bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II trial of pazopanib alternating with bevacizumab in treatment-naïve metastatic clear cell renal cell carcinoma (CCRCC) patients: Phase I results.
Authors: George Saby , Herbst Laurie , Sikorski Marcus , Diraddo Ann Marie , Azabdaftari Gissou , Roche Charles , Kauffman Eric , Li Qiang , Schwaab Thomas , Levine Ellis Glenn , Pili Roberto , Chatta Gurkamal S. , Appleman Leonard Joseph , Groman Adrienne , Parikh Rahul Atul , Hutson Alan
Published: March 2019

561

Background: Pazopanib as single agent and bevacizumab plus interferon were approved for use in metastatic RCC (MRCC) based on their ability to modulate the vasculature and prolong progression free survival. VEGF levels rose unopposed while using VEGF tyrosine kinase inhibitors (TKI) without break. We hypothesized that adding a break as well as bevacizumab which removes VEGF could prolong PFS in MRCC pts. Methods: This phase I trial was conducted in VEGF treatment naïve MRCC pts. This trial utilized a unique regimen of alternating Pazopanib (day 1-28) with bevacizumab (on days 36 and 50) in a 10-week cycle. The study employed a classic 3+3 design for dose escalation (dose levels in table 1). Safety utilized CTCAE version 4.0 and response evaluation was done using RECIST 1.1 criteria. The primary endpoint of this phase I trial was to find the recommended phase 2 dose (RP2D) of this novel regimen. Key secondary endpoints included objective response rate (ORR), safety/ toxicity and pharmacokinetics. Phase I safety committee acknowledged the completion and approved reporting of Phase I portion of this study. Results: This phase I study was conducted at two academic centers. Twenty-five pts were enrolled in the phase I portion. Median age was 64 years and 68% were male patients. The Commonest adverse events (AE) included fatigue (64%), diarrhea (52%), hypertension (48%), nausea (36%), dysgeusia (36%), vomiting (24%) and proteinuria (28%). The commonest grade 3/4 AE of more than 5% frequency included hypertension (20%) and proteinuria (12%). The dose levels 1 and 4 were expanded due to one DLT each and RP2D was established at dose level 4. The ORR was 25% among evaluable pts who completed at least one cycle of therapy (n=20). The median PFS of the ITT cohort (n=25) was 20.9 months. Conclusions: These data demonstrate that this novel regimen could be safely tested in a phase II trial. The safety and efficacy data suggest that this novel regimen could be optimal for MRCC patients with favorable/intermediate risk. Clinical trial information: NCT01684397. [Table: see text]
A phase II study of cabozantinib as first-line treatment in metastatic collecting ducts carcinoma: The BONSAI trial.
Authors: Procopio Giuseppe , Ratta Raffaele , Colecchia Maurizio , Sensi Marialuisa , Sepe Pierangela , Claps Melanie , Rivoltini Licia , De Braud Filippo G. , Pagani Filippo , Verzoni Elena
Published: March 2019

578

Background: Metastatic collecting ducts carcinoma (mCDC) is a rare and aggressive disease, characterized by a poor prognosis; its treatment represents an unmet medical need. We aimed to evaluate the activity and safety of cabozantinib (cabo) in mCDC. Methods: This is a prospective, monocentric, single-arm phase II trial evaluating cabo in patients (pts) with untreated mCDC. Cabo was administered at the dose of 60 mg orally once daily until disease progression (evaluated by RECIST 1.1 criteria) or unacceptable toxicity. Primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival and safety profile. Exploratory objectives include the identification of somatic mutations and the mutational load on tissue samples; plasma and viable peripheral blood mononuclear cells were studied for immune related biomarker profiling. Results will be crossed with clinical data in terms of response rate, to detect any predictive value of blood immune cell profiling. A central pathological review before study entry is mandatory. The study design is based on a Simon’s two stage optimal design: in the first step at least 2 responses in 9 pts enrolled are needed to go to the second stage of the study (14 additional pts). Results: From January 2018 to September 2018, 11 pts with mCDC have been so far enrolled, nine of which started study treatment. Median age was 58 years, 8 pts were male and 1 female, 7 pts received a previous nephrectomy. The most common metastatic sites were bone and abdominal lymphnodes (5 pts each), followed by liver and lung (2 pts each). Two pts had a partial response as best response, 2 had a stable disease, 3 had a progressive disease and 3 pts died for early progression. Treatment was feasible and well tolerated. All pts reported at least one grade (G) 1-2 adverse events (AEs): the most common were asthenia, diarrhea, anorexia and nausea, hand-foot syndrome, hypertension and dysgeusia. No G3-4 AEs were reported. Genetic and immunological essays are ongoing to assess the immunomodulatory properties of cabozantinib and potential predictive factors. Conclusions: Cabo was safe and active in CDC. The second stage and biomarkers analyses are ongoing. Clinical trial information: NCT03354884.
Outcomes in patients (pts) with advanced renal cell carcinoma (aRCC) who discontinued (DC) first-line nivolumab + ipilimumab (N+I) or sunitinib (S) due to treatment-related adverse events (TRAEs) in CheckMate 214.
Authors: Tannir Nizar M. , Motzer Robert J. , Plimack Elizabeth R. , McDermott David F. , Barthelemy Philippe , Porta Camillo , George Saby , Powles Thomas , Donskov Frede , Kollmannsberger Christian K. , Gurney Howard , Amin Asim , Grimm Marc-Oliver , Rini Brian I. , Tomita Yoshihiko , McHenry M. Brent , Mekan Sabeen Fatima , Escudier Bernard , Hammers Hans J.
Published: March 2019

