bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC).
Authors: Chamie Karim , Chang Sam S. , Gonzalgo Mark , Kramolowsky Eugene V. , Sexton Wade J. , Bhar Paul , Reddy Sandeep K. , Soon-Shiong Patrick 
Published: June 2022

4508 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase 1b data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Pembrolizumab was approved in 2020 with a 41% complete response (CR) rate in a single arm phase 2 trial of 96 patients. We report data on 160 subjects from an open-label, 3 cohort multicenter study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825). Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A (CIS) is incidence of CR of CIS at any time. The primary endpoint for Cohort B (Papillary) is disease-free rate (DFS) at 12 months. Results: To date, we enrolled 160 patients (83 CIS, 77 Papillary). In the overall population, median age is 72.3 years, 81% male, with mean number of prior TURBT = 4. Median number of prior BCG doses = 12. CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. Median time to cystectomy in responders (N = 4) is 12.9 months versus 7.8 in non-responders (N = 8) for a 5.1 month delay in cystectomy. PK data shows no systemic levels of N-803; activity is confined to the bladder. Low grade treatment related AEs (grade 1-2) include dysuria (22%), pollakiurua (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at 7% or less. No treatment related grade 4 or 5 AE were seen. No SAE's were considered treatment related. No immune related SAE's have been seen. Conclusions: In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months median duration of response, and 53% DFS rate at 18 months in Papillary disease. Cystectomy was avoided in over 90% of patients with 2 years of follow-up. The efficacy and safety profile of N-803+BCG exceeds that of other available intravesical and systemic options for BCG-unresponsive NMIBC. Clinical trial information: NCT03022825.
Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Analysis of progression after first subsequent therapy in KEYNOTE-426.
Authors: Powles Thomas , Plimack Elizabeth R. , Stus Viktor , Waddell Tom , Gafanov Rustem , Pouliot Frédéric , Nosov Dmitry , Melichar Bohuslav , Soulieres Denis , Borchiellini Delphine , Vynnychenko Ihor , McDermott Raymond S. , Azevedo Sergio Jobim , Tamada Satoshi , Kryzhanivska Anna , Li Chenxiang , Burgents Joseph E. , Molife L. Rhoda , Rini Brian I. , Bedke Jens 
Published: June 2022

4513 Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) met its primary and key secondary end points of improved OS, PFS, and ORR with pembro + axi versus sunitinib as first-line treatment for patients with advanced ccRCC. Extended follow-up (42.8-mo median follow-up) continued to show the superior efficacy of pembro + axi versus sunitinib in this patient population. We describe the results of PFS2 for all randomly assigned patients and across IMDC risk categories. Methods: Treatment-naive patients with advanced ccRCC, Karnofsky Performance Status Scale score ≥70% and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 doses (̃2 y) + axi 5 mg orally twice daily or sunitinib 50 mg orally once daily on a 4-wk on/2-wk off schedule. The end point of this exploratory analysis was PFS2, defined as time from randomization to progression after first subsequent therapy or any-cause death. The Kaplan-Meier method was used to estimate PFS2 and hazard ratios were estimated using a Cox regression model. Results: Of 861 patients, 432 were assigned to receive pembro + axi; 429, to sunitinib. Median time from randomization to the database cutoff date (January 11, 2021) was 42.8 mo (range, 35.6-50.6). Overall, 47.2% of patients (204/432) in the pembro + axi arm and 65.5% of patients (281/429) in the sunitinib arm received ≥1 line of subsequent anticancer therapy. For patients who received subsequent therapy, anti–PD-1/PD-L1 agents were the first subsequent treatment for 11.3% of patients (23/204) in the pembro + axi arm and 54.8% of patients (154/281) in the sunitinib arm. In the pembro + axi arm, 82.8% of patients (169/204) received a VEGF/VEGFR inhibitor as first subsequent therapy, as did 43.4% (122/281) in the sunitinib arm. PFS2 results are displayed in the Table. Conclusions: In this exploratory analysis, PFS2 was longer for patients randomized to pembro + axi compared to sunitinib. Results were consistent across IMDC risk groups. These data support use of pembro + axi for the first-line treatment of patients with advanced ccRCC. Clinical trial information: NCT02853331. [Table: see text]
A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.
Authors: Xu Huayan , Sheng Xinan , Zhou Li , Yan Xieqiao , Li Siming , Chi Zhihong , Cui Chuanliang , Si Lu , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Bai Xue , Li Juan , Guo Jun 
Published: June 2022

