bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-primary endpoint analysis of HCRN GU 16-257: Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer (MIBC).
Authors: Galsky Matt D. , Daneshmand Siamak , Lewis Sara C , Chan Kevin G. , Dorff Tanya B. , Cetnar Jeremy Paul , Mamtani Ronac , Kyriakopoulos Christos , Gogerly-Moragoda Mahalya , Izadmehr Sudeh , Yu Menggang , Zhao Qianqian , Jun Tomi , Mehrazin Reza , Sfakianos John P. , Pal Sumanta Monty
Published: March 2023

447

Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by a lack of (a) prospective studies, (b) rigorous approaches to assess and define clinical complete response (cCR), and (c) integration of novel therapies. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance. Patients not achieving cCR were recommended to undergo cystectomy. Coprimary endpoints included (1) cCR rate and (2) association between cCR and 2-year outcomes. The key secondary endpoint was the impact of pre-specified baseline genomic alterations on outcomes. Additional biomarkers to refine patient selection were also explored. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%). Median follow-up is 27 months. 72/76 patients underwent clinical restaging and a cCR was achieved in 33/76 (43%; 95% CI: 32%, 55%). One cCR patient opted for immediate cystectomy (ypTaN0M0). Outcomes are summarized in the Table. Baseline ERCC2, ATM, FANCC, or RB1 alterations were not, but tumor mutational burden ≥ 10 mutations/mb was, significantly associated with the composite endpoint of ypT0 (immediate cystectomy) or 2-year bladder-intact metastasis-free survival (BIMFS). On landmark analysis, VI-RADS (Vesical Imaging–Reporting and Data System) score (3-5 versus 1-2) on restaging MRI (central blinded review) was associated with inferior BIMFS (HR 4.5; p = <0.01) and MFS (HR 19.3; p <0.01). Circulating tumor DNA data will be presented at the meeting. Conclusions: TURBT followed by gemcitabine, cisplatin, plus nivolumab achieves stringently defined cCR in a substantial subset of patients with MIBC. ≥2-year bladder-intact survival is achieved in the majority of patients with a cCR. Clinical trial information: NCT03558087 . [Table: see text]
Incidence and survival in patients with urachal carcinoma: Cancer registry analysis between 2008 and 2019.
Authors: Darr Christopher , Möller Lennart , Schürger Niklas , Szarvas Tibor , Reis Henning , Stang Andreas , Hadaschik Boris A. , Kajüter Hiltraud , Grünwald Viktor
Published: March 2023

480

Background: Urachal carcinoma (UrC) is a rare and poorly studied cancer without evidence-based treatment strategies. Due to the low prevalence of this cancer, only sparse data on its incidence and survival are available. Therefore, we analyzed the incidence and survival rates of patients with UrC in North Rhine-Westphalia (NRW), a state of the Federal Republic of Germany. Methods: UrC (ICD-O-3: C67.7) diagnosed between 2008 and 2019 were identified via the NRW Cancer Registry (population 18 million) and classified according to Mayo-staging and T-category. Mayo stage was based on the TNM classification. We calculated age-standardized incidence rates using the European standard and Kaplan-Meier overall survival (OS). Age was stated as mean and standard deviation (SD). Results: A total of 121 UrC patients were described, of which men were more frequently affected at 57%. The distribution for women was 43%. The mean age was 61.1 (SD: 15.5) years for men and 58.8 (SD: 15.3) years for women. The overall age-standardized incidence rate was 0.43 per 1.000.000 person-years, which was 0.5 for men and 0.37 for women. 85.1% had adenocarcinomas, 6.6% urothelial carcinoma, 4.1% unspecified cancer, 2.5% epithelial carcinomas, 0.8% squamous cell carcinomas or others, respectively. The 5-year OS rate were 60.4% (CI-95%: 48.9%; 74.7%) for men and 41.7% (CI-95%: 28.8%; 60.2%) for women. According to TNM classification, 33% of the patients presented with T1-2, 29.8% with T3-4, while for the Mayo staging a distribution of 17.4% for stage I-II and 13.2% for stage III-IV was shown. Data regarding T-category and Mayo-satging were available in 63.6% (44 patients) and 30.6% (84 patients), respectively. The 5-year OS was 73.3% (CI-95%: 59.3%; 90.6%) in T1-2, 37.2% (CI-95%: 23.6%; 58.6%) in T3-4. and 69.3% (CI-95%: 47.6%; 100%) and 25.6% (CI-95%: 9.89%; 66.49%) in Mayo stage I-II and III-IV, respectively. Conclusions: UrC is a rare cancer and OS rate in NRW were comparable to historical data. The prognosis was stage-dependent and identified poor outcome in patients with advanced disease. Our data underscored the role of proper staging and diagnosis for future clinical studies that investigate optimal treatment strategies.
A SEER-Medicare based quality score for patients with synchronous and metachronous metastatic upper tract urothelial carcinoma and its association with cost of care and survival.
Authors: Joyce Daniel D , Shan Yong , Stewart Courtney A. , Chamie Karim , Boorjian Stephen A. , Williams Stephen B. , Sharma Vidit
Published: March 2023

