bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with the quality of end-of-life care for patients with metastatic renal cell carcinoma.
Authors: Dzimitrowicz Hannah Elizabeth , Wilson Lauren E. , Jackson Bradford E. , Spees Lisa , Baggett Christopher , Greiner Melissa A. , Kaye Deborah , Zhang Tian , George Daniel J. , Scales Charles D. , Pritchard Jessica , Leapman Michael S. , Gross Cary Philip , Dinan Michaela Ann , Wheeler Stephanie B.
Published: February 2022

300

Background: Although oral anti-cancer agents (OAAs) have improved outcomes for patients with metastatic renal cell carcinoma (mRCC), most patients still die from the disease. High quality end-of-life (EOL) care remains a crucial component of optimal care for patients with mRCC, but neither it nor systemic therapy use at EOL have been well characterized in these patients. Methods: We conducted a retrospective study of decedents with mRCC in 2 cohorts analyzed in parallel: 1) patients aged ≥18 years (diagnosed with RCC in 2004 through 2015) drawn from the University of North Carolina Cancer Information Population Health Resource (NC-CIPHR) and 2) patients aged ≥66 years (diagnosed with RCC in 2007 through 2015) from SEER-Medicare. OAA use was measured from date of mRCC diagnosis until 30 days prior to death. We assessed use of hospice in the last 30 days of life as well as established measures of low EOL care quality: receipt of systemic therapy, hospital admission, and ICU admission in last 30 days of life, and death in hospital. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence limits (95%CL) for associations between OAA use, patient and provider characteristics, and EOL care quality in both cohorts. Results: We identified 410 (NC-CIPHR) and 1508 (SEER-Medicare) patients with median ages of 69 and 75 years, respectively. 53.4% and 43.5% of decedents received an OAA in NC-CIPHR and SEER-Medicare, respectively. OAA use was associated with increased systemic therapy in the last 30 days prior to death in both datasets, increased hospice in the last 30 days prior to death in SEER-Medicare, and increased death in hospital in NC-CIPHR. OAA use was not associated with inpatient or ICU admission near EOL in both cohorts. Older patients were less likely to receive chemotherapy, be admitted, or die in the hospital near EOL in both cohorts. Dual-enrolled beneficiaries (Medicare and Medicaid) had decreased likelihood of hospice use in 30 days prior to death (OR = 0.71; 95%CL: 0.54, 0.94) and increased death in hospital (OR = 1.40; 95%CL: 1.02, 1.93) in SEER-Medicare. Conclusions: Patients with mRCC who received OAAs were more likely to receive systemic therapy at the EOL, however, they were also more likely to receive hospice care at EOL in the SEER-Medicare cohort with no differences in hospitalization near EOL. Future directions include characterization of EOL care in the era of immunotherapy treatments. [Table: see text]
Real-world assessment of changing treatment patterns and sequence for patients with metastatic renal cell carcinoma (mRCC) in the first-line (1L) setting.
Authors: Shah Neil J. , Sura Sneha , Shinde Reshma , Shi Junxin , Perini Rodolfo F. , Puneet Singhal , Robert Nicholas J. , Vogelzang Nicholas J. , Motzer Robert J.
Published: February 2022

302

Background: Several immune-oncology (IO) agents and/or tyrosine kinase inhibitors (TKIs) have received approval for treatment of mRCC in 1L setting by Food and Drug Administration (FDA) over last few years. Limited data exists on evolving real-world treatment patterns and sequence in mRCC patients receiving these agents, especially at the community oncology setting. Methods: We used data from The US Oncology Network of over 1,300 providers from over 480 sites across United States from 01/01/2018 to 12/31/2020 (study period). Eligible study population included mRCC patients who received ipilimumab + nivolumab (Ipi+nivo) (IO+IO); pembrolizumab + axitinib (Pembro+axi) (IO+TKI); and axitinib (Axi) or cabozantinib (Cabo) or pazopanib (Pazo) or sunitinib (Suni) (TKIs monotherapy) in 1L setting until 09/30/2020. Descriptive statistics were used for cohort characterization. Results: We identified 3,756 mRCC patients, of which 1,538 were eligible including 42% (n=641) IO+IO, 18% (n=279) IO+TKI, and 40% (n=618) TKI monotherapy. The median age for the entire cohort was 67.1 years (range 25.0, 93.3), 70% (n=1,076) were male, 70% (n=1,081) were white, 38% (n=587) had BMI ≥ 30 and 79% (n=1,208) had clear cell histology. Among entire cohort, 87% (n=1,338) had intermediate/poor risk score as per International mRCC Database Consortium risk model. We noted a trend towards increased utilization of IO+IO and IO+TKI following their respective FDA approvals (IO+IO: April 2018, IO+TKI: April 2019) (Table). During the study period, overall, 35% (n=535), 12% (n=184), and 4% (n=62) mRCC patients received second-line (2L), third-line (3L) and fourth-line (4L) treatments, respectively. Cabo (49%) and pazo (12%); cabo (51%) and ipi+nivo (23%); and nivo (45%) and ipi+nivo (20%) were the most common 2L treatments in IO+IO, IO+TKI, and TKI monotherapy cohorts, respectively. Conclusions: This large real-world study examined use of new FDA approved mRCC treatments and their impact on treatment paradigm. The results show a rapid adaptation of these newer treatments in the community oncology settings. A longer follow-up is needed to assess their clinical impact and optimal treatment strategy in subsequent setting.[Table: see text]
First-line therapy for metastatic renal cell carcinoma with pancreatic metastases: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Roussel Eduard , Kinget Lisa , Beuselinck Benoit , Albersen Maarten , Wells Connor , Ernst Matthew Scott , Donskov Frede , Schmidt Andrew Lachlan , Szabados Bernadett , Pal Sumanta K. , Meza Luis A , Agarwal Neeraj , Weickhardt Andrew James , Davis Ian D. , Alva Ajjai Shivaram , Wood Lori , Porta Camillo , Choueiri Toni K. , Heng Daniel Yick Chin , Navani Vishal
Published: February 2022

