bluuebunny/crossref_metadata_2025 huggingface dataset:
A tale of lineage plasticity: Intense neoadjuvant testosterone lowering therapy in localized prostate cancer (PCa) harboring high-risk genomic signatures.
Authors: Karzai Fatima , Madan Ravi Amrit , Sowalsky Adam G. , Bilusic Marijo , Chun Guinevere , Cordes Lisa M. , Wilkinson Scott C. , Terrigino Nicholas , Harmon Stephanie , Pinto Peter A. , Choyke Peter L. , Turkbey Baris , Gulley James L. , Dahut William L.
Published: February 2020

368

Background: PCa is driven by androgen receptor (AR) signaling and neoadjuvant therapy with AR inhibitors offer an opportunity to improve cure rates in high-risk PCa particularly with utilization of multiparametric MRI (mpMRI). A loss of AR-regulated lineage characteristics and genomic loss of tumor suppressors RB1 and TP53 or mutations in DNA damage repair (DDR) genes can represent aggressive prostate variants. We conducted a feasibility study using mpMRI to evaluate tumor responses and resistance in newly diagnosed, high-risk PCa (NCT02430480). Methods: Pts were treated with androgen deprivation therapy (ADT) + enzalutamide (enza) 160 mg daily for 6 months (mos). Pts underwent 2 mpMRIs: baseline and post 6 mos treatment (trt). Post-trt mpMRI was followed by radical prostatectomy (RP). Primary endpoint: feasibility of mpMRI for localization and detection of PCa before and after ADT + enza. Results: 39 pts were enrolled on-study with 36 pts completing 6 mos trt and undergoing RP. Of 39 pts, 3 had disease progression. Conclusions: Neoadjuvant intense testosterone lowering therapy shows activity in PCa but a subset of pts not respond to AR-targeted therapies through lineage plasticity enabled by characteristic loss of RB1 and TP53 or due to genetic alterations. Identification of this high-risk patient population, along with development of treatment options, needs further investigation. Clinical trial information: NCT02430480. [Table: see text]
The SEMITEP trial: De-escalating chemotherapy in low-volume metastatic seminoma based on early FDG-PET.
Authors: Loriot Yohann , Texier Matthieu , Culine Stephane , Flechon Aude , Nguyen Thierry , Gravis Gwenaelle , Geoffrois Lionnel , Chevreau Christine , Gross-Goupil Marine , Barthelemy Philippe , Bompas Emmanuelle , Mahammedi Hakim , Laguerre Brigitte , Abadie Lacourtoisie Sophie , Helissey Carole , Ladoire Sylvain , Massard Christophe , Grimaldi Serena , Fizazi Karim
Published: February 2020

387

Background: A negative FDG-positron emission tomography/computerized tomography (PET) predicts the absence of viable seminoma cells after chemotherapy in men with metastatic seminoma. In this study, we assessed whether patients (pts) with low-volume metastatic seminoma can be treated with 2 cycles of etoposide-cisplatin (EP) followed by only one cycle of carboplatin (CARBO) on the basis of a negative interim PET, thereby limiting the burden of toxicity. Methods: In this non-randomised, multiple-center, phase 2 trial (NCT01887340), we enrolled pts with low-volume metastatic seminoma (with good prognosis according to IGCCCG and the Medical Research Council classifications). All pts with baseline PET-positive received EP for two cycles. After completion of first two cycles, pts underwent a second PET to assess response. Patients with a persistent positive PET (based on local review) proceeded directly to two additional EP cycles (for a total of 4); those who achieved a PET-negative received only one cycle of CARBO (AUC=7). The primary outcome was the proportion of pts who were PET-negative on interim PET and received de-escalating chemotherapy. Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Results: Between June 2013 and July 2017, 102 pts were enrolled in the study. Three pts were deemed ineligible or not evaluable and thus 99 patients received treatment. After 2 first EP cycles, PET was available in 94 pts. Interim PET was negative in 68 pts (72%) and positive in 26 pts (28%). Overall, 63 pts (67.0%; 95% CI 57.5-76.5) were PET-negative and proceeded to one single cycle of CARBO. Overall, 24 (25.5%, 95% CI 17.1-34.9) patients had a PET positive after 2 EP and received 2 additional cycles of EP. After a median follow-up of 34.4 months, only 8 patients relapsed (2 in EP group and 6 in CARBO group). 2-year PFS rates were respectively 93.7% (95% CI 84.9-97.5) in the CARBO group and 92.9% (95% CI 77.4-98.0) in the EP group. Only one patient died during the 2 first cycles. Conclusions: De-escalating treatment based on a negative PET after 2 cycles of chemotherapy appears to be safe and feasible in the majority of patients with low-volume metastatic seminoma. Clinical trial information: NCT01887340.
Real-world prognostic model for overall survival (OS) in patients (pts) with advanced urothelial cancer (aUC) treated with immune checkpoint inhibitors (ICI).
Authors: Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Miller Natalie J. , Bilen Mehmet Asim , Sacristan Santos Victor , Morales-Barrera Rafael , Devitt Michael Edward , Nelson Ariel Ann , Shreck Evan , Assi Hussein , Zakopoulou Roubini , Rodriguez-Vida Alejo , Lythgoe Mark , Drakaki Alexandra , Joshi Monika , Isaacsson Velho Pedro , Alonso Lucia , Galsky Matt D. , Sonpavde Guru , Grivas Petros
Published: February 2020

