bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of immune-related adverse events on survival in patients with metastastic urothelial carcinoma treated with immune-checkpoint inhibitors.
Authors: Morales-Barrera Rafael , Suarez Rodriguez Cristina , Gonzalez Macarena , Ros Javier , Semidey Maria Eugenia , Serra Hernandez Ester , Mateo Joaquin , Fernández Sáez Carlos , Lozano Fernando , Mast Richard , Roche Sarai , Quintana Angela , Gutiérrez Fernández Sara , Serrano Cesar , Valverde Claudia , de Torres Ines , Maldonado Xavier , Morote Juan , Carles Joan
Published: May 2019

4531

Background: Immune-checkpoints inhibitors (ICIs) represents the standard of care for platinum-pretreated advanced urothelial cancer patients (pts). By enhancing T-cell activation, a unique spectrum of inflammatory side effects has emerged, also known as immune-related adverse events (irAEs). Data regarding the association between irAEs and pts outcomes are conflicting. Here we conducted a retrospective analysis to investigate the association between irAEs profile and disease outcome in metastastic urothelial carcinoma (mUC) pts. Methods: Medical records from pts with mUC included in clinical trials between July 2013 and June 2018 and treated with ICIs were reviewed. Pts previously treated with platinum-based chemotherapy or cisplatin ineligible pts who had not been previously treated with chemotherapy were included. Clinical responses were assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST v1.1. Adverse events were graded based CTCAE v4.03. Overall survival (OS) was calculated from the date of initiation of ICI to the date of death. X2 test was used to determine differences in rates. OS was estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: From a total of 52 pts, 44 (84.6%) were treated with ICI monotherapy and 8 (15.3%) in combination (anti-CTLA4 or targeted therapy). Median age was 65 years, 42 pts (80.8%) were male, 44 patients (84.6%) had ECOG PS 0-1, 14 pts (26.9%) had liver metastasis. Overall irAEs were observed in 30 pts (57.7%) and 10 pts (19.2%) developed grade 3/4 irAES. Most common grade 3/4 irAEs were diarrhea (6.6%), rash (6.6%) and hepatitis (6.6%). Disease control rate (CR [26%]+PR[33%]+SD[20%]) was higher for patients with irAEs compared to those patients who did not developed irAEs (CR [13.6%]+PR[0%]+SD[22.7%], this difference was statically significant (P = 0.002). Median OS was 11.23 mo (CI 95%, 3.76-18.70) for the overall cohort, while median OS was 21.91 mo for those patients with irAEs compared to 6.47 mo in patients who did not developed irAEs (P = 0.004). Conclusions: In this analysis we found that the development of irAEs was a strong predictor of improved OS in mUC patients treated with ICI.
Bladder Cancer Multidisciplinary Clinic (BCMC) model: Impact on imaging, pathology and treatment recommendations.
Authors: Winters Brian , Diamantopoulos Leonidas Nikolaos , Tretiakova Maria S. , True Lawrence D. , Lee Jean H , Zeng Jing , Liao Jay Justin , Cheng Heather H. , Schweizer Michael Thomas , Hsieh Andrew Caleb , Yu Evan Y. , Schade George R , Gore John L. , Lin Daniel W. , Dighe Manjiri , Vakar-Lopez Funda , Russell Kenneth J. , Grivas Petros , Montgomery Robert B. , Wright Jonathan L.
Published: May 2019

