial cancer (UC, N = 2229) or VH (N = 629) who received RC +/- NAC. Kaplan-Meier and Cox regression analyses compared cancer-specific survival (CSS) between SCC and UC with NAC stratification. Logistic regression models tested the odds of clinical-to-pathological downstaging (cT > pT). Foundation Medicine (FMI) dataset was queried for SCC-VH. 97 pts were assayed with hybrid-capture based comprehensive genomic profiling (CGP). Finally, we looked at the results from the PURE-01 study, that is now amended and enrolling pts with VH (NCT02736266). Results: Overall, 127 (4.4%) had predominant SCC-VH, 157 (5.5%) UC+SCC. Among the NAC-treated pts, SCC was the only VH (N = 44) significantly associated with worse CSS, (p < 0.001) and higher mortality (HR 2.10, p = 0.003) vs. UC. After NAC adjustment, SCC-VH showed lower rate of downstaging (3.7 vs 9.3%, OR 0.4, p = 0.028) vs. UC. Similar negative trends were confirmed in pN0 pts, where SCC exhibited worse CSS (p = 0.006) and higher mortality (HR 5.15, p = 0.002). In the FMI cohort, the median tumor mutational burden (TMB) of SCC was 6.25 mut/mb (vs 6.9 mut/mb of 1984 UC), 27% of pts having > 10 mut/mb and 14% > 20 mut/mb. Clinically relevant alterations occurred in PIK3CA (42%), CCND1 (15%), PTEN (9.3%), FGFR3 (9.3%), and ERBB2 (6.2%). In the PURE-01 study, 13/84 (15.5%) SCC-VH pts received pembrolizumab before RC. PD-L1 combined positive score was ≥10 in 11/13 pts; results yielded 4 pT0 (30.8%), 10 pT≤1 (76.9%), and no deaths (median FUP: 10.4 mo). Conclusions: We present a comprehensive assessment of SCC-VH in MIBC. SCC represents the VH with the lowest activity of NAC. While CGP revealed multiple opportunities for targeted therapy, the efficacy of neoadjuvant pembrolizumab in SCC is encouraging.
PD-L1/PD-1 expression as a predictor of response to BCG in patients with high-risk non–muscle invasive bladder cancer.
Authors: Roumiguie Mathieu , Comperat Eva , Neuzillet Yann , Nouhaud Francois-Xavier , Graffeille Vivien , Masson-Lecomte Alexandra , Colin Pierre , Audenet Francois , Houede Nadine , Larre Stephane , Xylinas Evanguelos , PIana Thomassin Jeanne , Cotte Juliette , Pignot Geraldine , Chaltiel Leonor , Roupret Morgan 
Published: May 2019

4550 Background: Intravesical BCG instillation (IBI) is the gold standard adjuvant treatment after transurethral resection of the bladder in high risk non muscle invasive bladder cancer (HR-NMIBC). IBI induce a type of Th1 immune response requiring a recruitment of cytotoxic cells. This response is downregulated by the PD-1/PD-L1 checkpoint inhibitors through an inhibition of the action of CD8+ T cells against their target. Our purpose was to assess whether PD-1/PD-L1 expression was associated with IBI response in HR-NMIBC. Methods: Histologically confirmed HR-NMBC from 5 academic French institutions which underwent maintenance IBI were retrospectively included. The following data were collected: pathological stage, grade, concomitant carcinoma in situ, number of lesions and size. From a paraffin embedded samples of initial resection, a unique dedicated uropathologist quantified immunochemistry expression of CD3, CD8, PD-L1 (antibody SP263/ SP142, E1L3N, 28 8) in both tumour cells and tumoral microenvironment. Univariate and multivariate analyses were performed using Cox proportional hazards model. Results: Overall 140 patients (median age 66.5 years, range:35-87; sex ratio male vs female:6:1) were included. The distribution of NMIBC tumour for stage and grade was: Ta 37.2% (n = 52), T1 62.8% (n = 88) and high grade 100% (n = 140) respectively. The median number of IBI which were delivered was 12 (range 7-36). The median length of follow-up was 54.24 mo (95% CI = 49.91-58.68). Overall, 25 patients (17.9%) had a recurrence/or progression. The 72mo Disease free survival (DFS) rate was 81.11% (95% CI = 72.20-87.41). Using univariate analysis, we found that Age (HR = 1.07; [1.02-1.12] p = 0.005), CD3/CD8 ratio (HR per 10 units = 3.43 [1.62-7.23] p = 0.014) and PD-L1(HR per 10 units = 1.65 [1.15-2.38] p = 0.046) were associated with DFS. In multivariate analysis, Age (HR = 1.07 [1.02-1.13] p = 0.009), CD3/CD8 ratio (HR per 10 units = 1.96 [1.28-3.00] p = 0.02) and PD-L1 expression in tumour cells (HR per 10 units = 3.38 [1.61-7.11] p = 0.01) remained significantly associated with DFS. Conclusions: PD-L1 expression in tumour cells and the T cells population in tumour microenvironment were both predictive factors of BCG response in HR-NMIBC. These results build a scientific rationale for pharmacological intervention on a molecular target using immuno-oncology.