581

Background: The phase 3 CheckMate 214 trial demonstrated superior efficacy for N+I vs S in aRCC, although more patients discontinued N+I compared with S due to TRAEs. This is a post hoc analysis of outcomes in pts who DC N+I or S due to TRAEs. Methods: Untreated pts with clear cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg Q3Wx4 (induction) and then N 3 mg/kg Q3W (maintenance), or S 50 mg daily for 4 wk on, 2 wk off (6-wk cycles). This analysis includes all pts who DC due to TRAEs reported during extended follow-up (≤100 d after last study dose). Results: Of 550 N+I randomized pts, 135 (25%) DC due to TRAEs, most commonly increased ALT, diarrhea, and increased AST (all 3%); 64 (12%) of 535 S randomized pts DC due to TRAEs, most commonly increased ALT, diarrhea, and pancreatitis (all 1%). In N+I pts who DC due to TRAEs, 47% DC during N+I induction, 7% completed induction but no N maintenance, and 46% completed induction and received N maintenance (median [range] 8 [1–47] doses). At 30-mo minimum follow-up, ORR per investigator, CR rate, and 24-mo OS rate were higher in pts who DC N+I vs S due to TRAEs. Outcomes in pts who DC S due to TRAEs were similar to those in all S ITT pts and worse than in N+I pts who DC due to TRAEs (Table). At 24 mo, 42% of pts who DC N+I due to TRAEs were alive and free from second-line therapy. Consistent outcomes were seen in pts who DC N+I due to TRAEs across IMDC risk groups (data to be presented). Pts who DC N+I due to TRAEs experienced more immune-related select TRAEs and received more high-dose steroids (≥40 mg prednisone daily or equiv.), but times to onset and resolution and resolution rates of select TRAEs were similar vs all treated N+I pts. Conclusions: Discontinuation of first-line N+I due to TRAEs did not result in impaired outcomes, and a high proportion of pts remain alive and free from second-line therapy. Clinical trial information: NCT02231749. [Table: see text]
RNAseq in addition to next generation sequencing in advanced genitourinary cancers reveals transcriptomic silencing of DNA mutations: Implications for resistance to targeted therapeutics.
Authors: Adashek Jacob J. , Kato Shumei , Parulkar Rahul , Szeto Christopher , Reddy Sandeep K. , Kurzrock Razelle
Published: March 2019

583

Background: Next generation sequencing (NGS) for advanced tumors is becoming more routine. However, not all patients respond to precision matched treatments. We hypothesized that one potential reason for treatment failure with targeted therapy could be discrepancies between DNA alterations and RNA expression. Methods: Tumor samples from patients with metastatic kidney, bladder, and prostate cancer were analyzed by whole exome or whole genome NGS and RNA sequencing (CLIA-certified laboratory; NantOmics LLC, Santa Cruz, CA). Only known pathogenic driver alterations were analyzed in the current study. Results: Of 45 patients, 10 had kidney cancer, 18 had bladder cancer; and 17 had prostate cancer. Median age was 66 years (range, 28 - 86). The most commonly altered genes were TP53 (35.6% [16/45]), PIK3CA (15.6% [7/45]), FGFR3 (11.1% [5/45]), ALK (8.9% [4/45]), and ATM (8.9% [4/45]). In total, 86 pathogenic DNA alterations were identified; 17 of these (19.8%) were not observed at the RNA level. Among 45 patients, 31.1% (14/45) had ≥1 DNA alteration that was not expressed at the RNA level. Discordance between DNA and RNA was seen in 40% of patients with kidney cancer (4/10), 28% of patients with bladder cancer (5/18), and 29% with prostate cancer (5/17). Examples of genes that had pathogenic DNA alterations not seen at the RNA level included ALK (four discordant cases), KDR (three discordant cases) and GNAS (one discordant case). On the other hand, alterations involving certain genes showed 100% concordance between DNA and RNA: TP53 [N = 16], PIK3CA [N = 7], and FGFR3 [N = 5]). Conclusions: A significant number of patients with genitourinary tumors had DNA alterations that are silenced at the RNA level (19.8%). Transcriptomic silencing merits additional investigation as a mechanism that could mediate resistance to therapeutics targeted at cognate alterations.
Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).
Authors: Labriola Matthew , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , White James R , Weingartner Elizabeth , Kong Eric , Simone Peter , Papp Eniko , Gerding Kelly , Simmons John , George Daniel J. , Zhang Tian
Published: March 2019

