bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of subsequent therapy on survival in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as first-line therapy for advanced urothelial carcinoma (UC).
Authors: Alva Ajjai Shivaram , Csőszi Tibor , Ozguroglu Mustafa , Matsubara Nobuaki , Geczi Lajos , Cheng Susanna Y. , Fradet Yves , Oudard Stephane , Vulsteke Christof , Morales-Barrera Rafael , Flechon Aude , Gunduz Seyda , Loriot Yohann , Rodriguez-Vida Alejo , Mamtani Ronac , Yu Evan Y. , Nam Kijoeng , Imai Kentaro , Homet Moreno Blanca , Powles Thomas 
Published: March 2021

439 Background: The phase III KEYNOTE-361 study examined the efficacy and safety of 1L pembro + chemo or pembro alone vs chemo for pts with advanced UC. The PFS and OS benefit of pembro + chemo vs chemo did not reach statistical significance; no further formal tesing was done. We present an exploratory analysis of OS by subsequent therapy in KEYNOTE-361 (NCT02853305) to assess how 1L and 2L therapy selection affected survival outcomes; no formal comparisons were conducted. Methods: OS was estimated for pts by whether they received subsequent therapy, and by whether subsequent therapy included an anti–PD-(L)1 agent. Results: 351 pts were randomized to pembro + chemo, 307 pts to pembro, and 352 pts to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. 124/351 pts (35%) in the pembro + chemo arm, 126/307 pts (41%) in the pembro arm, and 215/352 pts (61%) in the chemo arm received any subsequent therapy. Similar rates of subsequent therapy (pembro + chemo: 32%; pembro: 43%; chemo: 59%) were observed for pts who experienced progressive disease (PD) by blinded independent central review (BICR). A higher rate of pts (169/352 [48%]) in the chemo arm received subsequent anti–PD-(L)1 therapy than in either the pembro + chemo arm (23/351 [7%]) or pembro arm (14/307 [5%]). Due to the small pt numbers, pts in the pembro + chemo or pembro arms who received subsequent anti−PD-(L)1 were not considered further. This analysis included all pts who received 2L therapy (465/1010 pts [46%]); the rate of 2L therapy was similar in pts with PD by BICR (274/615 [45%]). Chemo agents alone or in combination, specifically carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, and paclitaxel, were the most commonly received subsequent therapies for pts who did not receive anti–PD-(L)1 in 2L. Pts who received 1L chemo followed by subsequent anti–PD-(L)1 had longer mOS (19.1 mo [95% CI 16.2-22.2]) than pts with 1L pembro followed by 2L therapy not including an anti−PD-(L)1 agent (16.0 mo [95% CI 11.8-19.2]) (Table). Conclusions: In this exploratory analysis, favorable survival outcomes were observed for pts who received 1L chemo followed by anti–PD-(L)1 compared with pts who received 1L pembro followed by 2L therapy not including an anti–PD-(L)1 agent. These data underline the continued importance of immunotherapy as 2L therapy for advanced UC. Clinical trial information: NCT02853305 . Research Sponsor: Merck & Co., Inc[Table: see text]
Efficacy of enfortumab vedotin in advanced urothelial cancer: Retrospective analysis of the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) Study.