317

Background: Metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) is characterised by heightened angiogenesis, which is associated with improved outcomes with vascular endothelial growth factor (VEGF) inhibitors. We aimed to compare the efficacy of first-line (1L) ipilimumab/nivolumab (IOIO) vs. anti-PD(L)1/anti-VEGF (IOVE) vs. VEGF monotherapy (VE) in mRCC patients with and without PM. Methods: We performed a retrospective analysis of patients with and without PM, using the IMDC. Sites of metastases were captured at initiation of 1L. Patients with PM could also have metastases at other sites. We studied overall survival (OS) from start of 1L therapy using Cox regression, adjusted for IMDC risk groups. Kaplan Meier survival curves were generated. Results: 543/7,634 (7%) patients had PM. Patients with PM in the overall population had improved OS compared to those without, 56 vs 25.6 months respectively (HR 0.63, 95% CI 0.55-0.73, p<0.0001). When examining the effect of PM within 1L options, those treated with IOVE exhibited a longer OS if PM were present vs absent, median not reached vs 45 months respectively (HR 0.41, 95% CI 0.18-0.93 p=0.03). This association was also seen in patients with treated with 1L VE, in those with PM vs absent, median 53.1 vs 25.1 months respectively (HR 0.65, 95% CI 0.55-0.76, p <0.0001). Contrastingly there was no difference in median OS of patients with or without PM in patients receiving IOIO, 41.4 vs 44.4 months respectively (HR 0.86, 95% CI 0.48-1.56, p=0.62). Comparing the outcomes between 1L therapies in patients with PM the median OS of IOVE vs VE was not reached vs 53.1 months respectively (HR 0.37, 95% CI 0.16-0.83 p=0.02). Conversely, upfront VE and IOIO had a similar median OS of 53.1 vs 41.4 months respectively (HR 0.81, 95% CI 0.45-1.47 p=0.49). We were unable to find any difference in OS between those treated with IOVE vs IOIO, median not reached vs 41.4 months respectively (HR 0.52 95%, CI 0.19-1.45, p=0.21), but the low event rate limited this interpretation. Conclusions: We found that the presence of PM leads to an indolent biological behavior and was associated with improved outcomes when 1L therapy included a VE component. PM patients had comparable OS outcomes on 1L VE and 1L IOIO therapy, but improved OS when treated with 1L IOVE. Anti-angiogenic therapy may be necessary to optimize outcomes in PM and this warrants prospective evaluation. [Table: see text]
Tivozanib (T) as first-line (1L) treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in North-West of England (NWE), UK.
Authors: Heseltine Jonathan , Allison Jennifer , Wong Sam , Prasad Kellati , Wong Helen , Oong Zhu , Charnley Natalie , Law Andrea , Parikh Omi , Pillai Manon Rhys , Waddell Tom , Griffiths Richard , Chow Shien
Published: February 2022

335

Background: The TIVO-1 study demonstrated improved PFS in mRCC patients (pts) undergoing 1L treatment with T compared with sorafenib. We previously presented outcomes of our experience of T in 4 cancer centres in NWE. Here we present updated outcomes with longer follow-up (FU). Methods: mRCC pts commencing 1L T March 2017- May 2019 were identified. Outcomes of interest included overall response rate (ORR), survival (OS, PFS) and toxicity. Data cut off for this update was 30/11/2020. Results: 113 pts were identified with characteristics as in the table. Median FU was 25.9 mo (18.3-44.7mo), 18% pts remain on treatment at data cut-off. 88.5% commenced T at full dose, of which 67% maintained dose intensity. 11.5% commenced T with dose reduction due to prior TKI toxicities or comorbidities. Median number of cycles was 7 (1-33). In terms of efficacy, ORR was 29% (CR 0%, PR29%, SD39%, PD26%, NE 6%) and median PFS was 9.0 months (95% C.I. 6.0-12.1mo). Median PFS by IMDC risk group was: F= 23.0 months (95% C.I. 7.6-38.4mo); I= 10.0 months (95% C.I. 6.3-13.7mo); P= 3.0 months (95% C.I. 1.5.- 4.5mo), p value<0.0001. Median OS was 25.0 months (95% C.I. 15.4-34.6mo). Median OS by IMDC risk group was: F= NR with 72% alive at data cut-off; I= 26.0 months (95% C.I. 17.9-34.1mo); P= 7.0 months (95% C.I. 4.4-9.6mo), p value<0.0001. Adverse events (AEs) of any grade occurred in 77% (≥G3 13%) including fatigue 42% (≥G3 0%), diarrhoea 19% (≥G3 < 1%), mucositis 24% ( ≥G3 2%), anorexia 12% (≥G3 < 1%); and hypertension 7% (≥G3 2%). Notable ≥G3 events included abnormal liver function 3%; vascular events 2% and seizure < 1%. 18% of patients discontinued treatment due to toxicity with no treatment-related deaths. Conclusions: Our real world experience of 1L T suggests comparable activity with randomized data and other TKIs, particularly in F and I IMDC risk groups. The low incidence of serious AEs makes it an attractive option if unsuitable for combination therapies. [Table: see text]
The impact of baseline peripheral cytokines on survival in metastatic clear cell renal cell carcinoma (RCC) treated with nivolumab: NIVOREN GETUG-AFU 26 Translational study.
Authors: Carril Lucia , Naigeon Marie , Dalban Cécile , Desnoyer Aude , Rioux-Leclercq Nathalie , Sautes-Fridman Catherine , Meylan Maxime , Vano Yann-Alexandre , Beusenlick Benoit , Chouaib Salem , de Oliveira Caroline , Tantot Florence , Escudier Bernard , Albiges Laurence , Chaput Nathalie
Published: February 2022