4537

Background: Despite guideline-based standard of care recommendations in BC and upper tract urothelial carcinoma (UTUC), treatment remains variable across US. Experts recommend focusing BC care in tertiary centers. We hypothesized that a BCMC model, with expert central pathology and radiology review, may result in changes in corresponding reports, and, thus, treatment recommendations. Methods: Our BCMC clinic format includes simultaneous consultation with Urologic, Medical and Radiation Oncology, with real time expert genitourinary pathology and radiology review. We retrospectively assessed the concordance between outside (pre-BCMC) imaging & pathology review and BCMC review. Differences between pre- and post- BCMC recommendations on management were also assessed; descriptive statistics were used. Results: We identified 233 BC/UTUC patients (pts) referred to BCMC. Complete radiographic and pathologic data were available for 209 pts. Median age at time of evaluation was 68 (27-93) and 85% were PS ECOG 0-1. After BCMC review of outside records, 112 (53.6%) imaging and/or pathology changes were noted, with 57 (27%) pts upstaged. Overall, imaging interpretation was changed in 25% of cases, and 20% of pts were upstaged. BCMC pathology review resulted in changes in 59 (28%) pts. Among those, 42 (71%) had histologic subtype addition or change, 9 (15%) had LVI/CIS status change, and 2 (3.4%) had low to high grade conversion. In terms of pathology staging, 7 (12%) were downstaged, and 5 (8.5%) upstaged. Further diagnostic work-up was recommended in 71/209 (34%) pts, resulting in upstaging in 11/71 (15.5%) of cases. Pre- and post- BCMC-recommended treatment modality differed in 55/209 (26%) pts, while a new treatment modality was added in 28/209 (13%) pts. These recommendations were followed 91.4% of the time (191/209 pts). Conclusions: BCMC initiation at our institution resulted in imaging and/or pathology diagnostic changes in almost half of cases, with approximately a quarter of pts being upstaged. Findings reveal the importance of expert radiology and pathology review in BC. Further study is needed to confirm the proposed benefits and impact of BCMC on treatment response and outcomes.
Towards the noninvasive identification of pathologic responders to neoadjuvant pembrolizumab in muscle-invasive urothelial bladder cancer (MIBC).
Authors: Calareso Giuseppina , Bandini Marco , Raggi Daniele , Farè Elena , Gallina Andrea , Colombo Renzo , Colecchia Maurizio , Luciano Luciano Roberta , Salonia Andrea , Pederzoli Filippo , Ross Jeffrey S. , Madison Russell , Ali Siraj Mahamed , Chung Jon , Montorsi Francesco , Briganti Alberto , Messina Antonella , Necchi Andrea
Published: May 2019

4540

Background: The possibility to predict the pathologic complete response (pT0) or pT≤1 after neoadjuvant immunotherapy may deeply impact the management of MIBC and orient clinical trials. The PURE01 study ( Necchi, JCO 2018) evaluated preoperative pembrolizumab before radical cystectomy (RC) in T2-3bN0MO patients (pts). The trial was amended to increase the sample size. Methods: Pts were assessed with bladder multiparametric magnetic resonance imaging (mpMRI: T2-weighted imaging, diffusion-weighted imaging, dynamic contrast enhancement [CE]) before and after treatment (3 cycles every 3 weeks) prior to RC. All mpMRI were made with bladder catheterization. We tested the following complete response (CR) definition: any measurable residual disease (T2W, morphology), but no residual restricted diffusion and no early CE signals. Exams were independently assessed by 2 senior radiologists and tested against the pT0/pT≤1 endpoints. Logistic regression models analyzed mpMRI and biomarker data on comprehensive genomic profiling (CGP) with FoundationONE CDx assay and PD-L1 combined positive score (CPS). Results: From 02/17 to 11/18, 84 pts were assessed before and after treatment (168 total mpMRI) and had the pathological response available from RC. Baseline CR (TURB effect) was observed in 14 (16.7%) pts. The mean overall percentage of agreement (OPA) across the mpMRI data was 98.2%. The sensitivity of post-therapy (PT) CR for pT0 response was 0.80 (95%CI: 0.61-0.92); the specificity for pT≤1 response was 0.94 (95%CI: 0.80-0.99). PT-CR was associated with both pT0/pT≤1 endpoints (p < 0.001) after adjusting for clinical T-stage and histology. Baseline CPS≥10 and TMB≥20 mut/Mb were strongly associated with pT0 response (OR: 4.46 and 14.9). mpMRI CR post-pembrolizumab significantly improved the c-index of the CPS/TMB models: up to 0.81 and 0.87 for pT0/pT≤1 endpoints. Conclusions: In post-pembrolizumab MIBC, the proposed definition of radiological CR through mpMRI is endowed with limited inter-observer variability and high accuracy in predicting pT≤1. CPS/TMB-selected pts who achieve CR with mpMRI can be reliably spared any surgical treatment. Clinical trial information: NCT02736266.
Treatment sequencing of anti-PD-1/PD-L1 and carboplatin (carbo)-based chemotherapy (chemo) in cisplatin-ineligible patients (pts) with metastatic urothelial cancer (mUC).
Authors: Wei Xiao X. , Werner Lillian , Teo Min Yuen , Rosenberg Jonathan E. , Koshkin Vadim S , Grivas Petros , Szabados Bernadett , Morrison Laura , Carril Lucia , Castellano Daniel E. , Velho Pedro Isaacsson , Hahn Noah M. , McKay Rana R. , Raggi Daniele , Necchi Andrea , Kanesvaran Ravindran , Alerasool Parissa , Gaines Jacob , Bellmunt Joaquim , Sonpavde Guru
Published: May 2019