Authors: Koshkin Vadim S , Sun Yilun , Freeman Dory , Osterman Chelsea K. , Su Christopher , Natesan Divya , Khaki Ali Raza , Makrakis Dimitrios , Jain Jayanshu , Olsen Anders , Basu Arnab , Barata Pedro C. , Zakharia Yousef , Bilen Mehmet Asim , Emamekhoo Hamid , Davis Nancy B. , Milowsky Matthew I. , Kilari Deepak , Sonpavde Guru , Alva Ajjai Shivaram 
Published: March 2021

443 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is FDA approved for patients (pts) with treatment-refractory advanced urothelial cancer (aUC). The activity of EV in pt subsets of interest such as those with distinct histological variants has not been well defined. Methods: A retrospective study of pts with aUC treated with ≥1 dose of EV as standard of care (SOC) or on a clinical trial (if trial results already reported) at 12 US sites was undertaken. Objective response rate (ORR) was investigator-assessed for pts with at least one post-baseline scan or clear evidence of clinical progression. ORR was compared across subsets of interest using proportion test. Results: A total of 184 patients with aUC were included; median age at diagnosis 70, 20% women and 60% with definitive surgery. Most common primary sites included bladder (70%) and upper tract (28%). Majority of pts (72%) had pure urothelial histology (UH) per local review, but 26% had at least a component of variant histology (VH), most commonly squamous (14%), micropapillary (8%) or plasmacytoid (3%). EV was given as monotherapy in 84% and as SOC in 58%; and 81% had ≥ 1 prior treatment in the metastatic (met) setting. ECOG PS was ≥2 in 15%; 37% had baseline neuropathy, 15% diabetes and 9% had GFR≤30. At median follow-up of 37.0 (IQR: 20.5-60.2) months from initial diagnosis, median time from met diagnosis to EV start was 11.7 (IQR: 4.3 – 20.5) months. Median duration of EV was 5.5 (IQR: 1.4 – 6.7) months, and 84% of pts were evaluable for response. ORR for evaluable pts was 53% (8% CR, 45% PR); 25% had SD and 21% PD. Median PFS and OS were not yet reached. At data cutoff in 9/2020, 55% had stopped EV (36% due to PD, 19% intolerance) and 65% were alive. Comparison of ORR in subgroups of interest for 127 evaluable pts treated with EV monotherapy is shown in the table below. Notably, among 31 pts with FGFR3 alterations, 26 were evaluable and ORR was 46%. Conclusions: In a large, retrospective, multi-institutional cohort, responses to EV were observed across a broad range of aUC pts, including pts with variant histology component, FGFR3 alterations and also in populations previously excluded from clinical trials such as pts with GFR<30 and significant baseline comorbidities. No significant differences in ORR were demonstrated for patient subsets of interest. [Table: see text]
Genomic landscape of variant urinary tumor histologies.
Authors: Abou Alaiwi Sarah , Nassar Amin , Adib Elio , Akl Elie W. , Mouw Kent William , Curran Catherine , Freeman Dory , Ravi Praful , Mantia Charlene , Acosta Andres , Preston Mark A. , Mossanen Matthew , Kwiatkowski David J. , Sonpavde Guru 
Published: March 2021

467 Background: The genetics of urothelial carcinoma (UC), the most common histology of urinary tract (UT) tumors, is well characterized; much less is known about the genomic features of rare histologic variants of UT tumors. We aim to compare the genomic alterations (GA) of UT tumors with adenocarcinoma (AD), small cell (SC), squamous cell (SQ), or plasmacytoid (PC) histologies, to UC tumors. Methods: We identified patients with pure variant (AD, SC, SQ, PC) or UC histology with genetic characterization through the GENIE registry. Patient tumor genomic data were captured by Memorial Sloan Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Tumors with mixed histology were excluded. We limited our analysis to genes tested >1000 times (N=211). Mutation frequencies and copy number variants (CNVs), collectively called GAs, were determined for AD, SC, SQ, PC, and UC, and were compared using the Fisher’s Exact test and Kruskall Wallis test. Nominal p values were obtained, and FDR correction was employed (q < 0.1). Results: We identified 1199 patients with available genomic data who met the inclusion criteria. Histologic distribution was: 32 AD, 13 SC, 15 SQ, 11 PC, and 1128 UC tumors. The median age was 68 years and 77% of patients were male. Statistically significant differences in genetic alterations by subtype are shown in the table below. ARID1A and KDM6A GAs were higher in UC; PC and SC; CDH1 GAs higher in PC; RB1 and TP53 GAs higher in SC; SMAD4 GAs higher in AD; and NFE2L2 GAs higher in SQ. Conclusions: Variant UT histologies exhibit a distinct pattern of alterations compared to UC, consistent with their divergent clinical behavior. This suggests different biological origins for these variant histologies and possibly different therapeutic vulnerabilities. Exploring the GAs of these UT tumors in larger datasets is warranted. [Table: see text]
Hyperthermia, bladder pressure, and intravesical drug delivery.
