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Introduction: Immune-related hepatitis (irH) is a serious but unpredictable immune-related adverse event of checkpoint inhibitor (CPI) therapy. The impact of underlying liver pathology, including liver cirrhosis or metastasis, on the incidence of irH remains poorly understood. We hypothesized that presence of underlying liver pathology would increase the risk of irH in patients with cancer treated with CPI. Methods: We conducted a retrospective case-control study of irH in patients with cancer receiving CPI at the University of Washington/Seattle Cancer Care Alliance between 2016 and 2020. Cases of irH were first identified through relevant ICD-10 codes, followed by systematic chart review to confirm provider-documented diagnosis and biochemical criteria for ≥ grade II immune related hepatitis. Controls were matched to cases in a 2:1 ratio based on age (± 5 years), sex, time of CPI initiation (± 1 year), and available follow-up time. Cases were excluded if there were no available controls. Conditional logistic regression was used to estimate the relationship between irH, liver metastasis at CPI initiation and history of cirrhosis, and adjusted for covariates, including ECOG performance status at CPI initiation, combination (vs single agent) CPI, history of autoimmune disease, and hepatitis B or C infection. Results: Of the 97 cases of irH identified, 43% were women and median age was 61; 45% were undergoing treatment for skin, 22% for genitourinary, 16% for lung, 8% for head/neck cancers and 5% for GI cancers including HCC. 94% of cases had metastatic disease at CPI initiation, including 27% of cases with liver metastases. Cirrhosis was present in only 4.9% (n=5) of cases. Among cases, median doses of CPI received prior to onset of irH was 2 (IQR 1-4). Biochemical liver injury presented with transaminase elevation with median peak values of AST 152 (IQR 101-316), ALT 221 (IQR 139-327), alkaline phosphatase 142 (IQR 92-330) and total bilirubin 0.9 (IQR 0.5-1.6). History of cirrhosis was associated with lower odds of irH (adjusted OR 0.15, 95% CI 0.03-0.76). Presence of liver metastasis was associated with an increased odds of irH (OR 2.61, 95% CI 1.42-4.80), although the association between irH and liver metastasis lost significance (OR 2.0, 95% CI 0.94-4.26) when adjusted for covariates, particularly combination CPI therapy. Conclusion: We demonstrated an independent negative association between liver cirrhosis and irH, while liver metastasis was not significantly associated with increased odds of irH after adjustment for covariates. The former might be related to misattribution, low number of cases with cirrhosis, and/or potentially due to suppressed transaminase elevation due to underlying hepatocyte exhaustion. Limitations include retrospective nature, small sample size of specific case subsets, potential selection and confounding biases; our findings are hypothesis-generating and warrant external validation. Citation Format: Erica M. Storm, Dimitrios Makraki, Genevieve I. Lin, Laura C. Kennedy, Eshana E. Shah, Amanda I. Phipps, Iris W. Liou, David Hockenbery, Petros Grivas, Ali R. Khaki. Immune related liver toxicity and potential risk factors: A case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1981.

The UC-GENOME study was designed to capitalize on The Cancer Genome Atlas (TCGA) findings in real world patients with metastatic urothelial carcinoma (UC) with co-equal aims: 1) to provide targeted DNA sequencing for potential clinical decision making at no cost to patients; and 2) to create a clinically annotated biorepository (including tissue, plasma, and PBMCs) for collaborative research. Patients with metastatic UC (n=209, median age 68 y, 74% male) were accrued at 8 academic medical centers between 2016-2019. We report on the first analysis of the targeted DNAseq (n=191) and total RNAseq (n=176) from FFPE specimens (n=169 overlap). Recurrently mutated genes were observed in a similar frequency to TCGA, including TP53 (54%), KMT2D (30%), ARID1A (26%) and FGFR3 (18%). Somatic variant patterns were correlated with previously annotated mutational signatures (COSMICv3), revealing a subset of tumors enriched for APOBEC signatures. Molecular subtypes were defined using the Bladder Cancer Molecular Taxonomy Group's consensus subtyping schema (Ba_Sq=54 [31%], Stroma-rich=64 [36%], LumP=26 [15%], LumU=24 [14%], LumNS=4 [2%], NE=4 [2%]). To further understand the tumor immune features and whether they correlate with durable clinical response, tumor microenvironment deconvolution was performed by applying MiXCR and immune gene signatures. An inflamed phenotype and enhanced T cell receptor richness but not clonality was observed within Ba_Sq and Stroma-rich subtypes, which also had the highest disease control rate (CR/PR + SD ~75%) to immunotherapy. The Stroma-rich subtype had the highest disease control rate (~88%) to chemotherapy. Future efforts will leverage the clinical, DNA and RNAseq data along with other biobanked specimens for collaborative research initiatives. Citation Format: Jeffrey S. Damrauer, Jeff Klomp, Wolfgang Beck, Mi Zhou, Elizabeth Plimack, Matthew Galsky, Petros Grivas, Noah Hahn, Peter O'Donnell, Gopa Iyer, David I. Quinn, Katherine A. Hoadley, William Y. Kim, Matthew I. Milowsky. Urothelial cancer-GENOmic analysis to improve patient outcomes and research (UC-GENOME): a bladder cancer advocacy network (BCAN) led collaborative research study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2188.

