bluuebunny/crossref_metadata_2025 huggingface dataset:
A framework for living evidence synthesis in cancer: Living, interactive network meta-analysis for first-line treatment of metastatic renal cell carcinoma (mRCC).
Authors: Riaz Irbaz Bin , He Huan , Ryu Alexander J. , Siddiqi Rabbia , Naqvi Syed Arsalan Ahmed , Yao Yuan , Husnain Muhammad , Maheswari Deepa , Sipra Qurat Ul Ain Riaz , Montori Victor , Joseph Richard Wayne , Liu Hongfang , Wang Zhen , Herasevich Vitaly , Singh Parminder , Ho Thai Huu , Bryce Alan Haruo , Pagliaro Lance C. , Murad M. Hassan , Costello Brian Addis
Published: March 2021

335

Background: Systematic reviews are outdated quickly when the evidence is rapidly evolving as the process is laborious and there is little incentive for primary author team of an index SRMA to update the evidence. Consequently, there is an epidemic of redundant SRMAs performed by different teams—sometimes with conflicted results—for treatment of first line mRCC. Methods: We have created a living, interactive systematic review (LISR)and network meta-analysis(LINMA) for the treatment of first line mRCC using an Artificial intelligence (AI) assisted framework for evidence synthesis (Living, Interactive evidence synthesis framework) (LIvE) . The framework is implemented in five-layered architecture (application layer, shared module layer, core service layer, middleware layer, and storage layer) which work together to automate the identification of new studies and analysis and semi-automate the screening and data extraction. Dynamic features such as interactive tables, figures and evidence maps are enabled using Python and JavaScript programming languages. Results: We have maintained a living, interactive evidence profile for the first line treatment mRCC since September 2019 ( LIVING WEBSITE) . Living search strategy identifies new studies as they become available. As of October 13, 2020 LISR, includes data 14 clinical trials ( PRISMA ). Baseline characteristics are summarized in an interactive table ( TABLE) . Cabozantinib& Nivolumab (Cabo-Nivo) is the highest ranked drug for improving Overall Response (OR), Progression Free Survival (PFS) and Overall Survival (OS) whereas Ipilimumab in combination with Nivolumab (Ipi-Nivo) is highest ranked drug for achieving complete response (CR). Ipi-Nivo and Atezolizumab & Bevacizumab (Ate-Bev) ranked highest and Cabo-Nivo ranked lowest for treatment related Adverse events (TRAEs). Results of network meta-analysis are summarized as interactive tables and plots ( NMA ), summary of findings tables ( MULTIPLE COMAPRISONS ) and evidence maps ( MAP ). Conclusions: LISRs can potentially reduce redundancy, increase transparency, reproducibility, enable shared-decision making (at a guideline level, or in a patient-clinician dyad) and support living guidelines.
Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.
Authors: Tucker Matthew D , Beckermann Katy , Ancell Kristin Kathleen , Schaffer Kerry , McAlister Renee , Wallace Deborah , Kaiser Elizabeth , Davis Nancy B. , Rathmell W. Kimryn , Rini Brian I.
Published: March 2021

341

Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]
Absolute eosinophil count as predictive biomarker of irAEs in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Giorgione Roberta , Pillozzi Serena , Mela Marinella Micol , Giommoni Elisa , Paderi Agnese , Doni Laura , Pellegrini Elisa , Di Costanzo Alessandro , Antonuzzo Lorenzo
Published: March 2021

345

Background: Nivolumab and ipilimumab are associated with immune-related adverse events (irAEs) and, to date, few biomarkers predictive of ICIs toxicity are reported in mRCC. Methods: We conducted a single-center, observational, retrospective study at Clinical Oncology Unit, Careggi University Hospital, Florence, Italy. We evaluated 43 patients (pts) with mRCC treated with ICIs from April 2013 to May 2020. Absolute Eosinophil Counts (AEC, N°/μL) were registered at baseline and at time of occurrence of irAEs. This study aims to evaluate whether the AEC could be a predictive biomarker of irAEs in patients with mRCC treated with ICIs. Results: Median age was 65 years and males were 81.4%. 10 pts received Nivolumab+Ipilimumab, while 33 pts received Nivolumab single agent. 74.4% pts (32/43) developed at least 1 irAE, 11.6% with G3-G4 irAEs. The most frequent first irAE was endocrine event (40.6% pts; 37.5% with hypo-/hyper-thyroidism). The baseline mean AEC was 163.1/μL in our cohort, in particular 132.2/μL in pts who did not develop irAEs and 176.7/μL in pts who developed irAEs (p=0.134). Among the pts who developed irAEs, the mean AEC was lower in pts with G1-G2 (153.1/μL) than in those with G3-G4 (330/μL; p=0.0013) irAEs. At the time of onset of the first irAE, the mean AEC increased to 247/μL (Δ 140.1%). Analyzing the trend of AEC from baseline to time of occurrence of irAE for the 32 pts who had developed at least one irAE, 53.1% (17 pts) showed an increasing trend; among these pts, the most frequent irAEs were endocrine occurring in 4/17 pts (23.6%). An increasing trend was also observed in the majority of pts who developed G1-2 (14/27, 51.9%) and G3-4 (3/5, 60.0%) irAEs. Additional analyzes are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Conclusions: There is little evidence in the literature about the potential role of absolute eosinophil counts as a predictive biomarker of irAEs in patients with solid tumors treated with ICIs, and most refer to patients with melanoma. In this study we observed that the baseline AEC values in patients that will develop irAEs are higher than in those without irAEs and, among the former, the values are lower for patients with toxicity G1-G2 vs G3-G4. We also found an increase of the mean AEC from baseline to the onset of the first irAE. Of the patients who experience toxicity, most have an upward trend in AEC at the onset of the first irAE. Compatibly with all the limitations of a retrospective analysis, our is the first experience exploring the role of the eosinophil count in the development of irAEs in mRCC patients treated with ICIs, and a prospective study is ongoing in our Unit to confirm the role of the eosinophil count in patients treated with ICIs.
Insights on oncologist and urologist gaps in bladder (UC) and kidney (RCC) cancer education.
Authors: Parikh Kinjal , Chen Pan
Published: March 2021