447

Background: While ICI prolong OS after platinum chemotherapy in aUC, outcomes vary based on clinical confounders. We aimed to develop a prognostic model in pts receiving ICI in a non-clinical trial setting. Methods: We used a hypothesis driven approach of clinician selected covariates to develop a new prognostic model. Data source was a retrospective cohort of pts treated with ICI at 19 institutions. Demographics, clinicopathologic data, treatment patterns, and OS were collected. Univariate (UVA) Cox regression was done on 24 variables hypothesized to be associated with OS. Variables were retained for multivariate analysis (MVA) if they had statistical relationship with OS (p<0.2) and were included in the final model if p<0.05 on MVA. Each retained covariate was assigned 1 point in the final prognostic model. Stratified median OS and c-statistic were calculated. Results: 415 pts with mean age 69, 26% female, 66% ever smokers, 69% pure UC, 15% upper tract UC, 54% with prior extirpative surgery, Bellmunt risk factors 17%, 51%, 28% and 4% for 0, 1, 2, 3, respectively were included. Non-White race, ECOG PS≥1, albumin<3.5g/dL (lower limit of normal), hemoglobin<10g/dL, absolute neutrophil count (ANC)>8x106/ul (upper limit of normal), and presence of bone or liver metastases (mets) were all associated with worse OS on UVA Cox regression; albumin<3.5 g/dL, ANC>8x106/uL, presence of bone or liver mets remained significant on MVA and were included in the prognostic model. Median (m)OS by new model and Bellmunt are shown in table. C-statistic of the new model was 0.67. Conclusions: Albumin<3.5 g/dL, ANC >8x106/ul, presence of bone or liver mets were negative prognostic factors in pts with aUC treated with ICI. This has comparable features to recently reported 5-factor model using clinical trial data, including LDH (unavailable in our cohort). External validation is being pursued. The proposed model may be used for prognostication, clinical trial design, eligibility and stratification. [Table: see text]
Disease progression among patients who receive available bladder preservation therapies after failure of BCG therapy in the SEER-Medicare data.
Authors: Kamat Ashish M. , Georgieva Mihaela V. , Song Jinlin , Bocharova Iryna , Qian Kun , Guo Amy , Yang Min
Published: February 2020

453

Background: For patients with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) who recur after Bacillus Calmette-Guérin (BCG) therapy, treatment options other than radical cystectomy have been limited. This study examined real-world utilization and outcomes of current bladder preservation therapies (BPT) after BCG treatment. Methods: We analyzed the SEER-Medicare database and identified patients diagnosed with HG NMIBC between 2008 and 2015 who received at least one BCG induction course (defined as ≥5 weekly instillations). Use of BPT within six months of the last consecutive BCG instillation was identified and included BCG + interferon alpha, docetaxel, doxorubicin, epirubicin, gemcitabine, mitomycin C, nab-paclitaxel, thiotepa, valrubicin, or their combinations. Progression was identified as initiation of treatment for muscle-invasive bladder cancer, radical cystectomy, or presence of metastases. Time to progression (TTP) was defined as time from BPT initiation to progression event. Progression-free survival (PFS) was assessed from BPT initiation and defined as the absence of progression or death due to bladder cancer. TTP and PFS were assessed using Kaplan-Meier analysis. Results: A total of 7,074 patients were diagnosed with HG NMIBC and received ≥ 5 BCG weekly induction instillations. Of these, 8.8% (620 patients) initiated BPT. The most commonly used agents were mitomycin C (66.0%), followed by BCG + interferon alpha (22.9%), valrubicin (4.0%), doxorubicin (2.9%), and gemcitabine (2.1%). Disease progression occurred in 18.7% of patients within 1 year of treatment initiation (40.5% due to metastases), 36.4% within 3 years (50.0% due to metastases), and 45.4% within 5 years (50.2% due to metastases). The rate of PFS was 80.9%, 61.8%, and 52.3% at 1, 3, and 5 years, respectively. Conclusions: High rates of metastatic disease are noted in HG NMIBC following available BPT treatments after failure of BCG therapy. A high unmet need remains for novel bladder-sparing therapies to improve outcomes in this difficult-to-treat population.
A phase Ib study of combination of avelumab and taxane-based chemotherapy in platinum refractory or ineligible metastatic urothelial cancer (AVETAX study).
Authors: Garje Rohan , Ginader Timothy , Laux Douglas Earl , Nepple Kenneth Gerard , Milhem Mohammed M. , O'Donnell Michael A. , Zakharia Yousef
Published: February 2020

487

Background: Advanced bladder cancer is the most common malignancy of the urinary system with 5-year OS rates of 5-7%. Platinum based chemotherapy and checkpoint inhibitors are currently available treatment options but with limited benefit. We hypothesize that combining Avelumab (anti-PD-L1 immunotherapy) with Docetaxel is safe and will lead to cancer cell death releasing neoantigens with enhanced anti-tumor immune mediated cytotoxicity. Methods: This is a phase 1b, single arm, non-randomized, open label prospective clinical trial to evaluate the combination of Avelumab and Docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. It has two phases: Phase 1b dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) to establish phase 2 dose in the standard 3+3 design. In the dose expansion phase, the phase 2 dose of docetaxel with avelumab will be evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles and then avelumab alone is continued every 2 weeks. Primary endpoint is safety. Efficacy endpoints include objective response rate, progression free survival and overall survival. Results: At the cutoff date of 10/21/2019, 10 eligible patients were enrolled in the study. Only one of the six patients treated with level 0 dose of docetaxel had a dose limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. Additional 4 patients were enrolled in the dose expansion cohort. Efficacy data is preliminary with 1 patient achieving CR, 2 pts had PR, 2 pts had SD, 1 pt PD and 4 pts are not yet evaluable. The most common Grade 3 or 4 AEs were febrile neutropenia, urinary tract infection and confusion. No treatment related deaths were noted. Conclusions: The combination of docetaxel in combination with avelumab is safe and the preliminary data showed promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT03575013.
The real-world efficacy of abiraterone acetate (ABA) and docetaxel (DOC) in the treatment of African-American (AA) patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Smith Katherine E.R. , Brown Jacqueline T , Liu Yuan , LaFollette Jennifer Ann , Moore Melvin R. , Bilen Mehmet Asim
Published: February 2020