589

Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICI therapy at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also analyzed with the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies.
Using PSMA (prostate-specific membrane antigen) evaluation on prostate biopsies for risk stratification at time of initial diagnosis.
Authors: Hupe Marie C. , Philippi Christian , Roth Doris , Kuempers Christiane , Ribbat-Idel Julika , Becker Finn , Joerg Vincent , Duensing Stefan , Lubczyk Verena , Kirfel Jutta , Sailer Verena , Kuefer Rainer , Perner Sven , Merseburger Axel Stuart , Offermann Anne
Published: March 2019

6

Background: Stratifying prostate cancer (PCa) patients into risk groups at time of initial diagnosis for individual treatment decision is still a major clinical challenge. PSMA expression has emerged as a promising prognostic biomarker since its overexpression in radical prostatectomy specimens (RP) has been linked to disease recurrence. Aim of our study was to assess the prognostic value of PSMA on prostate biopsies (Bx) thus improving risk stratification at time of initial diagnosis. Methods: Immunohistochemistry for PSMA expression was performed on 294 Bx with corresponding RP, 621 primary tumor foci from 242 RP, 43 locally advanced or recurrent tumors, 34 lymph node metastases, 78 distant metastases, and 52 benign prostatic samples. Grade group, PSA, TNM-, and R-status were assessed as clinico-pathologic features. Primary endpoint was recurrence-free survival (RFS). Chi-square, ANOVA-analyses, Cox regression and log rank tests were performed for statistical analyses. Results: PSMA expression significantly associates with grade group and initial PSA level. Elevated PSMA expression on both RP and Bx significantly correlates with an increased risk of disease recurrence after curative surgery. 5-year RFS rates are 88.2%, 74.2%, 67.7%, and 26.8% for patients with no, low, medium, or high PSMA expression on Bx, respectively. Elevated PSMA level on Bx predict a 4-fold increased risk of disease recurrence independently from initial PSA and grade group on Bx. PSMA expression significantly increases during PCa progression. Conclusions: PSMA qualifies as an independent prognostic biomarker on Bx at time of initial diagnosis in addition to the established markers PSA and grade group. PSMA predicts disease recurrence following curative surgery and potentially improves the discrimination indolent vs. aggressive disease. We propose the routine assessment of PSMA expression on Bx for outcome prediction and risk stratification at time of initial diagnosis prior to treatment decision.
Postoperative long-term prognosis of localized renal cell carcinoma after partial or radical nephrectomy: Analysis of cancer metastasis and deaths during a more than five-year follow-up.
Authors: Park Sang Hyun , Kim Taek Sang , Joung Jae Young , Kim Sung Han , Chung Jinsoo
Published: March 2019

604

Background: We performed a long-term follow-up study to evaluate the survival and metastatic outcomes of non-metastatic renal cell carcinoma (RCC) after curative removal of tumor. Methods: We retrospectively reviewed the clinical and pathological features of 5434 patients with localized renal cell carcinoma admitted to five Korean tertiary-care institutions between 2000 and 2012, who had undergone curative surgeries with partial or radical nephrectomy with/without lymph nodal dissection. The patients below the age of 19 years (N=9) with benign histology (N=24), and with no follow-up records (N=540) were excluded. A total of 4861 patients, followed-up for at least 1 year after the surgery, were enrolled finally. The deaths were defined as intraoperative, postoperative or RCC-related deaths. We analyzed the metastasis-free survival, cancer-specific survival, and overall survival outcomes according to the pathological stages. Results: The median age of patients at the time of surgery, male-to-female ratios, median follow-up duration, overall survival and metastasis-free survival times were 56 years (range: 19-94 years), 3471/1390 (71.4%/28.6%), 33.7 months (range: 12-297 months), 175.1 months (12-297.1 months), and 61 months (range: 12-94 months), respectively. A total of 518 (10.7%) deaths, including 338 (7.0%) RCC-related death and 164 (3.3%) deaths related to other causes were reported. Metastasis and recurrences were observed in 140 (2.9%) and 462 (9.5%) patients, respectively. The respective pathologic T1/2/3/4/x and N1 stages, namely, 3757/389/644/57/6 (77.3/8.0/13.3/1.2/0.1%) and 133 (2.7%) were observed. The rates of histological types of clear cell papillary/ chromophobe/ collecting duct/ unclassified/ MLCRCCLMP/ mixed cell papillary/ unknown were 83.4%/ 1.5%/ 7.1%/ 0.4%/ 1.1%/ 0.5%/ 0.2%/ 0.3%/ 0.1%/ 5.3%. The 10-year metastasis-free survival rate was 86.0% including 100%, 91.0%, 64.1%, and 11.8% incidence for stages I, II, III, and IV, respectively. Conclusions: The long-term survival was seen among patients who underwent nephrectomy for non-metastatic renal cell carcinoma.
Patterns of response of organ specific metastasis in patients with metastatic renal cell cancer (mRCC) treated with an immune checkpoint inhibitor (CPI) post tyrosine kinase inhibitor (TKI).
Authors: Picardo Sarah Louise , Iafolla Marco Adelmo James , Sridhar Srikala S. , Sacher Adrian G. , Hansen Aaron Richard
Published: March 2019