358

Background: Treatment paradigms for bladder (UC) and kidney (RCC) cancers is evolving with the advent of novel treatment approaches, personalized medicine, and combinatorial strategies. As the medical literature in the space evolves, identifying oncologists’ (oncs) and urologists’ (uros) educational gaps is important to inform continuing medical education (CME) needs and, ultimately, to improve patient outcomes. Methods: Medscape Oncology conducted a 16 question, online, incentivized survey in June 2020 targeting genitourinary (GU) cancer physicians. Respondents’ confidentiality was maintained and responses were de-identified and aggregated for analysis. Results: Results are reported for 100 respondents (50 oncs & 50 uros): In UC: Learners identified CME as mostly/very important for: Managing treatment related adverse events (trAEs) – 84% Clinical trial outcomes – 77% Timely/appropriate biomarker testing – 68% Understanding mechanism of action (MOA) and rationale of novel agents – 66% Treatment planning CME was considered mostly/very important for: All stages: non-muscle invasive (NMIBC), muscle-invasive (MIBC), and first line (1L) metastatic – 72%, 85%, 92% respectively Determining the optimal role for immunotherapy (IO) – 82% Sequencing therapies – 72% In subgroup analyses More oncs vs. uros identified biomarker testing and treatment selection as mostly/very important (p < .01) More general oncs vs. GU oncs identified education on clinical trial outcomes and sequencing of therapies as mostly/very important (p < .05) More uros vs. oncs identified NMIBC treatment education as mostly/very important (p < .01) More low vs. high volume treaters identified education on sequencing and MIBC as mostly/very important (p < .01) Rating % very experienced: Counseling on trAEs – 41% but mitigating AEs of FGFR therapies, ADCs, or IO was only: 16%, 19%, and 26% respectively In RCC: Learners identified CME as mostly/very important for: Selecting optimal 1L therapy – 80% Clinical trial outcomes – 77% Sequencing therapies – 69% Managing trAEs – 64% Understanding MOA and rationale of novel agents – 62% In subgroup analyses More general oncs vs. GU oncs identified importance of education on clinical trial outcomes and 1L treatment selection (p < .05) More low vs. high volume treaters identified importance of education on 1L treatment selection and clinical trial outcomes (p < .05) Rating % very experienced: Counseling on trAEs – 30% but mitigating AEs of targeted therapy or IO was only: 22% and 23% respectively Determining risk score – 22% Selecting 1L therapy – 28%. Conclusions: Medscape Oncology surveys provide valuable information to guide education for oncs and uros and individualize education unique to their treatment setting, patient volume, and practice coverage.
Sarcopenia prior to and following chemotherapy to predict morbidity in patients undergoing post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND).
Authors: Baky Fady , Woldu Solomon L. , Margulis Vitaly , Bagrodia Aditya
Published: March 2021

