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Introduction
Skills and Expertise
Publications
Publications (155)
5074
Background: PC commonly expresses PSMA and has dose-responsive radiosensitivity. ¹⁷⁷ Lu-based radioligands usually use an empiric dosing regimen. This 1st dose-escalation study of ¹⁷⁷ Lu-PSMA-617 employed a dose-dense fractionation schedule intended to allow delivery of higher total doses to overcome radioresistance due to repopulation. Here,...
Background: We have previously reported that 177Lu-PSMA-617 given as a single-cycle, dose-intense regimen for patients (pts) with pretreated mCRPC is efficacious even without selection by PSMA (ESMO 2021). Quantitative analyses of pre-treatment PSMA PET may allow for better patient selection and prediction of toxicities. Analyses of sequential PET...
Introduction: Predictors of outcomes after PSMA-TRT are still being established. Liver metastases (mets) have been associated with poor response. Mutations in genes encoding DNA damage repair (DDR) and TP53 affect radiosensitivity. Here we describe a cohort of patients with mCRPC and liver metastases treated on clinical trials of PSMA-TRT.
Methods:...
279
Background: Screening for prostate cancer (PC) reduces PC-specific deaths. African American (AA) individuals have a ~2-fold higher risk of developing and dying from PC and may benefit from screening at a younger age. To increase access to PC screening for high-risk communities, we developed a portable, rapid point of care (POC) PSA test that qu...
TPS248
Background: Recent studies have shown that targeting lipid synthesis is a novel therapeutic strategy to overcome androgen resistance in mCRPC. TVB-2640 is a first-in-class FASN inhibitor, a key enzyme in de novo lipogenesis that is overexpressed and androgen-regulated in CRPC. FASN promotes the synthesis of palmitate that can be elongated an...
161
Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to...
PURPOSE
Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dos...
ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual . The goal of these articles is to dis...
Background
Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning whic...
Purpose:
Improving clinical outcomes with novel drug combinations to treat metastatic castration-resistant prostate cancer (mCRPC) is challenging. Preclinical studies showed cabazitaxel had superior antitumor efficacy compared with docetaxel. Gene expression profiling revealed divergent effects of these taxanes in cycling cells. mCRPC are RB defic...
Background:
Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT).
Methods:
Data of 180 men wi...
TPS5098
Background: Obesity promotes a chronic inflammatory state that is associated with PC progression. ADT can cause significant side effects including weight gain, accumulation of body fat, insulin resistance, and an increased risk of diabetes and cardiovascular disease. A WFPBD has been shown to promote weight loss, decrease chronic inflammati...
5018
Background: PSMA may be targeted by antibodies (mAb) or small molecules (SML), with different kinetics and biodistribution. mAb with longer circulation time and marrow exposure, but decreased access to luminal PSMA expression (e.g. salivary glands, intestine, kidney). SML diffuse to all sites of PSMA expression and then excreted. Alpha radionu...
Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of ma...
Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose...
181
Background: Only a small fraction of patients with PC respond to immunotherapy; radiation increases responses. PSMA targeted radionuclide therapy (PSMA-TRT) radiates multiple sites of disease simultaneously. ARSI can lead to radiosensitization and upregulate PSMA and PD-L1 expression. We hypothesize that the addition of potent alpha-PSMA-TRT (2...
225
Background: Metastatic, castration-resistant prostate cancer (mCRPC) is commonly the deadly form of PC. Among these, a subset of tumors are androgen-indifferent with the most aggressive often manifesting variant histology, including neuroendocrine or small cell changes. Neuroendocrine PC can be de novo (NEPC) or develop in response to therapy a...
36
Background: At Weill Cornell Medicine (WCM), we have had a research program utilizing anti-PSMA mAb J591 since the year 2000. With the addition of PSMA ligand-based therapies in 2017, we have enrolled around 300 patients on investigational PSMA-TRT clinical trials. Since the approval of ¹⁷⁷ Lu-PSMA-617 (Pluvicto; Lu-177 vipivotide tetraxetan), w...