52

Background: The landscape of mCSPC treatment changed with the addition of ABA and DOC. The prevalence of AA pts in the trials that led to these approvals was < 10%. We characterized the clinical outcomes (CO) of a cohort of AA pts treated with these agents. Methods: We retrospectively reviewed 51 AA pts with mCSPC treated with ABA or DOC at Grady Memorial Hospital from 2015-2018. The CO included median overall survival (mOS), progression-free survival (mPFS) and PSA response (PSAr) as defined by a ≥ 50% drop in PSA over the 1st 12 weeks of treatment. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS and logistic regression model for PSAr. Results: Median age was 63 years, 64% were grade group 5 and 67% had an ECOG status of 0-1. 82% had high volume disease per CHAARTED; 51% did per LATITUDE. 21 pts received ABA; 30 received DOC. The groups (ABA vs DOC) were balanced except for high volume disease per LATITUDE (28.6 vs. 66.7%) and lymph node metastases (66.7 vs. 96.7%). The DOC cohort received a mean of 5.2 cycles. Median follow-up was 10.3 months (mos). The overall mOS was 37.8 mos, mPFS was 10.3 mos, and PSAr was 89.6%. CO trended toward favoring ABA over DOC but did not differ significantly with a 12-month OS of 100% vs. 81.7% and PFS of 53.7% vs. 35.4%, respectively. Albumin and hemoglobin at baseline were associated with CO (Table). Conclusions: We present the first real world efficacy of ABA and DOC in a cohort of AA pts with mCSPC and found similar outcomes between the two groups. These findings warrant a larger study for validation.[Table: see text]
Pathogenic variants in PTEN to predict for increased risk of relapse and death in patients with limited stage small cell bladder cancer.
Authors: Burgess Earle Frederick , Steuerwald Nury , Symanowski James Thomas , Livasy Chad , Farhangfar Carol J. , Gatalica Zoran , Arguello David , Zhu Jason , Grigg Claud , Clark Peter E. , Raghavan Derek
Published: February 2020

526

Background: Small cell bladder cancer (SCBC) is a rare histologic subtype with insufficient genomic characterization. Patients with limited stage (LS) SCBC have a poor prognosis, and no biomarker exists to optimize treatment selection. We sought to identify genomic aberrations in patients with LS-SCBC using a comprehensive next generation sequencing (NGS) platform. Mutations in the PTEN/AKT pathway are important in urothelial tumor biology but have an undefined role in SCBC. Methods: 23 LS-SCBC cases were identified. NGS was performed on diagnostic transurethral bladder tumor resection or cystectomy specimens containing SCBC. Detected variants were filtered by in silico algorithms predicting for a deleterious impact on protein function. Variant allele frequencies (VAF) greater than 2% were permitted in this analysis. Variants in the PTEN gene were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: Median follow up for the cohort was 4.02 years. 14/23 (60.9%) patients have died. Six unique deleterious PTEN mutations were observed in 9/23 (39.1%) patients. p.W274C was the most common PTEN variant and was detected in 5 (21.7%) patients. Three variants were detected at > 10% VAF. All 9 patients with a deleterious PTEN variant died. The presence of deleterious PTEN variants [HR = 4.68 [(1.54, 14.27), p = 0.003]] predicted for inferior OS. In the 19 patients with known relapse history, 6/7 (85.7%) with and 3/12 (25%) without any deleterious PTEN mutation relapsed. The presence of deleterious PTEN variants [HR = 9.41 [(2.32, 38.23), p < 0.001]] also predicted for inferior RFS. Conclusions: Pathogenic variants in tumor suppressor PTEN were associated with inferior RFS and OS in this pilot cohort of patients with LS-SCBC, suggesting that disruption of PTEN function may be a critical genomic event underlying the progression of small cell bladder cancer. Our findings also support prior reports that pathogenic gene variants detected at low allele frequencies may be clinically important.
Association of myeloid suppressor cells with resistance to checkpoint blockade immunotherapy in urothelial carcinoma.
Authors: Sundi Debasish , Duggan Megan Christina , Savardekar Himanshu , Kwon Hyunwoo , Sun Steven , Benner Brooke , DiVincenzo Mallory , Lee Cheryl T. , Svatek Robert S. , Carson William Edgar
Published: February 2020

