bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value and therapeutic implications of an integrative molecular subtype and immune content classifier in localized muscle-invasive bladder cancer.
Authors: Farha Mark , Cotta Brittney , Vince Randy , Nallandhighal Srinivas , Kaffenberger Samuel D. , Palmbos Philip , Alva Ajjai Shivaram , Morgan Todd Matthew , Palapattu Ganesh S. , Salami Simpa , Udager Aaron M.
Published: February 2022

530

Background: Localized muscle-invasive bladder cancer (MIBC) exhibits heterogeneous molecular features and outcomes, with a 5-year mortality rate of approximately 30%. Immune checkpoint blockade (ICB) has the potential to improve oncological outcomes but molecular tools are needed to identify those most likely to benefit. Here, we integrate transcriptomically derived tumor immune microenvironment (TIME) data with molecular subtypes to create a novel integrative classifier with prognostic and therapeutic implications. Methods: RNAseq data from patients with localized muscle-invasive bladder cancer (MIBC) from the Cancer Genome Atlas BLCA (TCGA-BLCA) project was utilized (n = 187). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Consensus molecular clustering information for the cohort was obtained from Kamoun et al. Overall survival (OS) of each cluster were analyzed. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB. Results: In the TCGA-BLCA cohort, there were two distinct clusters enriched with macrophages, CL1-M0Hi (n = 18) and CL5-M2Hi (n = 35). Compared to the rest of the cohort, these two macrophage enriched clusters combined exhibited a decreased OS (33.1 mo vs. NR, p = 0.01). TIDE tool predicted ICB response was lowest in CL1 (6/18, 33%; p = 0.09), CL5 (12/35, 34%; p = 0.02), and the Ba/Sq molecular cluster (16/57, 28%; p = 1.3x10-5). Patients designated as CL1 or CL5 by immune clustering and Ba/Sq by molecular consensus were combined into a subgroup (n = 20). Compared to the rest of the cohort, this Ba/Sq_MacrophageHi subgroup had a higher body mass index (31.0 vs. 25.8 BMI, p = 0.0004), more whites (95% vs. 64%, p = 0.03), and had a higher stage (80% Stage III/IV vs. 20% Stage I/II, p = 0.05). The Ba/Sq_MacrophageHi cluster demonstrated higher PD-L1 expression (mean Z score 0.15 vs. -0.09; p = 0.008), there was a higher degree of T cell exclusion (mean Z score 0.16 vs. -0.06; p = 0.003) and cancer-associated fibroblasts (mean Z score 0.03 vs. -0.02; p = 3.4x10-5). Overall, the predicted response to ICB by TIDE in the Ba/Sq_MacrophageHi was lower (OR 0.15, 0.03-0.55 p = 0.002) and OS was significantly shorter (median 16.7 mos vs. 54.9 mo, p = 0.04). Conclusions: We demonstrated the prognostic significance of the Basal/Squamous subtype with macrophage enrichment in patients with localized MIBC. Pending further prospective validation, this sub-population may be less amenable to ICB treatment.
Development and clinical application of PredicineBEACON next-generation minimal residual disease assay for genitourinary cancers.
Authors: Xie Feng , Zang Jingyu , Zhang Yue , Zhang Ruiyun , Huang Yong , Zhuang Guanglei , Chen Haige , Du Pan , Jia Shidong
Published: February 2022

539

Background: Tumor-informed minimal residual disease (MRD) assay has been studied in muscle invasive bladder cancer (MIBC) in IMvigor010 study. However, the current methods require the use of tumor tissue and lacking actionable insights. In this study, a tumor-agnostic and actionable MRD assay (PredicineBEACON) is developed with high sensitivity and capability to detect actionable mutations in blood- or urine-based circulating tumor DNA. Methods: PredicineBEACON tumor-agnostic MRD assay includes three components, i.e., baseline mutation identification, personalized panel design, and ultra-deep next generation sequencing of cancer variants. Step 1: whole exon sequencing with boosted depth in 600 cancer-related genes is performed using baseline tumor tissue or liquid biopsy (blood or urine) to identify somatic mutations. Step 2: Up to fifty somatic mutations are selected for personalized MRD panel design, in combination with the use of a fixed core panel of 500 actionable/hotspot variants. Step 3: MRD and actionable mutations were called from ultra-deep sequencing (100,000X). A companion low-pass whole-genome sequencing (LP-WGS) is performed to monitoring copy number variation (CNV). In the current study of patients with MIBC, urine samples at baseline were used for personalized variant generation. Urine samples under neoadjuvant immunotherapy and blood samples after radical cystectomy were collected and tested with the PredicineBEACON MRD assay. Results: PredicineBEACON MRD assay demonstrated a sensitivity of 0.005% tumor fraction. In patients of MIBC, urine-based MRD assay detected the dynamic changing of disease evolution under neoadjuvant therapy and preceded the radiographic response. Actionable mutations, including FGFR3, TERT and PIK3CA mutations, were detected. Copy number burden revealed by LP-WGS correlated with disease evolution. Plasma-based MRD assay on the patients after radical cystectomy is currently ongoing. Conclusions: PredicineBEACON tumor-agnostic MRD assay provides an ultra-sensitive and actionable MRD detection with high sensitivity and specificity. Assessment of MRD could potentially be leveraged, for example, to avoid overtreatment of early stage of genitourinary cancers such as non-metastatic prostate cancer, non-muscle invasive bladder cancer and muscle invasive bladder cancer.
Characterization and functional analysis of microbiome in bladder cancer.
Authors: Bukavina Laura , Calaway Adam C. , Isali Ilaha , Prunty Megan , Ghannoum Mahmoud , Retuerto Mauricio , Mishra Kirtishri , Sindhani Mohit , Castro Bigalli Alberto , MacLennan Gregory , Ponsky Lee Evan , Markt Sarah C. , Abbosh Phillip
Published: February 2022