379

Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with RCC in a “real world setting”. A translational research program was launched to quantify baseline cytokine levels and correlate them with outcomes to nivolumab. Methods: Extreme responder patients (pts) treated with nivolumab as part of the phase II NIVOREN GETUG-AFU 26 were included in this TRAINING cohort. A panel of 14 different plasma cytokines and proteins (VEGF, VCAM-1, IL-6, IL-7, IL-8, IL-10, APRIL, BAFF, 4-1BB, BCA, SDF-1, MDC, IFN-gamma and TNF-alpha) were quantified for each plasma sample using the Elisa-based Meso Scale Discovery electrochemiluminescence assay. The association between baseline cytokine levels and objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) was evaluated. Results: Overall, 80 pts, 40 responders and 40 progressors, were included for cytokine analysis. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 11.3% good, 56.3% intermediate and 32.5% poor. With a median follow-up of 21.2 months, mOS data was immature at data cut-off. Overall survival rate was 67.3% at 12 months and median PFS was 3.8 months. Increased levels of IL-6 (75th percentile=P75), IL-7 (P75), IL-8 (P50) and VEGF (P50) were significantly negatively associated with survival (IL-6: HR=2.44, p=0.0112; IL-7: HR=2.38, p=0.0123; IL-8: HR=2.80, p=0.0045, and VEGF: HR=2.43, p=0.0133). 4-1BB (P50) was associated with improved OS (HR=0.39, p=0.0375). Higher levels of IL-8 (P50) and VEGF (P50) were associated with worse PFS (IL-8: HR=2.50, p=0.0133, and VEGF: HR=1.96, p=0.0132) and worse ORR (IL-8: p=0.013, and VEGF: p=0.044). Except for IL-8 and VEGF, no other associations with response were observed. Conclusions: Higher baseline plasma levels of IL-6, IL-7, IL-8 and VEGF were significantly associated with worse survival outcomes in mRCC pts treated with nivolumab within TRAINING cohort of the NIVOREN trial. In contrast, 4-1BB was significantly associated with improved OS. IL-8 and VEGF were also associated with worse PFS and ORR. VALIDATION cohort within the entire NIVOREN study is ongoing.
Racial, ethnic, and geographical differences in testicular cancer mortality trends in the United States.
Authors: Ghosh Anushka , Goldberg Saveli , Chino Fumiko , Efstathiou Jason A. , Kamran Sophia C.
Published: February 2022

409

Background: Incidence rates of Testicular cancer (TC) have been slowly increasing in the United States in recent decades. Prior research has identified racial disparities in mortality; however, these trends have not been extensively evaluated. Given that TC has a diverse presentation, this study was undertaken to establish racial, ethnic, geographical differences in longitudinal mortality trends. Methods: Age-adjusted cancer mortality rates for TC were obtained for men in the United States from the CDC Wide-ranging Online Data for Epidemiologic Research database. Testicular cancer-specific mortality (TCSM) rates from 1999-2019 were calculated using linear regression. Trends in mortality by race (White versus Black), ethnicity (Hispanic versus non-Hispanic), urbanization, and census region were analyzed using SAS 9.4. TCSM rates were compared by F-test. A two-sided hypothesis test was performed for p-values, where values < 0.05 were considered statistically significant. Results: From 1999-2019, overall age-adjusted TCSM has been slowly, but not significantly, increasing per year (Table). There was worsening TCSM rates for Hispanics (+)0.0019 per 100,000 compared to non-Hispanics (-)0.003; p=0.010. Black men had slightly improved TCSM rates/year (-0.0007) compared to white men (+0.0006); p=0.049. Significant geographical differences in mortality rates were observed, with a decreasing TCSM rate of (-)0.00092 the Northeast and an increasing rate of (+)0.00086 in the West (p = 0.032 for difference between slopes). Among urbanization categories, TCSM rates in Large Central Metros regions (central counties in metro areas with population > 1 million) and Small Metro regions (counties with population 50,000-249,999) were significantly different [(-)0.0004 and (+)0.0022 respectively; p =0.048]. All other comparisons were not significant. Conclusions: Using comprehensive, contemporary data on TCSM over 2 decades, we found significant differences in TCSM rates. Mortality rates from TC have been increasing, particularly among Hispanics. Understanding racial, ethnic, and geographical trends in TCSM rates is important in treating men with the disease and, ultimately, reducing deaths caused by TC.[Table: see text]
Early changes in peripheral blood neutrophil-lymphocyte ratio (NLR) to predict outcomes with immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (mUC).
Authors: Thomas Jonathan , Riaz Irbaz Bin , Freeman Dory , Adib Elio , Nuzzo Pier Vitale , El Zarif Talal , Davidsohn Matthew , McClure Heather , Curran Catherine , Ravi Praful , Yadav Ritu , Kalluri Uttam , Zeineddine Jana , Matar Ayah , McGregor Bradley Alexander , Mantia Charlene , Sonpavde Guru P.
Published: February 2022