605

Background: Both TKIs and the novel immune CPIs targeting PD/PDL1 are now standard treatments for patients with mRCC. Mixed responses in metastatic lesions have been observed. We examined organ specific radiologic responses in a cohort of patients with mRCC who were initially treated with TKI followed by CPI. Methods: We identified patients who were treated with first line TKI followed by CPI from a prospectively maintained database of all mRCC patients treated at our institution from 2010 to 2018. We examined best response to TKI and CPI, as well as organ specific responses to TKI and CPI. Statistical analysis was performed using odds ratios and Fishers exact test. Results: We identified 31 patients with evaluable disease who were treated with a TKI followed by CPI. Best responses to TKI were partial response (PR) (n = 7), stable disease (SD) (n = 17) and progressive disease (PD) (n = 6). Of TKI responders, 4 had lesions in ≥2 organs respond and 3 had a lesion in a single organ respond. Of the 3 patients who responded to CPI, all had lesions in ≥2 organs respond. Patients who had PD to TKI did not respond to CPI. Organ specific metastases at time of initiation of TKI and CPI are described in the table. In lung lesions, the odds of a response to CPI with or without an initial response to TKI were 0.16 and 0.57 respectively (OR 0.29, p = 0.595). In lymph node (LN) metastases, the odds of a response to CPI with or without an initial response to TKI were 0.16 and 0.62 respectively (OR 0.27, p = 0.354). Two patients had a response to TKI in the liver but none had a response to subsequent CPI. Of 3 patients who had a response to TKI in the renal primary, 1 had a response to CPI. Conclusions: In this small series, these data suggest that first line TKI response may dictate subsequent CPI response in an organ specific manner, with higher numbers of CPI responses in lung and LN metastases in patients who did not have TKI response in these organs. This may be due to immune modulation by prior TKI or to tumor heterogeneity. Studies are needed to further elucidate this phenomenon. [Table: see text]
Body mass index (BMI) and toxicities and association with clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Bilen Mehmet Asim
Published: March 2019

613

Background: BMI has been explored as a prognostic factor in cancer pts and treatment-related toxicities have been associated with responses to VEGF-targeted therapy in mRCC pts. We investigated the association of BMI and adverse events (AEs) and CO in mRCC pts treated with cabo. Methods: A retrospective analysis of 65 pts with mRCC treated with cabo at Winship Cancer Institute from 2016 to 2018 was performed. Overall survival (OS), progression-free survival (PFS), and objective response (OR) were used to measure CO. OS and PFS were calculated from first cabo dose to death and radiographic or clinical progression, respectively. An OR was defined as a partial response (PR) or a complete response (CR) using RECISTv1.1. BMI was collected at baseline (BL) and 6 (±2) weeks after cabo initiation. AEs were obtained from clinic notes. Univariate analysis (UVA) of association between BMI and CO was carried out using logistic regression model for OR and proportional hazard model for OS and PFS. Results: The median age was 63 years and 26% were African American. The majority were either IMDC intermediate or poor-risk (59% and 34%, respectively). Most pts (67%) had a BMI ≥ 25 and the median BMI at BL was 26.6. There was no difference in incidence of AEs between pts with BMI < 25 and pts with BMI ≥ 25. Gastrointestinal (GI) AEs incidence was also comparable among pts with a BMI ≥ 25 (62%) and pts with BMI < 25 (57%, p = 0.666). Increased BMI at 6W was significantly associated with prolonged OS and increased baseline BMI at BL showed a trend towards longer OS (Table). Conclusions: Increased BMI may be associated with improved CO in mRCC pts treated with cabo, but there may not be a difference in AEs based on BMI. Larger analyses are needed to validate these findings. [Table: see text]
Fecal microbiota transplantation for TKI-induced diarrhea in patients with metastatic renal cell carcinoma.
Authors: Rossi Ernesto , Ianiro Gianluca , Maiorano Brigida Anna , Iacovelli Roberto , Lopetuso Loris , Settanni Carlo Romano , Masucci Luca , Quaranta Gianluca , Sanguinetti Maurizio , Bria Emilio , Gasbarrini Antonio , Tortora Giampaolo , Cammarota Giovanni , Schinzari Giovanni
Published: March 2019