Background: Overall, patients with cancer experience a greater risk of adverse outcomes following SARS-CoV-2 infection; however, little is known for those with BC. Methods: CCC19 (NCT04354701) is an international cohort study aimed at investigating the impact of COVID-19 in patients with a history of or active cancer using de-identified data on patient demographics, cancer history, clinical course and outcomes of COVID-19. The current analysis includes patients from U.S. and Canada with invasive BC and laboratory-confirmed SARS-CoV-2 entered between March 17, 2020 and July 2, 2020. Co-primary outcomes were hospitalization during COVID-19 illness and 30-day all-cause mortality. Frequencies for categorical variables and medians (range) for continuous variables were estimated. Final presentation will include bivariable and multivariable Cox proportional hazards regression analysis to identify risk factors (including BC subtypes and therapies, for which data collection is ongoing) associated with 30-day all-cause mortality and severe COVID-19 illness (composite of any hospitalization requiring supplemental oxygen, admission to an intensive care unit [ICU], use of mechanical ventilation, or death). Results: During the study period, a total of 2683 patients with cancer and COVID-19 were accrued in the CCC19 registry including 529 (20%) with invasive BC. Among patients with BC, 352 (67%) were 60 years or older; 518 (98%) were women; 275 (52%) non-Hispanic White, 116 (22%) non-Hispanic Black, 70 (13%) Hispanic, 56 (11%) in other categorizations; 178 (34%) had a smoking history; 75 (14%) ECOG performance status ≥2; 191 (36%) with >2 active comorbidities; 64 (12%) with AJCC stage IV disease at BC diagnosis; and 267 (50%) were on anti-cancer treatment including systemic therapy, radiation, or surgery within 3 months of COVID-19 diagnosis. At least 323 (61%) patients with BC had 30-day follow-up after COVID-19 diagnosis, and 35 (7%) had 90-day follow-up. COVID-19 illness at initial diagnosis required outpatient care in 288 (54%), inpatient care in 193 (36%), and ICU care in 40 (8%). Overall, 247 (47%) were hospitalized and 30-day all-cause mortality was 9%. 30-day all-cause mortality rates by receipt of major BC treatment modalities (within past 3 months) were: 10% for those on cytotoxic systemic therapy vs 5% and 12% for noncytotoxic systemic therapy and local therapy, respectively. The table shows hospitalization and mortality outcomes by major demographic and BC treatment strata. The final presentation will incorporate the latest patient accrual and evaluate independent clinical risk factors associated with serious COVID-19 outcomes in patients with BC. Conclusions: This represents the largest study to date of COVID-19 outcomes in patients with invasive BC. Nearly half of the patients with BC required hospitalization during their COVID-19 disease course and we observed a 9% 30-day all-cause mortality. Submitted on behalf of the COVID-19 and Cancer Consortium (ccc19us.org) Table 1. COVID-19 related hospitalization and 30-day all-cause mortality for all patients with invasive BCNAny Hospitalization30-day all-cause MortalityN% [95% CI]N% [95% CI]Total population52924747 [42-51]499 [7-12]Age219112968 [60-74]2915 [10-21]Treatment IntentCurative1866434 [28-42]95 [2-9]Palliative743953 [41-64]1216 [9-27]Cancer StatusRemission/NED33115447 [41-52]247 [5-11]Active disease, stable or responding to treatment1194840 [31-50]76 [2-12]Active disease, progressing372773 [56-86]1130 [16-47]Treatment Modality (within 3 months)Cytotoxic chemotherapy833542 [31-54]810 [4-18]Noncytotoxic therapy1856435 [28-42]105 [3-10]Local therapy (surgery or radiation)341750 [32-68]412 [3-27] Citation Format: Ali Raza Khaki, Dimpy P Shah, Maryam B Lustberg, Melissa K Accordino, Daniel G Stover, Gayathri Nagaraj, Donna R Rivera, Edith A Perez, Sara M Tolaney, Jeffrey Peppercorn, Petros Grivas, Jeremy L Warner, Corrie A Painter, Gilberto de Lima Lopes, Jr, Solange Peters, Michael A Thompson, Toni K Choueiri, Brian I Rini, Gary H Lyman, Nicole M Kuderer, Shaveta Vinayak. Characteristics and outcomes of SARS-CoV-2 infection in patients with invasive breast cancer (BC) from the COVID-19 and cancer consortium (CCC19) cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-01.