541

Background: The role of microbiome in genitourinary cancer is an emerging field, with evidence implicating the important role of microbiome as causative factors or cofactors in tumorigenesis and drug metabolism. Our study aims to characterize healthy and bladder cancer enterotypes in the gut and identify functional alterations through the use of metagenomics data. Methods: After prospective collection of 29 rectal swab samples of bladder cancer (BCa) patients undergoing cystectomy, and 32 healthy volunteers, we perform 16S rRNA amplicon sequencing on 61 samples (29 with bladder cancer, 32 without cancer). Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. The p values were adjusted using the false discovery rate. The a- and b-diversity analyses were performed using QIIME. The Mann-Whitney U test was employed to evaluate the statistical significance of b-diversity distances within and between groups of interest. Results: Across all the bladder cancer stool samples, estimation of relative abundance revealed of the five most dominant bacterial populations was Bacteroidales ( 46.21%), Clostridiales ( 32.29%), Burkholderiales (9.07%), Erysipelotrichales (3.20%) and Lactobacillales ( 2.20%). In contrast, healthy controls exhibited an increased relative abundance of Enterobacteriales ( 10.75% vs 0.52%) and Pseudomonadales (8.33% vs 0.18%) as compared to tumor samples. The microbial diversity differences between Bca and normal samples showed no differences across alpha diversity metrics (Shannon diversity p>0.05) as compared to normal tissue. However, there was significant difference in clustering of organisms as determined by principal coordinate analysis ( PCoA) ordination of unweighted UniFrac Distances, (p=0.002). Furthermore, upon stratification of patients on smoking status (all healthy=nonsmokers), clustering persisted, albeit non smokers with bladder cancer displayed an intermediate across PCoA. Bca samples exhibited higher LDA score Campylobacterales (log change 8.0, p<0.001, padj <0.001) ,Fusobacteriales (log change 6.11, p<0.001/ padj<0.01), Epysipelotrichales (log 2.55, p<0.001/ padj <0.001 ), Actinomycetales (log change 1.86, p=0.001/ padj<0.001), Verrucomicrobiales (log change 1.78, p=0.017/padj=0.031) and Enterobacteriales (log change -1.54,p=0.017/ padj= 0.132). Conclusions: In conclusion, our study provides preliminary evidence that the GI microbiota is different in bladder cancer patients. Collectively, our study highlights distinct microbial overexpression of Campylobacter and Fusobacterium in Bca cohort not previously reported, both implicated in tumorigenesis, and could serve as a target that could be modulated to enhance treatment response.
PD-L1 expression and BCG response in nonmuscle invasive bladder cancer.
Authors: Woldu Solomon L. , Gerald Thomas , Margulis Vitaly , Halstuch Daniel , Ber Yaara , Lifshitz Karin , Margel David , Lotan Yair , Jia Liwei
Published: February 2022

