bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective exploratory clinical study of penpulimab plus anlotinib as first-line treatment for locally advanced or metastatic urothelial carcinoma.
Authors: Yang Bo , Xiong Qi , Song Qi , Long Yaping , Guo Gang , Li Hongzhao 
Published: June 2022

4567 Background: A high unmet need remains for first-line cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC).Immune checkpoint inhibitors have been implemented in the management of cisplatin-ineligible la/mUC. Penpulimab is a programmed death 1 (PD-1) inhibitor which had approved by the Chinese National Medical Products Administration (NMPA) on August 2021. Anlotinib is a novel oral multi-target tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. The current prospective single-arm phase Ⅱ clinical trial (ChiCTR1900028022) aimed to assess the efficacy and safety of penpulimab plus anlotinib as first-line therapy for la/mUC. Methods: Patients (pts) who had no prior systemic therapy and at least one measurable lesion according to RECIST v1.1 with histologically or cytologically confirmed locally advanced unresectable or metastatic urothelial carcinoma (including unresectable or metastatic urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis), 18-75 years, ECOG 0-2, were considered eligible for enrollment. Patients received 200 mg penpulimab intravenously on day 1 plus anlotinib, 8 mg oral daily for days 1-14 of a 21-day cycle until confirmed disease progression, intolerable toxicity, physician/patient decision to withdraw, or completion of 24 months of treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec. 2021, 10 pts were enrolled, 9 pts had the best overall response assessments which inferred the ORR of 66.7%（95% CI, 29.9-92.5）and the DCR of 88.9% (PR in 6 pts and SD in 2 pts; 95% CI, 51.8-99.7). The median PFS was 8.2 months（(95% CI, 8.0-8.4). Any grades of adverse events (AEs) were observed in 90% (9/10) of pts, containing hyperthyroidism (33%), Creatinine increased (33%),haematuria (22%), anaemia (22%), hypertension (11%), fatigue (11%). High grade AEs of grade Ⅳ liver dysfunction were observed in one patient (11%). Conclusions: An effective treatment strategy for cisplatin-ineligible patients and for patients unable to receive chemotherapy is an important unmet clinical need. Penpulimab in combination with anlotinib in pts with la/mUC showed encouraging efficacy and satisfactory safety. Clinical trial information: ChiCTR1900028022.
Benchmarking maintenance therapy survival in first-line advanced urothelial carcinoma using disease modeling.
Authors: Galsky Matt D. , Wirtz Heidi , Bloudek Brian , Hepp Zsolt , Timmons Jack , Lenero Enrique , Powles Thomas 
Published: June 2022

4575 Background: First-line (1L) maintenance avelumab (maintA) in patients with advanced urothelial carcinoma (aUC) prolonged overall survival (OS) in the JAVELIN Bladder 100 trial. JAVELIN measured OS from the initiation of maintA among a subgroup of the overall aUC 1L treated population, including only patients who did not progress with 1L platinum-based therapy (PBT) and remained progression free during a 4-10 week treatment-free interval following completion of 1L PBT. As such, patients who progressed on or immediately following PBT were not included in the trial. To address this, we used disease modeling to estimate maintA OS measured from initiation of 1L PBT to align maintA OS with the common initiation point to benchmark with other 1L clinical trials. Methods: We developed a simulated cohort to estimate OS from initiation of 1L PBT in all aUC patients including those who received maintA. Eligibility for maintA (PBT progressed vs not progressed) was assessed at 5.6 months post-initiation of 1L PBT, accounting for 6 PBT cycles and a nominal 6-week treatment-free interval. Median OS of 14.3 months from the 1L PBT arm of a recent 1L trial, KEYNOTE-361, was used to represent the OS of the simulated cohort of 1L aUC patients. The simulated cohort was stratified by eligibility for maintA. Among the 1L treated population, 57% were projected to be progression-free and eligible for maintA based on progression-free survival (PFS) from KEYNOTE-361. Among those eligible, 85% were assumed to receive maintA based on expert clinical input. OS of maintA eligible patients was 21.4 months from JAVELIN. Our disease model estimated OS among a maintA ineligible simulated cohort, which was combined with the maintA eligible cohort to yield an estimated OS in the overall aUC population measured from initiation of 1L PBT. Results: Approximately 50% of the 1L modeled population receive maintA (i.e., 57% eligible x 85% treated). Our approach estimated a median OS of 9.9 months for the maintA ineligible cohort and 27.0 months for the maintA eligible cohort. Combined, the estimated median OS with maintA, measured from initiation of 1L PBT, in all 1L-treated aUC patients was 15.8 months (vs 14.3 months with PBT only in 1L). Conclusions: MaintA improves OS for eligible patients, however our simulation model suggests a significant proportion of patients will not receive MaintA. The estimated OS of 15.8 months for the population-level impact of maintA, accounting for patients ineligible for 1L maintA, demonstrates remaining unmet need in the overall 1L aUC population.
Phase Ib study of avelumab and novel AXL inhibitor avb-S6-500 in patients with metastatic urothelial carcinoma (mUC).
Authors: Tripathi Abhishek , Clingerman Melissa , Fabreo Riza Celine , Ayanambakkam Adanma , Cross Brian , Stratton Kelly Lynn , Cookson Michael , Pal Sumanta K. , Agarwal Neeraj 
Published: June 2022