Purpose: SCBC is an aggressive subtype of bladder cancer with high metastatic potential and few effective treatment options. We developed the first orthotopic murine model of SCBC to study the development of this aggressive variant, identify epigenetic drivers of urothelial transdifferentiation, and explore novel therapeutic approaches. Methods: Lentiviral particles designed to transduce Cre recombinase gene were produced (Lenti-sgNeo#2/Cre). High titer virus was prepared and confirmed using a fluorescent Cre reporter assay. Transurethral catheterization of the bladder was performed using Rb1fl/fl Trp53fl/fl MycLSL/LSL (RPM) mice and 30 minute lentivirus instillations were conducted under anesthesia. Mice were monitored by micro-ultrasound (mUS) and tumor bearing mice were sacrificed, examined for metastases, and tissues were harvested for analysis by a genitourinary pathologist. SCBC / high grade neuroendocrine histology was confirmed by H&E and synaptophysin IHC. Whole transcriptome (RNAseq) analysis was performed to correlate transcriptomic profile of neuroendocrine mouse tumors to a cohort of human SCBC tumors. Results: Transurethral catheterization was successfully performed in RPM mice (n=10); the bladder urothelium was transduced without evidence of exposure to ectopic (non-urothelial) tissues. RPM mice developed SCBC visible on mUS with a latency of 8-10 weeks. 4/10 mice had liver or lung metastases grossly or had microscopic metastatic deposits upon analysis of tissues. High grade neuroendocrine morphology and NE marker expression were confirmed by H&E and IHC, respectively, in all harvested tumors. Western blot analysis confirmed cMyc expression and suppression of TP53 and RB1. Synaptophysin expression was confirmed by IHC. Transcriptomic profiling of mouse and human SCBC demonstrated largely concordant gene expression (R2=0.47) and upregulation of neuroendocrine genes. Conclusions: To our knowledge, this is the first genetically engineered orthotopic murine model of SCBC. Current work seeks to identify reversible epigenetic drivers of neuroendocrine transdifferentiation and novel therapeutic targets in this aggressive variant of bladder cancer. In addition, we are assessing the activity of immune checkpoint inhibitors in this immunocompetent model. Citation Format: Aysegul Balyimez, Shinjini Ganguly, Sitalaximi Thirunavukkarasu, Petros Grivas, Moshe Ornstein, Shilpa Gupta, Byron Lee, Chris McFarland, Monte Winslow, Jesse McKenney, Omar Y. Mian. An orthotopic murine model of neuroendocrine bladder cancer offers insights into the phenotypic plasticity of small cell bladder cancer (SCBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 436.