4541

Background: Anti-PD-1/PD-L1 agents and carbo-based chemo are therapy options in 1st-line (1L) setting for cisplatin-ineligible pts with mUC. However, optimal sequencing is unclear. Methods: We conducted a multicenter retrospective analysis of cisplatin-ineligible pts with mUC treated with 1L PD-1/PD-L1 monotherapy followed by carbo-based chemo (IO→Cb) or the reverse order (Cb→IO) without intervening systemic therapy. Perioperative cisplatin-based chemo was allowed if completed > 1 year from 1L mUC therapy initiation. To assess association between overall survival (OS) and therapy sequence, a multivariate analysis (MVA) was performed from initiation of 2L therapy, adjusted for treatment sequence, time interval between initiation of 1L and 2L therapies, Hb ( < 10 vs ≥10 g/dl), ECOG PS (0-1 vs 2-3), and metastatic site (LN/soft tissue only vs non-liver vs liver). Results: 146 pts (IO→Cb n = 43, Cb→IO n = 103) were evaluable with median age 72, 76% men, 78% ECOG PS 0-1, 17.8% with liver metastasis. Baseline factors were balanced except for higher proportion of men in IO→Cb group (91% vs 70%, p = 0.01). Median time interval between initiation of 1L and 2L therapy for IO→Cb and Cb→IO were 15.6mo (4.8-78.1) and 23.0mo (2.1-103.3), respectively. Response rates are summarized (Table). On MVA, treatment sequence was not associated with OS (HR 1.05, p = 0.85). Site of metastasis was the only factor significantly associated with OS (p = 0.002). Conclusions: In our retrospective analysis of cisplatin-ineligible pts with mUC regardless of PD-L1 expression, anti-PD-1/PD-L1 followed by carbo-based chemo or the reverse sequence appeared to confer comparable OS. The observed response rates and time interval between initiation of 1L and 2L therapy are likely contributed by pt selection, where all pts received 2L. Further investigation of the ‘PD-L1 high’ population is warranted, given higher response rates with anti-PD-1/PD-L1 vs ‘PD-L1 low’ population. Ongoing phase III trials will help inform optimal sequencing. [Table: see text]
Clinical and economic outcomes associated with sequential treatment in patients with advanced renal cell carcinoma (aRCC).
Authors: Regan Meredith M. , McDermott David F. , Atkins Michael B. , Ambavane Apoorva , Yang Shuo , Rao Sumati , Michaelson M Dror
Published: May 2019