559

Background: Myeloid immune cells such as myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) have been hypothesized to cause resistance to immune checkpoint blockade (ICB). This is a pressing clinical problem for patients with bladder cancer. Here we determined if we could identify immune cells associated with resistance to ICB in the BBN963 mouse model, and if we could identify therapeutic strategies to target those same suppressor immune cells from patients with bladder cancer. Methods: BBN963 subcutaneous allografts were established in C57BL6/J mice. Response to anti-PD-L1 ICB was classified as partial or complete response according to RECIST criteria. Immune cell subsets with the tumors was evaluated by gene expression profiling and flow cytometry. Peripheral blood from patients with bladder cancer was collected under an IRB-approved protocol. MDSC were purified by flow sorting (CD11b+ CD33+ HLA-DRlow/neg) and screened for viability (Annexin-V staining) after 24 hours of exposure to a panel potential MDSC inhibitors. Results: 16/22 (72%) subjects met criteria for partial or complete response, while 6/22 (28%) were classified as anti-PD-L1 non-responders. Mice in the control group had a 0/10 (0%) response to isotype control (IgG) treatment. Monocytic MDSC (CD11b+ Ly6C+) were much more frequent among the intratumoral CD45+ cells of non-responding subjects as compared to control mice. Nanostring immune panel gene expression profiling revealed that combination treatment of tumor bearing mice with anti-PD-L1 plus ibrutinib (a putative MDSC inhibitor) decreased mRNA biomarkers of tumor-infiltrating macrophages. In vitro screening of patient-derived peripheral blood mononuclear cells showed that an inhibitor of the bromodomain and extraterminal domain (BET) family BRD4 specifically decreased MDSC viability. Conclusions: Monocytic MDSC appear to be associated with resistance to anti-PD-L1 ICB in a new murine model. Analysis of MDSC from patients with bladder cancer suggests that these myeloid suppressor cells can be specifically targeted.
Discrepancy between clinical stage and pathological stage based on the tumor location of urothelial carcinoma: A hospital-based cancer registry in Japan.
Authors: Nagumo Yoshiyuki , Kojima Takahiro , Kojo Kosuke , Kimura Tomokazu , Kandori Shuya , Kawai Koji , Okuyama Ayako , Higashi Takahiro , Nishiyama Hiroyuki
Published: February 2020

579

Background: Accurate staging in patients with urothelial carcinoma (UC) of the bladder (UCB) or the upper urinary tract (UTUC) is essential for planning the appropriate treatment strategy. Although an underestimation of the pathological stage may result in missing the opportunity to perform preoperative treatment, the actual rate of the discrepancy between the clinical and pathological stages in UC is not known. Methods: We used Hospital-Based Cancer Registry (HBCR) data in Japan to extract 3,747 cases of UCB and 6,831 cases of UTUC with cT1-4N0M0 that were diagnosed in 2012–2015, histologically confirmed, and treated with radical surgery. We excluded patients who received chemotherapy or radiotherapy and those with an unknown clinical or pathological stage. Results: The proportion of UCB patients whose pathological stage was up-staged was 25%, and that of the UTUC patients was 30%. Among the patients with cT1 at each tumor location, up-staging to muscle-invasive cancer occurred in 30.9% (UCB, n=1132: pT2, 21.6%; pT3, 7.9%; pT4, 1.5%) and 37.5% (UTUC, n=2526: pT2, 16.9%; pT3, 20.2%; pT4, 0.4%), respectively. In particular, in the group of UTUC patients with cT1, the proportion of up-staging for pT3 was higher than that in the group of UCB patients with cT1. In the cases with cTis, up-staging to muscle-invasive cancer occurred in 10.5% (UCB, n=391: pT2, 6.9%; pT3, 1.8%; pT4, 1.8%) and 18.5% (UTUC, n=872: pT2, 9.7%; pT3, 8.7%). In contrast, the proportion of down-staging to non-muscle-invasive cancer in cases with cT2 or higher was 12% in the UCB group (n=2291) and 15% in the UTUC group (n=504). Conclusions: Among UC patients, up-staging from non-muscle-invasive cancer to muscle-invasive cancer is relatively common, and the frequency of this discrepancy in clinical and pathological stages tends to be especially higher in UTUC patients. More accurate diagnostic imaging techniques and biomarkers are urgently needed for the identification of the appropriate UC candidates for preoperative treatment.
Using natural language processing (NLP) tools to identify veterans with metastatic prostate cancer (mPCa).
Authors: Alba Patrick R. , Lynch Julie Ann , Gao Anthony , Lee Kyung Min , Anglin-Foote Tori , Robison Brian , Shelton Jeremy B. , Efimova Olga , Patterson Olga V , DuVall Scott L.
Published: February 2020

60

Background: Veterans may benefit from promising innovations in treatments for mPCa. The Veterans Affairs (VA) and Prostate Cancer Foundation (PCF) leadership issued a challenge to identify, in real time, the national census of Veterans receiving care for mPCa. Administrative diagnostic and procedural coding do not accurately identify the risk status or disease state of prostate cancer (PCa). This study reports the development and validation of NLP tools deployed on clinical notes to identify risk status or disease state. Methods: Using diagnosis and histology codes, we queried the VA Corporate Data Warehouse to identify Veterans with prostate cancer. We included structured laboratory tests, medications, procedures, and surgeries related to prostate cancer diagnosis or treatment in the analysis. Using structured data, we identified 1000 likely mPCa cases and controls. Medical records were reviewed to confirm status and to extract term dictionaries related to cancer, anatomy, metastasis, and other diagnostic concepts. We went through several iterations of testing to refine and validate the NLP tool on a limited set of known cases and controls. We deployed the tool on all cancer, urology, pathology, and radiation oncology notes. Results: The NLP system was able to identify the patients' history of metastatic disease with 0.975 precision and 0.828 recall. Among the 1,081,137 Veterans with prostate cancer, NLP identified 63,222 (5.8%) with mPCa. There are 16,282 Veterans alive with mPCa. Mean age of diagnosis was 67 and 8,847 (54.3%) were diagnosed in the VA. Demographics were: White 9,756 (60%), Black 4,466 (27%), and other 2,060 (13%). Conclusions: NLP is a reliable tool for identifying Veterans who may benefit from novel innovations in mPCa diagnosis and treatment.[Table: see text]
Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Plimack Elizabeth R. , Bauer Todd Michael , Merchan Jaime R. , Papadopoulos Kyriakos P. , McDermott David F. , Michaelson M Dror , Appleman Leonard Joseph , Thamake Sanjay , Zojwalla Naseem J. , Jonasch Eric
Published: February 2020