Purpose: There is risk of clinical under-staging of muscle invasive bladder cancer (MIBC) by trans-urethral resection (TURBT) alone. Circulating biomarkers may improve the staging and pre-treatment risk stratification of patients with bladder cancer by discriminating non-muscle invasive (NMIBC) and MIBC. Methods: Peripheral blood from 74pts with BC (30NMIBC, 15 MIBC and 29 Met BC was collected in Streck BCT tubes and processed to obtain cfDNA. Total cfDNA quantity (ng/mlof plasma) was assessed by fluorimetry. cfDNA fragment size was measured by Bioanalyzer DNA analysis. Wilcoxon rank sum test, Cochran-armitage trend test, Fisher's exact t-test were used to compare cfDNA quantity and fragmentation pattern (small fragments are indicative of circulating tumor DNA) among pts with NMIBC, MIBC, met BC to predict invasiveness of BC. Results: There was no significant difference in cfDNA concentration between MIBC and met BC, however, cfDNA levels were significantly lower in pts with NMIBC vs MIBC and met BC. The difference was even more pronounced in case of cfDNA fragment (100-400bp) conc. Total cfDNA (ng/ml) was a good predictor in bladder cancer invasiveness, AUC 0.8 (95% CI 0.7-0.9). The risk of invasion was significantly lower inpatients with total cfDNA &lt 1.5 ng/ml and significantly higher in patients with cfDNA &gt 7.0ng/ml. In 18 pts with cfDNA&lt1.5ng/ml, only 1 pt (5.6%) had invasive cancer (at 1.2). The percent risk of invasive disease was 70.6% for cfDNA concentrations between 1.5-7.0ng/ml and 79.0% for cfDNA &gt 7.0. No invasion was observed among 13 pts with total cfDNA less than 1. This exploratory study suggests that cfDNA levels may correlate with BC stage and hence can be used in juxtaposition with TURBT, exam under anesthesia and CT to better predict clinical staging. Conclusions: Circulating cfDNA may be a dynamic, low-cost and minimally invasive biomarker that can be used in conjunction with TURBT to predict tumor invasiveness, reduce under-staging, and risk stratify patients for appropriate curative intent therapy. cfDNA variation with BC stagingcfDNA parametersTotalNMIBCMIBCMET BCp-value(N=74)(N=30)(N=15)(N=29)cfDNA_ng/ml of plasma7.3[2.9,12.5]1.3[0.48,7.4]9.7[4.0,13.3]8.7[6.1,14.4] Citation Format: Shinjini Ganguly, Jaleh Fallah, Hong Li, Wei Wei, Aysegul Balyimez, Claudia Marcela Diaz, Pat Rayman, Marcelo Lamenza, Priscilla Dann, Donna Company, Rahul Tendulkar, Jacob Scott, Mohamed Abazeed, Jorge A. Garcia, Moshe C. Ornstein, Brian R. Rini, Byron Lee, Petros Grivas, Omar Mian. Circulating cell-free DNA (cfDNA) levels and fragmentation patterns discriminate muscle invasive from non-muscle invasive urothelial cancer of the bladder [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1159.

Background: For patients with metastatic urothelial carcinoma (mUC) that has progressed on or after platinum-based chemotherapy (cisplatin or carboplatin) and/or immune checkpoint inhibitors, there are currently no standard treatments, emphasizing the urgent unmet need for additional treatment options. Based on analysis of The Cancer Genome Atlas bladder cancer dataset, ≈60% of muscle invasive bladder tumors have homologous recombination (HR) deficiency (HRD), as defined by high genomic loss of heterozygosity (LOH) or a deleterious mutation in a DNA repair pathway gene. Poly(ADP-ribose) polymerase (PARP) inhibitors such as rucaparib exert their antitumor activity through synthetic lethality in cancer cells with HRD. Tumors with HRD have been shown to be sensitive to PARP inhibitors in breast, ovarian, and prostate cancers, and PARP inhibitors are approved for the treatment of patients with breast or ovarian cancer. Although there are little data on their activity in mUC, we hypothesize that PARP inhibition may have antitumor activity in this tumor type. The ATLAS (NCT03397394) trial is evaluating the efficacy and safety of the PARP inhibitor rucaparib as monotherapy for patients with locally advanced (unresectable) urothelial carcinoma or mUC previously treated with 1-2 anticancer treatments for advanced/metastatic disease. Methods: Eligible patients must have received 1-2 prior treatments (eg, platinum-based chemotherapy, immune checkpoint inhibitor, and/or clinical trial agent) and have radiographic progression, measurable disease (RECIST version 1.1), and adequate organ function. Tumor HRD is not required as rucaparib may potentially benefit patients with HR-proficient or HR-deficient tumors; however, fresh tumor or recently obtained archival tissue is mandatory for central HRD profiling. Prior PARP inhibitor treatment is an exclusion criterion. All patients will receive rucaparib monotherapy (600 mg BID) until disease progression or other reason for discontinuation. The primary endpoint is confirmed objective response rate (investigator assessed per RECIST version 1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluating plasma and tumor samples for biomarkers associated with response and resistance to rucaparib. The study has >90% power to reject the null hypothesis (P=0.10) at a one-sided 5% significance level if the true response rate for rucaparib is 20%. ATLAS is currently enrolling at ≈65 sites in 6 countries (France, Germany, Italy, Spain, United Kingdom, and United States), with a target enrollment of 200 patients. Citation Format: Petros Grivas, Min Yuen Teo, Nicholas Vogelzang, Ajjai Alva, Yousef Zakharia, Nabil Adra, Alexandra Drakaki, Arif Hussain, Rafael Morales-Barrera, Andrea Necchi, Alejo Rodriguez-Vida, Susan Feyerabend, Sumati Gupta, Debra H. Josephs, Yohann Loriot, Sandy Srinivas, Kenton Wride, Daleen Thomas, Rachel Dusek, Andrew D. Simmons, Dale Nepert, Simon Chowdhury. ATLAS: A Phase II, open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT179.