545

Background: Intravesical bacillus Calmette Guerin (BCG) is the standard of care adjuvant therapy for high risk non-muscle invasive bladder cancer (NMIBC), yet many patients experience recurrence or disease progression. The mechanism of action of BCG is believed to be related to stimulation of immune surveillance. Relatedly, systemic immune checkpoint inhibition is currently being utilized in advanced bladder cancer and approved for BCG unresponsive NMIBC. We sought to determine the association between PD-L1 expression and BCG treatment. Methods: We identified 102 BCG-naïve patients with high grade (HG) NMIBC treated with BCG. All patients underwent initial transurethral resection (TUR) for pathologic diagnosis. Dako 22c3 assay was used to determine PD-L1 expression. Patients were defined as PD-L1 positive if the combined positive score (CPS) > 0. BCG unresponsiveness was defined by presence of high grade disease at 6 months following adequate BCG (one induction and maintenance cycle or two induction cycles) for pT1 or 12 months for CIS or presence of pT1 at 3 months following induction. HG relapse was defined as presence of any HG disease after being followed for 6 months after BCG. Results: The median follow-up time was 57 months. Median number of BCG maintenance cycles was 1, and 17 (16.7%) patients underwent immediate reinduction BCG. PD-L1 expression was observed 5.9% of pTa, 30.0% of pT1, and 3.6% of CIS. BCG unresponsiveness and HG relapse were observed in 32 (35.6%) and 29 (34.5%) patients, respectively. On univariate analysis, PD-L1 expression was inversely associated with BCG unresponsiveness (OR = 0.112; 95% CI 0.014-0.898) but not high grade relapse (OR = 0.296; 95% CI 0.061-1.440). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression for BCG responsiveness were 22%, 97%, 93%, and 41%, respectively. The post-test probability of BCG responsiveness was 93% in patients positive for PD-L1 based on a positive likelihood ratio of 7.33 for PD-L1 expression. On multivariate regression, pT1 (OR = 0.159; 95% CI 0.045-0.600), CIS (OR = 0.247; 95% CI 0.071-0.857), and PD-L1 expression (OR = 15.625; 95% CI 1.779-142.857) were independently associated with BCG responsiveness. Conclusions: PD-L1 expression in HG NMIBC was low, and patients with PD-L1 expression at initial TUR were more likely to harbor invasive disease. Patients showing PD-L1 expression were more likely to demonstrate BCG responsiveness. These findings suggest a role of PD-L1 in the immune surveillance mechanism of BCG at initial pathologic diagnosis and may assist in predicting responses to BCG among patients with HG NMIBC. Further investigation is required to determine if additional immune checkpoint markers have strong correlation with BCG response, particularly among patients without PD-L1 expression.
Expanding the use of targeted therapy for urothelial bladder cancer (UBC): Non-FGFR3 receptor tyrosine kinase (RTK) gene rearrangements (ReAr) and fusions (fus).
Authors: Necchi Andrea , Pavlick Dean C. , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Spiess Philippe E. , Grivas Petros , Parini Vamsi , Decker Brennan , Lin Douglas I. , Danziger Natalie , Levy Mia Alyce , Ross Jeffrey S.
Published: February 2022

550

Background: After the regulatory approval of erdafitinib targeting FGFR genomic alterations (GA), molecular profiling and targeted therapy indications may further expand in UBC. We queried a large database of advanced UBC to study the landscape of RTK ReAr and Fus to categorize additional targets beyond FGFR1-3 that have potential to further personalize treatment of this disease. Methods: We analyzed data from 8,233 UBC cases, which underwent hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression in tumor cells was assessed by IHC (Dako 22C3). Results: A total of 1,210 (14.7%) UBC featured known and likely large-scale (LS) internal ReAr with 414 (5%) ReAr in RTK genes. The ReAr/fus were distributed among ABL1 (3), ALK (3), BRAF (29), CDK12 (44), CDK8 (1), EGFR (10 ), ERBB2 (3), FGFR1 (2), FGFR2 (16 ), FGFR3 (231), FLT3 (1), MAO2K4 (4), NTRK1 (7 ), NTRK2 (5), NTRK3 (7), RAF1 (31 ), RET (8) and ROS1 (9). LS ReAr were divided into LS ReAr-associated gene deletions (1%), truncations (1%), rearrangements (61%) and fusions (37%). FGFR3 fus accounted for 81% of RTK fus with BRAF and RAF1 both at 2%. The greatest frequencies of kinase ReAr were in CDK12 (29%), FGFR3 (16%), RAF1 (13%) and BRAF (12%). Additional noteworthy ‘targetable’ RTK ReAR and fus included NTRK1-3 (19 cases), ROS1 (9 cases), RET (8 cases) and ALK (1 case). 407 (98.4%) of the RTK ReAr/fus-positive UBC had only 1 RTK ReAr/fus GA and 7 (1.6%) had 2 ReAr ReAr/fus, 6 (85.7%) of which involved FGFR3. Compared with LS ReAR negative UBC, the LS ReAR UBC cases revealed similar gender and age characteristics, MSI status, similar frequencies of TMB ≥ 10 mut/Mb and PD-L1 expression in tumor cells ≥1% and ≥50%. Conclusions: At a 5% frequency, potentially ‘targetable’ RTK gene rearrangements and fusions are a rare but important opportunity to further personalize treatment selection of UBC, including RTK inhibitors, PARP inhibitors ( CDK12) and immunotherapy. This potential for clinical trials supports broader CGP, compared to targeted FGFR sequencing, in order to uncover additional opportunities for precision therapies that have the potential to improve patient outcomes.[Table: see text]
Integrative analysis of urine cell-free DNA for the detection of residual disease in localized bladder cancer patients.
Authors: Chauhan Pradeep S. , Shiang Alexander , Chen Kevin , Babbra Ramandeep , Feng Wenjia , Szymanski Jeffrey J. , Harris Peter K. , Hatcher Casey , Roussin Jessica , Basarabescu Franco , Brunt Lindsey , Mayer Lindsey R. , Borkowski Ariel , Maguire Lenon , Baumann Brian C. , Reimers Melissa Andrea , Kim Eric H , Arora Vivek K , Smith Zachary L , Chaudhuri Aadel A
Published: February 2022