611

Background: Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in RCC. MK-6482 is a first-in-class small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β and induces regression in mouse xenograft RCC models. Methods: Pts with advanced ccRCC who had received at least 1 prior therapy were enrolled in an expansion cohort from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Pts were administered 120 mg of MK-6482 orally once daily. Primary end point: safety. Key secondary end points: ORR, duration of response (DOR), and PFS. Results: Fifty-five pts were enrolled in the dose expansion cohort. Median (range) number of prior therapies was 3 (1-9); 67% received anti–PD-1 and anti-VEGF agents. Five pts (9%) were favorable risk, 40 (73%) were intermediate risk, and 10 (18%) were poor risk by IMDC criteria. With a median follow-up of 13 mo the most common all-grade, all-cause AEs > 30% were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common grade 3 AEs. No grade 4/5 drug-related AEs were observed. ORR was 24% with 13 confirmed PRs. Thirty-one pts (56%) had SD, with a disease control rate (CR+PR+SD) of 80%. Thirty-five of 52 (67%) pts with baseline and postbaseline assessments had tumor shrinkage. Median DOR was not reached; 81% of pts had response ≥6 mo per Kaplan-Meier estimate. Sixteen pts (29%) continued treatment beyond 12 mo. By IMDC risk, 2/5 pts with favorable risk had PR (ORR = 40%), 10/40 with intermediate risk had PR (ORR = 25%), and 1/10 with poor risk had PR (ORR = 10%); disease control rate was 100%, 80%, and 70%, respectively. Median PFS for the total population was 11.0 mo; the 12 mo PFS rate was 49%. Median PFS for favorable, intermediate, and poor IMDC risk was 16.5, 11.0, and 6.9 mo, respectively. As of May 15, 2019, 30 pts (55%) discontinued due to PD, 2 (4%) due to AEs. Sixteen pts (29%) had treatment ongoing. Conclusions: MK-6482 is well tolerated with a favorable safety profile and demonstrated promising single-agent activity in heavily pretreated pts with ccRCC across IMDC risk groups. A phase 3 trial in a similar population is planned. Clinical trial information: NCT02974738.
Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with >5 years of follow-up in patients with advanced renal cell carcinoma (aRCC).
Authors: Motzer Robert J. , Tykodi Scott S. , Escudier Bernard , Oudard Stephane , Hammers Hans J. , McDermott David F. , George Saby , Castellano Daniel , Choueiri Toni K. , Alva Ajjai Shivaram , Richardet Martin Eduardo , Plimack Elizabeth R. , Srinivas Sandy , Procopio Giuseppe , Donskov Frede , Gurney Howard , Tomita Yoshihiko , McHenry M. Brent , Saggi Shruti Shally , Tannir Nizar M.
Published: February 2020

617

Background: CheckMate 025 demonstrated superior overall survival (OS) in previously treated patients (pts) with aRCC, with improved safety and tolerability in the NIVO arm compared with EVE. The primary analysis was based on 14-months minimum follow-up. Here, we report an updated, final analysis with an extended minimum follow-up of 64 months. Methods: Previously treated pts with predominantly clear cell aRCC were randomized (1:1) to NIVO 3 mg/kg IV every 2 weeks or EVE 10 mg orally once daily until progression or unacceptable toxicity. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and safety. Confirmed ORR and PFS were per investigator (inv) using RECIST v1.1. Results: Overall, 410 vs 411 pts were randomized to NIVO vs EVE, respectively. OS benefit was maintained and PFS favored NIVO vs EVE with long-term follow-up (HR 0.84 (95% CI 0.72–0.99). (Table) ORR was higher (23% vs 4%) with NIVO vs EVE and median duration of response (DOR) was longer (18.2 vs 14.0 months). Ongoing response was observed in 28% vs 18% of pts with NIVO vs EVE. Most pts received subsequent systemic anticancer therapy: 276 pts in the NIVO arm (67%; most commonly EVE [35%] or axitinib [33%]) and 296 pts in the EVE arm (72%; most commonly axitinib [41%] or NIVO [26%]). No new safety signals or treatment-related deaths emerged with long-term follow-up in either arm. More pts in the EVE arm (37%) experienced a grade 3/4 treatment-related AE compared with pts in the NIVO arm (21%). Conclusions: At >5-years minimum follow-up, response rates and survival remain superior with NIVO vs EVE, and 28% of responses to NIVO are ongoing. Long-term follow-up highlights the efficacy and safety of NIVO monotherapy in pts with aRCC. Clinical trial information: NCT01668784. [Table: see text]
The prognostic value of body fat components in metastasis renal cell carcinoma patients treated with TKIs.
Authors: Dai Jindong , Zhang Xingming , Liu Zhenhua , Song Tingni , Zhu Xudong , Zhang Haoran , Zeng Hao , Shen Pengfei
Published: February 2020