482

Background: Population-based studies evaluating outcomes exclusively for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and often only capture patients with de novo (synchronous) metastases as opposed to those who progress to metastatic disease (metachronous). We sought to evaluate the outcomes and costs associated with mUTUC and employ a novel methodology to identify both synchronous and metachronous mUTUC patients using claims data. Additionally, we created a guideline-based quality score to improve quality of care in this space. Methods: Using the SEER-Medicare database we identified patients aged 66 years and older diagnosed with mUTUC between 2004 and 2012. Achievement of the following quality criteria was assessed: 1) cancer-specific survival greater than 12 months; 2) receipt of systemic therapy; 3) receipt of hospice/palliative care. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare overall survival between quality scores (0 vs. ≥1) and synchronous vs. metachronous mUTUC. Total healthcare and Medicare Part D out-of-pocket costs within two years of diagnosis were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. Results: Of the 1,223 patients identified, 381 (31.2%) and 842 (68.8%) had synchronous and metachronous mUTUC, respectively. At least one quality criterion was met in 40.2% of patients. Notably, only 54 patients (4.4%) received palliative care services. On multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41–0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47–0.98), were less likely to achieve at least one quality criterion. Patients meeting quality criteria had longer survival compared with patients who did not meet criteria (HR:0.52, 95%CI: 0.46–0.59). Meeting at least one quality criterion was independently associated with increased costs ($94,677, 95%CI: 87702–101652 vs. $63575, 95%CI: 59598–67552) on multivariable regression analysis. Conclusions: Less than half of mUTUC patients met at least one quality criterion. Quality score achievement was associated with longer overall survival at a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.
Variation of renal function in patients with urothelial carcinoma treated by tislelizumab-based immunochemotherapy.
Authors: Wu Zhouliang , Hu Hailong , Shen Chong , Chen Houyuan , Zhao Gangjian , Huang Shiwang , Jia Kaipeng , Bai Yiduo , Guo Shizheng , Zhang Zhe , Li Zhi , Da La , Lin Yuda
Published: March 2023

494

Background: Treatment based on PD-1 ICIs brings advances to the treatment of urothelial carcinoma (UC). Although acute renal insufficiency is not common in iRAEs, the safety of immunotherapy in patients with renal impairment is still unknown. Consequently, we intend to investigate the effect of immunochemotherapy on nephritic function in the short term. Methods: Between July 2019 and September 2022, data of patients (pts) with UC that underwent tislelizumab based immunochemotherapy, including demographic information (age, gender), and creatinine level in baseline, after the first, second and third cycle (C1, C2 and C3) of immunotherapy in the Second Hospital of Tianjin medical University was collected and analyzed retrospectively. Estimated glomerular filtration rate (eGFR) is calculated according to CKD-EPI formula 2009, while pts were subdivided into different groups according to baseline eGFR, referencing to CKD categories in the K-DIGO 2012 guidelines for CKD classes. Data analyses were conducted using paired samples Wilcoxon Signed Rank Test and Kruskal-Wallis H test. Results: 163 pts have been included in our analyse totally. The median age was 67 years (IQR 61-74) and 128 (78.5%) were male. 135 (82%) pts received ICIs as perioperative treatment, while 19 (12%) pts were treated after radical operation. Metastasis is found in 9 (6%) pts before firstly received immunotherapy. Median creatinine (Cr) in baseline was 80.2umol/L (IQR 68.3-95.8), while median EGFR was 82.6 (IQR 64.3-93.8) mL/min/1. 73m2 in all pts. According to CKD categories in the K-DIGO 2012 guidelines, at baseline, 57 pts are classified as G1 (eGFR≥90 mL/min/1.73m2), 74 pts as G2(eGFR <90 mL/min/1.73 m2 and≥60 mL/min/1.73 m2), 30 as G3 (eGFR <60 mL/min/1.73 m2 and≥30 mL/min/1.73 m2), and 2 as G4 (eGFR <30 mL/min/1.73 m2 and≥15 mL/min/1.73 m2). No significant difference in eGFR between pts with CKD G1-2 in comparison to baseline and after the first (C1), second (C2) or third cycle(C3) of tislelizumab based immunotherapy (All p >0.05). Notably, we found that eGFR improved in pts with CKD G3-4 when the first, second and third cycle completed, in comparison to the baseline.(p<0.001, <0.001, =0.002). Conclusions: Despite renal impairment is common in pts with UC, no evidence suggests that it is contraindicated for tislelizumab based treatment. More importantly, PD-1 immunotherapy may provide better nephritic benefits in patients with renal insufficiency. [Table: see text]
Safety, tolerability, and preliminary efficacy of TAR-200 in patients with intermediate risk non–muscle-invasive bladder cancer: A phase 1 study.
Authors: van Valenberg F. Johannes P. , van der Heijden Toine , Cutie Christopher , Bhanvadia Sumeet Kaur , Keegan Kirk A. , Hampras Shalaka , Sweiti Hussein , Maffeo John , Jin Shu , Chau Albert , Reynolds Don , Iarossi Crysti , Kelley April , Li Xiang , Stromberg Katherine , Sedelaar Michiel , Steenbruggen Jessica , Somford Diederik Meindert , Witjes Alfred Alfred
Published: March 2023