615

Background: Diarrhea is a common adverse event of tyrosine kinase inhibitors (TKI). No standard treatment for TKI-induced diarrhea has been established, although probiotics are commonly used. In several patients TKI dose reduction is necessary. Data showing the interplay between microbiota and TKI-induced diarrhea are reported. The therapeutic modulation of gut microbiota could be useful to ameliorate TKI-related diarrhea. Our study aims to explore the efficacy and safety of fecal microbiota transplantation (FMT), compared with current clinical practice approach, for the treatment of TKI-associated diarrhea in patients with metastatic renal cell carcinoma. Methods: Patients on treatment with Pazopanib/Sunitinib as first line therapy for metastatic renal cell carcinoma and TKI-associated diarrhea (³ 4 stools per day over baseline) were randomize to receive FMT from healthy donor by colonoscopy (fresh faeces) or probiotics (L. casei DG). The primary endpoint was the resolution of TKI-related diarrhea. Baseline fecal samples were collected from all patients and donors. All patients were followed up 7, 15, 30 and 60 days after the treatment for diarrhea. Results: 21 subjects, 10 in FMT arm and 11 in control arm, have been enrolled. At 7 day-follow-up, TKI-related diarrhea disappeared in 10 patients of the FMT group and in 6 patients of the control group (100% vs 54.5%, p = 0.02). At 15-day and 30-day, 9 patients in the FMT group and 0 patients in the control group experienced resolution of diarrhea (90% vs 0%, p = 0.0001). At 60-days 8/10 patients in FMT arm did not have diarrhea. Dose reduction was necessary in 4 patients of the control group. No serious adverse events associated with any of the two treatment protocols were observed. Metagenomic analyses on collected stool samples are ongoing. Conclusions: This open-label randomised controlled trial showed the effectiveness and safety of FMT compared with probiotics in curing TKI-related diarrhea in patients with metastatic renal cell carcinoma, avoiding the necessity of dose reduction. Considering the increasing evidence, the modulation of microbiota trough FMT could also affect the efficacy of immunotherapy for metastatic renal cell carcinoma.
Genomic biomarkers of response to nivolumab/ipilimumab (nivo/ipi) and nivolumab (nivo) monotherapy in 108 patients with advanced renal cell carcinoma.
Authors: Lee Chung-Han , Di Natale Renzo G , Chowell Diego , Makarov Vladimir , Redzematovic Almedina , Murray Samuel J. , Carlo Maria Isabel , Voss Martin Henner , Feldman Darren R. , Motzer Robert J. , Chan Timothy An-thy , Hakimi A. Ari
Published: March 2019

641

Background: Both the combination of nivo/ipi and nivo monotherapy have shown efficacy across multiple malignancies including clear cell Renal Cell Carcinoma (ccRCC). Biomarkers such as tumor mutation burden (TMB) are prognostic in other malignancies, however, remain unvalidated in ccRCC. This study investigates genomic biomarkers associated with nivo/ipi and nivo clinical response. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor derived DNA from nivo/ipi and nivo treated patients from MSKCC and publicly available WES datasets (Miao D, Science, 2018, 359: 6377). Somatic mutations, TMB, neoantigen load (NA), and HLA zyogosity were correlated to objective response rate (ORR), progression free survival (PFS), and Overall Survival (OS). Alterations occurring in < 10% of the cohort were considered non-evaluable (NE). Results: 108 patients had tumors studied; 32 patients with nivo/ipi and 76 patients with nivo therapy. No individual factors showed significant correlations to ORR or both PFS and OS. In the combined cohort, homozygosity at HLA-C was associated with shorter OS (HR=2.55 95% CI 1.17-5.57; P=0.02). In the nivo/ipi cohort, TMB (HR=0.36 95% CI 0.16-0.84; P=0.02) and NA (HR=0.43 95% CI 0.19-0.98; P=0.04) were associated with longer PFS. Conclusions: Increased TMB and NA load may predict for improved outcomes, and homozygosity at HLA loci may predict for worse outcomes. The predictors of response to nivo may not be generalizable to nivo/ipi. To rule out artifacts of multiple testing in a small cohort, validation in a larger dataset is necessary. [Table: see text]
Effect of immunotherapy (IO) on primary renal tumor in metastatic renal cell cancer (mRCC).
Authors: Jamet Antoine , Caramella Caroline , Guida Annalisa , Arfi-Rouche Julia , Merabet Zahira , Colomba Emeline , Escudier Bernard , Albiges Laurence
Published: March 2019