559

Background: We previously developed a liquid biopsy assay to measure urine tumor DNA (utDNA) levels based on detection of single nucleotide variants (SNVs) in urine cell-free DNA (cfDNA). Nonsilent SNV detection in urine from muscle-invasive bladder cancer (MIBC) patients prior to radical cystectomy (RC) was associated with pathologic residual disease and worse progression-free survival (Chauhan et al., PLOS Medicine, 2021). Given the multiple types of genomic alterations present in bladder cancer (BC), here we developed a multi-omics approach for estimating utDNA levels without restricting our approach to SNVs. We performed ultra-low pass whole genome sequencing (ULP-WGS) based copy number analysis and urine Cancer Personalized Profiling by deep Sequencing (uCAPP-Seq) of urine cell-free DNA to predict pathologic complete response (pCR) in localized BC patients. Methods: We acquired urine preoperatively from 65 BC patients (69% muscle-invasive) on the day of standard-of-care RC, and after neoadjuvant chemotherapy in 48% of patients. We performed ULP-WGS of urine cfDNA from all 65 BC patients and 11 healthy adults. utDNA levels based on genome-wide copy number alterations (CNAs) in urine cfDNA was estimated using ichorCNA. In order to derive a SNV-based utDNA level as well, uCAPP-Seq was applied to urine cfDNA samples derived from 42 patients using a 145 kb panel of 49 consensus driver genes commonly mutated in MIBC. Results: In our cohort of 65 BC patients, 55% of patients achieved pCR ( n = 36) while 45% had residual disease detected in their surgical sample (no pCR; n = 29). Comparing ULP-WGS-derived utDNA levels between the groups, patients with no pCR had significantly higher CNA-derived tumor fractions in urine compared to patients with pCR (median 8.9% vs 1.8%, p = 0.01) and healthy adults ( n = 11) (median 8.9% vs 0%, p = 0.006). Further analysis with uCAPP-Seq in 42 patients revealed that nonsilent SNV-based utDNA detection correlated significantly with the absence of pCR ( p < 0.001) with a sensitivity of 81% and specificity of 81%. Moreover, utDNA-positive patients exhibited significantly worse progression-free survival compared to utDNA-negative patients (HR = 7.4; 95% CI: 1.4–38.9; p = 0.02). Conclusions: Bladder cancer patients who did not attain a pCR at the time of RC had greater genome-wide copy number alterations and nonsilent single nucleotide variants in their urine cfDNA compared to patients with pCR. These results suggest that integrative multi-omics of urine derived from MIBC patients has potential real-world clinical impact for bladder-sparing approaches in select patients.
Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UBC) genomic alteration (GA) profile.
Authors: Grivas Petros , Necchi Andrea , Spiess Philippe E. , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Lin Douglas I. , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S.
Published: February 2022

563

Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.[Table: see text]
Long-term follow-up of intravesical gemcitabine and docetaxel as rescue therapy for nonmuscle-invasive bladder cancer.
Authors: Chevuru Phani T. , McElree Ian Mitchell , Martin Alexander C. , Richards Jordan , Mott Sarah L. , Gellhaus Paul T. , Nepple Kenneth G. , Steinberg Ryan L. , O'Donnell Michael A. , Packiam Vignesh T.
Published: February 2022