449

Background: ICIs have provided advances in the therapy of mUC. However, the objective determination of benefit from ICIs determined by radiographic imaging may take months and may be confounded by pseudoprogression. Peripheral blood cells appear to reflect tumor microenvironment immune infiltrating cells. Given the known prognostic impact of baseline peripheral blood NLR, we aimed to investigate dynamic early changes in NLR as a biomarker of benefit in patients (pts) with mUC. Methods: Deidentified data from mUC pts who were treated with ICIs at Dana Farber Cancer Institute from 2015 to 2020 were reviewed retrospectively. Demographic data (age, gender), setting (untreated vs. post-platinum), sites of metastasis, performance status (PS), platelet count, and NLR at baseline and 3-4 weeks after initiating the ICI were collected. We assessed the association of NLR at baseline and 3-4 weeks after starting the ICI with any regression of tumor (ART) and overall survival (OS). A multivariable logistic regression model and Cox proportional-hazards model was employed to identify the association of NLR changes with ART and OS, respectively, using backward selection. Results: A total of 144 pts were included. The median age was 76 years and 100 (69.3%) were male. Overall, 54.8% (n=79) had ART and the median OS was 15.2 (12.2-23.5) months. 37.5% (n=54) were platinum naive and the remaining received post-platinum ICI therapy. In the multivariable models (Table), an increase in NLR, defined as an increase in NLR by ≥1.0 from baseline at 3-4 weeks was significantly associated with lower odds of ART (Odds Ratio (OR)= 0.80; 95% CI = 0.70-0.90; p = 0.0004) and worse OS (HR = 1.08; 95% CI = 1.05-1.11; p < 0.0001). The presence of liver metastasis was associated with lower odds of ART (OR = 0.30; 95% CI = 0.13-0.70; p = 0.006) and OS (HR 2.73; 95% CI 1.71 - 4.36; p<0.0001). Conclusions: Change in NLR in the first 4 weeks after initiating ICI for mUC was associated with tumor regression and survival in pts with mUC. Change in NLR may assist in early identification of benefit as well as identification of pts who may have progression of disease. Further validation is warranted to facilitate the early discrimination of benefit from ICIs in pts with mUC.[Table: see text]
Impact of selection bias on outcomes in veterans with muscle-invasive bladder cancer receiving bladder preserving trimodality therapy.
Authors: Kumar Abhishek , Kotha Nikhil V. , Nelson Tyler J. , Cherry Daniel R. , Stewart Tyler F. , McKay Rana R. , Rose Brent S.
Published: February 2022

462

Background: Retrospective studies using large registries comparing outcomes between radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) to trimodality therapy (TMT), which includes transurethral resection of bladder tumor followed by chemoradiation, often cannot distinguish whether patients receiving TMT were eligible for cystectomy but declined or simply ineligible for cystectomy. The objective of this study was to compare survival outcomes of patients with MIBC receiving TMT stratified by whether they were cystectomy-eligible to patients receiving RC +/- NAC. Methods: We used the national Veterans Affairs’ (VA) database to identify patients diagnosed between 2000-2017 with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent RC or TMT. Overall survival (OS) was evaluated with multivariable Cox proportional hazards model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. We conducted a chart review of clinical notes to ascertain if patients were eligible for cystectomy. Results: Overall 2306 Veterans with MIBC were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 107 (4.6%) with TMT eligible for RC, and 221 (9.4%) with TMT ineligible for RC. Median follow up time was 4.7 years. Patients receiving RC were on average 10 years younger, had higher creatinine clearance, and fewer comorbidities than those receiving TMT. Cystectomy-eligible TMT patients had higher creatinine clearance and fewer comorbidities than those ineligible for cystectomy. On multivariable analysis, compared to RC-NAC, TMT in cystectomy-eligible patients was associated with similar OS (hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.76 - 1.28; p = 0.93) and BCSM (HR 1.02; 95% CI 0.71-1.47; p = 0.91). Compared to RC-NAC, TMT in cystectomy-ineligible patients was associated with inferior OS (HR 1.39; 95% CI 1.13 - 1.71; p = 0.002) and BCSM (HR 1.61; 95% CI 1.23 - 2.10; p < 0.001). Conclusions: There is a significant selection bias among patients with MIBC receiving TMT. Cystectomy-eligible patients receiving TMT likely have similar survival outcomes as those receiving RC. Comparisons between RC and TMT in large registry data that lack information regarding eligibility for cystectomy in the TMT arm may be unreliable.
Management, surveillance patterns, and costs associated with low-grade papillary (Ta) nonmuscle-invasive bladder cancer.
Authors: Bree Kelly K. , Shan Yong , Hensley Patrick J. , Lobo Niyati , Hu Chengrui , Tyler Douglas S. , Chamie Karim , Kamat Ashish M. , Williams Stephen B. ,   IBCG Center for Bladder Cancer Population Health and Health Services Research
Published: February 2022

464

Background: Low-risk non-muscle invasive bladder cancer (NMIBC) is associated with extremely low rates of progression and cancer-specific mortality, however, these patients may often receive non-guideline recommended and potentially costly surveillance and treatment(s). We sought to describe current surveillance and treatment practices, oncologic outcomes, and cost of care for low-grade papillary (LG Ta) NMIBC and identify predictors of increased cost of care. Methods: This population-based cohort study identified 13,054 patients diagnosed with LG Ta tumors in the Surveillance, Epidemiology and End Results-Medicare linked database from January 1, 2004 through December 31, 2013. The primary outcome was to characterize trends in population-level surveillance and treatment practice patterns over time among LG Ta patients. The secondary outcomes were recurrence, progression, and costs of care. Results: Of the 13,054 patients who met inclusion criteria, 9,596 (73.5%) were male and 3,485 (26.5%) were female, with a median age of 76 (Interquartile Range (IQR): 71–81) years. Rates of surveillance cystoscopy increased over the study period (79.3% to 81.5%, p = 0.007) with patients undergoing a median of three cystoscopies per year (IQR: 2–4). Rates of upper tract imaging utilization also increased, namely the use of computed tomography (CT) or magnetic resonance imaging (MRI) (30.4% to 47%, p < 0.001), with most patients undergoing a median of two imaging tests per year. Similarly, the use of urine cytology or other urine biomarkers also increased (44.8% to 54.9%, p < 0.001). Rates of compliance with current guidelines decreased over time suggesting overutilization of all surveillance testing modalities. A total of 17.2% of patients received intravesical bacillus-Calmette Guerin (BCG) and 6.1% received intravesical chemotherapy (excluding single perioperative dose). Among all LG Ta patients, 1.7% and 0.4% experienced disease recurrence and progression, respectively. Total annual median costs of LG Ta surveillance and care increased 1.6-fold from $34,792 to $53,986 over the study period, with increased expenditures noted among those with disease recurrence ($53,909 and $76,669). Conclusions: Despite low rates of disease recurrence or progression, rates of surveillance testing increased during the study period. Annual cost of care increased over time, particularly among patients with recurrent disease. Efforts to improve adherence to current practice guidelines, with the focus on limiting overutilization of surveillance testing and overtreatment, may mitigate associated rising costs of care.
Avelumab first-line (1L) maintenance + best supportive care (BSC) versus BSC alone in Asian patients with advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis.
Authors: Eto Masatoshi , Lee Jae-Lyun , Park Se Hoon , Tsuchiya Norihiko , SU Po-Jung , Chan T.W. , Desai Chirag Jyotiker , Di Pietro Alessandra , Wang Jing , Laliberte Robert J , Gao Seasea , Gurney Howard
Published: February 2022