4519 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefited from the treatment of RC48-ADC.This study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, single-arm, phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1,and treated with ≥1 prior systemic treatment. Patients received RC48-ADC 2mg/kg q2w until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The primary objectives were activity (ORR) and safety. Second objectives included progress-free survival, disease control rate and overall survival. Results: As of February 2022(date cutoff),19 patients were enrolled. The median age was 64 years old(range:36-77). At baseline, there were 6 patients with HER2(IHC 0), and 13 patients with HER2(IHC 1+).Most patients (13/19) had visceral metastasis. 15(79%) patients had received≥2 lines treatment.At date cutoff, 19 patients were assessable for response. The objective response rate was 26.3% (95% CI:9.1%,51.2%) and the DCR was 94.7% (18/19). The mPFS was 5.5months (95% CI:3.9,6.8) and mOS was 16.4months (95% CI:7.1,21.7).All of the 6 patients with HER2(0) were SD in the study. The ORRs were 38% (5/13) in patients with HER2(IHC 1+),31% (4/13) in visceral metastasis,17% (1/6) in liver metastasis patients,27% (4/15) in patients post to ≥ 2 lines of treatment. Common treatment-related AEs were leukopenia (52.6%), hypoesthesia (47.4%),alopecia (47.4%), AST increase (42.1%), ALT increase (42.1%), and neutropenia (42.1%), fatigue (42.1%),nausea (26.3%), vomiting (15.8%).Most of these AEs were Grade 1 or 2. The AE of Grade 3 was neutropenia (10.5%). The SAE was CPK increased (5.3%). Conclusions: This study showed that RC48-ADC was safe and the ORR was 26.3% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. The enrollment was completed and data will be updated later. Clinical trial information: NCT04073602.
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) compared to computed tomography (CT) for advanced renal cell carcinoma (RCC).
Authors: Pathmanathan Shivanshan , Tariq Arsalan , Gan Chun Loo , Pearce Adam , Rhee Handoo , Kyle Samuel , Raveenthiran Sheliyan , Wong David , McBean Rhiannon , Marsh Philip , Goodman Steven , Dhiantravan Nattakorn , Esler Rachel , Dunglison Nigel , Navaratnam Anojan , Yaxley John , Thomas Paul , Pattison David A. , Goh Jeffrey C. , Roberts Matthew 
Published: June 2022