TPS399
Background: The objective of this randomized clinical trial is to demonstrate that 2 treatments of real-time MRI-guided radiotherapy (RT) does not significantly increase patient-reported GI and GU symptoms compared to 5 treatments of RT 2 years after treatment completion (24 months). Methods: Key Eligibility Criteria: Inclusion Criteria 1. M...
TPS288
Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based tar...
TPS400
Background: The objective of this randomized clinical trial is to demonstrate that 2 weeks (5 fractions) of real-time MRI-guided radiotherapy (RT) with an MR Linac does not significantly increase patient-reported GI and GU symptoms compared to 4 weeks (20 fractions) of RT 2 years after treatment completion. Methods: Key Eligibility Criteria:...
Objectives
The non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine whether this modification could potentially retain efficacy benefits while improving on the manageable safety profil...
PURPOSE
To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC).
METHODS
An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations.
RESULTS
The panel considered peer-reviewed reports published in English.
RECOMMENDATIONS
The diagnosis o...
Background: PSMA is overexpressed by the majority of PC and may be targeted by both antibodies (mAb) and small molecule ligands (SML), each with differing PSMA binding sites, kinetics, and biodistributions. mAbs have long circulating times (exposing organs such a bone marrow) but are too large to target normal tissue luminal PSMA expression in sali...
TPS5100
Background: PSMA is overexpressed by most prostate cancers and can be successfully targeted by both antibodies (mAb) and small molecule ligands (SML), each with overlapping and distinct binding sites, kinetics, and biodistributions [Kratochwil Sem Nuc Med 2019]. mAbs are larger, with longer circulating times resulting in greater exposure to...
4529
Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T...
Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed Whole Exome Sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated gen...
532
Background: It is not known whether serial circulating tumor DNA (ctDNA) can augment imaging for assessing treatment response in patients (pts.) with advanced urothelial carcinoma (UC). We hypothesized that serial ctDNA measurements predict the clinical progression of advanced UC and map its evolutionary trajectories. Methods: We analyzed 182 s...
77
Background: Prostate Specific Membrane Antigen (PSMA) is a conserved cell surface protein in PC and is used for targeted imaging and therapeutics. Antibodies circulate longer than small molecules and are less likely to reach luminal PSMA on normal organs. Here we report PROs and longer-term AEs from the dose-escalation and expansion cohorts of a...
37
Background: We have previously reported a dose-intense single-cycle of ¹⁷⁷ Lu-PSMA-617 was effective in pretreated patients with mCRPC without requiring PSMA-positive imaging for enrollment. Prior post-hoc analyses of these data using approximate quantification of exclusively the most PSMA-positive disease sites have demonstrated associations be...
TPS216
Background: The role of immune checkpoint inhibition (ICI) in prostate cancer remains undefined outside of the subset with mismatch repair. Several studies have suggested that ICI combined with androgen receptor signaling inhibitors (ARSI) or kinase inhibitors may result in improved and/or more durable response in a proportion of men with mC...
291
Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab...
Background:
Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC).
Methods:
We performed targeted sequencing of 182 serial ctDNA samples from 53 patients w...
Background
Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long‐term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954)...
Background:
Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still needs to be proved.
Materials and methods:
In this retrospective study, w...
Introduction
The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC).
Methods and Materials
Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in...
5015
Background: Antibodies and small molecule ligands target PSMA with different kinetics and biodistribution, with certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel less accessible to large antibodies. Alpha emitters such as ²²⁵ Ac have high potency, but short range. We report dose-escalation plus expansi...
5055
Background: PSMA-TRT is a promising investigational treatment for patients with mCRPC. Expected short-term toxicities associated with PSMA-TRT include dose-dependent myelosuppression and xerostomia. However, there is a lack of information regarding long-term effects of PSMA-TRT on marrow, renal, and liver function. Additionally, potential orga...