Background: Treatments for 1L advanced, unresectable, or metastatic UC include platinum-based chemotherapy, immune checkpoint blockade, or clinical trial enrollment. Not all patients benefit from, or are eligible for, specific therapies due to comorbidities and performance status. There is an urgent need for biomarker-directed strategies to enable patient selection and improve outcomes. Currently the only clinically used molecular biomarker is programmed cell death ligand-1 (PD-L1) protein expression in tumor tissue. Although variably defined with different assays, higher PD-L1 expression generally correlates with increased response rates to immune checkpoint blockade. Improved understanding of the prevalence and potential prognostic role of PD-L1 testing can further enhance its clinical utility and guide novel clinical trial designs. Methods: This observational study will enroll 250 patients diagnosed with advanced UC either prior to or during 1L therapy, as initiated at the discretion of participating clinicians from 60 US community sites. The primary endpoint is prevalence (with exact [Clopper-Pearson] 95% CI) of PD-L1 high expression by VENTANA SP263 Assay on pretreatment tumor tissue (classified as PD-L1 high if ≥25% of tumor cells [TCs] exhibit staining; or if immune cells [IC] present >1% and IC with staining ≥25%; or IC present =1% and IC with staining =100%). Secondary endpoints include the association of pretreatment PD-L1 expression with pretreatment tumor tissue mutational burden (tTMB), descriptions of treatment response and outcomes (objective response rate based on RECIST 1.1, progressive-free survival [PFS], and overall survival [OS]) and assessment of their correlations with PD-L1 expression. Exploratory endpoints include the association of pretreatment tumor tissue PD-L1 with pretreatment blood-based tumor mutational burden (bTMB), changes in circulating tumor DNA levels, the correlation between tTMB and bTMB values, and the association of those biomarkers with PFS and OS. Enrollment will take place over 24 months. Patients will be followed for up to 30 months after enrollment. With 250 patients, the 95% CI for 30%, 45%, and 60% observed prevalence of PD-L1 high expression are (24.4%, 36.1%), (38.9%, 51.2%), and (53.6%, 66.1%), respectively; the various secondary and exploratory analyses will be descriptive. Citation Format: Petros Grivas, Alicia K. Morgans, Yair Lotan, Jeffrey Gregg, Daniel Geynisman, Terence Friedlander, Piyush K. Agarwal, Marija Tesic-Schnell, Andrew Bernstein, Doris Makari, Joshua J. Meeks. Prevalence of PD-L1 expression in 1st-line (1L) locally advanced/unresectable or metastatic urothelial carcinoma (UC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT178.