486

Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance therapy + BSC showed significantly longer overall survival (OS) vs BSC alone in patients with advanced UC that had not progressed with 1L platinum-based chemotherapy. We report efficacy and safety results in patients enrolled in Asia. Methods: Patients with unresectable locally advanced or metastatic UC without disease progression after 4-6 cycles of gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab 1L maintenance + BSC or BSC alone, stratified by best response to 1L chemotherapy and visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in all patients and patients with PD-L1+ tumors (Ventana SP263 assay). Results: 147 Asian patients were enrolled at sites in Japan, South Korea, Taiwan, Hong Kong, and India; 73 and 74 were randomized to receive avelumab + BSC or BSC alone, respectively. Median OS (95% CI) was 25.3 mo (18.6 mo-not estimable [NE]) with avelumab+ BSC vs 18.7 mo (12.8 mo-NE) with BSC alone (HR, 0.74 [95% CI, 0.434-1.260]) in all patients, and 26.1 mo (18.2 mo-NE) vs 19.4 mo (11.9 mo-NE), respectively (HR, 0.66 [95% CI, 0.279-1.541]), in the PD-L1+ subgroup (n = 71). With avelumab + BSC vs BSC alone, median (95% CI) progression-free survival was 5.6 (2.0-7.5) vs 1.9 (1.9-1.9) months (HR, 0.58 [95% CI, 0.383-0.864]) in all patients and 6.8 (1.9-11.2) vs 1.9 (1.9-3.8) months (HR, 0.63 [95% CI, 0.336-1.172]) in the PD-L1+ subgroup; objective response rates (95% CI) were 9.6% (3.9%-18.8%) vs 2.7% (0.3%-9.4%) and 12.5% (4.2%-26.8%) vs 3.2% (0.1%-16.7%), respectively. The most common treatment-emergent adverse events (TEAEs) of any grade (any causality) in the avelumab + BSC arm were pyrexia (23.6%), constipation, nasopharyngitis, and rash (19.4% each); grade ≥3 TEAEs were anemia (9.7%), amylase increased (5.6%), and urinary tract infection (4.2%). Conclusions: Efficacy and safety data support the use of avelumab 1L maintenance as the standard of care in Asian patients with advanced UC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432.
Reduction of residual tumors by photodynamic diagnosis-assisted TURBT using 5-aminolevulinic acid for high-risk nonmuscle-invasive bladder cancer (BRIGHT study).
Authors: Kawai Taketo , Kume Haruki , Inoue Keiji , Fujimoto Kiyohide , Oyama Masafumi , Miyake Hideaki , Azuma Haruhito , Nishiyama Hiroyuki , Shinohara Nobuo , Ohyama Chikara , Mitsui Takahiko , Mizokami Atsushi , Kawakita Mutsushi , Matsuyama Hideyasu
Published: February 2022

489

Background: High-risk non-muscle invasive bladder cancer (NMIBC) has high tumor residual rate of 40–60% after TURBT, and second TUR is strongly recommended. Photodynamic diagnosis-assisted TURBT (PDD-TURBT) using 5-aminolevulinic acid (5-ALA) has been reported to reduce residual tumors and intravesical recurrence. The purpose of this study is to investigate the residual tumor-reducing effect of PDD-TURBT for high-risk NMIBC and to explore the possibility that second TUR could be omitted by PDD-TURBT. Methods: We conducted an investigator-initiated multicenter prospective observational study (BRIGHT study; UMIN000035712) involving patients who underwent PDD-TURBT using 5-ALA and second TUR for high-risk NMIBC (high-grade UC or pT1 or concurrent CIS). The primary endpoint was tumor residual rate and the secondary endpoint was recurrence-free survival, which were compared with historical data (conventional TURBT) using propensity score-matching (PSM; caliper: 0.2). Assuming that the difference between the two groups was 20%, the planned number of cases was statistically set to 200 PDD-TURBT cases and 300 historical data cases, and the registration period was 2 years from January 2019 to December 2020, and the follow-up period was 2 years after second TUR. Results: In this study, 188 patients in the PDD-TURBT group and 313 patients in the historical group were enrolled, and 177 patients and 306 patients were included in the final analysis, respectively. After PSM adjustment, 167 patients in both groups were compared, and no significant differences were observed in age, gender, history of bladder cancer, tumor diameter, number of tumors, history of upper tract urothelial cancer, and period from initial TURBT to second TUR. The tumor residual rate was 25.8% in the PDD-TURBT group compared with 47.3% in the historical group, showing a significant decrease (odds ratio 0.39 [95% CI: 0.24–0.63]; p = 0.000064). Logistic regression analysis revealed that significant factors predicting residual tumors in PDD-TURBT were current or past smoking history, multiple tumors, and non-pTa (pT1 or pTis) tumors. Focusing on these three factors, patients with 0–1 of these three factors have a significant less tumor residual rate compared with patients with 2–3 factors (8.33% vs. 33.3%; odds ratio 5.46 [95% CI: 1.81–22.3]; p = 0.00052). Conclusions: PDD-TURBT for high-risk NMIBC significantly reduced the tumor residual rate at the second TUR compared to the conventional TURBT. PDD-TURBT using 5-ALA may enable to omit second TUR in some high-risk NMIBC cases. Clinical trial information: UMIN000035712.
Atezolizumab (atezo) with or without Bacille Calmette-Guérin (BCG) in patients (pts) with high-risk nonmuscle-invasive bladder cancer (NMIBC): Results from a phase Ib/II study.
Authors: Hahn Noah M. , Steinberg Gary D. , Stratton Kelly Lynn , Kopp Ryan P. , Sankin Alexander , Skinner Eila C. , Pohar Kamal S. , Gartrell Benjamin Adam , Pham Song , Rishipathak Deepali , Mariathasan Sanjeev , Davarpanah Nicole N. , Carter Corey , Inman Brant Allen
Published: February 2022