505

Background: TAR-200 is a novel intravesical drug delivery system designed to provide a continuous, slow release of gemcitabine within the bladder. Prolonged gemcitabine exposure over days, instead of hours, such as with current standard intravesical installations, may achieve more efficient and effective tumor response. We report on the safety and tolerability of TAR-200 in patients with non-muscle–invasive bladder cancer (NMIBC). Methods: In this phase 1b, open-label, prospective study, patients with a papillary recurrence after prior histologically proven, intermediate risk (IR)-NMIBC received two 1-week TAR-200 dosing cycles over a 4- to 6-week period. The study used a marker lesion/ablation design. Cystoscopy was performed to assess for recurrent papillary disease and for complete transurethral resection of the residual bladder tumor. The primary outcome was safety of TAR-200. Secondary outcomes were tolerability, pharmacokinetics, preliminary efficacy, and immunohistochemistry. Results: In total, 12 patients received TAR-200 treatment. Insertion and removal of TAR-200 was uneventful. No TAR-200-related serious adverse events (AEs) occurred. Four patients had no TAR-200-associated AEs; the remainder had varying degrees of AEs (all grade ≤2 [CTCAEv4.0]), mainly consisting of low-grade urinary urgency, urinary frequency, and dysuria, with no delay in the treatment schedule. Two patients refused a second dosing cycle due to urinary urgency and frequency. Plasma gemcitabine concentrations remained below the lower limit of detection. Five of 12 patients (42%) had complete response (CR); of these, 4 had a pathologic CR and 1 had CR based on visual assessment (with no biopsy available for pathologic assessment). Conclusions: In this small, phase 1 series, TAR-200 appears to be safe and well tolerated in patients with IR-NMIBC. Clinical trial information: NCT02720367 .
Oncological outcome of intraarterial chemotherapy combined with radiotherapy compared to radical cystectomy for patients with muscle invasive bladder cancer.
Authors: Higashijima Katsuyoshi , Tomisaki Ikko , Minato Akinori , Harada Kenichi , Fujimoto Naohiro
Published: March 2023

515

Background: Although radical cystectomy (RC) has been a standard treatment for muscle invasive bladder cancer (MIBC), some patients are unfit or refuse RC. Intraarterial chemotherapy combined with radiotherapy (IAC-RT) is one of the bladder preservation techniques, but there are a few data in patients who performed IAC-RT without salvage RC. The aim of this study was to evaluate the efficacy and tolerability of IAC-RT without RC compared to RC in patients with MIBC. Methods: We retrospectively reviewed patients with MIBC (T2-4N0M0) who had received either IAC-RT or RC in our hospital between January 1999 and December 2019. Intraarterial chemotherapy consisted of cisplatin (30mg/m2) and adriamycin (20mg/m2) on day 1 of each 1st, 2nd, 5th, 6th week. Concomitant radiotherapy (2 Gy/session, total 60 Gy) to whole pelvis was performed during chemotherapy. Salvage RC was not performed in all patients. Overall survival (OS), disease-specific survival (DSS), and metastasis-free survival (MFS) were compared between patients who received IAC-RT and RC. The prognostic factors of IAC-RT associated with OS were also investigated. Results: Forty-two and 143 patients received IAC-RT and RC, respectively. Of 42 patients who received IAC-RT, 28 (67%) and 14 (33%) were elective (refused RC) and imperative (comorbidity:7 poor PS:6 unresectable:1) cases, respectively. The patients who underwent IAC-RT were older (median; 77 vs 69 years old) and had poorer PS (≥2; 43% vs 4.9%) and shorter follow-up time (median; 21.9 vs 40.0 months) than those of RC. During follow up periods, metastasis, bladder cancer death, death of any cause was observed in 20, 19, and 27 patients with IAC-RT, 59, 55, and 49 patients with RC. In survival analyses, median OS was 38.7 months (95%CI, 16.9-74.7) with IAC-RT versus 154.0 months (95%CI, 70.6- not estimable (NE)) with RC, these OS curves were significantly different (P=0.001). There were not significant differences between two groups in DSS (median 46.5 vs not reached, P=0.06) and MFS (median 38.7 vs not reached, P=0.21). In multivariate analysis, clinical stage (≥T3; HR, 1.89; 95% CI, 1.04-3.46; P=0.04) and PS (≥2; HR, 2.24; 95% CI, 1.16-4.33; P=0.02) were suggested as risk factors associated with poor OS, however, treatment procedure (IAC-RT or RC) did not associate with OS. Forty of 42 (95%) patients with IAC-RT had any adverse events (AEs). Although grade3 AEs were observed in 21 (50%) patients, most of them were hematological AEs and Grade 4/5 AEs was not observed. Conclusions: IAC-RT was a useful and tolerable treatment option for patients with MIBC who were unfit or refused RC.
Characteristics and outcomes for patients (pts) with metastatic small cell urothelial carcinoma (mSCUC).
Authors: Wilson Nathaniel R. , Khandelwal Jaanki , Xiao Lianchun , Shah Amishi Yogesh , Gao Jianjun , Goswami Sangeeta , Kovitz Craig A. , Guo Charles , Czerniak Bogdan , Logothetis Christopher , Corn Paul Gettys , Tannir Nizar M. , Siefker-Radtke Arlene O. , Alhalabi Omar
Published: March 2023

522

Background: mSCUC is an aggressive cancer with historically poor outcomes. Methods: We performed a retrospective analysis of 216 pts with mSCUC treated at MD Anderson from 1985-2020. We captured baseline demographic and clinical characteristics, metastatic sites, systemic treatments, and survival. Median overall survival (mOS) was calculated from start of frontline (1L) therapy for metastatic disease. Results: Median age was 67 years, 84% male sex, 91% primary tumor in bladder, and 88% white race. Histology included pure SCUC (30%), predominant SCUC (44%), focal SCUC (25%) and large cell (1%). Metastatic sites were lymph nodes (54%), bone/peritoneum (39%), liver (38%), brain (31%) and lung (26%). Brain metastases frequency varied across histology (pure SCUC 48%, predominant SCUC 24.5%, focal SCUC 24%, p=0.06). Treatment regimens and mOS by frontline regimen are listed (Table). mOS was 11.91 months for treated pts with sufficient follow up (n=155). mOS by 1L treatment: EP (9.51 months), IA/EP (14.10 months), other platinum chemotherapy (13.26 months), nonplatinum chemotherapy (9.74 months), immune checkpoint inhibitor (ICI) (6.51 months), EP+ICI (undefined). Of 140 pts treated with 1L chemotherapy, 43 (31%) were able to receive second line (2L) therapy. mOS among those who received 2L chemotherapy (n=27) was 13.65 months vs those who received 2L ICI (n=16) was 22.53 months (HR=0.53, 95% CI=0.26-1.10; p=0.11). Conclusions: mSCUC is a devastating malignancy with high degree of brain involvement, and poor prognosis. 1L ICI therapy alone has suboptimal survival outcomes and a chemotherapy backbone remains necessary. A deeper understanding of SCUC’s driver biology is essential for developing better therapies. [Table: see text]
Impact of neoadjuvant chemotherapy on pathological stage and survival in sarcomatoid bladder cancer.
Authors: Roy Arya Mariam , Jatwani Karan , Muthusamy Kumarasamy Vasanthan , Perimbeti Stuthi , Jiang Changchuan , Gupta Kush , Guru Khurshid , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

