bluuebunny/crossref_metadata_2025 huggingface dataset:
Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) 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: February 2022

435

Background: Up to 25% of all 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 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 locally advanced or metastatic urothelial cancer pts in Phase II and III 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 (yp T0,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, with 1 case pending central pathology review. 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 II and III programs evaluating EV in MIBC. Clinical trial information: NCT03288545.
Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).
Authors: Grimm Marc-Oliver , Grün Barbara , Niegisch Guenter , Pichler Martin , Roghmann Florian , Schmitz-Dräger Bernd , Baretton Gustavo Bruno , Schmitz Marc , Foller Susan , Leucht Katharina , Schumacher Ulrike , Schostak Martin , Meran Johannes , Loidl Wolfgang C. , Zengerling Friedemann
Published: February 2022

441

Background: Nivolumab (nivo) is an approved 2nd line treatment after platinum-based chemotherapy in metastatic urothelial carcinoma (mUC). Recent studies suggest improved outcomes for dual checkpoint inhibition in mUC in particular with higher ipilimumab (ipi) doses (nivo 1mg/kg + ipi 3mg/kg). TITAN-TCC uses a response-based approach starting with 4 doses of nivo (8 weeks) followed by nivo+ipi boosts in non-responders. Here we report cohort 2 of TITAN-TCC applying nivo1/ipi3 boost doses in patients after prior platinum-based chemotherapy (2nd/3rd line). Methods: Between April 2019 and February 2021 83 patients with histologically confirmed mUC (TITAN-TCC cohort 2) started with nivo 240mg Q2W induction. After 4 doses and tumor assessment at week 8 (i) non-responders (stable (SD)/ progressive disease (PD)) received 2-4 doses nivo1+ipi3 while (ii) responders (complete (CR)/ partial response (PR)) continued with nivo maintenance but could receive nivo1+ipi3 for later PD. Primary endpoint was confirmed investigator-assessed ORR per RECIST1.1. Using a Fleming single-stage phase II design 77 evaluable patients would provide a 90% power to reject the null-hypothesis that ORR was ≤20% at a one-sided 5% type I error if the true ORR was ≥35%. Secondary endpoints included activity of nivo monotherapy at week 8, remission rate with nivo+ipi boosts, progression-free survival (PFS), overall survival (OS), and safety. Results: Median follow-up time was 5.6 months. Of the patients, 78 (94%) were 2nd line. Median age was 68 years (range 37-84) and 57 patients (69%) were male. ORR with nivo monotherapy at first assessment (week 8) was 20.5%. Of the patients, 44 and 6 received nivo+ipi boosts after week 8 and for later PD, respectively. Confirmed objective response with nivo induction ± nivo+ipi boosts was achieved in 27/83 (32.5%) of the patients (significant > 20%, p < 0.01). Patients with PD-L1 expression in ≥1% of tumor cells had a numerically higher ORR (46% vs. 24% for PD-L1 negatives). Of the patients with initial SD after nivo induction, 4/13 (31%) achieved response upon boost. Of the patients boosted for PD, 9/37 (24%) improved. Median PFS was 1.9 months (95% CI 1.8-3.2), median OS was 7.6 months (95% CI 5.1-14.9). No new safety signals emerged. Conclusions: In patients after prior platinum-based chemotherapy treatment with nivo and nivo+ipi boosts in non-responders significantly improved ORR compared to the one reported for nivo as 2nd line monotherapy. Patients with PD-L1 positive tumors appear to benefit most. Our study provides further evidence for the added value of high dose (3mg/kg) ipilimumab in mUC. Clinical trial information: NCT0321977.[Table: see text]
Response to neoadjuvant chemotherapy in histologic variants of bladder cancer.
Authors: Viala Caroline , Viala Marie
Published: February 2022