493

Background: Standard treatment (tx) for high-risk NMIBC is transurethral resection of bladder tumor (TURBT) followed by BCG induction and maintenance. However, ≈50% of pts experience recurrence and/or progression after tx and may be ineligible for or refuse cystectomy. The PD-L1/PD-1 pathway may be involved with immune escape in NMIBC following BCG exposure. Here, we report results of atezo (antiPD-L1) ± BCG in BCG-unresponsive, high-risk NMIBC. Methods: This multicenter study (NCT02792192) enrolled pts with BCG-unresponsive NMIBC with carcinoma in situ who had repeat TURBT. Cohort 1A and 1B pts received atezo 1200 mg IV q3w for ≤96 wk. Cohort 1B pts also received standard BCG induction (qw × 6 doses) and maintenance (qw × 3 doses at 3 mo), with optional maintenance courses at 6, 12, 18, 24, and 30 mo. For cohort 1B only, de-escalation was allowed for ≤3 BCG dose levels (full dose 50 mg, 66% and 33% of full dose). Co-primary outcomes were safety and complete response (CR) rate at 6 mo (6-mo bladder biopsy required). Duration of CR and 3-mo CR rate (key secondary outcomes) and 12-mo CR rate (exploratory) were also shown. Results: Cohorts 1A and 1B enrolled 12 pts each. Median age was 74 y; most pts had ECOG PS 0 (n = 7 [58%] in each cohort). At data cutoff (Sep 29, 2020), median atezo tx duration was 22.7 wk in cohort 1A and 31.6 wk in 1B. Following dose de-escalation in cohort 1B, the recommended BCG dose was 50 mg. BCG dose modification/interruption occurred in 4 pts (33%) due to an AE. The most common reason for tx discontinuation was disease recurrence or progression in both cohorts. Three pts (25%) in cohort 1A had atezo-related Gr 3 AEs (most common: maculopapular rash, n = 2); no atezo- or BCG-related Gr ≥3 AEs were seen in cohort 1B. Three dose-limiting toxicities occurred (1 [8%] in cohort 1A and 2 [17%] in cohort 1B), all reported as AEs of special interest. No Gr 4/5 AEs were reported. CRs, which appeared durable, were seen in both cohorts (Table). Conclusions: In this first report of atezo + BCG in NMIBC, atezo as mono- and combination therapy was well tolerated, with no new safety signals or tx-related deaths. Preliminary data suggested clinically meaningful activity, especially with atezo + BCG, requiring confirmation in a larger setting. Clinical trial information: NCT02792192. [Table: see text]
Futibatinib plus pembrolizumab in patients (pts) with advanced or metastatic urothelial carcinoma (mUC): Preliminary safety results from a phase 2 study.
Authors: Koshkin Vadim S , Sonpavde Guru P. , Hwang Clara , Mellado Begona , Tomlinson Gareth , Shimura Masashi , Chisamore Michael Jon , Gil Maciej , Loriot Yohann
Published: February 2022

501

Background: Immune checkpoint inhibitors (ICIs), including pembrolizumab, are among the few treatment options available for platinum-ineligible pts with mUC, but only 25–30% of pts achieve responses with ICIs. FGFR DNA alterations (in 15–20% of mUCs) may contribute to poor responses to ICIs, and FGFR inhibition may sensitize tumors to ICIs by direct action on cancer cells or by altering the tumor microenvironment. In an open-label phase 2 study (NCT04601857), futibatinib, a highly selective, potent, irreversible FGFR1–4 inhibitor with activity in FGFR-deregulated tumors, is being assessed in combination with pembrolizumab in pts with mUC. Here, we report preliminary findings from the safety lead-in phase. Methods: Eligible pts (≥18 y; ECOG PS ≤1) had mUC, were treatment naive in the advanced/metastatic setting, and unfit for, intolerant to, or refusing platinum-based chemotherapy. Prior anti–PD-1/PD-ligand 1/2 or FGFR inhibitor therapy were not permitted. Pts (regardless of FGFR alteration status) were first enrolled in a safety lead-in and received futibatinib 20 mg orally once daily (QD) and pembrolizumab 200 mg IV every 21 d. Dose-limiting toxicities (DLTs) were assessed during the first 21-d treatment cycle. Results: As of September 27, 2021, 6 pts were enrolled in the safety lead-in. Median age was 73.5 y (range, 46–84 y) and 17% (1/6) of pts had an ECOG PS of 1. Median duration of treatment was 48 d (range, 21–141 d) with futibatinib and 35 d (1–114 d) with pembrolizumab. Two pts (33%) remained on treatment at data cutoff. Adverse events (AEs) were reported in all 6 pts; AEs in > 2 pts were diarrhea (83%), hyperphosphatemia (67%), increased aspartate aminotransferase (50%), and pruritis (50%). Grade 3 AEs were reported in 2/6 pts: increased aspartate aminotransferase, maculopapular rash, myositis (17% each). There were no grade 4–5 AEs. AEs led to any study drug discontinuation in 3 pts, dose interruption in 3 pts, and dose modification in 3 pts. All 6 pts were evaluated for DLTs after 1 treatment cycle; no DLTs were reported. Conclusions: Preliminary safety results support tolerability of futibatinib plus pembrolizumab in platinum-ineligible pts with mUC. As no DLTs were observed in the safety lead-in, the recommended dose of futibatinib in combination with pembrolizumab is 20 mg QD. Enrollment in pts with or without FGFR alterations is ongoing to evaluate antitumor activity by FGFR alteration status. Clinical trial information: NCT04601857.
Interim results of a phase Ib single-center study of pembrolizumab in combination with chemotherapy in patients with locally advanced or metastatic small cell/neuroendocrine cancers of the prostate and urothelium.
Authors: Chin Arnold I. , Drakaki Alexandra , Rodriguez Sara , Sachadeva Ankush , Bradley Margaret , Zomorodian Nazy , Zhang Hanwei , Li Shanpeng , Li Gang , Rettig Matthew , Liu Sandy
Published: February 2022