4515
Background: Combination therapy with nivolumab plus ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability in patients with previously untreated advanced renal cell carcinoma (aRCC). Previous phase 3 clinical trials of patients with advanced or metastatic cancers have mostly excluded patients with brain metastases. CheckMat...
TPS5095
Background: Despite a variety of therapy classes extending survival in mCRPC – and excepting select population eligible for PARP inhibitors – no molecularly selected drugs are FDA approved in mCRPC. Previously, cabo, an inhibitor of multiple tyrosine kinases ( e.g. MET, VEGFRs 1-3, RET, KIT, TRKB, FLT-3, AXL, TIE-2), was evaluated in phase...
Background
Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy.
Objective
To determine the safety and efficacy of lenvatinib plus eve...
Background
Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow‐growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature.
Methods
This was a prospective observational study of patients with mRCC across 46 US community a...
158
Background: CTC counts are an independent prognostic factor in men with mCRPC; certain changes following treatment (conversion from detectable to undetectable or unfavorable to favorable) are associated with improved overall survival. Most PSMA-TRT efficacy data have focused on PSA or imaging changes. Here, we describe baseline and post-treatme...
120
Background: Elevated CTC counts are associated with a poor prognosis in men with mCRPC. PSMA targeted radionuclide therapy has been associated with decline in CTC count, but it remains unclear whether this effect results from radionuclide-induced cytotoxicity. J591 was engineered to have antibody-dependent cytotoxicity. A subset of patients was...
TPS188
Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicit...
140
Background: The combination of AR inhibition plus taxane chemotherapy has demonstrated clinical benefit in PC ( i.e. CHAARTED, STAMPEDE), indicating efficacy when targeting the AR signaling pathway at different points. We launched a phase I study to test the hypothesis that the combination of Apa (AR signaling inhibitor), AA (CYP17 inhibitor) +...
Background
Prostate-specific membrane antigen (PSMA) imaging has been suggested as highly sensitive modality for detection of metastases in patients with biochemically recurrent or advanced prostate cancer (PCa). PSMA expression is associated with grade and stage and has a relationship with androgen receptor signaling. The aim of this study was to...
Background
Prostate‐specific membrane antigen (PSMA)‐targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose–response effect in phase I/II trials in men with metastatic castration‐resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA‐TRT to select patients is largely practiced, but its...
The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs)...
Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids and have synergistic anti-tumor activity when combined. We performed a Phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor vorinostat and isotretinoin in patients with advanced ren...
Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited...
Background
We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional pa...
Background: PSMA may be targeted by antibodies or small molecule ligands labeled with potent alpha emitters. Certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel are not accessible to antibodies such as J591. Following binding, immunoreactivity, and xenograft studies, we performed a first in human study of ²²⁵...
Background: Prostate-specific membrane antigen is a cell-surface glycoprotein commonly expressed on prostatic adenocarcinomas (PC). PSMA expression is related to AR signaling, generally with increased PSMA expression with dysregulation of the AR pathway. Targeted radionuclide therapies (TRT) involving radionuclides (¹⁷⁷Lu, ²²⁵Ac, ⁹⁰Y) conjugated to...
Background
The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histo...
Background
Docetaxel remains a standard of care for metatsatic castration resistant porstate cancer (mCRPC) and has radiosensitizing properties. The dose limiting toxicity (DLT) of radioimmunotherapy is myelosuppression; dose fractionation of ¹⁷⁷Lu-J591 allows similar administered doses with less toxicity. This study (NCT00916123) was designed to d...
12090
Background: Malnutrition is an underrecognized predictor of inferior cancer related outcomes. Subjective global assessment (SGA), a brief validated survey for malnutrition, may predict increased CT toxicity. This phase II RCT was performed to validate SGA as a predictive tool for malnutrition and to evaluate the impact of MINT on CT associate...
TPS5096
Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichm...