458

Background: Localized muscle invasive bladder carcinoma is mostly treated with neoadjuvant chemotherapy (NAC) before surgery in order to improve the outcome. Urothelial carcinoma (UC) is the most frequent histological type. Histological variants (pure or mixed) occur in 10% of bladder carcinoma. There is a lack of data on NAC efficacy for these histological subtypes. In this study, we evaluated the histologic response to NAC in the variant population of bladder cancer. Methods: Patients from 2 french hospitals (CHU de Nantes and ICM) treated with NAC for bladder cancer from 2010 to August 2021 were included in this retrospective study. We compared response to NAC between UC and histologic variants (pure or mixed) on cystectomy piece. The histological response was defined by the tumor downstaging after NAC (≤pT1Nx). We also collected the pathological complete response (pCR), which was defined by no residual tumor on the cystectomy piece. Results: 87 patients were included. 31 patients harbored a variant pattern: 7 squamous component, 3 adenocarcinoma component, 5 micropapillary component, 2 sarcomatoid component, 4 neuroendocrine carcinoma, 4 nest, 1 lymphoepithelial carcinoma, 2 giant cell, 1 undifferentiated, 1 micropapilallary and adenocarcinoma component and 1 adenosquamous component; 56 were conventional UC. NAC was MVAC in 77% of patient in the variant group, and 82% in the UC group. Others chemotherapy drugs were used as gemzar cisplatine, and platine etoposide. Downstaging was observed in 55% of patients in the variant group (17/31) and in 59% in the UC group (33/56). The difference was not statistically significant (p <0,44). pCR was observed in 39% of patients in the variant group (12/31) and 43% in the UC group (24/56), the difference was not significant (p< 0.44). Conclusions: NAC can be effective in the histologic variant population of bladder carcinoma, nevertheless these data could be confirmed in a larger cohort.
Real-world treatment patterns, survival outcomes, and health care resource utilization among individuals with nonmuscle-invasive bladder cancer in Canada.
Authors: Jarada Tamer N. , Gotto Geoffrey , Bhindi Bimal , Beaton Natalie , Feroz Tahir , Maier-Downing Teagan , Brenner Darren , Cheung Winson Y. , Boyne Devon J.
Published: February 2022

470

Background: Real-world evidence pertaining to high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) is limited. We aimed to describe real-world treatment patterns and outcomes of this study population within a Canadian setting. Methods: A retrospective cohort study was conducted by linking various population-based administrative datasets from a large Canadian province. The study population consisted of all individuals ≥ 18 years who were diagnosed with Tis or high-grade Ta/T1 NMIBC in Alberta, Canada between 2010-2019. High-grade disease was defined using the WHO 1973 system. Individuals who initiated BCG therapy were classified as having received adequate induction therapy if they completed 5+ cycles. BCG unresponsive was defined as receipt of TURBT, intravesical chemotherapy, cystectomy, or radiation within 1 year of the last BCG dose. Overall survival (OS), cystectomy-free survival (CFS), progression-free survival (PFS), and healthcare resource utilization (HCRU) were examined from the time of being classified as BCG unresponsive following adequate induction therapy. CFS was defined as time until death or radical cystectomy and PFS was defined as time until death or disease progression. Disease progression was classified using a proxy based on subsequent receipt of cystectomy, systemic therapy, or radiation. Kaplan-Meier survival curves were estimated for OS, CFS, and PFS and the mean number of healthcare encounters within each year of follow-up were estimated for HCRU. Results: 5369 individuals were diagnosed with NMIBC in Alberta between 2010-2019, of whom 2679 (49.9%) had Tis or HG Ta/T1 disease at initial diagnosis. Among individuals with high-risk NMIBC, 1044 (39%) initiated BCG therapy. 885 (84.8%) individuals received 5+ BCG doses. Despite receiving adequate induction treatment, 249 (28.1%) individuals became unresponsive. The mean age at BCG unresponsive was 72.9 years and 213 (58.5%) were males. Among those who were BCG unresponsive, 25.7% underwent radical cystectomy (median time to cystectomy: 4.4 months, IQR: 1.7 to 8.2). Median OS was 50.7 months (95% CI: 37.2-65.5), CFS was 22.4 months (18.9-31.1), and PFS was 14.4 months (11.6-20.9). Within the first year of becoming BCG unresponsive, individuals spent an average of 6.2 days in hospital, had 28.8 visits with healthcare practictitioners, and had 2.2 emergency and 13.6 non-emergency encounters with ambulatory care services. Conclusions: A considerable proportion of individuals with high-risk NMIBC became unresponsive to BCG therapy despite adequate treatment. The time from becomining BCG unresponsive to radical cystectomy was relatively short. These findings highlight an unmet need in this patient population for alternative therapeutic options.
The prognostic impact of preoperative health-related quality life on bladder cancer-specific survival in patients treated with radical cystectomy.
Authors: Westhofen Thilo , Eismann Lennert , Buchner Alexander , Schlenker Boris , Giessen-Jung Clemens , Becker Armin , Stief Christian G. , Kretschmer Alexander
Published: February 2022