510

Background: Small cell/neuroendocrine cancers irrespective of origin share aggressive phenotypes. Pembrolizumab (MK-3475) is a humanized antibody targeting programmed cell death protein 1 (PD-1) that has shown activity against small cell lung cancers. Preclinical studies showed molecular commonality amongst small cell/neuroendocrine cancers across multiple tissue types. This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and urothelium. Methods: Patients with locally advanced or metastatic small cell cancer of the bladder or upper urinary tract (cohort 1) and primary small cell or treatment-derived neuroendocrine prostate cancer (NEPC) (cohort 2) received pembrolizumab and standard of care chemotherapy (etoposide and cisplatin/carboplatin for cohorts 1 and 2, with option of docetaxel and carboplatin for cohort 2) with maintenance pembrolizumab for 2 years until unequivocal progressive disease or unacceptable toxicity. The primary endpoint was to estimate ORR and PFS compared to historical controls as well as safety and tolerability. Pretreatment targeted gene mutation sequencing was performed. Results: 14 patients were enrolled (7 cohort 1, 7 cohort 2) with mean age 64.9 (range 53 to 81). ORR across cohorts was 43% (95% CI: (0.17, 0.69)), and 43% (95% CI: (0.06, 0.80)) within each cohort. PFS rate at 12 months (proportion of patients who have not progressed at 12 month) was 61% (95% CI: (0.40,0.95)) across cohorts, 86% (95% CI: (0.63,1.00)) within cohort 1, and 36% (95% CI: (0.12,1.00)) within cohort 2. 3 patients in cohort 1 with locally advanced disease exhibited SD and underwent radical cystectomy, with one patient pT0 and no PD at a mean follow up of 20 months. Grade 3 or higher AEs occurred in 71% of patients, while 29% of patients experienced grade 3 or higher AEs related to pembrolizumab. No patients died or discontinued therapy secondary to adverse treatment effects. In 12 patients where tissue was sufficient, all patients had genomic alterations in either p53 (75%) or Rb (58%). Of the 5 available patients with NEPC, 60% had alternations in DNA damage response genes. Conclusions: In patients with locally advanced or metastatic small cell/neuroendocrine prostate and bladder cancers, combination pembrolizumab with standard of care chemotherapy and maintenance pembrolizumab showed promising efficacy with tolerable adverse events. Clinical trial information: NCT03582475.
Safety lead-in of phase II SBRT and durvalumab with or without tremelimumab for unresectable and cisplatin-ineligible, locally advanced or metastatic bladder cancer.
Authors: Kundu Palak , Lee Alan , Drakaki Alexandra , Liu Sandy , Shen John , Chin Arnold I. , Chamie Karim , Chang Albert
Published: February 2022

517

Background: Many patients with muscle-invasive bladder cancer are not ideal candidates for chemotherapy or radical cystectomy. Moreover, local progression may further impair quality of life. Bladder preservation with maximal transurethral resection of bladder tumor (TURBT) and stereotactic body radiotherapy (SBRT) is a viable treatment option for such patients, offering durable local control while potentiating the effect of immunotherapy. Herein, we report on the safety profile of SBRT in combination with durvalumab (anti-PDL1) and tremelimumab (anti-CTLA4) in the safety lead-in cohort of an institutional Phase II trial for cisplatin-ineligible, unresectable locally advanced or metastatic bladder cancer patients. Methods: Patients with locally advanced or metastatic urothelial carcinoma, who were unwilling or unable to undergo radical cystectomy and/or systemic chemotherapy were eligible. Patients received maximal TURBT, followed by durvalumab 1500mg IV every 4 weeks and bladder SBRT 33Gy in 5 fractions between the first 2 cycles. After 6 such patients did not experience a dose limiting toxicity, tremelimumab 75mg IV was added for cycles 1-2. Patients were followed with CT Chest/Abdomen/Pelvis and cystoscopy every 3 months. Treatment-related adverse events (TRAEs) were assessed per CTCAE 5.0 and progression was assessed per RECIST 1.1. Results: Between January 2019 and May 2020, 10 patients received TURBT followed by SBRT and durvalumab (Age 73-96, 3 Female, 7 ECOG 1, 3 ECOG 0). Five patients had localized disease and 5 had nodal or distant metastases. Median cycles of durvalumab was 12.5 (2-13), and 4 patients received 2 cycles of tremelimumab. At a median follow-up of 16.8mo (6.4-30mo), there were 2 Grade 3+ immunotherapy-related TRAEs (1 Grade 3 lipase elevation self-resolved, 2 Grade 3 myositis treated with steroids). The most common TRAEs of any grade included pancreatic enzyme elevation (3 patients), rash (3 patients), and urinary symptoms related to RT (3 patients). Disease control rate 70% and local control was 90%. There were 3 non-treatment related deaths. Conclusions: Bladder SBRT with durvalumab and tremelimumab was well tolerated and demonstrated promising local control in the safety lead-in cohort. Clinical trial information: NCT03601455.
Association of TMB and PD-L1 with efficacy of first-line pembrolizumab (pembro) or pembro + chemotherapy (chemo) versus chemo in patients (pts) with advanced urothelial carcinoma (UC) from KEYNOTE-361.
Authors: Morales-Barrera Rafael , Powles Thomas , Ozguroglu Mustafa , Csoszi Tibor , Loriot Yohann , Flechon Aude , Matsubara Nobuaki , Rodriguez-Vida Alejo , Geczi Lajos , Cheng Susanna Y. , Fradet Yves , Oudard Stephane , Gunduz Seyda , Ma Junshui , Rajasagi Mohini , Vajdi Amir , Cristescu Razvan , Imai Kentaro , Homet Moreno Blanca , Alva Ajjai Shivaram
Published: February 2022