5560
Background: Antibodies (Abs) or small molecules can target PSMA with different biodistribution. Certain sites of PSMA expression (e.g. salivary/lacrimal glands, kidneys, small bowel) are not accessible to Abs. Given radiosensitivity of PC and potency of alpha emitters plus the ability to minimize targeting off tumor PSMA+ sites with J591, we p...
Background
The open-label phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma. Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain me...
685
Background: Non-clear cell renal cell carcinoma (nccRCC) is an umbrella term that encompasses multiple RCC histological subtypes, including papillary, chromophobe, and undetermined RCC. Both increased expression of the vascular endothelial growth factor (VEGF) and dysregulation of the mammalian target of rapamycin (mTOR) pathway occur in nccRCC...
558
Background: Next-generation sequencing (NGS) of plasma ctDNA is a promising non-invasive method to detect somatic genomic alterations (GAs). We investigated whether serial ctDNA measurements can predict disease progression and map the molecular evolution of advanced UC (aUC) through successive treatments. Methods: We analyzed cohorts from 2 aca...
114
Background: Prostate-specific membrane antigen (PSMA) can be targeted by antibodies (Ab) or small molecule ligands labeled with potent α emitters (e.g. ²²⁵ Ac). Unlike ligands, Ab biodistribution does not include non-tumor organs such as the salivary glands, kidneys and small bowel. We performed a phase I single ascending dose Ab study. Methods...
TPS606
Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichme...
45
Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with ¹⁷⁷ Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with i...
84
Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production,...
Lessons learned:
Hyperfractionation of lutetium-177 (177 Lu)-J591 for patients with metastatic castration-resistant prostate cancer did not appear to have any additional advantage over the single dose 177 Lu-J591 or fractionated two-dose 177 Lu-J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and...
The accumulation of lipids is a hallmark of human clear cell renal cell carcinoma (ccRCC). Advanced ccRCC tumors frequently show increased lipid biosynthesis, but the regulation of lipid metabolism in early stage ccRCC tumors has not been studied. Here, we performed combined transcriptomics and metabolomics on a previously characterized transgenic...
Purpose
To validate prognostic factors and determine the impact of obesity, hypertension, smoking and diabetes mellitus (DM) on risk of recurrence after surgery in patients with localized renal cell carcinoma (RCC).
Materials and methods
We performed a retrospective cohort study among patients that underwent partial or radical nephrectomy at Weill...
Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-...
Background: PSMA-targeted radionuclide therapy (TRT) is being developed for treatment of pts with prostate cancer (PC). Several targeting agents were shown to be active and tolerable in early phase studies & randomized trials are underway. Because of the DNA damaging effects of ionizing radiation and the relationship between AR pathway & PSMA expre...
Background: PSMA-targeted radionuclide therapy (TRT) is being developed for treatment of pts with prostate cancer (PC). Several targeting agents were shown to be active and tolerable in early phase studies & randomized trials are underway. Because of the DNA damaging effects of ionizing radiation and the relationship between AR pathway & PSMA expre...
4517
Background: Previous clinical trials of patients (pts) with aRCC, including CheckMate 214, have mostly excluded pts with brain metastases. However, antitumor activity in pts with brain metastases has been observed in pts with melanoma treated with NIVO 1 mg/kg + IPI 3mg/kg and pts with non-small cell lung cancer treated with NIVO 240 mg + IPI...
5073
Background: Multi-gene hereditary cancer testing is common in prostate cancer (PC). We assessed the frequency of pathogenic mutations (mt) and examined associations with family history (FH), cancer recurrence, and overall survival (OS). Methods: Men with clinically localized or metastatic PC consented to germline DNA testing using a validated...
4567
Background: Drug combinations targeting vascular endothelial growth factor (VEGF) and the programmed death one (PD-1) pathway have demonstrated encouraging efficacy in patients (pts) with mRCC. We are conducting a phase I/II trial combining the VEGF-targeting tyrosine kinase inhibitor (TKI) axi and the PD-1 inhibitor nivo in mRCC pts. Methods:...