475

Background: Previous studies have shown that baseline health-related quality of life (HRQOL) is a valuable prognostic indicator of survival outcomes for various cancer entities in the metastatic setting, yet there is no evidence on the prognostic value of baseline HRQOL for patients undergoing radical cystectomy (RC) with curative intent. The goal of this study was to evaluate the influence of baseline preoperative HRQOL on cancer specific survival prognosis for patients undergoing RC. Methods: 407 patients with prospectively assessed baseline HRQOL prior RC were included. Patients were stratified by the global health status (GHS) domain of the EORTC QLQ-C30 questionnaire, and good general HRQOL was defined as GHS≥70 based on validated cut-off levels. A 1:2 propensity-score-matched analysis of n=357 patients [n=125 (GHS≥70), n=232 (GHS<70)] was performed. Primary endpoint was cancer-specific survival (CSS), secondary endpoints encompassed overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox regression models were performed to assess prognostic significance of baseline GHS on survival outcomes. Harrell’s discrimination C-index was assessed to calculate the predictive accuracy of the model (p<0.05). Results: Median follow-up was 40.5mo. Patients subcohorts were well-balanced. All baseline QLQ-C30 functioning scales were in favour of the GHS≥70 cohort (each p<0.001). 5-yr CSS (82% vs. 65%; p=0.001), 5-yr OS (76% vs 53%; p=0.001) and 5-yr-RFS (50% vs. 39%; p=0.04) and were significantly increased in the GHS≥70 cohort. GHS≥70 was confirmed as an independent predictor for increased CSS (HR 0.43, 95%CI 0.21–0.89; p=0.028), OS (HR 0.56, 95%CI 0.31–0.90; p=0.031) and RFS (HR 0.52, 95%CI 0.31–0.87; p=0.013) multivariate analysis. Conclusions: Our findings suggest preoperative baseline HRQOL to have a pronounced predictive value for patients undergoing RC with curative intent for bladder cancer. We found baseline good general HRQOL to accurately predict increased CSS, OS and RFS.[Table: see text]
Recombinant humanized Anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma (POLARIS-03 study): Two-year survival update and biomarker analysis.
Authors: Sheng Xinan , Chen Haige , Hu Bin , Yao Xudong , Liu Ziling , Yao Xin , Guo Hongqian , Hu Yi , Ji Zhigang , Luo Hong , Shi Benkang , Liu Jiyan , WU Jin , Zhou Fangjian , He Zhisong , Fan Jinhai , Huang Yiran , Guo Jun ,   Shanghai Junshi Bioscience
Published: February 2022

508

Background: Patients with advanced metastatic urothelial carcinoma (mUC) who experience disease progression after standard therapy have limited treatment options. Toripalimab was approved for the 2nd line treatment of mUC based on a phase II clinical study (POLARIS-03) in Chinese patients with mUC (Clinical trial ID: NCT03113266). Here we report the two-year OS update and biomarker analysis of the study. Methods: Metastatic UC Patients received toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response was assessed every 8 weeks. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 204 patients were screened and 151 patients were enrolled from 15 participating centers. By cutoff date of September 8, 2021, no emergent of new safety signal was identified compared with the previous one-year report. By the cutoff date, 91 patients have died, and the median OS was 14.6 months. Whole exome sequencing (WES) was performed on tumor biopsies and paired PBMCs and the results were available from 135 patients. Patients with mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1 were associated with better responses to toripalimab than patients with wild-type genes. The ORR was 30% (6/20) in patients with FGFR2/FGFR3 mutations or FGFR2/FGFR3 gene fusions, and 42% (5/12) in patients with NECTIN4 genomic alternations. The median TMB value was 4.1 mutations per million base pairs (Mb) in the cohort. Using 10 mutations/Mb as the cut off, TMB-high patients (n = 27) had better ORR than TMB low patients(n = 108) (48% versus 22%, p = 0.014). The TMB-high group also showed better PFS (12.9 versus 1.8 months, HR = 0.48 [95% CI:0.31-0.74], p < 0.001) and OS (not reached versus 10.0 months, HR = 0.53 [95% CI:0.32-0.88], p = 0.013) than the TMB low group. Conclusions: Toripalimab has demonstrated a manageable safety profile and encouraging clinical activity in metastatic UC patients refractory to 1st line chemotherapy. WES analysis identified divergent mutations in the study. We report the utility of TMB to predict not only the response rate but also the PFS and OS benefits in patients with mUC in response to an ICI monotherapy. Clinical trial information: NCT03113266.
Characterization of fungal mycobiome in bladder cancer.
Authors: Bukavina Laura , Prunty Megan , Calaway Adam C. , Isali Ilaha , Retuerto Mauricio , Ghannoum Mahmoud , Markt Sarah C. , Sindhani Mohit , Mishra Kirtishri , Ponsky Lee Evan , Abbosh Phillip
Published: February 2022