4566

Background: Immuno-oncology therapies (IOs) and tyrosine kinase inhibitors (TKIs) are recommended for the treatment of aRCC. As new drugs and combination regimens emerge, there is interest in gaining a deeper understanding of optimal treatment sequencing. We aimed to assess clinical and economic outcomes associated with treatment sequences for untreated aRCC patients with IMDC intermediate/poor risk. Methods: A discrete event simulation model was developed to estimate the total costs and survival (in life-years; LYs) over patients’ lifetimes when receiving sequential treatment with nivolumab + ipilimumab (N+I), sunitinib (SUN), pazopanib (PAZ), or cabozantinib (CAB) as first-line (1L) treatment, and nivolumab (NIVO), axitinib (AXI), PAZ, CAB, or lenvatinib + everolimus (LEN+EVE) as second line (2L). Efficacy inputs were derived from the CheckMate 214 trial and a network meta-analysis based on available literature. Safety and cost data were obtained from literature and publicly available sources. Results: N+I initiating sequences were estimated to provide longer survival in mean LYs and lower mean costs/LY versus sequences with 1L TKIs (table). The estimates of incremental cost-effectiveness ratio (ICER) for N+I initiating sequences with 2L TKI monotherapy were well below the willingness-to-pay threshold of $50,000. Using 2L LEN+EVE, compared with 2L monotherapies, provided an incremental survival gain but at costs/LY close to $100,000. Conclusions: Use of 1L N+I followed by TKI monotherapy is estimated to provide longer survival while being more cost-effective versus TKIs followed by IOs or sequences cycling TKIs, mainly driven by a longer time to 2L treatment and longer treatment-free survival with N+I. Clinical trials with head-to-head comparisons of treatment sequences would be necessary to validate the findings of the study. [Table: see text]
Association of human endogenous retrovirus (hERV) expression with clinical efficacy of PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Shukla Sachet A , Braun David A. , Horak Christine , Wind-Rotolo Megan , Ishii Yuko , Catalano Paul J. , Freeman Gordon J. , Jennings Rebecca B , De Cubas Aguirre , Rathmell Kimryn , Choueiri Toni K. , Atkins Michael B. , McDermott David F. , Signoretti Sabina
Published: May 2019

4568

Background: hERV levels positively correlate with tumor immune infiltrate and were recently shown to be associated with clinical benefit to PD-1/PD-L1 blockade in two small cohorts of patients (pts) with mccRCC (Smith C.C. et al and Panda A. et al; 2018). We tested whether hERV levels correlate with efficacy of nivolumab in a prospective phase II study of pts with mccRCC (Checkmate 010). Methods: Reverse transcribed RNA extracted from 99 FFPE pretreatment tumors were analyzed by RT-qPCR to assess levels of pan- ERVE4, pan- ERV3.2, hERV4700 GAG or ENV, and the reference genes 18S and HPRT1. Normalized hERV levels were transformed as categorical value (high or low) using population quartiles as cutoffs. For each cutoff, samples with non-quantifiable hERV levels for which the limit of quantification was above the tested cutoff could not be categorized and were excluded from analysis. Log rank test was used to test the association of hERV levels with PFS/irPFS (RECISTv1.1/irRECIST) at each cutoff using Holm-Bonferroni correction for Type I error control; adjusted P-values are reported. Fisher’s exact test was then used to explore the association with ORR/irORR (RECISTv1.1/irRECIST). Results: Among the hERV studied, only hERV4700 ENV was significantly associated with PFS/irPFS. At the 25th percentile cutoff, 45 pts had high levels of hERV4700 ENV and 24 pts had low levels of hERV4700 ENV. Median PFS and irPFS were significantly longer in the high- hERV4700 ENV group [7.0 (95% CI: 2.2 - 10.2) and 8.5 (95% CI: 4.2 - 14.1) months, respectively] versus the low- hERV4700 ENV group [2.6 (95% CI: 1.4 - 5.4) and 2.9 (95% CI: 1.4 - 5.7) months, respectively] ( P = 0.010 for PFS and P = 0.028 for irPFS). At the same cutoff, ORR and irORR rates were significantly higher in the high- hERV4700 ENV group [35.6 (95% CI: 21.9 - 51.2) % for both ORR/irORR] versus the low- hERV4700 ENV group [12.5 (95% CI: 2.7 - 32.4) and 8.3 (95% CI: 1.0 - 27.0) %, respectively] ( P = 0.036 for ORR and P = 0.012 for irORR). Conclusions: hERV4700 ENV levels may predict outcome on nivolumab in mccRCC. Validation of our results and correlation of hERV levels with immune markers in a controlled phase III trial (CheckMate 025) is ongoing.
First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated results for KEYNOTE-427 cohort A.
Authors: Tykodi Scott S. , Donskov Frede , Lee Jae-Lyun , Szczylik Cezary , Malik Jahangeer , Alekseev Boris Yakovlevich , Larkin James M.G. , Matveev Vsevolod Borisovich , Gafanov Rustem , Tomczak Piotr , Geertsen Poul F. , Wiechno Pawel J. , Shin Sang Joon , Pouliot Frederic , Alonso-Gordoa Teresa , Silverman Rachel Kloss , Perini Rodolfo F. , Schloss Charles , McDermott David F. , Atkins Michael B.
Published: May 2019