Authors: Grimberg Dominic C. , Campbell Scott P. , Etienne Wiguins , Fan Ping , Maccarini Paolo F. , Spasojevic Ivan , Arcot Rohith , Shah Ankeet , Inman Brant Allen 
Published: March 2021

469 Background: Little is known about the pharmacokinetics of intravesical chemotherapies. Various parameters can be altered including temperature, dwell time, drug concentration, and bladder pressure. Here, we hypothesize that increasing bladder pressure during instillation will improve drug delivery. Methods: An ex-vivo porcine model was developed to evaluate determinants of drug penetration into the bladder wall. Porcine bladders were suspended in isotonic saline at 37°C with a three-way Foley catheter in the bladder. Temperature probes were positioned in the extravesical bathing solution, bladder lumen, and sutured to the detrusor to ensure maintenance of desired temperatures. 2g gemcitabine in 100mL normal saline was heated to 43°C and circulated through the bladder using the Combat Bladder Recirculation System. Bladder pressures were monitored throughout each trial. After 60 minutes of dwell time, rapid dissection was performed to obtain full-thickness bladder samples from the bladder dome, posterior wall, trigone, and left and right lateral walls. Tissue was homogenized and liquid chromatography with tandem mass spectrometry (LC/MS/MS) was performed to measure gemcitabine concentration within the bladder wall. Linear regression and Pearson correlation were performed to determine the association between mean bladder pressure during instillation and drug concentration within the bladder wall. Multiple linear regression was conducted to control for bladder location and thickness. Results: Gemcitabine concentration within the bladder wall was measured 25 times across five trials. Mean gemcitabine concentration within bladder wall was 3.68 mg/g (sd 1.35). Pressure ranged from 149.8 mmHg to 277.7 mmHg (mean 194.8, sd 22.0). On univariate analysis, higher pressure was associated with increased gemcitabine concentration within the bladder wall (correlation = 0.49, p = 0.013). This result persisted after adjusting for bladder location (ß = 0.49, p = 0.006) and thickness (ß = 0.70, p = 0.03). Unstandardized regression coefficient in each of the models was 0.099 (mmHg x g)/mg, demonstrating that for each pressure increase of 10mmHg there was an associated increase in gemcitabine concentration of approximately 1 mg/g (Table). Conclusions: Data suggest that bladder pressure dramatically improves the extent of gemcitabine penetration into the bladder wall. Future research is needed to evaluate the therapeutic effect of increased gemcitabine delivery to target tissue in patients with bladder cancer. [Table: see text]
Real-world clinical outcomes study of sequential novel antihormonal therapy (NAH) or radium-223 (Ra-223) treatment of metastatic castration-resistant prostate cancer (mCRPC) that progressed after first-line NAH.
Authors: Sartor Oliver A. , George Daniel J. , Tombal Bertrand , Higano Celestia S. , Sternberg Cora N. , Miller Kurt , Jiao Xiaolong , Guo Helen , Sandstrom Per , Verholen Frank , Saad Fred , Shore Neal D. 
Published: March 2021

48 Background: We assessed real-life clinical outcomes in patients with mCRPC treated in the USA who received sequential first-line (1L)/second-line (2L) NAH (abiraterone/enzalutamide or enzalutamide/abiraterone) or switched to a different mechanism of action (alpha-emitter Ra-223) after progression on 1L NAH. Methods: This was a retrospective study (PHENIX, NCT03896984) of the Flatiron electronic health record database in patients with mCRPC that progressed on 1L NAH and started 2L monotherapy with Ra-223 (n=120) or NAH (n=226) between Jan 2013 and Dec 2018. Patient characteristics, overall survival (OS) from 2L start, and symptomatic skeletal events (SSEs) were analyzed descriptively. Results: The two cohorts were generally similar at 2L start, including similar rates of bone-health agent (BHA) use, but the Ra-223 cohort had a higher incidence of bone-only metastases, shorter duration of 1L NAH, and higher rate of prior SSEs than the 2L NAH cohort (Table). Median treatment duration was 5.6 mo (median 4.5 doses) for Ra-223 and 4.7 mo for 2L NAH. Median OS from 2L start was 10.8 mo for Ra-223 and 11.2 mo for 2L NAH, with 49% and 39%, respectively, receiving subsequent therapy. Among those who received subsequent therapy, the proportion who received subsequent taxane was lower in the Ra-223 cohort (47%) than in the 2L NAH cohort (76%). SSEs were observed after 2L start in 32 patients (27%) on Ra-223 and 49 (22%) on 2L NAH. Conclusions: OS from start of 2L mCRPC treatment was similar for patients who received Ra-223 or alternative NAH in 2L. Slightly more patients received subsequent therapy in the Ra-223 cohort than in the 2L NAH cohort. Patients who received subsequent therapy were more likely to receive chemotherapy in the 2L NAH cohort, which is unsurprising as 2L NAH after 1L NAH is not highly active. Although the prior SSE rate before 2L start was higher in the Ra-223 cohort than in the 2L NAH cohort, and the two cohorts had similar rates of BHA use at 2L start, the rate of SSEs after 2L start was similar in both cohorts. Clinical trial information: NCT03896984. [Table: see text]
Multi-omics prognosis predictive model of metastatic urothelial carcinoma (mUCs) with immunotherapy.