542

Background: Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon, breast and pancreatic cancer. However, the role of fungal mycobiome has not been evaluated in bladder cancer. With the sexual dimorphism that exists within bladder cancer (Bca) prevalence and survival, our study aims to characterize fungal mycobiome composition in Bca. Methods: This is a single site, non-randomized, prospective study of patients with the diagnosis of muscle invasive bladder cancer (MIBC) undergoing cystectomy from September 2020 to May 2021. Stool samples were collected during surgery using aseptic technique. We utilized the ITS1 region from DNA sample extracts, which was amplified in triplicate using primers with high specificity for ascomycete fungi (fluorescently-labeled forward primer ITS1F (CTTGGTCATTTAGAGGAAGTAA) and unlabeled reverse primer ITS2 (GCTGCGTTCTTCATCGATGC). Fungal PCR products were separated on the SCE 9610 capillary DNA sequencer (Spectrumedix LLC, State College, PA) using GenoSpectrum software to convert fluorescent output into electropherograms. Hierarchical clustering by Bray-Curtis distance was performed using hclust2. Mean normalized abundance for each amplicon was calculated from the three PCR replicates of each sample, excluding means below 1%. Results: A total of 29 patients (17 males and 12 females) were enrolled. The median (IQR) age was 74 yo (63-77), males, and 68.5 yo (58-78), females. Per figure 1, Saccharomycecales dominated the fungal community at order level with mean relative abundance of 36.35% females, and 21.20%, males. (Figure 1D) Tremellales was the second most notable order, composing 8.22% and 5.13% of male and female samples. There were no differences seen in alpha and beta diversity (Figure 1C) (Figure 1A, C), notable differences were seen across orders. The greatest difference between sexes in LDA( M:F) were noted in Saccharomycecales (log change -4.686, p=0.001/ padj= 0.01), Tremellales (log change 5.119, p=0.001/padj= 0.01), and Sporidiobolales (log change 4.839, p=0.001 padj= 0.03). (Figure 1B). Female bladder cancer patients demonstrating an increase abundance of Saccharomycecale. When assessing differences in fungal composition in patients with history of neoadjuvant therapy( NAC) (receipt vs none), patients with history of NAC exhibited a 3.48 increase in Saccharomycecale (padj= 0.015 ), 4.81 increase Tremalles (padj= 0.009) and 4.37 increase Pleosporales(padj= 0.009) . Conclusions: Mycobiome is an integral part of gut microbiota, with fungal elements relatively poorly studied. Nevertheless, the association between fungal dysbiosis and carcinogenesis across multiple cancers exists. Our study is the first to characterize fungal profile in bladder cancer patients, stratified by sex and receipt of NAC, with results highlighting key fungal players: Saccharomycecale, Tremallales, Pleosoporales.
Tumor genomic landscape in smokers compared to non-smoker patients with locally advanced or metastatic urothelial carcinoma.
Authors: Tripathi Nishita , Sayegh Nicolas , Jo Yeonjung , Li Haoran , Nussenzveig Roberto , Haaland Benjamin , Thomas Vinay Mathew , Gupta Sumati , Sirohi Deepika , Swami Umang , Agarwal Neeraj , Maughan Benjamin L.
Published: February 2022

554

Background: Cigarette smoking is a known risk factor for bladder cancer. Smokers have been reported to have greater ERCC2-Signature mutations and APOBEC-Signature 13 mutations when compared to non-smokers in a TCGA based study (PMID: 33849962). Our objective was to assess the frequency of targetable genomic alterations in smokers (current or past) vs never smokers patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC). Methods: In this IRB approved retrospective study, smokers vs non-smokers pts with mUC undergoing tumor comprehensive genomic profiling (CGP) from CLIA-certified laboratory were included. Genes with alterations (GA) in < 5% pts and variants of unknown significance were excluded from the analysis. A chi square test was used to compare gene frequency aberration and the analysis was adjusted for false discovery using Benjamini-Hochberg (BH) correction. The median number of genomic aberrations per pt was compared using Wilcoxon rank-sum test. Results: 137 pts were eligible and included. Smokers (n=70) and non-smokers (n=67): median age, 67 vs 68 years; male vs female: 55/15 vs 42/25. The genomic aberrations enriched in smokers and non-smokers are shown in the table. The most common GA observed in smokers were TERT, TP53, CDKN2B, RB1 and KDM6A; and non-smokers were TERT, TP53, CDKN2B, PIK3CA and RB1 (Table). Tumor mutation burden and the frequency of genomic aberrations per pt were similar in both groups. Conclusions: Herein, we independently validate the findings by Walasek, Almassi et. al. (abstract B20, AACR 2020) of no significant difference in the tumor GA between smokers vs non-smokers pts with advanced urothelial carcinoma, despite high prevalence of targetable genomic aberrations in both cohorts. Future directions should include the investigation of epigenomic changes and transcriptomic profiling to further elucidate the effect of smoking on bladder cancer.[Table: see text]
Systematic literature review (SLR) and network meta-analysis (NMA) of first-line therapies (1L) for locally advanced/metastatic urothelial carcinoma (la/mUC).
Authors: Bloudek Lisa , Hepp Zsolt , McKay Caroline , Derleth Christina Louise , LIll Jennifer Susan , Lenero Enrique , Wright Phoebe , Ramsey Scott David , Sullivan Sean D. , Devine Beth
Published: February 2022