573

Background: Intravesical bacillus Calmette-Guérin (BCG) is the first-line treatment for high-risk non-muscle invasive bladder cancer (NMIBC). Unfortunately, disease recurrence/progression is common and associated with increased risk of death from bladder cancer. While radical cystectomy remains the preferred treatment for BCG unresponsive NMIBC, many patients are either unwilling or unfit to undergo surgery. Previous retrospective studies have demonstrated the efficacy of intravesical gemcitabine and docetaxel (Gem/Doce) for treating NMIBC after BCG failure. However, the long-term outcomes of this cohort are unknown. We report 5-year survival outcomes of patients treated with intravesical Gem/Doce after BCG failure. Methods: We retrospectively identified patients at our institution who were treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Initial responders received monthly maintenance instillations for 2 years. Surveillance was performed according to American Urological Association guidelines. Survival time was measured from start of Gem/Doce induction. Outcomes included high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS) and overall survival (OS). Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as recurrence of disease with stage T2 or greater, cystectomy or death due to bladder cancer. Survival probabilities were calculated with the Kaplan-Meier method. Results: A total of 97 patients with a median age of 73 years were treated with Gem/Doce after BCG failure. Median follow-up was 49 months. BCG failure was further stratified as BCG unresponsive (35%), BCG relapsing (38%), BCG intolerant (11%) or unspecified (16%). 71% and 21% of patients had carcinoma in-situ and high-grade T1 disease, respectively. Complete response at initial surveillance was 74% and median duration of response was 26 months. Overall HG-RFS at 1, 2 and 5 years was 60%, 51% and 31%, respectively. HG-RFS was similar among BCG unresponsive patients and the overall cohort (see table). During follow-up, 18 patients (19%) underwent radical cystectomy and 28 patients (29%) experienced disease progression. PFS, CFS, CSS and OS at 5 years was 68%, 75%, 91% and 64%, respectively. Conclusions: Intravesical Gem/Doce for high-risk NMIBC after BCG failure offers long-term efficacy and substantial durability of response with a high likelihood of bladder preservation at five years after induction. Future prospective trials assessing Gem/Doce are warranted.[Table: see text]
Phase 1b study of tarlatamab, a half-life extended bispecific T-cell engager (HLE BiTEimmune therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).
Authors: Aggarwal Rahul Raj , Rottey Sylvie , Aparicio Ana , Greil Richard , Reimers Melissa Andrea , Sandhu Shahneen Kaur , Zhang Yiran , Salvati Mark , Hashemi Sadraei Nooshin
Published: February 2022

TPS197

Background: NEPC is an aggressive cancer with no standard treatment approach and poor prognosis. It is usually treatment-emergent, occurring in 15%–20% of patients (pts) with metastatic castration-resistant prostate cancer following treatment with androgen signaling inhibitors (ASI) and is characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor.1 The tumor associated antigen delta-like ligand 3 (DLL3) has been identified as a promising target in both NEPC and small cell lung cancer (SCLC), as it is highly expressed in these tumors and minimally expressed on normal tissue. Tarlatamab is a DLL3-targeting HLE BiTE® immune therapy designed to bind DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In preclinical studies, tarlatamab induced T-cell dependent lysis of DLL3-expressing neuroendocrine tumor cell lines, including NEPC cells.2 Interim results of an ongoing first-in-human study in pts with SCLC (NCT03319940) show evidence for tarlatamab efficacy with an acceptable safety profile.3 Together, these findings support a clinical study of tarlatamab in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating tarlatamab infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with metastatic NEPC whose disease progressed/recurred after ≥1 prior line of systemic therapy (platinum-based regimen for de novo NEPC or an ASI if treatment-emergent), measurable disease per RECIST 1.1 with Prostate Cancer Working Group 3 modifications, and ECOG performance status ≤2. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of tarlatamab. Secondary objectives are to evaluate antitumor activity (as assessed by objective response, duration of response, progression-free survival, overall survival, and disease control rate) and characterize pharmacokinetics. Four US and international study sites have been activated with two enrolled pts. References: Aggarwal R, et al. J Clin Oncol. 2018;36:2492-2503. Cooke K, et al. Abstract 627. Presented at: SITC Annual Meeting, Nov 9–14, 2020; Virtual. Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual. Clinical trial information: NCT04702737.
Salvage radiotherapy (SRT) in combination with pembrolizumab in patients with PSA persistence or biochemical recurrence after radical prostatectomy due to prostate cancer.
Authors: Grabbert Markus , Zamboglou Constantinos , Josef Annika , Sigle August , Spohn Simon K.B. , Grosu Anca L. , Gratzke Christian
Published: February 2022