Background The common HSD3B1 (1245C) germline variant encodes for a 3βHSD1 missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition by the nonsteroidal drug ketoconazole. However, 3βHSD is also the first enzyme necessary in the conversion from abiraterone, a steroidal CYP17A1 inhibitor, to 5α-abiraterone, which stimulates the androgen receptor (AR) and prostate cancer progression. The HSD3B1 (1245C) variant might therefore increase 5α-abiraterone synthesis in patients on abiraterone therapy, possibly limiting clinical benefit. Significance This work aims to characterize the pharmacokinetics of steroidal metabolites of abiraterone and to determine the association between HSD3B1 genotype and the generation of 5α-abiraterone metabolites. Patients and Methods Part 1: 15 healthy male volunteers received a single oral dose of 1000 mg abiraterone acetate plus 240 mg of the AR antagonist apalutamide, steroidal metabolites of abiraterone were quantitated at 12 time points from 0.5-96 hours post-dose. Part 2: 5α-abiraterone metabolites and HSD3B1 genotype was determine in 30 patients with castration-resistant prostate cancer (CRPC) on abiraterone therapy. Metabolite concentrations were normalized to the 8 hour time point of the pharmacokinetic study and the association between HSD3B1 genotype and 5α-abiraterone metabolites was determined. Results There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. Patients who inherit 0, 1 and 2 copies of the HSD3B1 (1245C) variant have a stepwise increase in serum concentrations of 5α-abiraterone metabolites (p=0.002). Conclusion The generation of 5α-abiraterone preferentially in patients with the HSD3B1 (1245C) variant might negate the benefits of abiraterone specifically in a patient subset that is otherwise more likely to benefit from CYP17A1 inhibition by the nonsteroidal drug ketoconazole. Citation Format: Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Tae Hyun Hwang, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi. HSD3B1 genotype and abiraterone metabolism in patients with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2572.

Expression of DLL3 was examined in additional tumor types, as it was found to be highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where a DLL3-targeted antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T; SC16LD6.5; Saunders et al. 2015 Sci Transl Med 7:302ra136)) exerted clinically meaningful anti-tumor effects in a phase I trial (Spigel et al. 2016 Lancet Oncology; In Press). DLL3 expression was profiled by qRT-PCR, ELISA and immunohistochemistry in multiple tumor types. Patient-derived xenografts (PDX) from melanoma and ovarian small cell carcinoma were established and used for efficacy studies to determine the ability of Rova-T to impact tumor growth and TIC frequency. DLL3 expression was seen in metastatic melanoma (55%), low grade gliomas (90%), glioblastoma (70%), medullary thyroid cancer (65%), carcinoids (33%), dispersed neuroendocrine tumors in the pancreas (9%), bladder (57%) and prostate (24%), testicular cancer (90%), and lung adenocarcinomas with neuroendocrine features (80%). Unlike SCLC, where DLL3 does not predict clinical outcome on standard therapies, DLL3 expression negatively correlates with overall survival in melanoma and small cell bladder cancer. In mice bearing DLL3 positive melanoma PDX, treatment with a single dose of Rova-T resulted in effective and durable responses (>100 days), which correlated with a significant impact on TIC frequency. Similarly, in mice bearing DLL3-positive ovarian small cell PDX, a single dose of Rova-T resulted in effective and durable responses (>100 days). Our results show that DLL3 is expressed in many neuroendocrine tumors (lung, ovarian, prostate, bladder, etc), metastatic melanoma, medullary thyroid cancer, low-grade gliomas and glioblastoma. Given pre-clinical results showing efficacy of Rova-T in melanoma and ovarian small cell carcinoma, as well as encouraging clinical data with Rova-T in patients with recurrent/refractory SCLC, clinical evaluation of Rova-T in DLL3-positive melanoma, glioblastoma, medullary thyroid cancer and other high-grade neuroendocrine carcinomas is warranted. A “basket” trial enrolling patients with DLL3-positive solid tumors is now recruiting patients (NCT02709889). Citation Format: Laura R. Saunders, Samuel A. Williams, Sheila Bheddah, Kumiko Isse, Sarah Fong, Marybeth A. Pysz, Himisha Beltran, Loredana Puca, Verena Sailer, Juan M. Mosquera, Yu Yin, Jiaoti Huang, Andrew J. Armstrong, Jorge Garcia, Cristina Magi-Galluzzi, Vadim Koshkin, Petros Grivas, Farhad Kosari, John Cheville, Justin C. Moser, Thomas J. Flotte, Thorvardur Halfdanarson, Aaron Mansfield, Konstantinos N. Leventakos, Julian R. Molina, Douglas W. Ball, Barry D. Nelkin, Jill E. Shea, Courtney L. Scaife, Scott J. Dylla. Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2017-3093