570

Background: Standard of care (SOC) for 1L la/mUC is gemcitabine plus cisplatin (GC) or carboplatin (GCa), but the landscape is evolving with new therapies emerging. To compare outcomes of other approved/investigational 1L regimens with SOC in the context of recently published data on newer therapies, we updated a previously reported SLR/NMA of phase 2/3 randomized control trials. Methods: The SLR was conducted in line with PRISMA and NICE guidelines (01/2000-05/2020; updated 06/2020-06/2021). Three networks were formed: cisplatin (cis)-eligible/mixed eligibility; cis-ineligible (strict; studies including cis-ineligible patients only); and cis-ineligible (wide; expanded to also include study arms with an investigator’s choice of carboplatin in KEYNOTE-361, IMvigor130, and DANUBE). Comparative efficacy and safety were assessed under a Bayesian framework. Overall survival (OS) and progression-free survival (PFS) with 1L la/mUC regimens vs SOC (GC/GCa) are reported. Results: Among 2,312 citations identified, 55 unique trials were selected for data extraction. Of these, the NMA included 11 studies in the cis-eligible/mixed, 6 in the cis-ineligible (strict), and 8 in the cis-ineligible (wide) network. The NMA excluded therapies that were not effective or adopted in clinical practice; 6 maintenance trials were excluded due to differences in design precluding comparisons. Median OS in the SOC arms was 13.2 mo (95% confidence interval [CI] 12.4-14.0) for cis-eligible/mixed, 9.7 mo (95% CI 6.7-12.8) for cis-ineligible (strict), and 12.0 mo (95% CI 10.4-13.5) for cis-ineligible (wide); median PFS was 6.6 mo (95% CI 6.3-6.9) for cis-eligible/mixed and 5.6 mo (95% CI 5.0-6.3) for both cis-ineligible strict and wide. OS and PFS were similar to SOC across therapies in each network: hazard ratios (HR) ranged 0.7-1.4 for OS for cis-eligible/mixed, 0.9-1.4 for cis-ineligible (strict), and 0.8-1.4 for cis-ineligible (wide) (Table); HR for PFS ranged 0.5-1.6 for cis-eligible/mixed and 0.8-1.1 for both cis-ineligible strict and wide networks; all credible intervals (CrI) crossed or were close to 1. Conclusions: In this updated SLR/NMA, survival outcomes were similar and remained poor among established and emerging 1L la/mUC therapies, despite inclusion of recent trial data. This further highlights the unmet need in this population.[Table: see text]
Heterogeneity of BCG unresponsive bladder cancer clinical trials limits patients’ access to novel therapeutics.
Authors: Chandra Michael , Sundi Debasish , Pohar Kamal S. , Carson William Edgar , Li Roger
Published: February 2022

572

Background: Effective therapies for patients with non-muscle invasive bladder cancer that recurs or progresses after Bacille Calmette-Guérin (BCG) are lacking. This unmet need is the focus of many drug development efforts, reflected in many completed/ongoing/planned clinical trials for patients with BCG unresponsive bladder cancer. Though BCG unresponsive criteria are well defined, enrollment criteria are variable such that, even at centers with several open trials in this space, a given patient with BCG unresponsive bladder cancer might not qualify for any. To understand the scope of this dilemma, we systematically analyzed enrollment criteria for all BCG unresponsive protocols registered on ClinicalTrials.gov to quantify heterogeneity in enrollment criteria and to determine what proportion of trials were inclusive to patients meeting U.S. Food and Drug Administration (FDA) BCG unresponsive criteria. Methods: The ClinicalTrials.gov search tool was queried for relevant trials using the terms ‘bladder cancer’ ‘non-muscle invasive bladder cancer’ and ‘BCG’. Previously published review articles were cross-referenced to ensure that search results were comprehensive. Inclusion and exclusion criteria for the resulting 28 protocols pertaining to distinct categories such as performance status, laboratory parameters, co-morbidities, active medications, and prior therapies were recorded. Based on enrollment criteria, the trial was assessed to fully inclusive or not to patients considered to be BCG unresponsive by the 2018 FDA criteria. Results: Of 28 trials, 15 (54%) had inclusion/exclusion criteria that were consistent with (inclusive of patients that met) the BCG unresponsive bladder cancer definition. 13 (48%) of 27 trials that specified performance status excluded patients with ECOG > 2 (or KPS equivalent). The most common disease specific exclusion for patients with BCG unresponsive bladder cancer was a requirement for stage Tis (carcinoma in situ, CIS), which pertained to 5 (18%) of trials. Conclusions: Enrollment criteria for patients with BCG unresponsive bladder cancer are highly variable. Nearly half of patients who meet stringent criteria for this disease state do not qualify for clinical trials in this area. For patients who desire to enroll in clinical trials, this restricts access to novel agents. For bladder cancer treating physicians and regulatory bodies, this also hinders comparisons across agents.
CYCLONE 2: A phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.
Authors: Smith Matthew Raymond , Agarwal Neeraj , Todenhöfer Tilman , Piulats Josep M. , Lee Jae-Lyun , Trepiakas Redas , Rao Arpit , Horvath Lisa , Lithio Andrew , Johnston Erica L. , Hulstijn Maarten , Nacerddine Karim , Sweeney Christopher
Published: February 2022