TPS212

Background: Goal of our study is to evaluate the efficacy and safety of immunotherapy in combination with standard salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) or prostate-specific antigen (PSA) persistence after radical prostatectomy (RP). The combination of immunotherapy (IO) with radiation therapy might provide a clinical benefit to patients with recurrent prostate cancer due to an induction of increased activity of the immune system against cancerous tissue (abscopal effect). Primary endpoint is complete biochemical response (PSA level below detection level) 60 weeks after start of trial treatment, which further defines prognosis of patients. Further explorative endpoints like radiographic progression-free survival, PSA-nadir level and time to PSA-nadir, time to initiation of subsequent therapy (secondary ADT or NHA) and quality of life as well as adverse events will be evaluated. Methods: The trial is as a phase II, open-label, single arm monocenter trial which evaluates the combination of pembrolizumab as study medication in combination with SRT. Pembrolizumab will be administered in a three-weekly scheme up to one year of treatment. A concomitant ADT is administered in high-risk patients only (PSA > 0.7ng/ml or cN+ in imaging studies). All patients will be staged with PSMA PET-CT, if applicable. Additionally, blood and urine samples will be collected for correlative biomarker studies. A total of 49 patients are planned to be enrolled in this explorative study within 2 years. INCLUSION CRITERIA (excerpt) Histologically confirmed diagnosis of an adenocarcinoma of the prostate and a BCR or PSA persistence after RP. Histology of the RP specimen needs to fulfill the following criteria: adenocarcinoma of the prostate, Gleason score 7-10; pNX or pN0 or pN1 (max. 2 lymph nodes involved). Imaging within 30 days prior to study inclusion is mandatory (([68Ga] or [18F] PSMA PET-CT as standard imaging modality, alternatively CT abdomen and full-body bone scan). PSA value between ≥0.2 and ≤1.0 ng/ml, measured at least six weeks postoperatively. EXCLUSION CRITERIA (excerpt) Prior-therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration (like neo-adjuvant androgen deprivation therapy (ADT), secondary hormone ablation or taxan-based chemotherapy). Distant metastases or suspicious lymph nodes outside the lower pelvis in imaging with PSMA PET-CT (patients with PET positive bone lesions that are morphologically not clearly suspicious of metastases and would not change clinical practice can be included). Clinical trial information: NCT04931979.
A phase 2 study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Einstein David Johnson , Choudhury Atish Dipankar , Saylor Philip James , Patterson Jesse Christopher , Croucher Peter , Ridinger Maya , Erlander Mark G. , Yaffe Michael B. , Bubley Glenn
Published: February 2022

TPS219

Background: Metastatic CRPC is a leading cause of cancer death worldwide. Although abiraterone (abi) + prednisone in either castration-sensitive or castration-resistant disease increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic function and is upregulated in prostate cancer following androgen-deprivation therapy (ADT). Onvansertib is an oral and highly-selective PLK1 inhibitor that demonstrated safety and tolerability as a single agent in a Ph1 trial. Preclinical studies showed that PLK1 inhibition enhanced abi anti-tumor effect in cell line models and in patient-derived tumor xenografts via an AR-independent mechanism. Transcriptomic analyses revealed that abi induced mitosis-related gene sets in cells synergistic for abi + onvansertib, and identified an abi-onvansertib synergy gene signature. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib + abi on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients are enrolled at time of PSA progression while on standard abi. Prior treatment with enzalutamide or apalutamide is not permitted. Three onvansertib dosing schedules are tested in noncomparative arms: arm A (24 mg/m2 on days 1-5 of a 21-day cycle), arm B (18 mg/m2 on days 1-5 of a 14-day cycle), and arm C (12 mg/m2 on days 1-14 of a 21-day cycle). To-date, 24 patients were enrolled in Arm A, and 20 patients each in Arms B and C. With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if < 2 of the first 13 patients in each arm achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) in circulating tumor cells and targeted genomic profiling of circulating tumor DNA to assess associations between genomic alterations and response to treatment. Additionally, transcriptomic analysis of archived tumor tissue will be performed to identify gene expression signatures associated with clinical responses. Clinical trial information: NCT03414034.
PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase 3 trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients (pts) with localized or locally advanced high-risk prostate cancer (PC).
Authors: Kibel Adam S. , Gleave Martin , Brookman-May Sabine D. , Kim Won , Evans Christopher P. , Efstathiou Eleni , Kantoff Philip W. , Ross Ashley , Shore Neal D. , Briganti Alberto , Hadaschik Boris A. , Heidenreich Axel , Rooney Oliver Brendan , Tian Shaozhou Ken , Wetherhold Lisa , Xu Weichun , Parsons J. Kellogg , Yeruva Kesav , Taplin Mary-Ellen
Published: February 2022