4570

Background: KEYNOTE-427 (NCT02853344) is an open-label, single-arm, phase 2 study to evaluate efficacy and safety of first-line single-agent pembro, a programmed death 1 (PD-1) inhibitor, in patients (pts) with ccRCC (cohort A) and non–clear cell RCC (cohort B). Updated follow up from cohort A are presented. Methods: Pts with histologically confirmed ccRCC, measurable per RECIST v1.1, and no prior systemic therapy were eligible. Pts received pembro 200 mg IV Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point was objective response rate (ORR; per RECIST v1.1 blinded independent central review). Additional end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: 110 pts enrolled; median (range) follow-up was 18.0 (2.5-22.7) mo. Median age (range) was 64 (29-87); 38.2%, 47.3%, and 14.5% had favorable, intermediate, and poor IMDC risk, respectively; 47.3% were PD-L1 positive. Confirmed ORR was 36.4% with 3 (2.7%) CRs and 37 (33.6%) PRs. Median DOR was not reached. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached. Results by IMDC category are outlined in the table. By PD-L1 status, confirmed ORR was 44.2% and 29.3% for positive and negative, respectively. By sarcomatoid differentiation (n=11), confirmed ORR was 63.6%. Treatment-related AEs occurred in 80.9%, with pruritus (28.2%) and fatigue (28.2%) most commonly reported. One pt died of treatment-related pneumonitis. Conclusions: With a median 18-months’ follow up, first-line pembro monotherapy continued to show antitumor activity in pts with ccRCC. Meaningful responses were observed in pts with intermediate/poor IMDC risk, PD-L1 positive and sarcomatoid differentiated tumors. Safety profile was comparable to previously reported. Clinical trial information: NCT02853344. [Table: see text]
Sequential treatment with pazopanib (PAZO) followed by nivolumab (NIVO) in patients with advanced or metastatic renal cell carcinoma (mRCC): Third interim results of the non-interventional study PAZOREAL.
Authors: Boegemann Martin , Bedke Jens , Schostak Martin , Hering-Schubert Christiane , Welslau Manfred , Schleicher Jan , Wolf Thomas , Petzoldt Alexander , Doehn Christian , Grüllich Carsten , Grünwald Viktor , Steiner Thomas , Rogler Anja , Hanson Sven , Klein Dunja , Medinger Tanja , Goebell Peter-Juergen
Published: May 2019

4574

Background: Randomized clinical trials for the implementation of new therapies include only a selection of patients that are later treated with these new options. Thus, real-world evidence is urgently needed not only to monitor the translation of treatment approaches into routine practice but also to improve cancer treatment and survivorship care on a broader scale. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness [primary time on drug (TD)], tolerability, safety, and quality of life (QoL) in patients (pts) with mRCC, treated with 1st L PAZO followed by 2nd L NIVO or everolimus (EVE). Results: Between Dec. 2015 and Sep. 2017, 421 pts were enrolled and 402 pts started 1st L PAZO treatment (Tx), 127 and 5 pts received NIVO and EVE as 2nd L Tx, resp., 56 entered follow-up. At time of data-cut (08 Nov 2018) median TD was 6.6 months (95%CI 6.0-7.9) for 1st L PAZO and 4.1 months (95%CI 3.2-5.8) for 2nd L NIVO (all pts), 8.1 months (95% CI 6.6-9.5) for PAZO and 3.2 (2.7-6.5) for NIVO Tx for trial eligible pts (39.1% of 402 pts). Median TD for pts with or without prior nephrectomy was 7.6 vs 4.5 months, resp. The clinical benefit rate of 1st L PAZO was 58.2 % (95% CI 53.3-62.9) based on investigator assessment. Median OS of PAZO was 29.5 months (95%CI 23.6-NA) for all pts, 28.2 months (95% CI 22.2-NA) for NIVO in 2nd L. The most commonly reported AEs for PAZO Tx were diarrhea (35%), nausea (20.3%) and fatigue (17.5%). Most common PAZO-related grade 3/4 adverse events were hypertension (5%), hypertensive crisis (2.3%) and GGT increase (1.8%). QoL evaluated by EQ-5D-5L remained stable over different Tx lines. Conclusions: The interim results of the PAZOREAL study confirm a favorable overall survival in pts with mRCC treated with 1st L PAZO in a real-world setting, good benefit-risk profile of PAZO and sustained QoL monitored over several treatment lines. In Germany NIVO as 2nd L Tx is commonly applied after 1st L Tx with PAZO.
Consistent efficacy of nivolumab plus ipilimumab across number of International Metastatic Database Consortium (IMDC) risk factors in CheckMate 214.
Authors: Escudier Bernard , Motzer Robert J. , Tannir Nizar M. , Porta Camillo , Tomita Yoshihiko , Mekan Sabeen Fatima , McHenry M. Brent , Rini Brian I.
Published: May 2019