4540 Background: There is emerging role of the use of PSMA PET in RCC. Herein, we report our experience in use of PSMA PET in recurrent or metastatic RCC in Brisbane, Australia. Methods: Patients (pts) who underwent PSMA PET and conventional diagnostic CT for metastatic or recurrent RCC between 2015 and 2020 at three institutions were identified. Retrospective chart reviews were conducted using standardized collection template. The outcomes included percentage of patients who had a change in management secondary to PSMA PET findings, comparison of metastasis detection for PSMA PET vs. CT, and biopsy histology of PSMA avid sites. Results: 42 PSMA PET were performed in 40 patients. 10 pts (25%) and 30 pts (75%) had PSMA PET in the metastatic disease and recurrent disease setting, respectively. Table 1 highlights demographics. Overall, 12 pts (30%, n=3 metastatic, n=9 recurrent) had a change in management following PSMA PET. In the metastatic disease group, 2 pts (20%) underwent initial systemic therapy (after histological confirmation) due to higher burden of disease shown with PSMA PET than CT, while systemic therapy was changed for 1 pt (10%). In the recurrent disease group, PSMA improved delineation of suspected recurrence (compared to CT) resulting in resection rather than surveillance (n=4; 13%) or change in surgical approach for resection (n=1; 3%). PSMA PET distribution showed more metastatic sites than CT leading to systemic therapy rather than resection of recurrence (n=2; 7%), while absent PSMA activity for suspected recurrence on CT led to surveillance rather than resection (n=2; 7%). PSMA PET detected more sites of metastases compared with conventional scan in 6 pts (60%) with metastatic disease and in 9 pts (30%) with recurrent disease. 26 pts had biopsy of PSMA avid sites. Majority of pts had confirmed recurrence of clear cell renal carcinoma (n= 22; 85%). Other histology included sarcomatoid renal cell carcinoma (n=2; 8%), carcinoid (n=1; 4%), and urothelial cancer (n=1; 4%). In 2 instances, biopsy/resection was performed of a suspected recurrence on CT that was not PSMA avid, and neither showed malignancy. Conclusions: PSMA PET detected more accurately metastatic and recurrent disease, with high pathological concordance, to result in change in management for 30% of patients. Prospective study is warranted to further investigate the utility of PSMA PET scan in advanced RCC.[Table: see text]
Activity of tivozanib in non-clear cell renal cell carcinoma (nccRCC): Subgroup analysis from a phase 2 randomized discontinuation trial.
Authors: Barata Pedro C. , Allman Kim , Asnis-Alibozek Aviva G. , Kasturi Vijay , Pal Sumanta K. 
Published: June 2022

4542 Background: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogenous and biologically diverse RCC histologies including (but not limited to) papillary, chromophobe and unclassified subtypes. Tivozanib is a selective VEGFR tyrosine kinase inhibitor with demonstrated activity in RCC with clear cell component. Here we report efficacy of tivozanib in a histologically diverse nccRCC subset included in a phase 2 study. Methods: We conducted a subgroup analysis of patients with nccRCC enrolled in the study 201 (NCT00502307), a phase 2 randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGF targeted treatment. Clinical outcomes including overall response rate (ORR), disease control rate (DCR, defined by CR+PR+SD), and progression free survival (PFS) were examined. Safety outcomes for all patients are reported in the original publication (Nosov, JCO 2012). Results: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC. [11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) unclassified/mixed]. Of the 46 nccRCC patients, the ORR was 17.4% by investigator (INV) review and 15.2% by independent radiology review (IRR). The DCR was 80.4% by INV and IRR. The median PFS was 6.7 months (204 days) (95%CI: 125-366 days) by IRR (Figure 1). Of note, 14 patients with SD after 16 weeks on tivozanib were randomized to 12 weeks of placebo and may have progressed during that timeframe before unblinding and resuming tivozanib. Safety was not analyzed by histology but there were no new safety signals and was consistent with tivozanib labelling in the ITT population. Conclusions: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. This data adds to the body of evidence supporting VEGFR TKI use in advanced RCC including in non-clear cell histologies. Clinical trial information: NCT00502307. [Table: see text]
Variation in recurrence rate and overall survival (OS) outcomes by disease stage and incremental impact of time to recurrence on OS in localized renal cell carcinoma (RCC).
Authors: Haas Naomi B. , Bhattacharya Rituparna , Song Yan , Rogerio Jackie , Zhang Su , Carley Christopher , Anderson Annika , Signorovitch James , Sundaram Murali 
Published: June 2022