530

Background: Sarcomatoid bladder cancer is an extremely rare and aggressive histological variant with poor prognosis and limited consensus regarding its management given rarity and lack of high-quality data. Radical cystectomy (RC) is the mainstay of treatment in muscle-invasive disease and adjuvant therapy is often offered to eligible patients with high-risk features. Data regarding the role of neoadjuvant chemotherapy (NAC) for this variant is limited. Methods: The National Cancer Database was queried to identify patients diagnosed with sarcomatoid bladder cancer from 2004 to 2018. Patients older than 18 years with cT2-4aN0-1M0 sarcomatoid bladder cancer who received curative-intent surgery were included in the analyses. Clinical T4b/N2-3/M1 disease and receipt of adjuvant chemotherapy were employed as exclusion criteria. The population was divided into two cohorts based on the receipt of NAC. Chi-Square and Mann Whitney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed to adjust for confounding factors associated with overall survival. Models were adjusted for age, race, sex, income, stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 573 patients were identified - 70% were males and 93% were White; 139 (25%) received NAC (NAC+) while 434 (75%) did not (NAC-). NAC+ patients were younger (65 vs 71 years, p < 0.001). Downstaging to pT0-1N0 at the time of RC was significantly more frequent in the NAC+ group compared to the NAC- group (32 (24.5%) vs. 28 (6.8%), p = 0.001). Overall survival (OS) was also significantly longer in the NAC+ group (median of 40.8 vs. 19.4 months, log-rank p = 0.003). On multivariable analysis, NAC+ (Hazard Ratio (HR) = 0.73, 95% CI 0.56-0.91, p = 0.02), pathological downstaging to pT0-1N0 (HR = 0.5, 95% CI 0.31- 0.8, p < 0.001), and any pathological upstaging (HR 4.1, 95% CI 1.5-6.6, p < 0.001) were independently associated with all-cause mortality, while other factors were not (Table). Conclusions: In this large retrospective analysis, administration of NAC in muscle-invasive sarcomatoid bladder cancer was associated with higher rates of downstaging to non-muscle-invasive disease at the time of RC and reduced all-cause mortality. [Table: see text]
Association of biomarkers and outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICIs).
Authors: Reyes Kevin R , Zhang Li , Zhu Xiaolin , Jindal Tanya , Deshmukh Prianka , de Kouchkovsky Ivan , Kumar Vipul , Maldonado Edward , Kwon Daniel H , Chan Emily , Porten Sima P. , Borno Hala , Bose Rohit , Desai Arpita , Aggarwal Rahul Raj , Small Eric Jay , Fong Lawrence , Chou Jonathan , Friedlander Terence W. , Koshkin Vadim S
Published: March 2023

532

Background: ICIs form the backbone of treatment for mUC. However, only a minority of pts benefit and additional biomarkers of ICI response are needed. Methods: In our institution, we identified mUC pts treated with ICI monotherapy who had next generation sequencing (NGS). Somatic alterations present in ≥10% of pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), as well as DNA-damage response (DDR) alterations and tumor mutational burden (TMB) were analyzed as biomarkers. These biomarkers were individually evaluated in separate multivariate models while accounting for clinical factors including age, BMI, ECOG PS, primary tumor location, histology, hemoglobin, neutrophil to lymphocyte ratio and albumin. Multivariate cox regression and logistic regression models were used to measure hazard ratios (HR) and odds ratios (OR) for overall survival (OS), progression-free survival (PFS) and observed response rate (ORR). Results: Among 152 mUC ICI-treated pts, 107 had NGS data (FoundationOne, UCSF500, Strata), including 85 with TMB data. For the 107 pts with NGS, median age was 70 yrs, majority were male (69, 64%), Caucasian (70, 65%), had pure urothelial histology (57, 53%), and had first-line ICI (55, 51%). ORR was 35%, median PFS was 3.9 mos (95% CI: 2.6-7.5 mos), and median OS was 17.4 mos (95% CI: 14.1-30.6 mos). Biomarkers associated with improved outcomes to ICI, independent of relevant clinical factors, included alterations in ARID1A and DDR, as well as high TMB (>10 Mut/Mb). Inferior outcomes were seen in pts with CDKN2B, KDM6A, FGF3, FGF4, and FGF19 alterations (Table). Conclusions: In this large retrospective multivariate analysis controlling for clinical factors in ICI-treated mUC pts, we found multiple biomarkers associated with improved or inferior outcomes. These hypothesis-generating findings can inform clinical decision making and trial design for mUC pts treated with ICIs, and should be validated in larger cohorts. [Table: see text]
Germline mutational profile in metastatic urothelial malignancy.
Authors: Barry Emily , De Souza Andre Luiz , Holder Sheldon L. , Lagos Galina , Mega Anthony E. , Carneiro Benedito A. , Amin Ali
Published: March 2023