540

Background: The 3-arm, open-label, phase 3 KEYNOTE-361 study (NCT02853305) evaluated first-line pembro ± chemo vs chemo in advanced UC regardless of PD-L1 status. The trial did not meet its primary end points of superior PFS and OS with pembro + chemo vs chemo and thus analysis of pembro monotherapy (mono) vs chemo was exploratory. We explored the association of TMB status and PD-L1 combined positive score (CPS) with clinical outcomes in KEYNOTE-361. Methods: In pts with TMB and/or PD-L1 data, the association between TMB (via whole exome sequencing) and PD-L1 (via PD-L1 IHC 22C3 pharmDx) and clinical outcomes (ORR, PFS, and OS) was evaluated. In each treatment arm, the hypotheses regarding the associations were evaluated using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS), and 1-sided (pembro; pembro + chemo) and 2-sided (chemo) P values were calculated; significance was prespecified at α = 0.05 without multiplicity adjustment. Clinical utility was assessed using prespecified cutoffs of 175 mut/exome (TMB) and CPS 10 (PD-L1). Clinical data cutoff was April 29, 2020. Results: 820/993 pts (82.6%) had evaluable TMB data (pembro, 252; pembro + chemo, 282; chemo, 286). TMB (log10) was significantly positively associated with ORR, PFS, and OS for pembro ( P < 0.001, < 0.001, and 0.007, respectively) and PFS and OS for pembro + chemo ( P= 0.007 and 0.010, respectively). The area under the receiver operating characteristics (AUROC) curve (95% CI) for discriminating response was 0.64 (0.56-0.71) for pembro, 0.53 (0.46-0.60) for pembro + chemo, and 0.52 (0.45-0.59) for chemo. Efficacy by TMB cutoff is reported in the Table. All 993 pts had PD-L1 data (pembro, 302; pembro + chemo, 349; chemo, 342). PD-L1 was significantly positively associated with PFS for pembro ( P= 0.006) and ORR for pembro + chemo ( P= 0.042) but not chemo. Efficacy by PD-L1 CPS is reported in the Table. Conclusions: Strong associations were observed between TMB and all 3 clinical outcomes (ORR, PFS, and OS) with pembro mono in the first-line setting and a reduced association was observed between TMB and clinical outcomes with pembro + chemo. No consistent associations were observed between PD-L1 and clinical outcomes with pembro mono or pembro + chemo. Clinical trial information: NCT02853305. [Table: see text]
IRONMAN: The international registry for men with advanced prostate cancer.
Authors: George Daniel J. , Mucci Lorelei A , Kantoff Philip W. , Villanti Paul , Vinson Jake , Gerke Travis A. , Hyslop Terry , Rencsok Emily
Published: February 2022

TPS190

Background: Men with advanced prostate cancer (APC) experience high mortality and severely impacted quality of life due to the disease itself as well as its therapies, with Black men facing the highest disease burden. The treatment landscape for APC is rapidly changing; however, little is known about the real-life experience of men receiving new therapies. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease, based on patient and country demographics. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to meet these needs. Methods: IRONMAN is a population-based prospective cohort of men with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer aiming to enroll 5,000 men across 16 countries (Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, United Kingdom, Untied States). Patients are followed prospectively for overall survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). Data is collected via longitudinal electronic questionnaires from patients and providers as well as blood samples and medical records. IRONMAN is currently enrolling in 10 countries at 103 sites. Sites were selected to create a diverse cohort across race/ethnicity, rural/urban populations, socioeconomic factors, and geographic regions. Of the first 1,865 men enrolled to date, 60% have mHSPC and 40% have CRPC; overall, 9% of men (18% in the US) self-identify as Black and 82% identify as white (78% in the US). 60% (N = 1,111) of this cohort has been enrolled outside of the US, and the median age at study entry is 70 years. The distribution and demographics of patients are continuously monitored to inform ongoing enrollment efforts. The IRONMAN Diversity Working Group meets monthly to discuss barriers and strategies to enhance enrollment of a racially and ethnically diverse population. The Low- and Middle-Income Country Working Group addresses the unique needs of men being recruited from the Caribbean and African sites in addition to supporting broad oncology efforts in these regions. These efforts support IRONMAN’s larger goal to investigate disparities in the care of patients with APC, having potential implications for decreasing racial disparities in survival outcomes. Clinical trial information: NCT03151629.