668

Background: To assess the association between body fat components and survival status and tumor response for metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). Methods: Patients with pathologically diagnosed and radiologically indicated mRCC were enrolled into the retrospective study. Three body fat components: total fat accumulation (TFA), visceral fat accumulation (VFA) and subcutaneous fat accumulation (SFA) were measured using standard CT scans. The clinical outcomes included progression-free survival (PFS), overall survival (OS), and tumor response rates. Univariate analysis and multivariate Cox proportion hazard regression models were used to find associated parameters and to calculate the adjusted hazard ratio (HR). Results: A total of 146 patients were enrolled. The median follow-up time was 22 months. According to the univariate analysis, patients with an increased SFA and TFA had a longer PFS and OS. A similar phenomenon was observed among patients with ≥2 increasing body fat components about PFS and OS. As for multivariate analysis, SFA change (p=0.014) or the number of increasing body fat components (p=0.040) were independent indicators to predict PFS. In addition, SFA change (p=0.022) or the number of increasing body fat components (p=0.008) could independently predict OS. Moreover, a better disease control rate (p=0.028) was founded in patients with ≥2 increasing components. In the subgroup of patients with ≥2 metastasis sites, improved OS (p=0.017) and PFS (p=0.027) were found compared to those with <2 increasing components. Further multivariate analysis identified the number of increasing body fat components was an independent factor in predicting PFS (p=0.018) and OS (p=0.029). Conclusions: Body fat accumulation, such as high SFA or TFA at progression, could improve the survival of patients with mRCC treated with TKIs, especially patients with higher tumor burden. It should be considered as an important parameter to predict the survival status of patients with mRCC.
A randomized phase II trial comparing switch to nivolumab with TKI continuation after 12 weeks of TKI induction therapy in metastatic renal cell carcinoma patients (NIVOSWITCH).
Authors: Grünwald Viktor , Grüllich Carsten , Ivanyi Philipp , Wirth Manfred , Staib Peter , Schostak Martin , Dargatz Philip , Müller Lothar , Metz Michael , Bergmann Lothar , Steiner Thomas , Welslau Manfred , Lorch Anja , RAFIYAN Mohammad-Reza , Hellmis Eva , Hinke Axel , Meiler Johannes , Kretz Thomas , Loidl Wolfgang C. , Flörcken Anne
Published: February 2020

678

Background: Tyrosine kinase inhibitors (TKI) and Nivolumab (NIVO) are standard treatment options for mRCC. We tested whether TKI followed by early switch to NIVO improved outcome in mRCC patients (pts). Methods: Main inclusion criteria: measurable advanced or metastatic clear cell RCC, ECOG PS 0-2, adequate organ function, PR or SD to induction therapy with sunitinib (50 mg, 4-2 regime) or pazopanib (800 mg OD). 1:1 randomization at 12 wks.: TKI continuation vs. switch to NIVO (240 or 480 mg IV q2-4wks). Strata were MSKCC risk, TKI used and response to TKI. Imaging was performed q12w. 49 of 244 planned pts were randomized between Dec 2016 and Aug 2018, which led to premature closure of the trial. We report the second interim analysis with data base lock on 31.07.19. ORR was assessed according to RECIST 1.1. Efficacy and safety analyses were performed in ITT and safety population, respectively. Log-Rank analyses were used for survival analyses. Results: 25 and 24 pts received NIVO or TKI, respectively. Median age was 65 y (range: 35-79), 82% were male and 4% had ECOG PS 2. Metastases occurred predominantly in lung (47%), lymph nodes (27%) and liver (24%). MSKCC risks were: favorable (31%), intermediate (65%), and poor (4%), which were balanced between arms. 55% received sunitinib. ORR for NIVO vs. TKI differed when assessed from start of induction therapy (64 vs. 70%, P=0.76) or from time of randomization (16 vs. 48%; P=0.032). Accordingly, PFS from randomization was 3.0 vs. 11.9 mo. (HR = 1.72 [95% CI: 1.19 – 2.48]; P=0.0026) in favor of TKI continuation. At a median follow-up of 12.9 mo. median OS was not reached, but HR = 1.86 (95% CI: 0.85 – 4.07) P=0.10 showed a trend for TKI continuation. All grades AE for NIVO vs. TKI occurred in 96% vs. 100%, grade 3-5 48% vs. 71% and serious AE 40% vs. 46%. Conclusions: In TKI-sensitive pts, continuation of TKI is more efficacious than early switch to NIVO. The major limitation of our trial is the premature closure and its limited sample size. Clinical trial information: NCT02959554.
Efficacy of adjuvant vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (VEGFRi) in renal cell carcinoma (RCC): A systematic review and meta-analysis.
Authors: Botrel Tobias Engel Ayer , Clark Otávio , Bretas Francisco Flávio Horta , Sadi Marcus V. , Ferreira Ubirajara , Paladini Luciano , Matheus Wagner , Duraes Ronilson Oliveira , Pompeu Antônio Carlos Lima
Published: February 2020