4575

Background: The IMDC prognostic model was created based on anti-VEGF treatments for advanced renal cell carcinoma (aRCC), and may not be relevant for immunotherapy. Methods: In a post hoc analysis of CheckMate 214, we compared efficacy with nivolumab + ipilimumab (N+I) vs sunitinib (S) by number of IMDC risk factors present. Results: Among 1096 intent-to-treat (ITT) patients (pts) in both arms, 21%, 61%, and 18% had favorable, intermediate (int), or poor-risk, respectively. Of int-risk pts, 58% had 1 factor (most commonly <1 y from diagnosis [Dx], 52%; Hb < LLN, 27%; or KPS ≤70%, 10%); and 42% had 2 factors (of these pts, the most common combination of 2 factors was <1 y from Dx and Hb < LLN, 59%). Of poor-risk pts, 58% had 3 factors, 29% had 4 factors, and few had 5 (10%) or 6 (3%) factors. Due to small numbers, pts with 4–6 factors were pooled. At 30-mo minimum follow-up, RECIST v1.1-confirmed objective response rate (ORR) and complete response (CR) rate per investigator remained consistently higher with N+I vs S across pts with 1–4 factors, although with S, ORR decreased with increasing number of factors (Table). Improved progression-free survival (PFS) and overall survival (OS) were seen with N+I over S irrespective of the number of factors present, including in pts with only 1 risk factor (Table). Conclusions: N+I showed consistent efficacy across number of IMDC risk factors, while S decreased in efficacy with increasing number of factors. Efficacy of N+I was superior to S in all int- and poor risk pts. These CheckMate 214 results along with prior CheckMate 025 data showing consistent OS benefit with N monotherapy across IMDC risk categories show a need for improved prognostic models for immunotherapies in aRCC. Clinical trial information: NCT02231749. [Table: see text]
Dynamic contrast-enhanced MRI to predict intratumoral molecular heterogeneity in clear cell renal cell carcinoma.
Authors: Udayakumar Durga , Zhang Ze , Dwivedi Durgesh , Xi Yin , Wang Tao , Kapur Payal , Yousuf Qurratulain , Joyce Allison , Hajibeiji Asghar , Fulkerson Michael , Diaz de Leon Alberto , Lewis Matthew , Madhuranthakam Ananth J , Cadeddu Jeffrey A , Bagrodia Aditya , Margulis Vitaly , Brugarolas James , Pedrosa Ivan
Published: May 2019