4543 Background: Prior research shows that post-nephrectomy recurrence is correlated with significantly increased mortality in patients (pts) with intermediate-high (int-high) risk and high risk RCC. However, no study has quantified the incremental OS associated with increased time to recurrence (ToR). Additionally, limited evidence is presented on the variation of recurrence rate and OS by stage of RCC. Methods: The SEER-Medicare database (2007–2016) was used in this retrospective observational study. Post-nephrectomy pts with newly diagnosed, int-high risk (pT2 N0 high grade, pT3 N0 any grade) or high-risk (pT4 N0 any grade, pT any N1 any grade) RCC were identified and stratified based on tumor stage and grade. Grade was defined based on Furhman grading system and was reported in SEER Registry. Post-nephrectomy recurrence free rates and OS by disease stage were described using Kaplan-Meier analyses. OS from nephrectomy in pts with recurrence vs pts without recurrence was compared by disease stage. Multivariable regression analysis was used to quantify the incremental OS associated with increased ToR post-nephrectomy in all pts with recurrence. Results: 643 pts met the inclusion criteria (269 with vs 374 without recurrence; median follow-up: 23 months). The mean age was 75.5 years (yrs), 61% male, and 86% white. Results presented in the table showed wide variance in 5-yr recurrence-free rate in int-high risk group (28%-63%) and indicated substantial risk of disease recurrence in all subgroups of int-high risk pts. Among those with T3 Grade 1-2, T3 Grade 3, and T3 Grade 4 disease, pts with recurrence had significantly higher risk of death than those without (all ps<0.05;). Results for pts with T2 and T4 disease were not presented due to small sample size. Multivariable regression analysis indicated that 1 additional yr of ToR was associated with 0.73 additional yrs (8.8 additional months) of OS post nephrectomy (95% CI: 0.40, 1.05 yrs; p<0.001). Conclusions: The non-trivial recurrence rates observed in pts with T3 Grade 1-2 and T3 Grade 3 RCC highlighted the substantial risk of recurrence and unmet needs in the int-high risk RCC patients. This study also confirms the incremental nature of the association of ToR and OS in patients with int-high and high risk localized RCC. These findings highlight the need for effective early intervention with adjuvant treatments in int-high and high risk post-nephrectomy RCC pts. [Table: see text]
Outcomes with novel combinations in nonclear cell renal cell carcinoma (nccRCC): ORACLE study.
Authors: Kilari Deepak , Szabo Aniko , Ghatalia Pooja , Rose Tracy L , Dong Huaying , Weise Nicole , Zhuang Tony Z. , Alloghbi Abdurahman , Jain Rohit K. , Alva Ajjai Shivaram , Tripathi Abhishek , Basu Arnab , Davis Nancy B. , Brundage James , Emamekhoo Hamid , Zakharia Yousef , Koshkin Vadim S , Bilen Mehmet Asim , Heath Elisabeth I. , McKay Rana R. 
Published: June 2022

4545 Background: Despite recent advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of combination therapies (including IO-IO, IO-VEGF, VEGF-mTOR) in subtypes of advanced nccRCC is unknown. Methods: In this multicenter retrospective analysis, we evaluated the efficacy of combination systemic therapies in patients with nccRCC. Eligible patients included those with nccRCC as determined by local genitourinary pathology review and receipt of one of three combination regimens during any line treatment (IO-IO, IO-VEGF, mTOR-VEGF). The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints were progression- free survival (PFS), disease control rate (DCR), and overall survival (OS). Results: Among 128 included patients, median age was 57 years; 66% were male and 65% white. Histologies included papillary (37%), unclassified (33%), chromophobe (16%), translocation (9%), and other (5 %). Among all patients, 69% had prior nephrectomy; 80% were IMDC intermediate/poor risk; 20% had sarcomatoid and/or rhabdoid differentiation, 27% and 29% had liver and bone metastasis respectively and 63% received combination treatment as first line. Comparison of outcomes based on treatment regimen, line of treatment and subtype is shown in the table. Median PFS and OS were longer with IO/IO and IO/VEGF compared to VEGF/ mTOR at 8.5, 9.5 and 3.7 months and 24.4, 18.2 and 15.4 months respectively. Conclusions: Antitumor activity was observed with novel combinations in nccRCC in both frontline and later line setting. Optimal management of nccRCC remains an unmet need and prospective data is warranted to guide treatment selection for this population. [Table: see text]
Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.
Authors: Duan Rong , Liu Yixun , Hu Xuechun , Cui Chuanliang , Si Lu , Sheng Xinan , Liu Zhi , Xiang Ping , Yan Xieqiao , Li Siming , Zhou Li , Li Juan , Li Yu Jie , Ng Rachel , Dai Xiang Rong , Li Benjamin Xiaoyi , Chi Zhihong , Xiao Jun , Guo Jun , Tang Bixia 
Published: June 2022