Correlation of circulating tumor DNA (ctDNA), tissue-based genomic profiling and clinical efficacy in the biomarker directed Ph1b trial in metastatic bladder cancer (BISCAY).
Authors: Carroll Danielle , McEwen Rob , Kozarewa Iwanka , Harrington Elizabeth , L'Hernault Anne , Ratnayake Jayantha , Mather Richard , Hodgson Darren , Barrett J Carl , Cosaert Jan G. C. E. , Brachet Pierre Emmanuel , Grivas Petros , Chowdhury Simon , Powles Thomas , Landers Donal 
Published: May 2019

4553 Background: BISCAY is a biomarker-directed Ph1b multi-arm platform study exploring the combination of targeted therapies with anti-PD-L1, Durvalumab, in advanced urothelial cancer. Methods: Next generation sequencing (NGS) of tumour tissue samples from > 380 patients(pts) was performed using the FoundationOne assay alongside IHC for PD-L1. ct DNA from pts enrolled in trial modules at treatment initiation was profiled using the Guardant Health OMNI platform assessing a panel of 500 genes. For a subset of pts, serial plasma samples were also analysed to monitor early signs of response vs. resistance and changes in ct DNA dynamics using a bespoke NGS panel of 10 genes. Results: To date 149 pts have been actively enrolled across 7 different biomarker selected and unselected treatment modules. Across all screened pts the most prevalent genomic alterations in tumour tissue were TERT promoter (65%), TP53 (59%), KMT2D 21%, KDM6A 21%, with the most common CNV CDKN2A/ B loss (32 %). All enrolled pts tested had detectable ctDNA in plasma. Similar genomic alterations, both frequency and type, were detected in both plasma ctDNA and tumour tissue with high concordance for module specific biomarkers used for patient allocation (80% (8/10) for ATM, BRCA1 and 2). Alterations in putative biomarkers predictive of response to anti-PD-L1, such as HRR/MMR alterations and high bTMB levels ( > 20mut/Mb) were observed in22% and 40% patient plasma samples, respectively. Correlations between biomarkers across modules treatment efficacy have been explored. Conclusions: All pts with advanced bladder cancer enrolled on BISCAY who were plasma profiled had detectable ctDNA; frequencies of genomic alterations (in both tumour tissue and plasma) were comparable to prior published data sets. ctDNA may be an attractive alternative to tissue-based NGS, providing comprehensive dynamic snapshots of genomic landscapes at the start and during therapy, and warrants further prospective investigation in trials.
A pilot safety study of gemcitabine and cisplatin (GC) with atezolizumab (A) as first-line therapy in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Funt Samuel Aaron , Jatwani Karan , Makris Michelle , Regazzi Ashley Marie , Lee Chung-Han , Teo Min Yuen , McHugh Deaglan Joseph , McCoy Asia S. , Hettich Grace , Wong Phillip , Abu-Akeel Moshen , Wolchok Jedd D. , Merghoub Taha , Al-Ahmadie Hikmat , Ostrovnaya Irina , Chaim Joshua , Durack Jeremy C. , Iyer Gopa , Bajorin Dean F. , Rosenberg Jonathan E. 