550

Background: 24% of patients with high-risk urothelial carcinoma have pathogenic germline mutations (Nassar, Genetics in Medicine 2020). In that study, demographics, metachronous/synchronous tumors, and family history did not differ between germline and sporadic cases of bladder cancer. We report herein the prevalence of actionable mutations and de novo metastatic disease in patients with germline mutations who developed metastatic urothelial carcinoma. Methods: We retrospectively analyzed a database of 90 patients with metastatic urothelial carcinoma (urethral, bladder, and upper tract disease) at our institution who had genetic testing performed on tumor specimens. T-student test was performed to calculate statistical significance for the distribution of age, while Chi-square test evaluated the frequency distribution of gender, actionable mutations, and de novo metastatic disease. Patients’ tumors were sequenced by a 700 gene panel for both somatic and germline mutations. Comprehensive chart review was performed to extract clinical data. Results: Out of the 90 patients reviewed, 11 (11.1%) had germline mutations. Of these patients, 5 had upper tract urothelial carcinoma, 5 had bladder cancer, and 1 had urethral cancer. Nine patients had pathogenic germline mutations: MUTYH, BRCA2 (each representing 1.8% of patients); APC, BRCA1, CDKN2A, FH, MSH2 (each representing 0.9% of patients). Two patients had germline mutations of unknown significance ( APC, CHEK2). Age (T-value 1.62053, p=1.08453), gender (Chi-square 0.0024, p=0.961037) or de novo metastatic presentation (Chi-square 0.5, p=0.4795) were not statistically significant between patients with germline and sporadic mutations. Somatic actionable mutations included ATR, BRCA2, BRAF, CDK12, ERBB2, FBXW7, FGFR3, HRAS, MTAP, and PIK3CA. Microsatellite instability high (MSI-H) status was only present in the patient with germline MSH2 mutation. PD-L1 expression was high (CPS ≥10) in 4 patients with germline mutations. Tumor mutational burden ranged from 1.1 to 28.4 mutations per Megabase. Conclusions: Our findings further define the clinical and genomic characteristics of patients with metastatic urothelial carcinoma and germline mutations in a tertiary center. Further investigation is warranted to validate these findings in national sequencing databases.
The genomic landscape of TERT alterations in bladder cancer.
Authors: Jalkanen Aimee , Basu Gargi D. , Hall David W. , Hoag Jess R , LoBello Janine R. , Baehner Frederick L. , Thakkar Snehal Govind , Dorff Tanya B.
Published: March 2023

551

Background: Some of the most common mutations seen across cancers occur in TERT, where promoter mutations upregulate TERT transcription. In bladder cancer, TERT mutations are associated with poor prognosis, especially for recurrence. In this study, we identified TERT promoter mutations in bladder cancer and determined whether mutations at other genes were significantly associated. We also examined whether TERT mutation frequency is associated with age or gender. Methods: We utilized the Oncomap ExTra genomic profiling assay to identify alterations. This assay performs tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations. In addition to the exome, several noncoding regions are sequenced, including the TERT promoter. Single-nucleotide variants, indels, copy number alterations, alternative transcripts, and gene fusions are all detected. Tumor mutational burden (TMB) and microsatellite instability (MSI) are also calculated. Results: Of 194 bladder cancer patient specimens assayed between April 2018 and August 2022, 153 (78.9%) carried a TERT promotor mutation (Table). The C228T and C250T single base substitutions were the most common, at 57.7% and 15.5%, respectively. Of note, one patient had a TERT fusion caused by an inversion involving MARCHF6 as the partner gene. Many patients harbored mutations in other genes, with two possibly associated with TERT status: BRCA2 was mutated in 6 (3.9%) TERT-mutated and 7 (17.1%) TERT-wild type patients (Fisher’s Exact Test, p=0.007), and FGFR3 was mutated in 33 (21.6%) TERT-mutated and 3 (7.3%) TERT-wild type patients (p=0.042). In addition, TMB-high was in 93 (60.8%) TERT-mutated and 10 (24.4%) TERT-wild type patients (p=0.071). None of these associations were significant after correcting for the false discovery rate. There was no significant difference in median (or average) age of individuals with versus without a TERT mutation (71.0 and 70.0 yrs, respectively). In addition, there was no significant difference in frequency of TERT alterations in males (82.0%) versus females (70.9%). Conclusions: The Oncomap ExTra assay allowed identification of both commonly observed and rare TERT promoter mutations, including a fusion, in 78.9% of bladder cancer patients. Such assays are useful to identify both TERT alterations prognostic for progression and patients eligible for clinical trials evaluating TERT-directed therapies. In addition, TERT mutations may be associated with FGFR3 mutations and high TMB, which have matched therapies, though these associations need to be validated in an independent cohort. [Table: see text]
Differential treatment response of prostate and metastatic lesions in patients with newly diagnosed metastatic prostate cancer.
Authors: Esen Baris , Seymen Hulya , Falay Okan , Tarim Kayhan , Kılıç Mert , Bavbek Sevil , Kordan Yakup , Tilki Derya , Esen Tarik , Demirkol Mehmet Onur
Published: March 2023