TPS198

Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) in pts with mCRPC. CYCLONE 2 is an adaptive study which is designed in three parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to AA+P with abemaciclib at the RP2D or placebo. The study expands to enroll an additional 170 pts in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee (IDMC). Pts with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible. Prior docetaxel for mHSPC is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Status: Enrollment in Part 1 & 2 is completed. Based on the recommendation from the IDMC, Part 3 was opened in June 2021 and enrolls pts from about 112 sites across 12 countries. Clinical trial information: NCT03706365.
Relugolix in combination with abiraterone acetate, apalutamide, or docetaxel in men with advanced prostate cancer (aPC): A phase 1, three-part, open-label, parallel-cohort study.
Authors: De La Cerda Jose , Migoya Elizabeth , Brown Bruce , Lu Sophia , Zohren Fabian , Tutrone Ronald F. , Dunshee Curtis
Published: February 2022

TPS207

Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs or receptor antagonists is a cornerstone of prostate cancer treatment. As disease progresses, agents with complementary mechansims are co-prescribed with ADT to suppress extra-testicular testosterone production or block androgen receptors on cancer cells. Relugolix (120 mg) is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 study, relugolix maintained suppression of testosterone to castration levels in 96.7% of men for up to 48 weeks (wks), with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). To formally assess the safety and tolerability of combination treatment with relugolix, a phase 1 study in men with aPC has been undertaken. Methods: This is a three-part, open-label, parallel-cohort safety and tolerability study of relugolix in combination with abiraterone acetate in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) (Part 1), apalutamide in men with mCSPC or non-metastatic catration-resistant prostate cancer (nmCRPC) (Part 2), or docetaxel in men with mCSPC or mCRPC (Part 3). Each part of the study consists of a 45-day screening period, a 12-wk primary study treatment period and a 40-wk safety extension treatment period. All of the men are required to have been treated with leuprolide acetate or a GnRH receptor antagonist (eg, degarelix) in combination with abiraterone acetate for a minimum of 12 wks, apalutamide for a minimum of 6 wks, or docetaxel for a minimum of one treatment cycle prior to the baseline (Day 1) visit. Men will be transitioned from leuprolide acetate or degarelix to relugolix (120 mg [Part 1 and 3] or 240 mg [Part 2] once daily after a single loading dose of 360 mg); on the approximate date the next analog or antagonist injection is scheduled; treatment with each combination treatment will continue as previously prescribed. Hence, the study will provide safety and tolerability of relugolix and the three different combination agents for up to 1 year and in addition, will provide safety and tolerability data as men transition from injectable leuprolide acetate or degarelix to oral treatment with relugolix. Enrollment into the study began in March 2021. A protocol amendment was approved in July 2021 to include Part 2 and Part 3 of the study and to add the 40-wk safety extension treatment period. Screening for Part 2 was initiated in August 2021 and for Part 3 it is expected to initiate in January 2022. Clinical trial information: NCT04666129.
KEYNOTE-365 cohorts E and F: Phase 1b/2 study of pembrolizumab + lenvatinib combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).
Authors: Kramer Gero , Shore Neal D. , Joshua Anthony M. , Li Xin Tong , Poehlein Christian Heinrich , Schloss Charles , De Bono Johann S. , Yu Evan Y.
Published: February 2022