Authors: He Ning , Zhang Yiqun , Yang Yadong , Wang Jianfei 
Published: March 2021

482 Background: A fraction of mUCs patients can occur robust and durable responses in metastatic urothelial cancer patients treated with anti-PD-L1 agent (atezolizumab), and prognosis of immunotherapy exhibited a lack of attention. We aim to develop an effective prognosis for mUCs patients’ immunotherapy management. Methods: Public omics and clinical data of patients were collected from R package “IMvigor210CoreBiologies” (348 samples with RNA sequencing data, and 293 samples with DNA sequencing data). Immune cell infiltrations in the tumor microenvironment were quantified by single sample Gene Set Enrichment Analysis (ssGSEA). Prognosis model were trained by elastic net Cox proportional hazards algorithm, 10-fold Cross Validation were used for avoiding over fitting. Statistical analysis, survival analysis and data visualization were all carried out using the R. Results:Based on the whole transcriptome, whole exome sequencing, data were processed into five class parameters (including immunohistochemical, gene mutation, gene expression, signature score and molecular subtyping). With regularized Cox regression analysis, 17 genes ( CXCL9, GJB2, THBD, SEPT3, PLTP, LDLR, PPM1H, ACVR1C, MT1G, MT1L, ANXA2, LOC102725117, PCDHGB7, MCF2L2, APOL6, ITGAV, PCDH11X) were selected for evaluating mRNA expression level risk score, 11 immune cells (TIS, TGFβ, Activated CD8+ T cell, Central memory CD4+ T cell, Central memory CD8+ T cell, Effector memory CD4+ T cell, Gamma delta T cell, Memory B cell, Eosinophil, Immature dendritic cell, Monocyte neutrophil) were selected for evaluating pathway level risk score. Then we combined mRNA risk score, signature risk score, gene mutations, PD-L1 IHC, TMB and other clinical parameters for further dimension reduction. Finally, PD-L1 in tumor-infiltrating immune cells (ICs) (HR = 0.75, 95% CI 0.64-0.89, p < 1e-03), mRNA risk score (HR = 3.06, 95% CI 2.42-3.86, p < 1e-06) and TMB (HR = 0.75, 95% CI 0.64-0.89, p < 1e-03) were selected for Cox-model. Samples were divided into groups were by median of risk score, and there were significant difference of overall survival between high-risk and low-risk group, in training dataset (p < 1e-04, AUC( t = 6m/12m/18m) = 0.69/0.79/0.80) and validation dataset (p < 1e-04, AUC( t = 6m/12m/18m) = 0.77/0.82/0.85). In addition, high risk group was less response to PD-L1 immunotherapy than low risk group in our research (χ2 test, p < 2.23e-06). Conclusions: Wefirstlyconstructed a multi-omics prognosis prediction model for mUCs with immunotherapy, which may be related to different prognosis and immunotherapy response. This result may help further understanding the anti-immunotherapy of mUCs patient’s management.
Evaluating financial burdens of oral hormonal therapies for patients with prostate cancer.