4579 Background: AXL is a member of the mammalian Tyro3/AXL/Mer (TAM) receptor tyrosine kinase family, which upon binding to its ligand Gas6 promotes immunosuppression in the tumor microenvironment. AVB-S6-500 (AVB) is a novel AXL pathway inhibitor which binds to circulating Gas6 and inhibits ligand-dependent AXL signaling. In this phase Ib investigator-initiated trial (NCT04004442), we evaluated the safety, tolerability, pharmacodynamics, and preliminary antitumor efficacy of AVB with the anti-PD-L1 antibody avelumab in mUC. Methods: Patients with PD-1/L1 inhibitor naïve locally advanced unresectable or mUC with measurable disease were eligible if they were either in-eligible for, refractory to, or declined platinum-based chemotherapy. Employing a 3+3 dose escalation design, patients were treated with AVB 5mg/kg weekly (dose level; DL1), or 10 (DL2), 15 (DL3), or 20 (DL4) mg/kg every two weeks along with avelumab 800 mg every 2 weeks administered intravenously. The safety and tolerability of the combination as measured by the incidence of dose limiting toxicities (DLTs) was the primary endpoint while objective response rate (ORR) per RECIST 1.1 was key secondary endpoint. Pharmacodynamic studies evaluated baseline and on therapy (C2D1) Gas6 levels. Results: To date, a total of 15 patients have been enrolled (DL1: n = 3, DL2: n = 7, DL3: n = 3 and DL4: n = 2). Among the 13 evaluable patients, DLT was observed in 1 patient (grade 3 fatigue; DL2). Grade ≥3 adverse events irrespective of attribution were seen in 6 patients which included UTI (n = 3), hyponatremia (n = 1), elevated creatinine (n = 1), and anemia, thrombocytopenia, hematuria, anorexia and sepsis (n = 1 each; all in same patient). No treatment related deaths were noted. While enrollment on DL4 is ongoing, the maximum tolerated dose for AVB has not been reached. Treatment with AVB effectively suppressed circulating Gas6 levels from baseline (median: 28.4 ng/mL; range: 20.4-54.0 ng/mL) to below threshold of detection in 85% (n = 11/13) of patients. Median follow up was 10 months (95% CI: 3.9, 18.55). Confirmed ORR was 38% (n = 5/13) while 1 patient had stable disease as best response. Durable responses lasting > 6 months were seen in 3 patients (7, 19 and 21 mos) who continue to be on treatment without disease progression. Additional correlative studies investigating AXL, Gas6, PD-L1 expression and gene expression signatures are currently underway. Conclusions: Concurrent avelumab and AVB was safe and AVB effectively neutralized circulating Gas6 across DLs. Albeit small sample size, the efficacy of the combination was encouraging and ORR compares favorably to that previously reported with PD-1/L1 inhibitor monotherapy. Updated safety, efficacy and biomarker data will be presented. Clinical trial information: NCT04004442.
S1314 correlative analysis of ATM, RB1, ERCC2, and FANCC mutations and pathologic complete response (pT0) at cystectomy after neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC): Implications for bladder preservation.
Authors: Plimack Elizabeth R. , Tangen Catherine , Plets Melissa , Kokate Rutika , Xiu Joanne , Nabhan Chadi , Ross Eric A. , Grundy Erin , Choi Woonyoung , Dinney Colin P.N. , Lee I-Ling C. , Lucia Scott , Flaig Thomas W. , McConkey David James 
Published: June 2022