TPS215

Background: Standard of care for noncurative adenocarcinoma mCRPC is docetaxel or the next-generation hormonal agents (NHAs) abiraterone and enzalutamide. However, approximately 20% of patients develop t-NE after treatment for adenocarcinoma mCRPC; t-NE is associated with shorter survival, and it has no standard of care beyond combination platinum chemotherapy. The vascular endothelial growth factor (VEGF)/fibroblast growth factor receptor (FGFR) inhibitor lenvatinib inhibits proliferation and angiogenesis in preclinical models of adenocarcinoma prostate cancer. The phase 2 KEYNOTE-199 trial showed some antitumor activity with pembrolizumab monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC. VEGF/FGFR inhibition combined with PD-1 inhibition may have enhanced benefit in mCRPC, for adenocarcinoma and possibly as a new treatment option for t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate different pembrolizumab combination therapies in several patient populations with mCRPC. Cohort E will enroll patients with confirmed adenocarcinoma of the prostate without small cell histology, per investigator. Cohort F will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort F requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score of 0 or 1. Both cohorts will receive pembrolizumab 200 mg IV every 3 weeks + oral lenvatinib 20 mg once daily until disease progression, withdrawal of consent, prespecified alanine aminotransaminase or aspartate aminotransaminase level increase, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.
DASL-HiCaP: Darolutamide augments standard therapy for localized very high-risk cancer of the prostate (ANZUP1801). a randomized phase 3 double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation.
Authors: McBride Sean Matthew , Niazi Tamim , Williams Scott , Davis Ian D. , Stockler Martin R. , Martin Andrew James , Bracken Karen , Roncolato Felicia T. , Horvath Lisa , Sengupta Shomik , Martin Jarad , Lim Tee , Hughes Simon , McDermott Raymond S. , Catto James W.F. , Kelly Paul J. , Parulekar Wendy R. , Morgan Scott Carlyle , Rendon Ricardo A. , Sweeney Christopher ,   Australia and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2022

TPS284

Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analog (LHRHA), is standard of care for men with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT in the setting of either primary definitive therapy, or salvage therapy for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind international trial for men planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by: RP; use of adjuvant docetaxel; pelvic nodal involvement. 1100 participants will be randomized to darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC: LHRHA for 96 weeks, plus RT starting week 8-24 from randomization. Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival (ICECaP-validated), with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353.
Trial in progress: A phase 2, randomized, open-label study of trilaciclib with first-line, platinum-based chemotherapy and avelumab maintenance in untreated patients with locally advanced or metastatic urothelial carcinoma (PRESERVE 3).
Authors: Sonpavde Guru P. , Grivas Petros , Milowsky Matthew I. , Galsky Matt D. , Malik Rajesh K. , Beelen Andrew Paul
Published: February 2022

TPS585

Background: Trilaciclib is an intravenous (IV) CDK4/6 inhibitor that has been shown to help protect hematopoietic stem and progenitor cells from chemotherapy (CT)-induced damage (myeloprotection) via transient cell cycle arrest. Trilaciclib is approved in the US to decrease the incidence of CT-induced myelosuppression (CIM) in adult patients with extensive-stage small cell lung cancer receiving certain treatment regimens. An exploratory phase 2 study (NCT02978716) in patients with triple-negative breast cancer showed improved overall survival (OS) in patients receiving trilaciclib prior to CT vs CT alone, regardless of PD-L1 expression. The aim of this exploratory, randomized, open-label, multicenter, phase 2 trial (PRESERVE 3; NCT04887831) is to assess whether trilaciclib administered with standard-of-care platinum-based CT and avelumab maintenance can improve antitumor efficacy and reduce CIM versus CT and avelumab without trilaciclib, in patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: Adult patients with measurable disease per RECIST v1.1, no prior systemic treatment for mUC, and ECOG performance status ≤2 will be randomized 1:1 to receive gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 or carboplatin area under the curve 4.5 (± trilaciclib 240 mg/m2 IV over 30 minutes, ≤4 hours prior to CT) in 21-day cycles. Patients will receive 4–6 cycles of CT. Those without progressive disease per RECIST v1.1 can receive avelumab 800 mg maintenance therapy (± trilaciclib) in 14-day cycles until disease progression, unacceptable toxicity, investigator/patient decision, or end of trial. Patients will be followed for survival. The sample size was calculated to support the primary endpoint of progression-free survival (PFS), using a stratified log-rank test accounting for two stratification factors (visceral metastasis and platinum agent [cisplatin/carboplatin]). 63 PFS events will be required to achieve 77% power to detect a hazard ratio of 0.6 with a 2-sided significance of 0.2, corresponding to a median PFS of 11.7 months for the trilaciclib arm. Assuming a 10-month enrollment period, final PFS analysis approximately 22 months after the first randomization, and 5% loss to follow-up, 90 patients are required for randomization. PFS will be analyzed in the intention-to-treat population. Secondary endpoints include objective response rate, disease control rate, PFS during maintenance, OS, multilineage myeloprotective effects, and safety/tolerability. Exploratory endpoints will assess pharmacodynamic parameters, including those related to immune-based mechanisms, and efficacy by CDK4/6-dependence. Enrollment opened in June 2021. As of September 29, 2021, 8 sites are open, and 1 patient randomized. Clinical trial information: NCT04887831.
Randomized comparator-controlled study evaluating efficacy and safety of pembrolizumab plus Bacillus Calmette-Guérin (BCG) in patients with high-risk nonmuscle-invasive bladder cancer (HR NMIBC): KEYNOTE-676 cohort B.
Authors: Kamat Ashish M. , Shariat Shahrokh , Steinberg Gary D. , Alanee Shaheen Riadh , Nishiyama Hiroyuki , Nam Kijoeng , Kapadia Ekta , Shore Neal D. , Hahn Noah M.
Published: February 2022