5013
Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorpor...
Background
Prostate cancer is radiosensitive. Prostate‐specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration‐resistant tumors. Lutetium‐177–labeled anti‐PSMA monoclonal antibody J591 (¹⁷⁷Lu‐J591) targets prostate cancer with efficacy and dose‐response/toxicity data when delivered as a single dose. Dose fractionation...
Urothelial carcinoma (UC) is a common and frequently lethal cancer. Despite the presence of genomic alterations creating dependency on particular signaling pathways, the use of targeted therapies in advanced and metastatic UC has been limited. We performed an integrated analysis of whole-exome and RNA sequencing of primary and metastatic tumors in...
283
Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed...
TPS339
Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. Prior studies of beta-emitting radiolabeled anti-PSMA antibody J591 demonstrated accurate targeting, efficacy with dose-response effect, and...
278
Background: NEPC, de novo or treatment-related in late stage CRPC, is a distinct entity with poor prognosis. Developing non-invasive methods for detection of NEPC is important for clinical practice and trial enrollment. We previously reported on the clinical and genomic characterization of NEPC (Conteduca et al ESMO 2018). A separate study (Agg...
675
Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Se...
401
Background: UC is characterized by extensive genomic heterogeneity. Access to genomic DNA from all metastatic lesions is infeasible. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) may recapitulate heterogeneity and offer an opportunity for continuous tracking of tumor evolution. Methods: We analyzed a cohort of advanced UC pa...
266
Background: Platinum compounds are active in pts with metNEPC/CRPC. The neutrophil-to-lymphocyte ratio (NLR) is a simple clinical metric of systemic inflammation with prognostic and predictive value in advanced PC treated with FDA-approved therapies (doc, abi, enza, cabaz, mitox). We hypothesized that pretreatment NLR may be associated with cli...
562
Background: Initial safety results from the phase 3b/4 CheckMate 374 study showed that flat-dose nivolumab (NIVO) at 240 mg every 2 wk (Q2W) had a consistent safety profile across patients (pts) with clear cell and non-clear cell advanced RCC. We report updated safety and first disclosure of efficacy for pts with non-clear cell RCC (nccRCC) in...
TPS137
Background: Prostatectomy has become the most common treatment for high-risk prostate cancer. After prostatectomy, risk features for local recurrence include extra-capsular extension and/or seminal vesicle invasion (pT3 disease) and positive surgical margins. Post-operative radiotherapy is recommended for patients with pT3 disease, positive...
Background: The immune contexture of cancers and the tumor-immune system interplay are becoming increasingly understood. Immunotherapy with checkpoint inhibitors is an established treatment for several cancer types, with PD-L1 immunohistochemical expression as a companion predictive biomarker in some tumors. Checkpoint blockade is not an establishe...
Introduction: Serial monitoring of genomic alterations in tumors is gaining interest as a research tool to better understand the biology of disease progression in different tumor types, including prostate cancer (PC). We hypothesized that intra-patient enrichment of mutations shared among different tumor samples from patients with advanced PC (cast...
Purpose:
To determine the safety, pharmacokinetics, and recommendedphase2 dose of an antibody drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).
Experimental design:
Two phase 1 studies were condu...
Background:
Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC...
627
Background: We previously reported on a phase II trial of E+B across various non-clear cell RCC histologies and observed significant activity among pts with papillary or unclassified RCC ( uRCC ) with PF (objective response rate [ORR] 39%, median progression-free survival [PFS] 12.9 months [m]; Voss, JCO, 2016). An expansion cohort limited to t...
223
Background: Germline DNA repair gene alterations in men with metastatic prostate cancer (PC) unselected for family history of malignancy occur in a greater frequency compared to localized PC and the general population. We hypothesized that assessing heritable alterations in a broader panel of high-susceptibility genes, may be relevant for detec...
TPS399
Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy wit...
Purpose
Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre-...