649

Background: Recent data showed that cytoreductive nephrectomy (CN) should not be performed prior to systemic therapy in intermediate and poor risk groups. Immune checkpoint inhibitors (ICI) are now approved in first and second line in mRCC, but ICI effect on the primary tumor is unknown. Methods: All patients (pts) treated with ICI for mRCC without prior CN were retrospectively collected and sequential computed tomography (CT) scan evaluated for response. Primary objective was Objective Response Rate (ORR) in the primary renal tumor in the primary RECIST 1.1. Secondary objective included systemic ORR and nephrometry score changes. Results: A total of 20 pts were treated with ICI with primary tumor in situ between 12/2012 and 10/2018. Among these, CT scans were available for evaluation of response for 19 primary tumors in 18 pts. Median age was 59.5 years. Pathology was 16 clear cell RCC, 2 translocation RCC, 1 Collecting duct carcinoma. Baseline median primary renal tumor size was 7.3 cm. ICI was used in first line setting in 7 pts, in second line or beyond in 13 pts. IMDC risk group at ICI start was favourable in 2 pts, intermediate in 9 pts and poor in 9 pts. ICI used was NIVOLUMAB(N) single agent in 13 pts or in combination in 7 pts (6 N-IPILIMUMAB and 1 N-VEGFRTKI). After a median follow up of 6.5 month from ICI start and a median duration of immunotherapy of 3.0 month, ORR on the primary tumor, was 3/19 (16%) (1 CR and 2 PR), 14 tumors (74%) were stable, and 2 had PD as best response. Median change in primary renal tumor was -1%. ICI use did not change nephrometry score. At extra renal assessment, ORR (systemic) was 5/18 (28%), (2 CR, 3 PR), 5 (28%) SD, and 8 (44%) PD (including 1 with new lesion and 1 with non-target lesion PD). Interestingly, 4 pts/18 (22%) had mixed response with opposite response between primary and systemic response. Furthermore, 11/18 (61%) would not classified in same RECIST group (CR, PR, SD, PD) between primary and metastatic sites assessment. Conclusions: To our knowledge, we report the first cohort of patients treated with ICI investigating the response on the primary tumor. ICI can induce a significant reduction in primary renal tumor, especially complete response and therefore raise the question of delayed CN in responders under ICI.
Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: A single center, single arm trial.
Authors: Chatzkel Jonathan Alexander , Swank Jennifer , Ludlow Steven , Lombardi Kristina , Croft Cortlin , Artigas Yesenia , Rodriguez Yazmin , Terraciano Tina , Hart Sarah , Rembisz Jennifer , Johnson Elaine , Schell Michael J. , Yao Jiqiang , Zhang Jingsong , Fishman Mayer N.
Published: March 2019

657

Background: Ligation of IL-2 receptor or blockade of PD-1 receptor may change lymphocytes to induce regression of cancers with diverse histology or site of origin. Single agent objective response rates of 14-25% have been reported for IL-2 therapy of metastatic clear cell RCC (ccRCC). A response rate of 33% was observed in pembrolizumab treated ccRCC patients. Nivolumab treated ccRCC patients were observed to have early intratumoral migration of lymphocytes. A case report of IL-2 induced major regression right after no change on nivolumab therapy suggested that combining the two means of lymphocyte stimulation could be effective. Other trials combining IL-2 receptor agonists (NKTR-214) and PD-1 blockade have also reported regression of ccRCC. Distinctive attributes of high dose IL-2 therapy are the required inpatient stay and the durability of the complete responses. Methods: This single-institution, single arm study addresses the safety and feasibility of the combination of IL-2 and pembrolizumab in the treatment of metastatic ccRCC. Subjects are treated on four nine-week blocks, as follows: Pembrolizumab is given on weeks 1, 4, and 7 of each block. Patients are admitted for 5 doses of high dose IL-2 (given over ~ 33 hours/3 days) on weeks 2, 3, 5, and 6 of blocks 2 and 3. Safety is monitored by a Pocock boundary of .05 likelihood of 0.15 dose limiting toxicity rate. The Simon 2-stage alternative hypothesis for the sample size was a 45+% major response rate vs null hypothesis < 20%, at alpha = 0.10, 90% power. Results: No accrual stop for safety was triggered. Thirteen of the first 18 patients responded, substantially exceeding the requirement of 8+/24 combination-treated patients to reject the null. Seven patients responded after receiving pembrolizumab alone, six after starting combination therapy in block 2. Accrual is completed; at 27. Kaplan-Meier analysis projects ORR of 69%, with ORR 90%-lower confidence bound of 55%. Conclusions: The combination of high dose IL-2 and pembrolizumab is feasible, with a high response rate, justifying further exploration of this dual immune treatment of metastatic ccRCC. Clinical trial information: NCT02964078.
Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial.
Authors: Armstrong Andrew J. , Szmulewitz Russell Zelig , Petrylak Daniel Peter , Villers Arnauld , Azad Arun , Alcaraz Antonio , Alekseev Boris Y. , Iguchi Taro , Shore Neal D. , Rosbrook Brad , Sugg Jennifer , Baron Benoit , Chen Lucy F. , Stenzl Arnulf
Published: March 2019

687

Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]
Typical hormone deprivation side effects compared to SM-88 therapy for rising PSA.
Authors: Gartrell Benjamin Adam , Del Priore Giuseppe , Retter Avi S. , Sokol Gerald H. , Vandell Alexander G , Roach Mack
Published: March 2019