Published: May 2019

4559 Background: GC has a high overall response rate (ORR) but a high relapse rate in pts with untreated mUC. Inhibition of programmed death-ligand 1 (PD-L1) with A can lead to long-term survival, but single-agent ORR is modest. We report the outcomes of GC+A in a cohort pts with mUC. Methods: This study was designed to assess the safety of GC + A in 10 pts with untreated mUC prior to testing GC + A in a neoadjuvant study in pts with muscle-invasive disease. The primary endpoint was safety as assessed by a predefined dose limiting toxicity (DLT) rate during the first cycle in the first 6 pts. Total accrual goal was 10 pts to collect preliminary data on ORR and progression-free survival (PFS). RECIST 1.1 assessments were performed every 9 wks. Pts received 6 cycles of GC + A induction and then A maintenance every 3 wks. Results: No DLTs occurred during the first cycle in the first 6 pts. Grades 3-4 neutropenia and anemia occurred in 6/10 and 7/10 pts, respectively. Three pts required gemcitabine dose reductions for hematologic toxicity and 2 pts had febrile neutropenia. One pt discontinued cisplatin after 2 cycles for grade 3 hearing impairment but completed induction with gemcitabine and A. Only 1 pt discontinued study therapy due to treatment-related adverse events (AEs), including A-related grade 4 encephalopathy and grade 3 polyneuropathy. Three of 10 pts had visceral (liver or bone) metastases. Of the 10 pts, 1 pt is completing induction but meets initial criteria for partial response (PR), 8 pts had confirmed PR, and 1 pt had progressive disease (PD). Of 9 pts with confirmatory scans, the median PFS was 10.6 months (95% CI 6.7, N/A). Of 8 pts with confirmed PR, 5 eventually had PD, 1 has just completed induction, 1 remains without PD at 25 months, and 1 had consolidation surgery with a pathologic complete response and remains disease-free at 21 months. Conclusions: This 10 pt study met its primary safety endpoint. The neoadjuvant study is ongoing (NCT02989584). Although there were a substantial number of grade 3-4 toxicities, therapy was discontinued due to treatment-related AEs in only 1 pt. Immune correlative studies are ongoing. Clinical trial information: NCT02989584.
Preliminary phase 2 clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients.
Authors: Chamie Karim , Lee John H. , Rock Amy , Rhode Peter R. , Soon-Shiong Patrick 
Published: May 2019

4561 Background: Patients with non-muscle-invasive bladder cancer (NMIBC) unresponsive to BCG therapy have limited treatment options. N-803 (also known as ALT-803) is an IL-15-based immunostimulatory protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase Ib data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Methods: An open-label, single-arm multicenter Phase 2 study of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. The study has two cohorts: Cohort A, patients with BCG-unresponsive carcinoma in situ (CIS) [with or without Ta or T1 disease] and Cohort B, patients with BCG-unresponsive high-grade Ta/T1 disease. All treated patients receive intravesical N-803 plus BCG, similar to a standard induction and maintenance treatment schedule. The primary endpoint for Cohort A is incidence of complete response (CR) of CIS at any time, and the primary endpoint for Cohort B is disease-free rate at 12 months. Results: To date, forty-six patients have enrolled in this phase 2 trial (Cohort A (CIS), n = 23, Cohort B (Papillary), n = 23). Of eleven evaluable patients in Cohort A, nine patients (82%) have a reported CR. In addition, seven out of nine (78%) patients in Cohort A demonstrated CR at their 6-month response assessment. Of thirteen evaluable patients in Cohort B, ten patients (77%) showed no evidence of recurrence at their 3-month response assessment; of these, none (0/8) evaluated past 3 months have had disease recurrence. Three serious adverse events (AEs) have been reported (E coli infection, anemia, and bacteremia), with no immune-related AEs. Conclusions: Nine out of eleven (82%) patients with BCG-unresponsive CIS of the bladder demonstrated a complete response. Ten out of thirteen patients with BCG-unresponsive papillary NMIBC show no evidence of disease at first assessment. Intravesical N-803 plus BCG was well-tolerated and no patients experienced immune-related AEs. Clinical trial information: NCT03022825.