381

Background: Patients undergoing post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) are subject to variable but substantial risks. Unlike those patients undergoing other extirpative GU surgeries, patients undergoing PC-RPLND are usually younger and possess fewer co-morbidities. Despite this, the burden of metastatic disease and the effects of pre-operative chemotherapy may leave patients poorly conditioned prior to undergoing surgery. Sarcopenia has previously been demonstrated to predict adverse clinical outcomes in a variety of abdominal surgeries. We hypothesized that sarcopenia would be similarly predictive of morbidity and mortality in patients undergoing PC-RPLND. Methods: The records of all patients undergoing post-chemotherapy retroperitoneal lymphadenectomy for the treatment of metastatic germ cell tumors at both a public safety net hospital and an academic tertiary medical center were reviewed. Sarcopenia was assessed by measuring cross sectional area of the psoas muscle at the middle of the third lumbar vertebral body on pre-chemotherapy and preoperative computerized tomography. Psoas Muscle Index (PMI) was calculated by adjusting total psoas area for patient height (cm2/m2). Univariate and multivariate analysis was performed to assess the predictive value of sarcopenia for morbidity and mortality following PC-RPLND. Results: 90 patients underwent PC-RPLND from the year 2006-2019, of whom 81 patients had both pre-chemo and preoperative cross sectional imaging available. Prior to chemotherapy the mean PMI for this cohort was 7.32 cm2/m2, and this did not significantly change following chemotherapy mean PMI = 7.06 cm2/m2 (p = 0.44). Lower PMI both prior to (p = 0.05) and following chemotherapy (p = 0.03) were predictive of a higher risk of post-operative complication. There was a trend towards longer hospital length of stay in patients with more significant sarcopenia, however this was not clinically significant (p = 0.09). Conclusions: Sarcopenia was predictive of morbidity in patients undergoing PC-RPLND. Although sarcopenia did worsen following chemotherapy this was not statistically significant. Further assessment of sarcopenia and pre-operative nutritional status in this population may provide opportunities to reduce morbidity following PC-RPLND.
Pre-orchiectomy serum tumor markers as a predictor of recurrence in stage I germ cell tumors.
Authors: Badia Rohit R , Ghandour Rashed , Howard Jeffrey , Cheaib Joseph G , Saoud Ragheed , Eggener Scott E. , Singla Nirmish , Pierorazio Phillip M. , Bagrodia Aditya
Published: March 2021

389

Background: Organ confined (stage IA/IB) testicular cancer has a high cure rate regardless of initial treatment modality, making it important to weigh the toxicities of treatment against potential benefits. While many clinicians routinely obtain serum tumor markers (STMs) prior to radical orchiectomy, their role in predicting recurrence in stage IA and IB testicular cancer has not been studied. Methods: A multi-institutional database of stage I testicular cancer patients diagnosed between 2006 and 2018 was created. Univariate and multivariate regression models were created to understand which factors predict recurrence. Recurrence analyses using Kaplan-Meier curves for elevated and normal pre-orchiectomy STMs were also generated. Results: 150 patients met the study criteria, of whom 16 (11%) relapsed (Table). 9 (56%) patients with recurrence had elevated pre-orchiectomy STMs, and 7 (44%) had normal pre-orchiectomy STMs. Similarly, 75 patients (56%) without relapse had elevated pre-orchiectomy STMs. Of 9 patients with elevated pre-orchiectomy STMs, 6 (67%) had normal STMs at recurrence; of 7 with normal pre-orchiectomy STMs, 4 patients (57%) had elevated STMs at recurrence. On Kaplan-Meier analysis, no association between level of pre-orchiectomy STMs and recurrence free survival was observed. Conclusions: Pre-orchiectomy STMs were not independently associated with recurrence in stage I testis cancer. Interestingly, there was also no association between positivity of pre-orchiectomy STMs and whether or not STMs were elevated at recurrence. These findings support the continued use of standard-of-care imaging and STMs in surveillance of stage IA/IB testicular cancer patients regardless of pre-orchiectomy STMs. [Table: see text]
Severe-COVID-19 and mortality among patients (pts) with prostate cancer (PCa) receiving androgen deprivation therapy (ADT).
Authors: Tucker Matthew D , Schmidt Andrew Lachlan , Hsu Chih-Yuan , Shyr Yu , Armstrong Andrew J. , Bakouny Ziad , Chapman Christina Hunter , Dawsey Scott , Gartrell Benjamin Adam , Halabi Susan , Joshi Monika , Khaki Ali Raza , Menon Harry , Puc Matthew , Sharifi Nima , Shaya Justin , Wulff-Burchfield Elizabeth Marie , Zhang Tian , Gupta Shilpa , McKay Rana R. ,   CCC19 Prostate Cancer Working Group
Published: March 2021

39

Background: The presence of progressing cancer, male sex and advanced age have been shown to increase the severity of coronavirus disease 2019 (COVID-19). Given that the androgen regulated gene TMPRSS2 has been implicated in SARS-CoV-2 viral entry, we hypothesized that ADT may improve COVID-19 outcomes. This analysis evaluated clinical outcomes of pts with PCa with concurrent SARS-CoV-2 infection and investigated the impact of ADT on occurrence of severe-COVID-19 and mortality. Methods: Data was obtained via the COVID-19 and Cancer Consortium (CCC19), a multicenter registry including >120 cancer centers with de-identified data from pts with COVID-19 and cancer. Men with confirmed SARS-CoV-2 infection and a primary diagnosis of prostate cancer were included: data cutoff of July 31, 2020. The primary endpoint was the development of severe-COVID-19 (death, ICU admission, or mechanical ventilation) among pts on ADT vs. those not on ADT at time of COVID-19 infection. Secondary endpoints included 30-day mortality based on ADT use. Mortality and development of severe-COVID-19 were assessed in Pts grouped by therapy: 1st generation androgen receptor inhibitor (ARI-1), 2nd generation ARI (darolutamide, enzalutamide, apalutamide, ARI-2), abiraterone/prednisone, and chemotherapy. Propensity score matching was utilized. Logistic regression was utilized to adjust for age, ECOG PS, comorbidities, and race. Results: 589 pts were included; median follow-up was 42 days (IQR 25-90) and 62% (363/589) were hospitalized. Severe-COVID-19 developed in 28% of pts and the all-cause 30-day mortality rate was 19%. There was no significant difference in the development of severe-COVID-19 or 30-day mortality between Pts on ADT vs not on ADT, whether using descriptive statistics with the entire population or using the propensity score matched population (Table). Among the descriptive population, the numerical rates of severe-COVID-19 and mortality were lowest in Pts receiving ARI-2, but sample size was low. Conclusions: The overall 30-day mortality rate and percentage developing severe-COVID-19 were high. There was no statistical difference in the development of severe-COVID-19 or mortality based on receipt of ADT; however, this analysis is limited by the retrospective nature and small N after propensity-matching. [Table: see text]
First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).
Authors: Bajorin Dean F. , Witjes Johannes Alfred , Gschwend Jürgen , Schenker Michael , Valderrama Begoña P. , Tomita Yoshihiko , Bamias Aristotelis , Lebret Thierry , Shariat Shahrokh , Park Se Hoon , Ye Dingwei , Agerbaek Mads , Collette Sandra , Unsal-Kacmaz Keziban , Zardavas Dimitrios , Koon Henry B. , Galsky Matt D.
Published: March 2021