56

Background: We aimed to evaluate the response of primary tumor to systemic treatment in patients with newly diagnosed mPCa with serial PSMA PET/CT scans. Methods: A total of 43 patients with newly diagnosed mPCa who had significant prostatic PSMA uptake at baseline PSMA PET/CT (bPSMA) and underwent at least one follow-up PSMA PET/CT (fPSMA) after receiving systemic treatment were included in the study. Those who received any definitive treatment at localized stage and those who underwent radiotherapy to prostate before fPSMA were excluded. Prostatic and metastatic PSMA response after systemic treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) as recommended by guidelines. Discordant behavior between prostate and metastases was defined as the condition when metastatic lesions are responding (CR or PR) to systemic treatment while prostate had progressed or vice versa. CHAARTED criteria was applied to categorize patients according to the volume of metastatic disease. Results: The mean age of patients at bPSMA was 67.7 ± 8.5 years. The median PSA at bPSMA was 31.7 ng/dL (IQR: 11.3 – 106.0). Patient characteristics and treatments are summarized. The median time interval between bPSMA and the first fPSMA was 5.7 months (IQR: 4.6 – 7.5). Nine patients (20.9%) had CR, 25 (58.1%) had PR, 5 (11.6%) had SD and 4 (9.3%) had PD at prostate following systemic treatment. Patients with low-volume disease had prostatic CR twice more commonly than those with high-volume disease (27.3% vs 14.3%). In 6 (13%) cases, a significant PSMA uptake at prostate was detected despite a complete response of all metastatic sites. Discordant treatment responses at the prostate and metastatic sites were observed in 6 out of 43 (16%) patients. Conclusions: Discordant behavior between prostate and metastases are not rare in mPCa. Almost one-fourth of patients with low-volume mPCa achieved a complete prostatic response with systemic treatment only. Prostatic response on PSMA PET/CT following systemic treatment can be used to select ideal patients for the treatment of the primary tumor in patients with mPCa. [Table: see text]
Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A).
Authors: Atkins Michael B. , Jegede Opeyemi , McDermott David F. , Haas Naomi B. , Bilen Mehmet Asim , Stein Mark N. , Sosman Jeffrey A. , Plimack Elizabeth R. , Alter Robert S. , Ornstein Moshe Chaim , Hurwitz Michael E. , Peace David J. , Einstein David Johnson , Catalano Paul J. , Hammers Hans J. , Regan Meredith M.
Published: March 2023

604

Background: Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Toxicity from therapy can also persist after cessation. TFS with and without toxicity can characterize survival time. Significant TFS was reported for CheckMate 067 trial in pts with metastatic melanoma (Regan et al JITC 2021) and CheckMate 214 trial for pts with aRCC (Regan et al CCR 2021), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16 260 trial, which was designed to reduce toxicity and to cap immunotherapy duration (Atkins et al JCO 2022). Methods: Data were analyzed from 128 patients (pts) with clear-cell aRCC treated with first-line nivolumab (NIVO) monotherapy for up to 2 years. As part of the protocol, salvage nivolumab/ipilimumab (NIVO/IPI) for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (28% of pts). TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, estimated from 36-month (mo) mean times. The time on treatment or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured. Results: At 36 mos from enrollment, 68.3% of pts were alive: 96.8% of IMDC favorable-risk (FAV) pts and 56.6% of those with intermediate/poor-risk (I/P), respectively. The 36-mo mean time on protocol therapy was 11.5 mos (16.0 mos for FAV pts and 9.6 mos for I/P pts). The 36-mo mean TFS for the whole population was 9.4 mos. For FAV pts the mean TFS was 12.9 mos, of which TFS with grade 3+ TRAEs was 1.5 mos. For I/P pts, the mean TFS was 8.0 mos, of which TFS with grade 3+ TRAEs was 1.0 mos. At 36 mos, 65.6% of FAV pts and 27.1% of I/P pts were alive and second-line treatment-free. Conclusions: NIVO monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve pts with aRCC and results in substantial TFS and toxicity-free TFS. TFS was particularly noted in pts with FAV disease, further supporting the use of an immunotherapy-only regimen in this population. Clinical trial information: NCT03117309 . [Table: see text]
Evaluation of eligibility criteria in contemporary renal cell carcinoma based on ASCO-FCR recommendations.
Authors: Prajapati Sweta R. , Feng Matthew I. , Castro Daniela V. , Lee Kyle O. , Chan Elyse H. , Sehgal Ishaan , Patel Jalen , O'Dell Anna , Zengin Zeynep Busra , Li Xiaochen , Chehrazi-Raffle Alex , Dizman Nazli , Tripathi Abhishek , Rock Adam , Liu Sandy , Mercier Benjamin D. , Meza Luis A , Philip Errol James , Dorff Tanya B. , Pal Sumanta Monty
Published: March 2023

612

Background: A consensus statement from the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FCR) collaboration highlights the importance of expanding eligibility criteria in cancer trials to more accurately reflect the real-world population (Kim et al., Clin Cancer Res 2021). We sought to characterize use of overly restrictive eligibility criteria in renal cell carcinoma (RCC) trials in the context of ASCO-FCR recommendations. Methods: Studies containing the MeSH terms “(metastatic OR advanced OR stage IV or unresectable) AND (kidney cancer OR renal cell carcinoma OR renal cell cancer)” from June 30, 2012 to June 30, 2022 were identified on the ClinicalTrials.gov platform. Our search query’s inclusion criteria identified international studies examining adult patients aged ≥ 18 in phase I-III trials. Exclusion criteria comprised pan-cancer studies, trials involving localized treatments, radiation therapy, and prognostic tools. Descriptive statistics were used to characterize the frequency of restrictive eligibility criteria across studies, while Fisher’s exact test or chi-square test were utilized to determine the association between treatment type and exclusion criteria. Results: The content of 423 RCC trials were analyzed, of which 112 (26.5%) had adequate data available. 48 (42.9%), 44 (39.3%) and 18 (16.1%) studies examined combination therapy, targeted therapy, and immunotherapy, respectively. The presence of HIV positivity, HBV/HCV positivity, brain metastases, and concurrent malignancies accounted for the most frequently cited exclusionary criteria, seen in 83/112 (74.1%), 60/112 (53.6%), 37/112 (33.0%), and 9/112 (8.0%) studies respectively. Differences in the use of HIV positivity (p<0.001) and HBV/HCV positivity (p<0.001) as eligibility criteria were observed across classes of therapy (see Table). Conclusions: A significant proportion of RCC studies utilize overly restrictive eligibility criteria as highlighted by the ASCO-FCR joint statement. Appropriate broadening of eligibility criteria to incorporate patient populations mirroring a real-world setting will provide more useful data going forward. [Table: see text]
Estimated cost of adverse event (AE) management for patients (pts) with metastatic renal cell carcinoma (mRCC) treated with a VEGFR TKI.
Authors: Yorio Jeffrey Thomas , Asnis-Alibozek Aviva G. , Kasturi Vijay , Hutson Thomas E.
Published: March 2023