4581 Background: SWOG S1314 (NCT02177695) was designed to validate the CoXEN classifier as a predictive biomarker in pts undergoing cystectomy after NAC. We repurposed banked DNA samples and prospective trial data from S1314 to further validate the predictive ability of the Philadelphia 4 gene signature (P4GS: any mutation in ATM, RB1, FANCC, ERCC2) to predict pT0 as previously reported (PMID: 26238431) and used in the RETAIN trial (NCT02710734). The RETAIN trial prospectively enrolled pts to receive NAC (DDMVAC) followed by allocation to bladder observation vs. intervention (cystectomy or RT) based on clinical evaluation and presence vs absence of P4GS. The primary objective of this correlative investigation was to determine whether presence of P4GS is predictive of pT0 at surgery. Methods: Eligibility for S1314 included cT2-T4a N0 M0 MIBC, cisplatin eligible, with plan for cystectomy; 237 pts were randomized between ddMVAC and gem/cis (GC) using standard dose/schedule. Of 167 pts who were evaluable for the original COXEN analysis (received 3+ cycles of chemo and evaluable for path response) adequate banked DNA was available for 105. Next-generation sequencing using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ) was performed. Pathogenic mutation or VUS of ATM, RB1, FANCC or ERCC2 was noted as present or absent for each pt and correlated with pT0 using logistic regression, adjusting for clinical stage. Results: Among the 105 pts, 51% ddMVAC, 49% GC. 15% female, 95% white, 15% clinical stage T3/T4a Prevalence of mutations: ATM (24%), ERCC2 (17%), FANCC (4%), RB1 (24%) and any variant 53%. Presence of any mutation correlated with pT0 (p = 0.0006), sensitivity 79%, specificity 59%. This association did not vary by treatment arm (MVAC vs. GC). The table below shows the contributions of each of the 4 genes with the greatest contribution from ATM and ERCC2. FANCC was non-contributory due to low prevalence. Conclusions: Patients with a mutation in ATM, RB1, FANCC or ERCC2 (P4GS) have a statistically significantly higher odds of a pT0 with GC or MVAC compared to those who do not have any variant. This signature was used to prospectively allocate patients to bladder observation as part of the RETAIN trial previously reported (ASCO GU 2021). RETAIN completed enrollment, final analysis of the primary endpoint – 2-year metastasis free survival – is expected later in 2022. Clinical trial information: NCT02177695.
Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle-invasive bladder cancer who are cisplatin-ineligible.
Authors: Petrylak Daniel P. , Flaig Thomas W. , Mar Nataliya , Gourdin Theodore Stewart , Srinivas Sandy , Rosenberg Jonathan E. , Guseva Maria , Yu Yao , Narayanan Sujata , Hoimes Christopher J. 
Published: June 2022

4582 Background: Up to 25% of all patients (pts) diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with muscle invasive bladder cancer (MIBC). Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit previously treated locally advanced or metastatic urothelial cancer pts in phase 2 and 3 trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (ypT0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating EV in MIBC. Clinical trial information: NCT03288545.
Clinical utility of urine DNA for noninvasive detection and minimal residual disease monitoring in urothelial carcinoma.
Authors: He Zhisong , Hu Hailong , Niu Yuanjie , Guo Zhaoxia , Ding Feng , Wang Yunkai , Wang Wang , Zhou Tao , Cao Shanbo , Lou Feng , Wang Huina 
Published: June 2022

4583 Background: Current methods for the early detection and minimal residual disease (MRD) of urothelial carcinoma (UC) are often invasive and/or possess sub-optimal sensitivity, especially in upper tract urothelial carcinoma (UTUC). Methods: We developed an efficient workflow named the urine tumor DNA multidimensional bioinformatic predictor, utLIFE, by using low-coverage whole-genome sequencing and targeted deep sequencing. We identified the UC specific mutations and large CNV in the discovery cohort. The utLIFE-UC model was trained in a bladder cancer retrospective cohort (n = 150) and validated in an bladder cohort(n = 674) and UTUC cohort(n = 22). 31 patients established diagnosis of BC who are on neoadjuvant were also enrolled, including a MRD training cohort (n = 16) with serial urine samples at baseline, during treatment and before surgery; a independent MRD validation cohort (n = 15) with urine samples before surgery. Results: The utLIFE-UC model could discriminate UC with high accuracy (94.3%), sensitivity (92.8%), and specificity (96.0%). Furthermore, compared to cytology, the assay achieved a great improvement in sensitivity in the detection of non–muscle-invasive bladder cancer (NMIBC, 94.7% vs. 31.6%,p = 0.0002), and muscle-invasive bladder cancer(MIBC, 82.6% vs. 69.6%, p = 0.4894). The utLIFE-UC model was also validated in independent BC cohort (sensitivity 94.3%, specificity 92.6%) and UTUC cohort (sensitivity 90.9%, specificity 90.9%). utLIFE-UC score also showed outstanding potential on dynamic surveillance of residual disease in UC as the score showed dramatically decreased in pCR patients. As expected, utLIFE-UC score could classify pCR and non-pCR(PR, SD, PD) with NPV 100% in MRD training and validation cohorts, which showed superior sensitivity over that of urine cytology (100% vs.37.5%, p = 0.0070) and FISH (100 vs. 42.9%, p = 0.0125). Conclusions: utLIFE-UC diagnostic model for early diagnosis, residual disease detection in UC is a cost-effective, rapid, high-throughput, noninvasive, and promising approach, which may reduce the burden of cystoscopy and blind surgery.
Chemotherapy with significant mortality benefit in patients with bladder cancer with variant and non-urothelial histologies (NUVH).
Authors: Perimbeti Stuthi , Jiang Changchuan , Deng Lei , Roy Arya Mariam , Gupta Shilpi , Kambam Greeshma , Chatta Gurkamal S. , George Saby , Gopalakrishnan Dharmesh 
Published: June 2022