391

Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]
Racial differences in aneuploidy in high-grade muscle-invasive bladder cancer.
Authors: Khan Adeel M , Markt Sarah C , Mucci Lorelei A , Stopsack Konrad H.
Published: March 2021

400

Background: Bladder cancer is marked by racial disparities in stage at presentation, treatment, and survival. It is unknown how somatic tumor genomes differ by race. Tumor aneuploidy, defined as aberrant counts of chromosome arms, is pervasive in tumors including bladder cancer. Its associations with race are incompletely understood. We sought here to characterize the relation of race with aneuploidy in high-grade muscle-invasive bladder cancer. Methods: To quantify how aneuploidy differs by race, we leveraged the cohort of patients with high-grade, muscle-invasive bladder cancer from The Cancer Genome Atlas. Chromosome arm gains and losses were identified based on Affymetrix SNP 6.0 arrays (Taylor 2018). We focused on aneuploidy burden defined as the count of chromosome arms altered by gains and losses per tumor, which was based on both p and q chromosome arms of all autosomes except for acrocentric autosomes (q arms only) and ranged from 0 to 34 altered chromosome arms. We used multivariable linear regression to obtain mean differences and 95% confidence intervals (CIs) in the number of altered chromosome arms between self-reported racial groups, adjusting for demographics (sex, age at diagnosis, smoking status) and tumor characteristics (grade, histology). We also evaluated associations between race and number of altered chromosome arms stratified by papillary/non-papillary histology and sex. Results: Of 362 participants, 315 self-identified as White (87%), 25 as Asian (7%), and 22 as Black (6%). 73% were men, 21% were current smokers, and 52% former smokers. Median age at diagnosis was 69 years (interquartile range [IQR]: 61 to 76). Asians and Blacks tended to be younger at diagnosis than Whites, with more never-smokers among Asians. More profiled tumors were of papillary histology among Asians (44%), and fewer among Blacks (18%), than among Whites (30%). Aneuploidy burden was high overall (median, 14 altered chromosome arms; IQR: 8 to 19); only 17% of tumors had five or fewer altered chromosome arms. Compared to Whites, aneuploidy burden overall was similar in tumors from Asians (adjusted mean difference, –2.3 fewer altered chromosome arms; 95% CI: –5.4 to 0.9) and Blacks (–1.7; 95% CI: –5.1 to 1.7). Asian race appeared more strongly associated with lower aneuploidy burden in non-papillary tumors (–3.9 altered chromosome arms; 95% CI: –7.7 to –0.1) than in papillary tumors (–0.3; 95% CI: –5.6 to 5.0), and in men (–3.5; 95% CI: –7.0 to 0.1) than in women (–0.8; 95% CI: –6.8 to 5.2). Conclusions: These findings suggest potential differences in aneuploidy burden between Asians and Whites among high-grade muscle-invasive bladder cancers. They also highlight a need for validation in cohorts that are more racially diverse and have a well-defined source population (study base) with detailed data on cancer risk factors and histopathology.
Is there a role for urine cytology following BCG therapy for non-muscle-invasive bladder cancer (NMIBC)?
Authors: Prattley Sarah , Jarvis Ruth , Featherstone Jon , Narahari Krishna , Varma Murali , Hughes Owen , Kynaston Howard
Published: March 2021