79

Background: Treatment for rising PSA non-metastatic prostate cancer (nmPC) includes multifaceted hormone therapies (HT) associated with increasing related toxicity; in aggregate the risk benefit ratio is not ideal. We report on the use before HT, of SM-88, a novel combination therapy (amino acid analogue, CYP3A4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect without known hormone related toxicity. Methods: Prospective ongoing Phase II of SM-88 (230 mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), no radiographically identified metastases at baseline and detectable CTCs. Results: From Sept 2016 to Dec 2017, there have been 31 consented (34 planned) with 23 evaluable (completed > 1 cycle). Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean testosterone (T) rose from 319 to 382 ng/dl (p=.19). Typical HT related side-effects were not observed: 96% of subjects reported no hot flashes, 91% no gynecomastia, 83% interest and 61% activity in sex, 78% excellent or nearly so overall health and 74% excellent QOL on at least 50% of their EORTC questionnaires; weight (-0.2 kg), hct (0%), glu (+2 mg/dl), urinary N telopeptide (-4.2 nmol), MAP (normotensives -2 mmHg, hypertensives -3 mmHg), heart rate (-2.4 beats/min), QTc (-3 ms) with no newly emergent >480 ms, serum Ca++ (-0.006 mg/dL), LDH (+6.4 u/L), bsAlkPhos (+6.2 u/L), triglycerides (-5.2 mg/dL), total protein (0.05 g/dL) and albumin (0.02 g/dL). Neutrophil lymphocyte ratio decreased at the end of cycle 1 in 100% (n=5, median 2.4) of those who progressed to subsequent therapy vs 47% of those who did not (p=.05). AEs occurred in 16 subjects: 1 unrelated Grade (G) 3; 0 G 4; 14/26 G 1-2 possibly related to drug. No AEs were related to T levels. From initial diagnosis of PSA rise (median 9, 3-18 months), 96% (22/23) have remained metastases free and 78% (18/23) remained free of additional HT (p<.05). There were no skeletal or cardiovascular events. Conclusions: SM-88 may be useful in delaying the start of HT. While on SM88 subjects did not report any T or therapy related AEs >G2. SM88 may be useful in prostate cancer patients who are more sensitive or vulnerable to HT related toxicity while maintaining stable PSA values. Prospective trials are planned to confirm its utility. Clinical trial information: NCT02796898.
TheraP: A randomized phase II trial of [177Lu]-PSMA-617 theranostic versus cabazitaxel in progressive metastatic castration-resistant prostate cancer.
Authors: Hofman Michael , Emmett Louise , Violet John A , Lawrence Nicola Jane , Williams Scott , Stockler Martin R. , Francis Roslyn J , Iravani Amir , Zhang Alison Yan , Martin Andrew James , Azad Arun , Yip Sonia , Langford Ailsa , McJannett Margaret Mary , Davis Ian D. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: March 2019

TPS332

Background: Lutetium-177 [177Lu]-PSMA-617 is a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), which is commonly overexpressed in prostate cancer. This treatment has demonstrated promising activity and tolerability in men progressing after multiple lines of chemotherapy and endocrine therapy. This trial will determine the activity and safety of 177Lu-PSMA-617 compared to cabazitaxel chemotherapy in men with progressive metastatic castrate resistant prostate cancer. Methods: TheraP is an open-label, randomised, two-arm, multi-centre, phase 2 trial comparing the activity and safety of experimental treatment with [177Lu]-PSMA-617 versus standard 2nd line chemotherapy with cabazitaxel. Key eligibility criteria include prior chemotherapy with docetaxel; rising serum PSA; sufficient PSMA avidity according to central reviewed of imaging with PSMA PET/CT and FDG PET/CT; no discordance between FDG PET and PSMA PET. The trial will include 200 participants randomised in a 1:1 ratio to either [177Lu]-PSMA-617 intravenously every 6 weeks, 8.5 GBq for cycle 1, decreasing by 0.5 GBq with each subsequent cycle, up to maximum 6 cycles (experimental group); or, chemotherapy with cabazitaxel (20 mg/m2) intravenously every 3 weeks, for 10 cycles (standard group). In the event of an exceptional response to [177Lu]-PSMA-617, according to centrally-reviewed, post-therapy SPECT imaging, treatment is suspended but can recommence subsequently on progression. The primary endpoint is a 50% or greater reduction from baseline in serum PSA. Secondary endpoints include overall survival, progression-free survival (PFS), PSA-PFS, pain-PFS, radiographic-PFS, health-related quality of life, pain response, and adverse events. The outcomes of patients excluded because of discordant disease on FDG PET and PSMA PET will be reported as a tertiary objective. The study has accrued 79 of 200 planned participants from 29 January 2018 to 23 October 2018. Clinical trial information: NCT03392428.
A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.
Authors: Narayan Vivek , Gladney Whitney , Plesa Gabriela , Vapiwala Neha , Carpenter Erica , Maude Shannon L. , Lal Priti , Lacey Simon F. , Melenhorst Jan Joseph , Sebro Ronnie , Farwell Michael , Hwang Wei-Ting , Moniak Michael , Gilmore Joan , Lledo Lester , Dengel Karen , Marshall Amy , Coughlin Christina Marie , June Carl H. , Haas Naomi B.
Published: March 2019