629

Background: Nearly all mRCC pts will be treated with one or more VEGFR TKI, alone or in combination with an immunotherapy (IO) or mTOR-inhibitor, during their therapeutic journey and may experience associated AEs. Evidence from the tivozanib (tivo) TIVO-3 trial suggests that median duration of clinically relevant VEGFR TKI class effect AEs is ≤90 days (range 14-90). Cost of AE management has not been clearly quantified to date. This study aimed to estimate how differences in TKI AE profile may impact treatment cost efficiency, particularly in later line (3L+) settings. Methods: iKnowMed EMR was used to identify mRCC pts from USON or Onmark Network, with matched 3rd party insurance claims, that initiated VEGFR TKI treatment between Jan 2015 and Mar 2021. First occurrence of each VEGFR TKI class effect AE was indexed, and associated costs for 90-day (longest median AE duration) follow-up was captured. To assess burden across different TKIs, average per-patient AE management cost was calculated using incidence data from trials supporting FDA approvals, and weight-adjusted to estimated number of commercially insured 3L/4L pts in a 1,000,000-member plan. Results: 5,958 mRCC pts were identified, of which 4,464 were on at least one TKI regimen. Among those, 1,777 experienced an index AE; 1,072 successfully matched to claims data [median 69 years (range 25-94); 55% ECOG PS 0/1; 69% male], accounting for 1,667 unique index AE cases. Most were on cabozantinib (cabo), axitinib (axi), or pazopanib; lenvatinib (len), sunitinib (sun), and sorafenib were also represented. >80% were TKI only, with the rest TKI+IO (18%) or TKI+mTOR (6%). AE costs largely originated from outpatient visits (range 38-77%), excluding renal failure (58% inpatient). Mean cost per AE ranged from $76 (proteinuria) to $1,687 (mucositis/stomatitis). Overall, estimated costs of managing VEGFR TKI class effect AEs in 3L/4L showed lowest resource burden with tivo, and highest with len+everolimus (len+ev; Table). Conclusions: Average VEGFR TKI AE management costs derived from real-world mRCC pts demonstrated differences in healthcare resource burden, with overall anticipated cost dependent on TKI regimen utilized. [Table: see text]
Evaluation of deep learning techniques (DL) in RNA sequencing data for the prediction of response to immune checkpoint inhibitors in patients with metastatic renal cell cancer m(RCC).
Authors: Alonso Paz Sandra , Duran Ignacio , Grande Enrique , Pinto Alvaro
Published: March 2023

641

Background: Immune checkpoint inhibitors have become a cornerstone in the management of mRCC. However, to identify the most suitable patients for this treatment is an unmet medical need. We aimed to explore the utility of DL integrating clinical and molecular data to predict response to immunotherapy. Methods: We conducted a retrospective analysis using publicly available data from patients treated with nivolumab in the clinical trials Checkmate 009, 010 and 025. The primary objective was to assess the performance of different DL models (autoencoder and convolutional neural network (CNN)) predicting the PFS of these patients. With that scope, we followed several research lines including the creation of combined datasets with clinic and RNA sequencing and comparing the results of the DL models against the performance of traditional machine learning (ML) models. Finally, we came up with an interpretability analysis of those black-box models using LIME and SHAP values. Results: Clinical and transcriptomic data were available from 181 nivolumab-treated patients. Outcomes achieved confirmed that we can model the response for NIVOLUMAB using RNA sequencing data. (Table) However, DL models have not demonstrated to be significantly better than traditional ML methods when predicting response (p= 0.068). Deep autoencoder provided 68.9% accuracy, but the most accurate model was logistic regression classifier which achieved 86.4% of hit rate. Interpretability results revealed that most relevant genes for the decision making were related with the immune response and the regulation of kinases. Regarding interpretability, best results were achieved integrating both transcriptomic and clinical data (7 out of 10 DL and ML tested models achieved higher hit rates with combined data set. Logistic regression classifier improved its accuracy in 11%). Conclusions: The integration of clinical and molecular data could lead to more accurate predictions of outcome than any dataset by its own. However, further research is intended in the field of the DL analysis, as data codification and data structure could bias the results. The ongoing study ART (Artificial Intelligence in Renal Tumors) will address this issue prospectively. [Table: see text]
Cabozantinib in the elderly with metastatic renal cell carcinoma undergoing geriatric G8 screening test: A prospective multicenter observational study (ZEBRA/MEET-URO 9).
Authors: Basso Umberto , Buti Sebastiano , Verzoni Elena , Sorarù Mariella , Di Napoli Marilena , Fratino Lucia , Santini Daniele , Grillone Francesco , Chiuri Vincenzo Emanuele Emanuele , Carella Claudia , Atzori Francesco , Roviello Giandomenico , Sartori Donata , Maruzzo Marco , Pierantoni Francesco , Bersanelli Melissa , Ballestrin Melissa , De Toni Chiara , Mattana Alvise , Zagonel Vittorina
Published: March 2023