404

Background: Voided urine cytology has been used as an adjunct in the diagnosis of non-muscle invasive bladder cancer (NMIBC), with a sensitivity and specificity ranging between 13-75% and 76-100% respectively. There is limited data on the accuracy and utility of cytology following BCG therapy. We reviewed the results of cytology in patients undergoing induction and maintenance BCG immunotherapy in our institution. Methods: Newly diagnosed patients who had received induction and maintenance intravesical BCG therapy from 2004 - 2019 were identified from a prospective database and their outcomes reviewed retrospectively. Histopathology results of biopsies / resected specimens and voided urine cytology results were examined for 273 patients. Results: A total of 2567 cytology results and 638 biopsy results were recorded. The average age was 73.2 years and median number of BCG treatments was four (induction followed by three maintenance courses). Median follow up was 38 months. 94 patients (34.4%) had recurrence following BCG therapy. Of those 33 patients (12.1%) had progression to muscle invasive disease. The number of cytology samples per patient after BCG therapy ranged from 1-23 (median 7), with several patients having repeated, potentially unnecessary negative urine cytology. Overall accuracy of cytology (n = 526) was sensitivity 44.2%, specificity 84.7%, PPV 38.9%, NPV 87.3%. Patients that had an erythematous bladder or red patch at flexible cystoscopy underwent subgroup analysis; this gave a very high NPV of 95.9%, with additional sensitivity being 65.5%, specificity 85.9% and PPV 33.3%. Number of positive cytology results (Chi2 = 44.30, P = 0.002), any positive cytology (Chi2 = 27.94, P < 0.001) and positive cytology after induction BCG therapy (Chi2 = 30.381, P < 0.001) were all strongly associated with recurrence. Conclusions: Positive urine cytology in patients undergoing intravesical BCG therapy predicts increased risk of recurrence and has good specificity. We would recommend using voided urine cytology in patients who have an erythematous bladder or red patch at flexible cystoscopy. If the cytology is positive then proceed to biopsy, however, if it is negative continue with surveillance. [Table: see text]
Treatment patterns among patients with advanced urothelial carcinoma following discontinuation of PD1/L1 inhibitor therapy.
Authors: Morgans Alicia K. , Grewal Simrun Kaur , Hepp Zsolt , Fuldeore Rupali , Odak Shardul , Macahilig Cynthia , Shillington Alicia C. , Sonpavde Guru
Published: March 2021

414

Background: There are a lack of published real-world data on treatment patterns for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) previously treated with programmed death 1/ligand 1 inhibitor (PD-1/L1i) therapy. The objective of this study was to characterize the clinical characteristics and treatments among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1i therapy. Methods: We performed a retrospective chart review at 26 geographically diverse clinical sites in the US. Patients aged ≥18 years with histologically or cytologically confirmed urothelial carcinoma and radiographic evidence of metastatic or locally advanced disease were identified. Included patients had initiated and subsequently discontinued PD-1/L1i therapy in the 1L or 2L setting for la/mUC between May 15, 2016-July 31, 2018. All patients had follow-up through October 31, 2019. Data were summarized using descriptive statistics. Results: Among the 300 patients included in the chart review, 198 (66%) received PD-1/L1i therapy as 1L and 102 (34%) as 2L therapy. Mean (SD) age at la/mUC diagnosis was 69.4 (8.7) years, and a majority of patients were male (66.0%) and White (74.7%). Consistent with age, most patients (82.7%) had comorbidities at la/mUC diagnosis; 39.7% hypertension, 23.7% coronary artery disease, 17.7% pulmonary disease, and 9.3% renal disease. At initiation of therapy, a higher proportion of patients who received 1L PD-1/L1i therapy had an Eastern Cooperative Oncology Group performance status of 2 or more than patients who received 2L PD-1/L1i therapy (36.8% vs 22.5%, respectively). Following discontinuation of PD-1/L1i therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The most common subsequent therapies in 2L were gemcitabine monotherapy (24%), gemcitabine plus cisplatin or carboplatin (22%), PD-1/L1i therapy (22%), and taxane monotherapy (19%). The most common subsequent therapies received in 3L were taxane monotherapy (50%), pemetrexed (17%), and PD-1/L1i therapy (16%). Overall, switching from one PD-1/L1i therapy to another distinct PD-1/L1i therapy occurred in approximately 20% of patients, with “better efficacy/survival” noted by treatment teams as the most common reason for switching therapy among this subgroup. Conclusions: In this real-world case series, only a minority of patients with la/mUC who discontinued PD-1/L1i therapy received subsequent therapy. Among those that did, no clear standard of care was observed and approximately one-fifth of patients were treated with a second PD-1/L1i therapy after the first failed to control disease. Collectively, the data highlight significant unmet need for patients with la/mUC who discontinue PD-1/L1i therapy.
Bladder cancer research funding in Canada and the United States: A comparison between stakeholder priorities and resource allocation from 2017 to 2019.
Authors: Kaiser Jeenan , Litt Ishjot , Smith Angela B. , Bhindi Bimal , Alimohamed Nimira S.
Published: March 2021