680

Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing the efficacy of adjuvant VEGFRi in locally advanced, non-metastatic clear renal-cell carcinoma (RCC). Methods:Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included studies that compared the addition of VEGFRi versus placebo, after nephrectomy. Analyzed endpoints were overall survival (OS) and disease-free survival (DFS). The data extracted from the studies were combined by using Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 121 references were identified and screened. The final analysis included 5 trials (S-TRAC, ATLAS, ASSURE, PROTECT and SORCE) comprising 6,128 patients that underwent previous nephrectomy for RCC. The DFS was similar in patients who received VEGFRi (fixed effect: HR=0.94, CI95%=0.87 to 1.03; p=0.19), with no heterogeneity (Chi2 = 4.33, df = 5 (P=0.50); I2 = 0%). Overall survival also was not statistically better in patients who received VEGFR inhibitors (HR=1.01, CI95%=0.90 to 1.15; p=0.84), with no heterogeneity (Chi2= 3.57, df = 5 (P=0.61); I2 = 0%). In the final combined analysis of the higher-risk disease group (pT3, pT4, or N+ disease), patients who received VEGFRi had a longer DFS (fixed effect: HR=0.85, CI95%=0.74 to 0.97; p=0.02), with no heterogeneity (Chi2 = 2.46, df = 3 (P=0.48); I2 = 0%). Overall survival was not statistically different for these higher-risk disease patients (fixed effect: HR=0.93, CI95%=0.74 to 1.16; p=0.5). Conclusions: This is the first meta-analysis including the five available RCTs in the literature (the previous meta-analysis reviewed only four), comparing adjuvant VEGFRi versus placebo in patients submitted to nephrectomy with a locally advanced, non-metastatic RCC. Adjuvant VEGFRi did not increase the OS in this group of patients. Amodest benefit of DFS with the use of adjuvant VEGFR inhibitors was restricted to patients with the highest risk of relapse.
Genomic biomarkers of response to lenvatinib/pembrolizumab (Len/Pembro) in patients with advanced renal cell carcinoma.
Authors: Lee Chung-Han , DiNatale Renzo G. , Chowell Diego , Krishna Chriag , Makarov Vladimir , Shapnik Natalie , Murray Samuel J. , Carlo Maria Isabel , Voss Martin H , Feldman Darren R. , Hakimi A. Ari , Adachi Yusuke , Minoshima Yukinori , Matsui Junji , Funahashi Yasuhiro , Perini Rodolfo F. , Nomoto Kenichi , Motzer Robert J. , Chan Timothy An-thy
Published: February 2020

733

Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]
Impact of metastasectomy on progression free and overall survival in metastatic renal cell carcinoma: Analysis of the REMARCC registry.
Authors: Meagher Margaret Frances , Autorino Ricardo , Kriegmair Maximilian , Mir Maria Carmen , Rubio Jose , Campi Riccardo , Mari Andrea , Heck Matthias , Porpiglia Francesco , Van Bruwaene Siska , Linares Espinos Estefania , Musquera Mireia , Ghali Fadi , Veccia Alessandro , Guruli Georgi , Rousel Eduard , Pavan Nicola , Antonelli Alessandro , Marchioni Michele , Derweesh Ithaar
Published: February 2020

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Background: The role of metastasectomy has been in flux as treatment paradigms for management of metastatic renal cell carcinoma (mRCC) have shifted. We examined outcomes of surgical metastasectomy stratified in the setting of different mRCC risk groups. Methods: Multicenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. The cohort was subdivided by Motzer RCC criteria (low, intermediate, and high risk), and impact of metastasectomy was analyzed via multivariable analysis (MVA) and Kaplan Meier analyses (KMA). Primary outcome was progression free survival (PFS) and secondary outcome was overall survival (OS). Results: 438 patients (46 low risk, 262 intermediate risk, 140 high risk) with median follow-up 16 months were analyzed. Metastasectomy was performed in 18 (39%), 63 (24%), and 32 (23%) of low, intermediate and high risk groups (p=0.04). Risk groups differed significantly with respect to ECOG performance status (p<0.001), metastases at diagnosis (low 1.72, intermediate 3.49, high 6.45, p<0.001), hemoglobin (p<0.001) and LDH (p<0.001). MVA for PFS revealed age (OR=1.03, p=0.05), BMI (OR=1.05, p=0.01), and higher risk category [vs. low (referent) intermediate OR=7.4, p<0.001, high OR=3.4, p=0.01] to be independent risk factors. MVA for OS revealed age (OR=1.03, p=0.02), BMI (OR=1.06, p=0.01), and higher risk category [low (referent) vs. intermediate OR=2.8, p=0.03, high OR=2.3, p=0.01] to be independent risk factors. KMA for PFS demonstrated that metastasectomy was associated with longer PFS in intermediate (24.0 vs. 6.7 months, p=0.01) but not high risk (4.2 vs. 4.0 months, p=0.58) and low risk (p=0.51) groups. KMA for OS demonstrated that metastasectomy was associated with longer median OS in the intermediate (56.9 vs. 29.3 months, p=0.01) and high risk (18.2 vs. 10.5, p=0.01), but not low risk (p=0.21) groups. Conclusions: Receipt of metastasectomy was associated with improved PFS in intermediate risk and improved OS in intermediate and high risk mRCC patients. These findings challenge prevailing assumptions about utility of metastasectomy. Further investigation is requisite to refine criteria for employment.
Apalutamide (APA) for metastatic castration-sensitive prostate cancer (mCSPC) in TITAN: Outcomes in patients (pts) with low- and high-risk disease.
Authors: Ozguroglu Mustafa , Chowdhury Simon , Bjartell Anders , Uemura Hirotsugu , Chung Byung Ha , Agarwal Neeraj , Merseburger Axel Stuart , Juárez Soto Álvaro , Lopez-Gitlitz Angela , Bhaumik Amitabha , Larsen Julie S. , McCarthy Sharon Anne , Chi Kim N.
Published: February 2020