647

Background: Cabozantinib (CABO) is an oral tyrosine kinase inhibitor registered for the treatment of metastatic renal cell carcinoma (mRCC) for the first or subsequent lines. Tolerability in real world elderly patients is poorly documented. G8 is a short test for vulnerability gaining increased interest as a screening tool for trials in geriatric oncology. Methods: ZEBRA/MEET-URO 9 was a prospective multicenter study of safety and activity of CABO administered to pts ≥70 years with mRCC, either in the first or subsequent lines of treatment, until progression or unacceptable toxicity. All pts underwent G8 score at baseline, with a cut-off for vulnerability of 14 or below. Data on tolerability and activity were collected prospectively after signature of informed consent. Results: A total of 104 pts started CABO at 13 Italian Centers, 38,5% as first line. Median age was 75.8 yrs (range 70.2-87.4 yrs, 26 pts ≥80 yrs), 73.1% males. IMDC score was good 19.2%, intermediate 53.9%, poor 26.9%. Primary tumor had been removed in 82.7% of pts, histology was clear cell 78.8%, papillary 8.7%, chromophobe 5.8%, unclassified 6.7%. G8 score was ≤14 in 65.4% of pts. Up-front dose reduction of CABO was more frequent in pts with low G8 score (79.4 vs 41.7%, p=0.003), but eventually the majority of pts (91.4%) underwent dose reductions of CABO. After a median treatment of 6.4 months (0.5-26.1 months), 38.4% of pts developed G3-4 toxicities, 22.1% interrupted treatment due to adverse events, 2.8% (3 pts) died due to cardiovascular or thromboembolic events. Median PFS was 7.6 months (95% CI=5.8-12.6 months) in first line, 10.0 months (5.8-15.6) in second or further lines, median OS was 20.1 months (11.1-not reached) and 15.6 months (12.5-not reached), respectively. G8 score ≤14 did not correlate with rate of temporary interruptions >7 days, hospitalization, incidence of G3-5 toxicities, as well as with PFS. Pts with G8 score ≤14 had a trend for reduced OS, but difference was not statistically significant both in the first and further lines of treatment. Conclusions: Screening G8 test was positive in more than a half of pts, underlying the need for detailed geriatric assessment and increased clinical monitoring of such patients. A G8 score ≤14 correlated with up-front dose reduction of CABO but not with G3-5 toxicities probably due to the high rates of dose reductions in the whole cohort. Correlation between low G8 score and OS could not be demonstrated in this population.
Characterization of clinical outcomes among patients with advanced chromophobe renal cell carcinoma (ChRCC) treated with first-line immunotherapy (IO)-based regimens.
Authors: Labaki Chris , Bakouny Ziad , Wells J Connor , Takemura Kosuke , Saliby Renee Maria , Meza Luis A , Gebrael Georges , Porta Camillo , Lee Jae-Lyun , Basappa Naveen S. , De Velasco Guillermo , McKay Rana R. , Pal Sumanta Monty , Agarwal Neeraj , Donskov Frede , Braun David A. , Henske Elizabeth , Xie Wanling , Heng Daniel Yick Chin , Choueiri Toni K.
Published: March 2023

654

Background: IO-based regimens have demonstrated substantial efficacy in the management of metastatic clear-cell RCC (mccRCC), where they currently represent the standard of care. ChRCC has a dismal prognosis in the metastatic setting. Recent clinical trials evaluating IO-based regimens across non-ccRCC subtypes identified a preliminary poor response in advanced ChRCC, but were limited by low sample sizes. We sought to comprehensively evaluate the outcomes of patients with ChRCC treated with IO-based regimens. Methods: Using real-world data from the International Metastatic RCC Database Consortium (IMDC), we conducted a retrospective analysis of patients with advanced ChRCC who received IO-based therapies, including dual IO therapy or IO + VEGF targeted therapy (VEGF-TT), in the first-line setting. The primary outcome was overall survival (OS). Secondary outcomes included time to treatment failure (TTF) and ORR. Cox proportional hazards models were used to adjust for age and IMDC risk groups as covariates. A logistic regression was used to determine the association between the odds of achieving a response and RCC subtype. Results: We identified 31 patients with advanced ChRCC and 856 patients with ccRCC treated with IO-based therapies in the first-line setting, with a median age of 61.5 years (IQR: 51.5-69.0). Compared to patients with ccRCC who received IO-based therapies as initial regimens, patients with ChRCC had a lower OS (median OS: 24.7 vs. 50.5 months, respectively; p<0.001) and a lower TTF (median TTF: 4.5 vs. 11.0 months, respectively; p<0.001). Among patients with an evaluable objective response, the ORR was lower among patients with advanced ChRCC, as opposed to those with ccRCC (ORR: 12.0 vs 47.1%, respectively; p<0.001). When evaluating first-line treatment with VEGF-TT monotherapy (sunitinib or pazopanib), no difference in outcomes was found between patients with ChRCC (n=122) and ccRCC (n=6,379) in relation to the primary endpoint of OS, while TTF and ORR suggested better outcomes for ccRCC (Table). Conclusions: In this real-world study, patients with metastatic ChRCC appear to display poor clinical outcomes even with IO-based regimens, as compared to ccRCC. The molecular determinants of poor response require further investigations. [Table: see text]