4586 Background: Non urothelial cancers and urothelial cancers with variant histologies(NUVH) have a more aggressive natural history and are at a higher risk of progression to muscle invasive disease(MIBC) when compared to their urothelial counterparts. Although surgical resection is the treatment of choice in localized disease, radiation(RT) is commonly used in patients who are not surgical candidates. The use of chemotherapy has shown modest benefit in some retrospective studies. Considering the low incidence of NUVH, there are no large-scale studies examining the benefits of chemoradiation(CRT) in MIBC with NUVH. Methods: The National Cancer Database was queried to identify MIBC patients with NUVH from the years 2004-2018.Inclusion criteria for the study are age > 18 years, Non urothelial or variant histologies and receipt of RT. Patients who underwent cystectomy or had metastatic disease were excluded. The population was divided into two cohorts if they received chemoradiation. Chi-Square test and Mann Whitney U tests were used to compare frequency distributions. Cox proportional Hazard regression was employed to control for confounding factors associated with overall survival. Covariates for confounding included age, race, sex, income, insurance status, charlson-deyo comorbidity index, education. Results: Among 1773 observations in the final analysis, 63.05%(n = 1118) received CRT. Small cell, large cell and neuroendocrine cancers composed of the majority of NUVH. 38.01% (n = 641). Other histologies composed of squamous cell cancer 30.34%(n = 538), spindle cell/sarcomatoid cancers10.15%(180), adenocarcinoma 11.44%(203). Patients who received CRT were found to be significantly younger (76 vs 82 years P: < 0.0001) with higher male predominance74.73%. 5 year overall mortality was significaantly lower in the CRT vs RT group ( 66.47% vs 81.55%, p < 0.001). After controlling for confounding factors, CRT was associated with lower risk of mortality Hazard Ratio(HR)of 0.41(0.36-0.47) p < 0.0001. Added, the survival benefit of CRT continued in the non small cell variant cohort HR: 0.43(0.37-0.51) P < 0.0001. Conclusions: In this large retrospective study, CRT was associated with reduced overall mortality among patients with non-urothelial MIBC. The findings suggest the importance of systemic therapy in providing a survival advantage to non-urothelial MIBC, including the non-small cell variants. [Table: see text]
Efficacy of hyperthermic-intra-vesical chemotherapy in patients with BCG-refractory nonmuscle-invasive bladder cancer.
Authors: Pignot Geraldine , Lorusso Vito , Doisy Laure , Guerin Mathilde , Vicier Cecile , Dermeche Slimane , Branger Nicolas , Maubon Thomas , Rybikowski Stanislas , Walz Jochen , Gravis Gwenaelle 
Published: June 2022

4592 Background: In Bacillus Calmette-Guérin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the standard of care. For patients unwilling or unable to undergo cystectomy, alternative intravesical therapies are currently being investigated to minimize the risk of recurrence and progression. Chemohyperthermia by HIVEC (Hyperthermic-Intra-Vesical Chemotherapy) is a therapeutic option in BCG-refractory patients. The objective of our study was to evaluate the 2-year oncological results of HIVEC in BCG-refractory patients. Methods: Between June 2016 and September 2021, patients treated with HIVEC (6 weekly instillations) for BCG-refractory NMIBC were prospectively included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints were 6-month complete response rate for Cis, 1-year overall and cancer-specific survival rates and bladder preservation rate. Results: Seventy patients, mean age 70 [42-89] years, were treated consecutively. After a mean follow-up of 20.9 months, 32 patients recurred (mean time of 10.6 months) and 7 patients finally had a cystectomy. The recurrence-free survival rate was 53.1% at 1 year and 20.5% at 2 years. Six patients progressed to a muscle-invasive disease, after a mean delay of 6.7 months. Four of them experienced metastatic progression and died from bladder cancer. Cancer-specific and overall survival rates were 95.1% and 92.9% at 1 year, and 87.5% and 77.8% at 2 years. The bladder preservation rate was 90%. For patients with Cis (34% of the entire series), the 6-month complete response rate was 75%. The presence of Cis was not a predictive factor of response to HIVEC. Tolerance was excellent with 38.2% grade 1-2 adverse events and no grade 3-4 adverse events. Conclusions: Chemohyperthermia using the HIVEC device achieved a RFS rate of 53.1% at 1 year and enabled a bladder preservation rate of 90%. While cystectomy remains the standard of care, HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.