TPS285

Background: In pts with localized high-risk PC, disease recurrence rate following RP is ̃50% (Kane et al. J Urol. 2007). Treatment (tx) with androgen blockade before RP can reduce tumor burden post RP (Taplin et al. J Clin Oncol. 2014; McKay et al. Prostate Cancer Prostatic Dis. 2018; Efstathiou et al. Eur Urol. 2019). This study examines if 12 months of perioperative APA + ADT tx before and after RP with pelvic lymph node dissection (pLND) in localized/locally advanced high-risk PC improves pathologic complete response (pCR) rate and metastasis-free survival (MFS) vs PBO + ADT. Methods: PROTEUS, an international multicenter study, is enrolling ̃2000 pts with localized/locally advanced high-risk/very high-risk PC who are candidates for RP with pLND over 3 years at > 203 sites in 18 countries. Stratification variables: Gleason score (7 vs ≥ 8), pelvic node status (N0 vs N1), international region. Randomization: 1:1 to APA (240 mg/d) + ADT or PBO + ADT. Pts receive 6-month neoadjuvant tx followed by RP and then 6 months’ adjuvant tx. Primary end points: pCR rate and MFS. In addition to MFS based on conventional imaging, MFS based on PSMA PET or conventional imaging will be assessed as a separate end point. Both pCR and MFS are assessed by blinded independent central review. Conventional imaging by CT or MRI and bone scan are done at screening, within 4 weeks after RP, at biochemical failure (BCF), and then every 6 months after BCF until distant metastasis or death. During the direct perioperative period, APA/PBO is stopped 2 weeks prior to planned RP and then resumed 4 weeks after RP if post-RP imaging has been conducted to assess for lymphocele and disease progression and resolution to grade ≤ 1 of any clinically significant adverse events considered related to RP. To reflect evolving standard of care, the following protocol amendments were added: PSMA-PET imaging at 3 months post adjuvant tx, at BCF, and every 6 months until distant metastasis or death; cardiovascular and thrombotic risk assessment at screening, prior to, and after RP; and guidance for standard thrombotic prophylaxis in the perioperative setting. An independent data monitoring committee will review trial data. Clinical trial information: NCT03767244.
Evaluation of safety and effectiveness of cryoablation in the treatment of renal angiomyolipoma related to tuberous sclerosis complex: The Cryo-TSC study.
Authors: Kashiwagi Eiji , Asayama Yoshiki , Hatano Takashi , Miki Jun , Egawa Shin , Takamoto Atsushi , Nasu Yasutomo , Osawa Takahiro , Shinohara Nobuo , Hongo Fumiya , Ukimura Osamu , Nishie Akihiro , Ushijima Yasuhiro , Kiyomi Fumiaki , Nakano Shuji , Arai Yasuaki , Eto Masatoshi
Published: February 2022

TPS397

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease that causes benign tumors called hamartoma all over the body as well as neuropsychiatric symptoms such as epilepsy. One-third of patients have a family history of the disease, but the remaining two-thirds are solitary cases and are caused by newly arising mutations. The TSC1 gene on chromosome 9 and TSC2 on chromosome 16 have been identified as the causative genes. Approximately 60%–80% of patients with TSC have renal lesions, and angiomyolipoma (AML) occurs bilaterally. The frequency of TSC-associated AML (TSC-AML) increases with age, reaching 60%–80% in adults, and the rate of death from renal disease increases with age in TSC patients. The current standard of care for AML is arterial embolization or surgery (partial nephrectomy or nephrectomy), but TSC is a hereditary disease and AMLs occur one after another with age. Repeated surgical procedures are technically difficult, and arterial embolization has a high recurrence rate. Under these circumstances, an mTOR inhibitor, everolimus, has shown a marked reduction of TSC-AML and is widely used. However, everolimus must be administered permanently because AML re-occurs after discontinuation of everolimus. Cryotherapy has been used as a treatment for renal tumors, and there have been some reports of cryotherapy for solitary AML, but the safety and efficacy of cryotherapy for TSC-AML have not been established. Therefore, we planned this study to establish the safety and efficacy of cryotherapy for TSC-AML. Methods: This is an open-label, single-arm, phase II study to evaluate the safety and efficacy of cryotherapy for TSC-AML of 4 cm or less in patients with 16 years of age or older. The exclusion criteria are an inability to withdraw from mTOR inhibitor and failure to maintain rest during cryotherapy. mTOR inhibitor medication should be withdrawn at least 7 days prior to cryotherapy and discontinued during the study period. Cryotherapy will be performed using Cryohit (GALIL MEDICAL LTD, Israel). Safety will be assessed at 1, 2, 6, and 9 months after cryotherapy, and efficacy will be assessed at 3 and 9 months after cryotherapy. The efficacy of cryotherapy will be evaluated according to modified RECIST or RECIST criteria. The primary endpoint will be the disease control rate of AML treated with cryotherapy, and secondary endpoints will be the overall response rate, safety, renal function, quality of life, and whether additional treatment is required. Clinical trial information: jRCTs072200039.
Phase 3 study of first-line treatment with pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib for advanced renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Plimack Elizabeth R. , Powles Thomas , Voss Martin H , Gurney Howard , Silverman Rachel Kloss , Perini Rodolfo F. , Rodriguez-Lopez Karla , Rini Brian I.
Published: February 2022