422

Background: There is an increasing emphasis on patient-centered research to encourage cancer care that is responsive to patients' needs. Previously, the Bladder Cancer Advocacy Network (BCAN) Patient Survey Network (PSN) engaged patients and other key stakeholders and compiled a prioritized list of research questions in bladder cancer. However, it is uncertain whether these priorities have successfully guided subsequent resource allocation by funding agencies. The purpose of this study was to understand how bladder cancer research funding has been allocated in recent years and to determine whether funding patterns have aligned with patient and caregiver priorities. Methods: We investigated publicly available research databases online or contacted agencies directly to determine bladder cancer research fund allocation in Canada and the US from 2017 to 2019. Each funding competition and all funded projects were evaluated to assess whether they aligned with previously identified priority research areas. Trends in funding allocation were assessed and several key variables including country, year, agency focus, cancer stage, and funding amount were analyzed. Results: Fifteen agencies provided funding to bladder cancer research between 2017 and 2019, amounting to a total of $78,525,974 in funding for 298 projects across Canada and the US. Of this funding, $23,268,258 (30%) went towards projects addressing the stakeholder-identified high priority research questions, $15,575,064 (20%) went towards projects addressing lesser priority questions, and the remaining $39,682,652 (50%) funded projects addressing questions which did not align with previously identified stakeholder priorities. General agencies (non-bladder cancer-specific) funded more priority (high and lesser) projects than bladder cancer-specific agencies (p < 0.001). Among projects addressing non-muscle invasive bladder cancer, 36% of funding went to high priority areas, compared to 13% and 27% for muscle-invasive bladder cancer and metastatic bladder cancer, respectively. Among the top 10% of projects (n = 30) with the greatest funding amount (combined $43,249,792), 45% of the funding went to high priority areas, 21% went to lesser priority areas, and 34% went to non-priority areas. Conclusions: Of nearly $80,000,000 USD allocated to bladder cancer research in recent years, approximately half was allocated to projects addressing stakeholder-identified priority areas while half was allocated to projects that were not aligned with stakeholder priorities. More work is needed to ensure stronger alignment between stakeholder-identified priority areas and funding allocation in bladder cancer research.
Avelumab (Ave) first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): JAVELIN Bladder 100 Japanese subgroup analysis.
Authors: Tsuchiya Norihiko , Yamamoto Yoshiaki , Uemura Hirotsugu , Kanayama Hiro-Omi , Eto Masatoshi , Miyake Hideaki , Powles Thomas , Yoshida Mizuki , Koide Yuichiro , Umeyama Yoshiko , Di Pietro Alessandra , Tomita Yoshihiko
Published: March 2021

425

Background: A randomized phase III trial (JAVELIN Bladder 100; NCT02603432) to investigate avelumab (anti–PD-L1) as 1L maintenance therapy in patients with advanced UC met its primary objective, demonstrating significantly prolonged overall survival (OS) with Ave + BSC vs BSC alone in all randomized patients and in patients with PD-L1+ tumors. We report efficacy and safety in Japanese patients enrolled in this study. Methods: Eligible patients with unresectable locally advanced or metastatic UC that had not progressed with 4-6 cycles of gemcitabine with either cisplatin or carboplatin were randomized 1:1 to receive maintenance Ave (10 mg/kg IV every 2 weeks) + BSC or BSC alone, stratified by best response to 1L chemotherapy (complete/partial response vs stable disease) and by visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in all randomized patients and in patients with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) per blinded independent central review and safety. Results: Japanese patients (n=73) were randomized to receive Ave + BSC (n=36) or BSC alone (n=37); 52.8% vs 62.2% had PD-L1+ tumors, respectively. Median OS (95% CI) was 24.7 months (18.2-not estimable [NE]) with Ave + BSC vs 18.7 months (12.8-33.0) with BSC alone (HR, 0.81 [95% CI; 0.409-1.585]) in all randomized patients and 18.6 months (9.4-NE) with Ave + BSC vs 19.4 months (11.7-33.0) with BSC alone (HR, 1.00 [95% CI, 0.413-2.412]) in patients with PD-L1+ tumors. Median PFS (95% CI) was 5.6 months (1.9-9.4) with Ave + BSC vs 1.9 months (1.9-3.8) with BSC alone (HR, 0.63 [95% CI, 0.358-1.113]) in all randomized patients and 5.6 months (1.8-11.2) with Ave + BSC vs 1.9 months (1.9-3.8) with BSC alone (HR, 0.62 [95% CI, 0.298-1.301]) in patients with PD-L1+ tumors. The most common treatment-emergent adverse events (all grade; grade ≥3) in the Ave + BSC arm were pyrexia (10 [27.8%]; 0), nasopharyngitis (7 [19.4%]; 0), and anemia (7 [19.4%]; 4 [11.1%]). Conclusions: Ave 1L maintenance + BSC was efficacious and tolerable in Japanese patients with advanced UC, and results were generally consistent with those in the overall population. Clinical trial information: NCT02603432.
An open-label, multicenter, phase IIIb study of patients with urinary tract carcinoma (UTC) (STRONG): Final analysis for fixed-dose durvalumab monotherapy (module A).
Authors: Sonpavde Guru , Marabelle Aurelien , Loriot Yohann , Sternberg Cora N. , Lee Jae-Lyun , Flechon Aude , Roubaud Guilhem , Pouessel Damien , Zagonel Vittorina , Calabro Fabio , Banna Giuseppe L. , Shin Sang Joon , Vera Badillo Francisco Emilio , Powles Thomas , Hellmis Eva , Palhares de Miranda Paulo Andre , Lima Ana Rita , Sawyer William , Hotte Sebastien J.
Published: March 2021