4563 Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs)0have demonstrated activity in the postplatinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 30% of patients with aUC can tolerate platinum standard treatment, first-line ICIs combined with non-platinum drugs have certain research value. Therefore we assessed the safety and efficacy of anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first line therapy in aUC (NCT04603846). Methods: This is a multi-center,single-arm, phase Ib study which enrolled aUC patients with treatment-naive or first recurrence more than 6 months after the end of adjuvant chemotherapy in China. Eligible patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) every 3 weeks. Primary endpoint was to investigate the safety and tolerability of nab-paclitaxel in combination with Socazolimab. Second endpoints were the objective response rate (ORR) and progression-free survival (PFS). Results: 20 patients were enrolled, including 5 renal pelvis urothelial carcinoma, 8 bladder urothelial carcinoma, and 7 ureteral carcinoma. The median age was 69 years. As of January 14, 2022, the median follow-up time was 5.49 months. Median number of treatment cycles was 6.5 cycles. No patients had dose limiting toxicity. Among the 17 patients who had received at least one tumor assessment, 8 patients achieved partial responses. ORR was 52.94% (95% CI, 27.81-77.02). DCR was 88.24% (95% CI, 63.56-98.54). Median PFS was 8.18 months (95% CI, 5.32-13.60). Adverse reactions related to the study drug were mainly Grade 1-2. Common adverse reactions included rash (6/20,30%), increased alanine aminotransferase (6/20, 30%), increased γ-glutamyltransferase (4/20, 20%),sinus bradycardia (4/20, 20%), increased aspartate aminotransferase (4/20, 20%),pruritus (3/20, 15%). Grade 3 or higher treatment-related adverse events occurred in 4 (20%) patients, mainly Grade 3 increases in alanine aminotransferase (2/20, 10%). No confirmed treatment-related deaths occurred, and no treatment-related deaths occurred, and no new safety signals were observed. Conclusions: Socazolimab combined with nab-paclitaxel as first-line treatment was effective and well-tolerated in Chinese patients with advanced urothelial carcinoma, warranting phase II trials. Clinical trial information: NCT04603846.
Assessment of a HER-2 scoring system and its correlation of HER2-targeting antibody-drug conjugate therapy in urothelial carcinoma.
Authors: Lei Huizi , Ling Yun , Yuan Pei , Guo Jun , Sheng Xinan , Zhou Ai-Ping , Ying Jianming 
Published: June 2022

4572 Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to many tumor treatments. RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, has shown a promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (mUC). The characteristic expression and scoring systems of HER2 have existed in breast cancer, gastric cancer for many years, but not in UC. We aimed to explore the expression pattern of HER2 in UC and develop a validated HER2 scoring system. Methods: A total of 137 patients and 43 patients in two studies of cohort 1 and cohort 2 were enrolled, respectively. The patients of the cohort 2 were enrolled in the open-label, multicenter, phase II study of RC48-ADC. Formalin-fixed paraffin-embedded urothelial cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) PathVysion HER2 DNA probe kit (PathVysion, Abbott Molecular, USA). Immunohistochemistry (IHC) was performed using the Ventana Benchmark XT (Ventana Medical Systems, USA). The 2018 ASCO/CAP HER2 scoring system of breast cancer was adopted and modified to score HER2 expression level in UC. Results: The expression rate of HER2 (IHC 2+/3+) was 24.1% (33/137). In HER2 IHC status 3+ or 2+ patients, the HER2 amplified rate was 31% (13/42). The objective response rates in RC48-ADC treatment patients with IHC 3+, IHC 2+ and FISH +, IHC 2+ and FISH - were 58.8%, 66.7% and 40%, respectively. Heterogeneity of HER2 protein expression was 55.5% (15/27) and the objective response rate had no significant difference between patients with tumor heterogeneity and homogeneity. Conclusions: The modified HER2 testing scoring system could be applied to UC to determine which patient might benefit from anti-HER2-ADC treatment. There was a trend towards a better benefit for patients with HER2 amplification and the tumor heterogeneity did not influence the drug efficacy.