TPS347

Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells has transformative potential for the treatment of cancer. However, a primary challenge to the success of these therapies in prostate cancer is the immunosuppressive microenvironment, including high levels of Transforming Growth Factor-beta (TGFβ), encountered by re-directed T cells upon tumor infiltration. Importantly, these immunosuppressive functions of TGFβ can be abrogated in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity. In in vivo disseminated prostate cancer models, co-expression of TGFβRdn on PSMA-redirected CAR-T cells led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater tumor eradication. Methods: We initiated a first-in-human phase 1 clinical trial to evaluate the safety and preliminary efficacy of lentivirally-transduced PSMA-directed/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in men with metastatic CRPC. In preliminary dose-escalation cohorts, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy in a 3+3 design. In Cohort 3, patients will receive the MTD of CART-PSMA-TGFβRdn following a lymphodepleting regimen of cyclophosphamide and fludarabine. All patients provide newly obtained metastatic tumor biopsies at baseline, as well as on day +10 following the CAR-T cell infusion and at disease progression. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CART-PSMA-TGFβRdn cells is evaluated via multiplex immunoassays. Additional correlative studies include enumeration and phenotyping of circulating tumor cells and DNA. Cohorts 1 and 2 have been completed without observed DLT. Interestingly, a reversible cytokine release syndrome has been observed that is responsive to tocilizumab. Enrollment in Cohort 3 began in September 2018. Cohort expansions will examine serial CART-PSMA-TGFβRdn re-treatment strategies. Clinical trial information: NCT03089203.
Phase II study of sitravatinib in combination with nivolumab in patients with advanced or metastatic urothelial carcinoma (UC) after checkpoint inhibitor therapy (CIT).
Authors: Doshi Gurjyot K. , Vogelzang Nicholas J. , Richards Donald A. , Chong Daniel , Shaffer David R. , Nordquist Luke T. , Picus Joel , Alvarez Delia , Der-Torossian Hirak , Christensen James , Yorio Jeffrey Thomas
Published: March 2019

TPS498

Background: Combination therapy with agents targeting molecular and cellular mechanisms of CIT resistance is a rational approach to restoring CIT efficacy in patients (pts) with immunotherapy-resistant UC. Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets multiple closely-related receptor tyrosine kinase (RTK) pathways, including the split RTKs VEGFR-2 and KIT, as well as the TAM (TYRO3, AXL, and MER) RTKs. Inhibition of the split RTKs enhances antitumor activity by reduction of immunosuppressive regulatory T cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME). Inhibition of TAM RTKs further restores a more immune-supportive TME by depletion of MDSCs and repolarization of tumor-associated macrophages to the M1 phenotype associated with secretion of pro-inflammatory cytokines. Given these pleiotropic immune-activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing CIT clinical activity in pts with immunotherapy-resistant UC. This combination has been shown to be safe and tolerable in an ongoing Phase 2 study in pts with metastatic non-small cell lung cancer. Methods: This open-label Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with advanced or metastatic UC who experienced disease progression on or after CIT as the most recent systemic therapy. Enrollment is stratified by prior receipt of platinum-based chemotherapy. If the initial 2 cohorts are of high interest for efficacy, the protocol allows for addition of new cohorts to include pts previously treated with selected immunotherapies (anti-CTLA-4, anti-OX40 or anti–CD137 therapy) or who are CIT-naïve. The primary objective is Objective Response Rate. A Predictive Probability Design will be applied allowing for expansion to 40 pts per cohort. Sitravatinib is administered orally daily in continuous 28-day cycles at 120 mg; nivolumab intravenously at 240 mg every 2 weeks or 480 mg every 4 weeks. Status: The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03606174.
Keynote-676: Phase 3 study of bacillus calmette-guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction.
Authors: Kamat Ashish M. , Shore Neal D. , Hahn Noah M. , Alanee Shaheen , Nishiyama Hiroyuki , Shariat Shahrokh , Nam Kijoeng , Kapadia Ekta , Frenkl Tara L. , Steinberg Gary D.
Published: March 2019

TPS502

Background: Intravesical instillation of BCG is the standard of care for patients with HR NMIBC. However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for progression, representing a significant unmet need. Programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment may attenuate responses to BCG. KEYNOTE-676 is a randomized, comparator-controlled, phase 3 trial to evaluate the efficacy and safety of the PD-1 inhibitor pembro plus BCG in patients with persistent/recurrent HR NMIBC after BCG therapy. Methods: Adult (≥18 years) patients with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy are eligible. Patients are required to have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks prior to randomization, to have no concurrent extravesical disease, and to have ECOG performance status score 0-2, adequate organ function, and tissue for biomarker analysis. Patients will be randomly assigned 1:1 to continue on BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment will be stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Primary end point is complete response rate in participants with CIS. Secondary end points will include event-free survival, patient-reported outcomes, and safety. Responses will be assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until pathology-confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Recruitment will begin November 2018 and will continue until ~550 patients are enrolled. (NCT03711032). Clinical trial information: NCT03711032.