429

Background: Patients (pts) with advanced UTC who fail first-line therapy have poor prognoses. Durvalumab (D; anti-PD-L1) 10 mg/kg every 2 weeks is approved for treatment of metastatic urothelial carcinoma (mUC) after progression on platinum-based chemotherapy (CT). Further understanding of long-term safety and efficacy of D in platinum and non-platinum pretreated pts, using a fixed dose every 4 weeks (Q4W), is of value. Methods: Module A of the phase IIIb STRONG study (NCT03084471) investigated the safety of fixed-dose D (1500 mg, Q4W) in pts with urothelial and nonurothelial UTC who progressed on or after platinum/non-platinum CT. The primary endpoint was the number of pts with adverse events of special interest (AESIs) – events with an inflammatory or immune-mediated mechanism that may require interventions (eg, steroids/immunosuppressants), including immune-mediated adverse events (imAE). AEs with onset date on or after the date of first dose and up to 90 days after study discontinuation were included. Secondary endpoints included serious AEs and overall survival (OS). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR) (investigator assessed per RECIST 1.1). Results: A total of 867 pts received D monotherapy. Median age was 68.1 yr and 80.0% were male; 87.1% had an ECOG PS 0-1 and 12.7% had ECOG PS 2. Most (96.3%) had urothelial UTC, including urothelial variants. Tumor PD-L1 expression was high (≥25%) in 239/577 (41.4%) pts with available data. Median treatment and follow-up duration were 12.1 wk (range 1-128) and 13.8 mo (range 0.0-28.8), respectively. Safety data are reported in the table. Deaths related to study treatment occurred in 9 pts (1.0%). At data cutoff (March 31, 2020), 30.8% of pts were in survival follow-up. Median OS was 7.0 mo (95% CI: 6.4-8.2); OS rate at 1 and 2 yr was 35.8% (95% CI: 32.5-39.2) and 20.2% (95% CI: 16.5-24.1), respectively. ORR was 17.7% with complete responses in 5.1% of pts. DCR at 6 mo was 33.0%. Median OS of subgroups: PD-L1 high or low: 9.3 mo (95% CI: 6.7-12.7) and 6.5 mo (95% CI: 5.8-8.1); ECOG PS 0-1 or 2: 8.4 mo (95% CI: 7.2–9.8) and 3 mo (95% CI: 2.0-4.1); urothelial and nonurothelial UTC: 7.0 mo (95% CI: 6.4-8.2) and 7.0 mo (95% CI: 2.7-10.2), respectively. Conclusions: Fixed-dose D monotherapy Q4W is convenient with an acceptable safety profile in previously treated pts for UTC. Long-term safety and efficacy data reported are consistent with published studies of D and other IO agents in this setting. Clinical trial information: NCT03084471 . [Table: see text]
Avelumab (Ave) first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis based on duration and cycles of 1L chemotherapy.
Authors: Loriot Yohann , Powles Thomas , Climent Durán Miguel Ángel , Sridhar Srikala S. , Bellmunt Joaquim , Petrylak Daniel Peter , Wang Jing , Costa Nuno Matos , Laliberte Robert J , Di Pietro Alessandra , Grivas Petros , Sternberg Cora N.
Published: March 2021

438

Background: Avelumab 1L maintenance is approved in the United States for patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy based on significantly prolonged overall survival (OS) vs BSC seen in the phase III JAVELIN Bladder 100 trial (NCT02603432). However, optimal duration of 1L chemotherapy is unknown and some patients are unable to receive 6 cycles. We report a post hoc analysis of efficacy by duration or number of cycles of 1L chemotherapy. Methods: Eligible patients with unresectable locally advanced or metastatic UC that had not progressed with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized to receive maintenance avelumab + BSC or BSC alone within 4-10 weeks. Subgroups were defined by quartiles (Qs) for duration (<Q1 [<15.0 weeks], Q1-Q2 [15.0 to <18.0 weeks], Q2-Q3 [18.0 to <20.1 weeks], and >Q3 [>20.1 weeks]) or estimated number of cycles (4, 5, or 6) of 1L chemotherapy. Duration of chemotherapy included dosing delays/interruptions, and the decision to stop 1L chemotherapy was at the investigator’s discretion. Treatment arms were compared using an unstratified Cox proportional hazards model for OS. The potential impact of baseline characteristics on treatment patterns or dose intensity was not explored. Results: Numbers of patients in 1L chemotherapy subgroups were generally well balanced between arms (Table). An OS benefit was observed for avelumab + BSC vs BSC alone across subgroups with differing durations or cycles of 1L chemotherapy (Table). A progression-free survival benefit was also observed for avelumab + BSC vs BSC alone across subgroups. No significant treatment-by-cycle interaction (at 0.05 level) was observed. Conclusions: Improved OS was observed with avelumab 1L maintenance vs BSC alone irrespective of duration or cycles of 1L chemotherapy received prior to entering the trial. Among patients who stopped 1L chemotherapy prior to 6 cycles, avelumab 1L maintenance still provided an OS benefit. Clinical trial information: NCT02603432 . Research Sponsor: Pfizer Inc, Pharmaceutical/Biotech Company[Table: see text]
Identification of characteristics associated with long-term survival in patients with metastatic urothelial carcinoma (mUC) who received durvalumab (D) with or without tremelimumab (T) in clinical studies.
Authors: Alt Marie , Stecca Carlos , Kabadi Shaum , Kazeem Benga , Sridhar Srikala S.
Published: March 2021