87

Background: TITAN showed that APA + androgen deprivation therapy (ADT) improves radiographic progression-free survival (rPFS) and overall survival (OS) in a broad group of pts with mCSPC (Chi et al. NEJM 2019). This post hoc analysis evaluates APA + ADT based on baseline (BL) prognostic risk as defined in LATITUDE (Fizazi et al. Lancet Oncol 2019). Methods: 1052 pts with mCSPC receiving ADT were randomized 1:1 to APA (240 mg/d; n = 525) or placebo (PBO; n = 527). Treatment cycles were 28 days. Risk included Gleason score ≥ 8, ≥ 3 bone lesions, or visceral metastasis. High risk was ≥ 2 risk factors, low risk was ≤ 1. Cox proportional hazards model was used to estimate HR and 95% CI for rPFS and OS. Results: Pt demographic and BL disease characteristics were similar between treatment groups (high risk: APA n = 289, PBO n = 286; low risk: APA n = 236, PBO n = 241). Median treatment duration was similar in the low-risk group with APA or PBO (21.8 mo and 20.3 mo, respectively). For the high-risk groups, treatment duration was longer with APA (APA 19.5 mo, PBO 14.7 mo). APA significantly reduced the risk of radiographic progression relative to PBO in both groups (Table). Risk of death (OS) was reduced by 38% in high-risk pts and 26% in low-risk pts with APA (Table). 24-mo survival rates: high risk, 76% APA, 63% PBO; low risk, 90% APA, 85% PBO. There were few deaths (≤ 33) in low-risk groups. Second PFS in APA pts: high risk, HR 1.9 (95% CI 1.2-3.0), p = 0.004; low risk, HR 2.2 (95% CI 1.5-3.2), p < 0.0001. Regardless of risk category, the safety profile of APA remained consistent with previously reported overall results. Conclusions: Addition of APA to ADT for pts with mCSPC prolonged rPFS and OS with a consistent safety profile compared with PBO + ADT regardless of BL risk. Clinical trial information: NCT02489318. [Table: see text]
Randomized phase II study of docetaxel (D) + abiraterone acetate (AA) versus D after disease progression to first-line AA in metastatic castration-resistant prostate cancer (mCRPC): ABIDO-SOGUG Trial.
Authors: Climent Duran Miguel Angel , Font Albert , Duran Ignacio , Puente Javier , Castellano Daniel , Sáez M Isabel , Mendez Vidal Maria Jose José , Santander Carmen , Arranz Arija Jose Angel , Gonzalez del Alba Aranzazu , Sanchez-Hernandez Alfredo , Esteban Emilio , Alonso Gordoa Teresa , Maroto Pablo , Lázaro Quintela Martín Emilio , Cassinello Javier , Perez Valderrama Begona , Juan Fita María José , Mellado Begona ,   Spanish Oncology Genitourinary Group
Published: February 2020

95

Background: Abiraterone acetate (AA) improves OS and rPFS in first line mCRPC patients (pts). After AA progression D is commonly used as standard second line therapy. However, the value of maintaining AA in combination with D despite progression has not been tested beyond small exploratory studies (Tagawa ST, Eur Urol 2016) ABIDO is a randomized-phase II trial that evaluates efficacy and safety of D + AA vs D after first-line AA progression in mCRPC. Methods: Asymptomatic or minimally symptomatic mCRPC pts with no visceral metastases, ECOG PS 0-1, and adequate organ functions were included. The study has two stages: In stage I pts receive AA (1000 mg/d + prednisone (P) 10 mg qd) until radiological or unequivocal clinical progression. In stage II pts were randomized to D 75 mg/m2 q3wk in combination with AA 1000 mg/d (arm A) or without AA (arm B) The primary endpoint was rPFS and the secondary endpoints radiological response (RR), OS, PSA-response, PSA-PFS and safety. Results: 88 pts were randomized, (46 arm A, 42 Arm B). Median age was 69 y/o, 43% had ECOG 0 and 91%/11%/5% had bone, liver and lung metastases. Median rPFS was 11.4 months (m) in arm A vs 10.5 m in ARM B; 12-m rPFS was 43% vs 45%; Median PSA PFS was 6.2 vs 5.5 m and median OS was 17.3 vs 16.9 m. Twenty four pts (52%) in arm A and 19 (46%) in arm B achieve ≥50% PSA response. RR was achieved in 15% vs 7% of pts and disease control rate in 74% in both arms. No statistically significant differences were found in efficacy parameters. Half of pts received 10 cycles of D (median 7 and 8). D median dose intensity was 86% and 90% for each arm and 91% for AA. Eleven pts discontinued treatment due to non-hematological toxicity, 5 in arm A and 6 in arm B. Most frequent G3-4 toxicities per arm (A/B) were: neutropenia (57%/29%; P=0.027), febrile neutropenia (17%/10%), diarrhea (9%/7%), and asthenia (11%/10%). Conclusions: ABIDO trial was unable to demonstrate the significant clinical benefit of maintenance AA approach + D after AA first-line therapy. No differences were observed in RR, PSA PFS, rPFS and OS. In AA + D cohort, more frequent and severe hematological toxicity (neutropenia and febrile neutropenia) were reported. Clinical trial information: NCT02036060.