4580

Background: Mutation/inactivation of VHL in clear cell renal cell carcinoma (ccRCC) leads to upregulation of hypoxia inducible factors ( HIFs) and angiogenesis. However, ccRCC is characterized by high intra-tumor heterogeneity (ITH). Random small samples such as those in percutaneous biopsies are likely limited for characterization of molecular alterations in heterogeneous ccRCCs. We hypothesize that whole-tumor dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is useful to noninvasively identify ITH in ccRCC. Methods: This IRB-approved, prospective, HIPAA-compliant study, included 62 ccRCCs. 3T DCE MRI was obtained prior to nephrectomy. Surgical specimens were sectioned to match MRI acquisition plane. 182 snap frozen samples (49 tumors) and adjacent uninvolved renal parenchyma (URP) were collected. RNA isolations, cDNA library preparation and mRNA sequencing were performed using standard protocols. RNA expression in 81 tumor samples were correlated (Spearman ranked) with % enhancement in a region of interest (ROI) drawn in the same location of the tumor on pre- and 3 different post-contrast DCE MRI phases. Gene function overrepresentation (OR) analyses were done on top positively and negatively correlated genes. False discovery rate (FDR) < 0.1 was considered statistically significant. Results: Principal component analysis of > 20,000 genes indicated distinct gene expression in tumors from URP. Unsupervised clustering showed enrichment of ccA samples (better prognosis) compared to ccB samples (worse prognosis). Importantly, ccA and ccB samples coexisted in 25% of tumors. DCE-MRI % enhancement correlated with expression of > 300 genes (p < 0.003, FDR < 0.1). OR analyses placed angiogenic pathway gene processes and the immune/inflammatory response processes within the top 5 positively- and negatively-correlated gene functions, respectively. HIF2 target genes correlated positively with % enhancement. Conclusions: DCE MRI detects specific molecular signatures and may help overcome the challenges of ITH in ccRCC. Further research is needed to explore the potential role of DCE MRI to assess response to antiangiogenic and immune-based therapies.
Comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma reveals opportunities for therapeutic and biomarker development.
Authors: Necchi Andrea , Pal Sumanta K. , Ross Jeffrey S. , Madison Russell , Agarwal Neeraj , Sonpavde Guru , Joshi Monika , Yin Ming , Miller Vincent A. , Grivas Petros , Chung Jon , Ali Siraj Mahamed
Published: May 2019

4581

Background: To understand the genomic landscape and inform the therapeutic development of UC, 2463 cases were analyzed by CGP for genomic alterations (GAs) and for genome wide signatures. Methods: 479 UTUC and 1984 BUC FFPE tissues (77%/70% primary [PT] and 23%/30% metastatic tumors [MT] from unmatched patients [pts]) underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Targetable GA and signatures were assessed according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Results: 48% of UC pts overall harbored ≥1 tier 1-2 GA suggesting benefit from approved or investigational targeted therapies (TT). Additionally, 17% had a tier 3 GA that provides a strong rationale for clinical trial consideration. Non- FGFR3 kinase fusions were observed in 1% of pts (0.6% UTUC v 1.1% BUC), including BRAF/RAF1 fusions in 0.5%. BRAF mut/fusions were observed in 2% (49/2463) of cases and were mutually exclusive with FGFR3 GA (p = 0.002). In comparing UC from anatomic sites, there were no differences of TMB-H (≥20 mut/mb)/MSI-H for PT and MT but UTUC was enriched for MSI-H (3.4%) relative to BUC (0.77%, p < 0.001, all TMB-H). Excluding MSI-H pts, UTUC has lower median TMB (4.35 mut/mb) than BUC (6.96 mut/mb). FGFR3 GA (26% v 19%, p < 0.05) and specifically short variants (SV) (20% v 13%) were enriched in UTUC vs BUC. HRAS SV were also enriched in UTUC vs BC (7.3% v 3.0%), attributed to an enrichment in renal pelvis UC (10.1%) v ureteral UC (1.8%, p < 0.05). RB1 GA were more frequent in BUC vs UTUC (21% v 7.8% p < 0.001). Conclusions: Against a background of 50% actionability in UC with opportunities for immunotherapy, TT, or combinations thereof, the UTUC cohort is enriched for FGFR3 and HRAS SV relative to BUC, with the observation of HRAS mutations predominantly in UC of the renal pelvis, that warrants further investigation into the distinct modes of oncogenesis for UC as stratified by anatomic origin. These results argue strongly for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.
Atezolizumab plus bevacizumab in non-clear cell renal cell carcinoma (NccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (ccRCCsd): Updated results of activity and predictive biomarkers from a phase II study.
Authors: Flippot Ronan , McGregor Bradley Alexander , Flaifel Abdallah , Gray Kathryn P. , Signoretti Sabina , Steinharter John A. , Van Allen Eliezer Mendel , Walsh Meghara K. , Gundy Katy , Wei Xiao X. , Harshman Lauren Christine , Vaishampayan Ulka N. , Choueiri Toni K. , McKay Rana R.
Published: May 2019