441

Background: Immune checkpoint inhibitors (ICI) have changed the landscape of mUC, yet outcomes are variable as some patients (pts) do not respond to treatment while others have a durable response. To optimally select pts who may derive benefit from ICIs, predictive factors are required. This retrospective, post-hoc analysis evaluated pt characteristics to determine differences between short and long-term survivors among pts with mUC who received D (anti–PD-L1) with or without T (anti–CTLA-4) in two clinical studies. Methods: Pts with platinum-refractory mUC who received D monotherapy in the phase I/II study 1108 (10 mg/kg Q2W, up to 12 mo) or D+T in the phase I study 10 (D at 20 mg/kg + T at 1 mg/kg Q4W for 4 mo, then D at 10 mg/kg Q2W for 12 mo) were included. Pt characteristics, tumor characteristics, radiological assessments, and biological assessments were collected. The primary outcome measure was long-term overall survival (OS). Pts were categorized as OS ≥2 yrs (from 1st dose of study drug) or OS <2 yrs. A univariate analysis was conducted on each baseline characteristic to assess independent associations with long-term OS; a multivariate logistic regression model was employed including each variable with a p-value ≤0.1 as factors or covariates. Results: A total of 367 pts with mUC were included in the analysis: 88 (24.0%) had OS ≥2 yrs (range: 2.09–4.99) and 279 (76.0%) had OS <2 yrs (range: 0.03–1.98). Pts with OS ≥2 yrs had a significantly higher objective response rates than those with OS <2 yrs (71.6% vs 5.7%; p<0.0001) and a significantly longer duration of response (median 2.3 yrs vs 0.39 yrs; p<0.0001). The characteristics included in the multivariate logistic regression model are listed in the Table. Long-term OS was significantly associated with ECOG PS, PD-L1 status, baseline hemoglobin level, and baseline absolute neutrophils count. Conclusions: Our analyses show that several characteristics, including tumor response to treatment, are associated with long-term OS for pts with mUC treated with D or D+T. Further investigation into these and other characteristics may provide additional insights into long-term survival outcomes with ICIs. [Table: see text]
Association between prior radical surgery (RS) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).
Authors: Makrakis Dimitrios , Castellano Daniel , de Kouchkovsky Ivan , Park Joseph J. , Bilen Mehmet Asim , Agarwal Neeraj , Zakharia Yousef , Morales-Barrera Rafael , Devitt Michael E. , Nelson Ariel Ann , Gartrell Benjamin A. , Tripathi Abhishek , Bamias Aristotelis , Rodriguez-Vida Alejo , Liu Sandy , McKay Rana R. , Alonso Buznego Lucia Andrea , Murgic Jure , Grivas Petros , Khaki Ali Raza
Published: March 2021

444

Background: It is unclear whether prior RS of primary tumor is associated with response and outcomes with ICI in aUC. We hypothesized that such response and outcomes would not differ based on prior RS. Methods: We performed a retrospective cohort study including patients (pts) with aUC who received ICI. We compared overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between pts with vs without RS [cystectomy or (nephro)-ureterectomy]. Analysis was stratified based on ICI therapy line (first-line vs salvage). A separate comparison between pts with prior RS or radiation (RT) only or none was also pursued. ORR was compared between groups using logistic regression, as well OS and PFS using cox regression analysis; a multivariable model was built adjusting for calculated Bellmunt score. P<0.05 was significant. Results: We identified 984 pts from 24 institutions; 682, 704 and 673 were included in OS, PFS and ORR analyses, respectively; 54% of pts had prior RS with median age 68 at ICI initiation with RS vs 71 without RS with similar proportion of men (73-74%) and ever smokers (70-71%). The RS group had higher proportion (%) of white pts (77% vs 71%), lower % of pts with Hb<10g/dL at ICI initiation (23% vs 32%) but not significantly higher % of liver metastasis at ICI initiation (23% vs 17%). Bellmunt score with vs without RS was 16% vs 11%, 50% vs 48%, 27% vs 37%, 7% vs 4% for 0, 1, 2, and 3, respectively. ORR and PFS were not significantly different between groups, while prior RS was associated with longer OS (unadjusted HR 0.8, p=0.03). However, after adjustment for Bellmunt score, this association was not significant (table). Upon stratification based on treatment line, OS was longer with prior RS (0.7, p=0.03) for those treated with salvage ICI but this was not significant after adjusting for Bellmunt score. ORR, PFS and OS were not significantly different between pts receiving prior RT only vs RS vs none. Conclusions: Prior RS was not significantly associated with longer OS in pts with aUC receiving ICI after adjusting for Bellmunt score. Further work is needed to interrogate tumor-host immune interactions and identify biomarkers that can be prognostic and/or predictive of ICI response. [Table: see text]