TPS597

Background: Cohort A of the phase 2 KEYNOTE-057 study showed that pembrolizumab monotherapy provided effective antitumor activity and acceptable safety in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS). Pembrolizumab in combination with BCG at earlier stages of HR NMIBC might provide benefit superior to that of BCG monotherapy. The open-label, comparator-controlled, phase 3 KEYNOTE-676 study (NCT03711032) will be conducted to investigate the efficacy and safety of pembrolizumab + BCG versus BCG monotherapy in patients with HR NMIBC. Cohort A will enroll patients with persistent or recurrent HR NMIBC after BCG induction. Cohort B is a new, randomly assigned cohort that will help evaluate pembrolizumab + BCG in BCG treatment–naive patients who either never received BCG treatment or received BCG treatment > 2 years before enrollment. Methods: Cohort B of KEYNOTE-676 will enroll approximately 975 patients with blinded independent central review (BICR)–confirmed HR NMIBC (T1, high-grade Ta CIS) and Eastern Cooperative Oncology Group performance status score 0-2 who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the past 2 years. Patients will be randomly assigned 1:1:1 to receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) + BCG reduced maintenance (≤6 months), pembrolizumab 400 mg IV Q6W + BCG full maintenance (≤18 months), or BCG monotherapy (BCG full maintenance). Stratification factors include NMIBC stage (CIS or no CIS) and PD-L1 expression (combined positive score [CPS] ≥10 or CPS < 10), determined by central laboratory. Disease status will be assessed by use of cystoscopy, urine cytology, and biopsy (as applicable) every 12 weeks (Q12W) through year 2, then every 24 weeks through year 5; imaging with computed tomography urography will occur every 72 weeks. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of study treatment (90 days for serious AEs). The primary end point is event-free survival (EFS). Secondary end points include complete response rate by BICR, duration of response (DOR), 12-month DOR rate (CIS only), 24-month EFS rate, disease-specific survival, time to cystectomy, overall survival, and safety. The study is enrolling or planning to enroll at sites in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT03711032.
Biomarker-Based Phase II Study of Sapanisertib (TAK-228): An mTORC1/2 Inhibitor in Patients With Refractory Metastatic Renal Cell Carcinoma
Authors: McGregor Bradley A. , Xie Wanling , Adib Elio , Stadler Walter M. , Zakharia Yousef , Alva Aijai , Michaelson M. Dror , Gupta Shilpa , Lam Elaine T. , Farah Subrina , Nassar Amin H. , Wei Xiao X. , Kilbridge Kerry L. , Harshman Lauren , Signoretti Sabina , Sholl Lynette , Kwiatkowski David J. , McKay Rana R. , Choueiri Toni K.
Published: February 2022

PURPOSE

Sapanisertib is a kinase inhibitor that inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. In this multicenter, single-arm phase II trial, we evaluated the efficacy of sapanisertib in patients with treatment-refractory metastatic renal cell carcinoma (mRCC; NCT03097328 ).

METHODS

Patients with mRCC of any histology progressing through standard therapy (including prior mTOR inhibitors) had baseline biopsy and received sapanisertib 30 mg by mouth once weekly until unacceptable toxicity or disease progression. The primary end point was objective response rate by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored.

RESULTS

We enrolled 38 patients with mRCC (clear cell = 28; variant histology = 10) between August 2017 and November 2019. Twenty-four (63%) had received ≥ 3 prior lines of therapy; 17 (45%) had received prior rapalog therapy. The median follow-up was 10.4 (range 1-27.4) months. Objective response rate was two of 38 (5.3%; 90% CI, 1 to 15.6); the median progression-free survival (PFS) was 2.5 months (95% CI, 1.8 to 3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events, with no grade 4 or 5 toxicities. Alterations in the mTOR pathway genes were seen in 5 of 29 evaluable patients ( MTOR n = 1, PTEN n = 3, and TSC1 n = 1) with no association with response or PFS. Diminished or loss of PTEN expression by immunohistochemistry was seen in 8 of 21 patients and trended toward shorter PFS compared with intact PTEN (median 1.9 v 3.7 months; hazard ratio 2.5; 95% CI, 0.9 to 6.7; P = .055).

CONCLUSION

Sapanisertib had minimal activity in treatment-refractory mRCC independent of mTOR pathway alterations. Additional therapeutic strategies are needed for patients with refractory mRCC.