TPS399

Background: Combination therapy with the PD-1 inhibitor pembrolizumab and the vascular endothelial growth factor (VEGF) inhibitor lenvatinib showed antitumor activity as first-line treatment for advanced clear cell RCC (ccRCC) in the phase 3 KEYNOTE-581/CLEAR study (NCT02811861). Antitumor activity has also been shown with the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) in ccRCC and with MK-1308A (coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab) in non–small cell lung cancer. Therefore, HIF-2α or CTLA-4 inhibition with a PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will compare first-line treatment with the novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) or MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C) for advanced RCC. Methods: Approximately 1,431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and KPS score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg orally once daily [QD] + pembrolizumab 400 mg IV every 6 weeks [Q6W]), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV [Q6W] and lenvatinib 20 mg orally QD), or arm C (pembrolizumab 400 mg IV [Q6W] + lenvatinib 20 mg orally QD). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (̃2 years). Stratification factors are International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, Q6W through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival for arm A or arm B versus arm C in patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. The study is recruiting patients at sites across, Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04736706.
SWOG S1931 (PROBE): Phase III randomized trial of immune checkpoint inhibitor (ICI) combination regimen with or without cytoreductive nephrectomy (CN) in advanced renal cancer.
Authors: Vaishampayan Ulka N. , Tangen Catherine , Tripathi Abhishek , Shuch Brian M. , Pal Sumanta K. , Barata Pedro C. , Tan Alan , Zuckerman Peggy , Mayerson Edward , Lara Primo "Lucky" N. , Agarwal Neeraj , Vogelzang Nicholas J. , Kim Hyung Lae , Thompson Ian Murchie
Published: February 2022

TPS402

Background: Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no change in overall survival with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of cytoreductive nephrectomy (CN) or primary resection has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary. Methods: Eligible patients with primary tumor and metastases are treated with one of the FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab, or axitinib and avelumab. Cabozantinib + nivolumab and lenvatinib + pembrolizumab combinations are being added into the next amendment. Urology evaluation and response assessment is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy. The primary endpoint is overall survival. We estimate the median survival from time of randomization for the non-surgical arm will be 25 months. The study hypothesis is that CN will result in improvement in OS outcomes in advanced synchronous RCC post-initial systemic immune checkpoint based combination therapy. With a sample size of 302 eligible, randomized participants (151 per arm) and a one-sided alpha = 0.025, the study has 85% power to detect a 47% improvement in median survival (HR = 0.68; 1/0.68 = 1.47) Clinical trial information: NCT04510597.
A phase II trial evaluating the efficacy of cabozantinib in the treatment of patients with refractory germ-cell tumors (GCT).
Authors: King Jennifer , Dropcho S , Beeler Sherry , Sastre Jessica , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: February 2022

TPS428

Background: While the majority of patients with metastatic testicular cancer are cured with first-line cisplatin-based chemotherapy, 20-30% of patients will relapse following initial treatment. Many will still be cured with second and even third-line chemotherapy options, but there remains a need for new therapeutic approaches for patients with relapsed/refractory disease. Cabozantinib is an oral tyrosine-kinase inhibitor (TKI) with multiple targets including c-MET, VEGF, RET, and AXL. Testicular GCT have low rates of somatic mutations, though have been shown to be associated with a gain of chromosome 7, a portion of which encodes c-MET. When hepatocyte growth factor (HGF) binds to its c-MET receptor, cell proliferation, migration, invasion, and apoptosis escape occurs. In addition, compared to normal testicular tissue, testicular GCT have been shown to have higher rates of VEGF expression. Based on these findings, we proposed a phase 2 trial with cabozantinib in patients with relapsed/refractory GCT. Methods: This phase II, single arm, open label trial with a Simon two-stage design is evaluating cabozantinib 60mg daily in patients with relapsed/refractory GCT. Eligible patients are adult men and women with GCT (seminoma, non-seminoma, or ovarian GCT) that have progressed after first-line cisplatin-based combination chemotherapy in addition to at least 1 salvage regimen and are considered incurable with standard therapies. Patients with primary mediastinal non-seminoma, late relapse, and treated stable brain metastases are eligible. 12 patients will be enrolled initially in the first stage of the Simon two-stage design. If at least one complete response (CR), partial response (PR), or stable disease (SD) for ≥3 months is achieved, the trial will be deemed worthy of further investigation and 9 additional patients will be enrolled. Patients will be treated daily with cabozantinib until time of progression or unacceptable toxicity. Primary outcome is clinical benefit rate (proportion of CR, PR, and SD for ≥3 months using RECIST 1.1, modified to include tumor markers, AFP and hCG). Secondary outcomes include objective response rate, progression-free survival, overall survival, and tolerability and toxicity of cabozantinib. Exploratory evaluation of MET overexpression by IHC and amplification by next generation sequencing in correlation with response will be performed. This study is currently enrolling patients. As of September 20, 2021, the prespecified goal for the Simon stage 1 has been met, and 7 of planned 21 patients have enrolled. Clinical trial information: NCT04876456.