Biomarkers of outcomes in a randomized phase II trial of first-line paclitaxel, ifosfamide, and cisplatin (TIP) versus bleomycin, etoposide, and cisplatin (BEP) for intermediate- and poor-risk germ cell tumors (GCT).
Authors: Feldman Darren R. , Hu James S , Patil Sujata , Reuter Victor E. , Srinivas Sandy , Stadler Walter Michael , Costello Brian Addis , Milowsky Matthew I. , Appleman Leonard Joseph , Dorff Tanya B. , Bromberg Maria , Joseph Gabriella , Funt Samuel Aaron , Bajorin Dean F. , Bosl George J. , Quinn David I. , Motzer Robert J. 
Published: May 2019

4563 Background: We previously reported no difference in favorable response rate (FRR) or PFS for TIP vs BEP. Here we present results of a pre-planned analysis of biomarkers of outcome. Methods: HCG and AFP were drawn on days 1 and 15 of each cycle and rates of decline classified as satisfactory [S] or unsatisfactory [US] by MSK (Motzer JCO 2007) and GETUG (Fizazi Lancet Oncol 2014) methods. IHC for ERCC1, RAD51, PARP1, HER-2, and p-AKT was performed on pre-treatment tumor samples. An H-score (0 – 300) was calculated for each stain (H = stain intensity [0 – 3] x % positive cells [0-100]). H-score and marker decline category were correlated with FRR (PR + CR) and PFS. Patients (pts) who received disease-stabilizing chemotherapy were excluded from marker analyses. Results: Of 91 pts, 80 did not receive disease-stabilizing treatment with 79 having sufficient marker values for analysis by the MSK method and 75 by GETUG. By MSK, 49 had S decline vs 30 US; by GETUG, 34 S vs 41 US. FRR and PFS were improved for pts with S vs US decline by both methods and remained significant by the MSK method when stratified by IGCCCG group (Table). IHC (n=77) quality was adequate in 71 to 73 pts (varied by stain) and was positive (H >0) for PARP in 68/73, ERCC1 in 54/71, RAD51 in 54/73, p-AKT in 5/72, and HER2 in 4/72. Only PARP1 was associated with outcome with worse PFS for the lowest expression tertile (H < 180; p=0.013). Conclusions: PARP1 expression and tumor marker decline rates, particularly by MSK method, were significantly associated with outcome to initial chemotherapy in int/poor risk GCT. Future trials incorporating marker decline into treatment allocation and validating the prognostic effect of PARP1 expression are warranted. Clinical trial information: NCT01873326. [Table: see text]
KEYNOTE-427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non‒clear cell renal cell carcinoma (NCC-RCC).
Authors: Lee Jae-Lyun , Ziobro Marek , Gafanov Rustem , Matveev Vsevolod Borisovich , Suarez Cristina , Donskov Frede , Pouliot Frederic , Alekseev Boris Yakovlevich , Wiechno Pawel J. , Tomczak Piotr , Climent Miguel Ángel , Shin Sang Joon , Silverman Rachel Kloss , Perini Rodolfo F. , Schloss Charles , McDermott David F. , Atkins Michael B. 
Published: May 2019

4569 Background: Efficacy of PD-1 inhibitors (or any therapy) in NCC-RCC has not been established. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced clear cell RCC (cohort A) and NCC-RCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed NCC-RCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Additional end points: duration of response (DOR), population description by sarcomatoid differentiation, histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26); 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At median follow-up of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CR, 33 [20.0%] PR). Median DOR was not reached. For responding pts, 81.5% had a response ≥6 mo. 12-mo PFS and OS rates were 22.8% and 72.0%, respectively. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified NCC-RCC; for responding pts, 82.1%, 50.0%, and 87.5% had a response ≥6 mo, respectively. Median DOR was not reached in any group. ORR (95% CI) was 44.7% (28.6-61.7) for pts with sarcomatoid differentiation (n = 38). ORR (95% CI) was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS < 1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts. 6 pts died of AEs, 2 of TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in NCC-RCC, especially with papillary or unclassified histology. Safety profile of pembro was as expected. Updated data with additional follow-up will be presented. Clinical trial information: NCT02853344.