Authors: Schwartz Eric B , Jeong Angelina , Roman Andrea , McDevitt Rachel , Henry Elyssa , Caram Megan Veresh 
Published: March 2021

70 Background: Numerous oral anticancer drugs approved for metastatic prostate cancer are expensive and put patients at risk for financial toxicity. Mechanisms available to mitigate these costs are complex to navigate. Furthermore, the ability to access these resources may not be the same for every insurance. We examined the out-of-pocket (OOP) liability of patients prescribed abiraterone or enzalutamide, the assistance mechanisms used, and the impact on timing of therapy. Methods: Patients with prostate cancer who were prescribed abiraterone or enzalutamide at our comprehensive cancer center between January 1, 2017 and March 31, 2019 were identified. Patients who filled prescriptions via an external pharmacy were excluded. Data regarding demographics, out of pocket costs and assistance mechanisms were evaluated. Results: We identified 219 patients. Of these, 33% had commercial insurance, 61% had Medicare part D, 3% had Medicaid and 8% had no insurance. Most patients (74%) were prescribed abiraterone and 26% enzalutamide. Among those with Medicare Part D, almost one third received significant financial assistance: 11% free drug from the manufacturer and 18% foundational grants. Patients with commercial insurance received a copay card from manufacturers 21% of the time. Patients with commercial insurance paid an average of $57 OOP; 94% with initial cost < $100. Patients with Medicare part D paid an average of $582 OOP; 22% with initial cost > $1000. Commercially insured patients started treatments in under 10 days from the prescription date 51% of the time vs 39% for Medicare patients. In contrast, 11% of commercially insured patients required > 30 days to fill vs 19% on Medicare. Only 1% of commercially insured patients were unable to fill due to cost issues compared to 7% of patients on Medicare. Conclusions: Financial assistance mechanisms such as grants and free drug programs help alleviate some financial burden for patients, but many still experience high OOP costs. These burdens appear to be disproportionately experienced by patients with Medicare Part D. We observed that patients with Medicare Part D had higher OOP costs for oral prostate cancer therapies. Those who required assistance often experienced delays in obtaining medication. Further evaluation is planned into how high costs and delays in treatment impacts prostate cancer treatment and patient care. [Table: see text]
PROSPER subgroup analysis by age and region: Overall survival and safety in men with nonmetastatic castration-resistant prostate cancer receiving androgen deprivation therapy plus enzalutamide.
Authors: De Giorgi Ugo , Hussain Maha H. A. , Shore Neal D. , Fizazi Karim , Tombal Bertrand , Penson David F. , Saad Fred , Efstathiou Eleni , Madziarska Katarzyna , Steinberg Joyce Leta , Sugg Jennifer , Lin Xun , Shen Qi , Sternberg Cora N. 
Published: March 2021

84 Background: Previous reports on the PROSPER trial have shown that enzalutamide (ENZA) plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival and overall survival (OS) over placebo (PBO) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rapidly rising prostate-specific antigen (PSA) levels. (Hussain et al. N Engl J Med. 2018;378:2465-2474/Sternberg et al. N Engl J Med. 2020;382:2197-2206). To inform decision-making for specific patients, we report here a post hoc analysis of OS and safety in subgroups of PROSPER by age and region. Methods: PROSPER included men with nmCRPC and a PSA doubling time ≤ 10 months. Enrolled men continued ADT and were randomized 2:1 to ENZA 160 mg once daily vs PBO. We performed a multivariable analysis for OS, including age (≤ 70 yrs and > 70 yrs), geographic region, and other variables and further examined exposure-adjusted adverse events (AEs) by age and region. Results: Based on this post hoc analysis, OS benefit with ENZA treatment was similar across geographic regions (table) and for patients aged ≥ 70 yrs (hazard ratio [HR] 0.73; 95% CI 0.58-0.9) and those aged < 70 yrs (HR 0.72, 95% CI 0.5-1.04). In our multivariate analysis, 3 factors emerged as significantly impacting estimated OS: Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0; HR 1.7; 95% CI 1.4-2.1), log of PSA (HR 1.2; 95% CI 1.1-1.3), and use of subsequent therapy (yes vs no; HR 2.5; 95% CI 2.1-3.1). Overall safety was consistent between age groups and across geographic regions. The proportion of patients reporting any grade treatment-emergent AEs (TEAEs) related to ENZA use was similar between age groups but decreased with increasing age. Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA plus ADT treatment reduced the risk of death, regardless of age or geographic location. Patients reported any grade TEAEs at a similar proportion in both arms. Variables impacting OS included ECOG status, log PSA, and subsequent therapy. Clinical trial information: NCT02003924. [Table: see text]