Vadim S. Koshkin

Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

Background Advances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient. Methods Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)]. Results The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0-767), after a median number of 0 (0-3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%-50%), and 17.1% (0%-50%) for those patients (n = 6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%-100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P < 0.001), number of known GA (P = 0.009) and number of variants of unknown significance (VUS) in F1 report (P < 0.001), and with total number of GA (non-VUS and VUS) in F1 report (P < 0.001). Conclusions This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

Emerging therapeutics in refractory renal cell carcinoma

ABSTRACT Introduction: Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies (‘refractory’ mRCC). Recently approved agents in this space have shown great promise. Areas covered: This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents. Expert opinion: Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.

Assessment of Imaging Modalities and Response Metrics in Ewing Sarcoma: Correlation With Survival

PURPOSE Despite the rapidly increasing use of [18F]fluorodeoxyglucose (FDG) -positron emission tomography (PET), the comparison of anatomic and functional imaging in the assessment of clinical outcomes has been lacking. In addition, there has not been a rigorous evaluation of how common radiologic criteria or the location of the radiology reader (local v central) compare in the ability to predict benefit. In this study, we aimed to compare the effectiveness of various radiologic response assessments for the prediction of overall survival (OS) within the same data set of patients with sarcoma. METHODS We analyzed assessments made during a clinical trial of a novel IGF1R antibody in Ewing sarcoma: PET Response Criteria in Solid Tumors (PERCIST) for functional imaging and WHO criteria (performed locally and centrally), RECIST, and volumetric analysis for anatomic imaging. We compared the effectiveness of the various criteria for the prediction of progression and survival. RESULTS For volume analysis, progression-defined as cumulative lesion volume increase of 100% at 6 weeks-was the optimal cutoff for decreased OS (P < .001). Assessment of the day-9 FDG-PET scan was associated with reduced OS in progressors compared with nonprogressors (P = .001) and with improved OS in responders compared with nonresponders. Significant variations in response (18% to 44%) and progression (9% to 50%) were observed between the different criteria. The comparison of central and local interpretation of anatomic imaging produced similar outcomes. PET was superior to anatomic imaging in identification of a response. Volume analysis identified the most responders among the anatomic imaging criteria. CONCLUSION An early signal with FDG-PET on day 9 and volume analysis were the best predictors of benefit. Validation of the volumetric analysis is required.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3&bgr;-hydroxysteroid dehydrogenase 1 (3&bgr;HSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3&bgr;HSD1 to multiple steroidal metabolites, including 3-keto-5&agr;-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5&agr;-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5&agr;-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5&agr;-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5&agr;-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute.

Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.

Emerging Role of Immunotherapy in Advanced Urothelial Carcinoma

Purpose of ReviewAdvanced urothelial carcinoma (aUC) has long been treated preferably with cisplatin-based chemotherapy, but many patients are cisplatin-ineligible whereas for those who progress on a platinum-based regimen treatment options are limited. We review key recent data regarding immune checkpoint inhibitors that are changing this treatment landscape.Recent FindingsSince May 2016, five different agents targeting the PD-1/PD-L1 pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have received FDA approval for the treatment of aUC in the platinum-refractory setting, while pembrolizumab and atezolizumab are FDA-approved for cisplatin-ineligible patients in the first-line setting. Clinical outcomes and safety profiles of these agents appear relatively comparable across separate trials; however, only pembrolizumab is supported by level I evidence from a large randomized phase III trial showing overall survival benefit over conventional cytotoxic salvage chemotherapy in the platinum-refractory setting.SummaryPembrolizumab has the highest level of evidence in platinum-refractory aUC, whereas pembrolizumab and atezolizumab have comparable level of evidence in the frontline setting in cisplatin-ineligible patients. Ongoing research is evaluating novel agents, various rational combinations, and sequences, as well as predictive and prognostic biomarkers.

Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function

Micro‐Abstract A retrospective analysis assessed chemotherapy tolerability and outcomes of patients with glomerular filtration rate (GFR) < 60 mL/min who received cisplatin‐based neoadjuvant chemotherapy for muscle‐invasive bladder cancer. Patients with impaired GFR had more treatment discontinuations and modifications relative to normal GFR patients, but most completed intended treatment cycles. For carefully selected patients with impaired GFR, cisplatin‐based chemotherapy remains a treatment option. Background: Cisplatin‐based neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care in muscle‐invasive bladder cancer. There are limited data regarding chemotherapy tolerability and outcomes for patients with low glomerular filtration rate (GFR) who receive cisplatin‐based NAC. Patients and Methods: A retrospective analysis of patients who received cisplatin‐based NAC at Cleveland Clinic (2005‐2016) was undertaken. Patients with pre‐NAC GFR < 60 mL/min by either Cockcroft‐Gault (CG) or Modification of Diet in Renal Disease (MDRD) formula were compared to patients with GFR ≥ 60 mL/min for NAC tolerability, pathologic complete and partial response (pPR), and the ability to undergo radical cystectomy. Results: Thirty patients with low GFR (34‐59 mL/min) and 94 patients with normal GFR (≥ 60 mL/min) were identified. Low GFR patients were older (median, 71 vs. 65 years), but other demographic and transurethral resection of bladder tumor characteristics were comparable. Low GFR patients more frequently had early NAC discontinuation (30% vs. 13%), NAC modifications (delays, dose reduction, or discontinuation, 66% vs. 40%), and cisplatin‐based NAC administered in split doses (37% vs. 16%). No differences in NAC tolerability or outcomes were noted among low GFR patients receiving split‐dose versus standard regimens. No differences were noted between low and normal GFR patients in NAC cycles (median, 3 for each), cystectomy rates (93% for each), time to cystectomy, and GFR change from baseline to after NAC. Pathologic complete response was higher among normal GFR patients (24% vs. 14%). Conclusion: Patients with low GFR had more NAC discontinuations and modifications, but most completed planned NAC cycles. For carefully selected patients with GFR < 60 mL/min, cisplatin‐based NAC remains a treatment option.

Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis.

BACKGROUND Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. OBJECTIVE To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. DESIGN, SETTING, AND PARTICIPANTS Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic±RP) only, first-line platinum-based chemotherapy given. INTERVENTION LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. OUTCOME MEASURES AND STATISTICAL ANALYSIS Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. RESULTS AND LIMITATIONS Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p=0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p=0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. CONCLUSIONS Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. PATIENT SUMMARY We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies.

Patient Characteristics, Treatment Patterns and Prognostic Factors in Squamous Cell Bladder Cancer

Background Squamous cell carcinoma (SCC) is an uncommon histologic subtype of bladder cancer with limited data on treatment patterns, outcomes, and prognostic factors. “Real world” information might inform decision‐making, prognostic estimates, and clinical trial designs. Patients and Methods A retrospective review of patients with tissue‐confirmed bladder SCC treated at Cleveland Clinic from 2007 to 2016 was performed. Data on patient characteristics, treatment patterns, and clinical follow‐up were extracted. Univariate analysis was used to identify predictors of overall survival (OS), recurrence‐free survival (RFS) and time to recurrence. Results Of 58 identified patients, 42 had complete data available. Median age at diagnosis was 67 years (range, 37‐90). Hematuria was the most common (71%) presenting symptom; 32 patients had pure SCC and 10 predominant/extensive squamous differentiation without major differences noted in clinicopathologic variables or outcomes among those 2 groups. Overall, 35 patients underwent cystectomy with 5 receiving neoadjuvant and 1 adjuvant chemotherapy, whereas 3 had chemotherapy for recurrent disease. Of patients with cystectomy, most had locally advanced disease (75% pT3/4, 35% pN+). Overall, 10 patients progressed and 14 died; median OS was not reached. The 2‐year estimated OS, RFS, and cumulative incidence of recurrence were 61% ± 9%, 50% ± 9%, and 32% ± 9%, respectively. Hydronephrosis, older age (70 years or older), lymphovascular invasion, nodal metastases, and advanced T stage were associated with 1 or more poor outcomes. Conclusion In patients with resectable bladder SCC, radical cystectomy remains the main treatment modality. The role of perioperative chemotherapy remains unclear. The identified prognostic factors might be helpful for prognostication, treatment discussion, and trial eligibility/stratification. Micro‐Abstract Bladder squamous cell carcinoma (SCC) is rare with limited data on prognosis and treatment patterns. Herein we present a retrospective review of patients with bladder SCC treated at our institution. Radical cystectomy was the main treatment for resectable disease. The identified prognostic factors might help prognostication, treatment decision, and trial eligibility/stratification.

Abstract 3093: 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)

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