4583

Background: NccRCC and ccRCCsd are aggressive tumors associated with poor prognosis and response to therapy. Combination strategies co-targeting VEGF signaling and inhibitory immune checkpoints are highly active in clear-cell renal cell carcinoma, but data is lacking in NccRCC and ccRCCsd. We conducted a multicenter, open-label, single arm phase II trial of atezolizumab plus bevacizumab in NccRCC and ccRCCsd. Methods: Patients with NccRCC and ccRCCsd ( > 20% sarcomatoid differentiation), and ECOG performance status of 0-2 were eligible. Prior systemic treatment was allowed with the exception of prior PD-1/PD-L1-directed therapy. Atezolizumab 1200mg and bevacizumab 15mg/kg were administered every 3 weeks until progression, unacceptable toxicity, or patient withdrawal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Exploratory biomarker analyses included PD-L1 expression on tumor (TC) and immune cells (IC), and spatial analysis of the immune infiltrate. Results: Sixty patients received at least 1 cycle of treatment, among whom 56 were evaluable for response (17 ccRCCsd and 39 NccRCC). ORR was 34% in the overall population, 53% in ccRCCsd and 26% in NccRCC. Median progression-free survival was 8.4 months (95%CI, 6.9-16.5). Baseline tumor tissue was available for 36 patients. TC PD-L1 expression ≥1% was associated with improved ORR (9/14, 64%) compared to patients with PD-L1 expression < 1% (4/20, 20%). Patients with TC PD-L1 expression ≥1% who experienced progressive disease as best response had shorter average distance between tumor cells and nearest neighboring immune cells at baseline. Further analysis of the immune tumor microenvironment on an expanded cohort, including IC PD-L1 expression and correlation with clinical outcomes, is ongoing and will be updated. Conclusions: The combination of atezolizumab plus bevacizumab is active in NccRCC and ccRCCsd. Candidate predictive biomarkers include PD-L1 expression in TC and topological analysis of the immune infiltrate. Clinical trial information: NCT02724878.
Neoadjuvant trastuzumab (H), pertuzumab (P), and chemotherapy versus trastuzumab emtansine (T-DM1) and P in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC): Final outcome results from the phase III KRISTINE study.
Authors: Hurvitz Sara A. , Martin Miguel , Jung Kyung Hae , Huang Chiun-Sheng , Harbeck Nadia , Valero Vicente , Stroyakovskiy Daniil , Wildiers Hans , Campone Mario , Boileau Jean-Francois , Beckmann Matthias W. , Afenjar Karen , Spera Gonzalo , Lopez Valverde Vanesa , Song Chunyan , Boulet Thomas , Sparano Joseph A. , Symmans William Fraser , Thompson Alastair Mark , Slamon Dennis J.
Published: May 2019

500

Background: KRISTINE compared neoadjuvant chemotherapy plus dual HER2- blockade (HP) with T-DM1 plus P (T-DM1+P), a targeted regimen that omits standard chemotherapy. T-DM1+P resulted in a lower pathologic complete response (pCR) rate, but a more favorable safety profile. Here we present the final outcomes from KRISTINE. Methods: KRISTINE (NCT02131064) was a randomized study of T-DM1+P versus docetaxel, carboplatin, and H plus P (TCHP). Patients with HER2-positive stage II–III BC received 6 cycles of neoadjuvant T-DM1+P or TCHP q3w. Patients receiving T-DM1+P continued adjuvant T-DM1+P; patients receiving TCHP received adjuvant HP, for 12 cycles in each arm. Patients in the T-DM1+P arm without pCR were encouraged to receive standard adjuvant chemotherapy before adjuvant T-DM1+P. Secondary endpoints, analyzed with descriptive statistics, included event-free survival (EFS; all events pre- and post-surgery), invasive disease-free survival (IDFS; invasive events post-surgery), overall survival and safety. Results: At median follow-up of 37 months, EFS favored TCHP (HR = 2.61 [95% CI: 1.36–4.98]), due to more locoregional progression events in the T-DM1+P arm before surgery (6.7% vs 0; Table). pCR was associated with reduced risk of an IDFS event (HR = 0.24 [95% CI: 0.09– 0.60]) regardless of treatment arm. There were 5 deaths (2.3%) in the TCHP arm and 6 (2.7%) in the T-DM1+P arm. There were more grade ≥3 AEs with TCHP but a higher rate of AEs leading to treatment discontinuation with T-DM1+P. Conclusions: EFS numerically favors TCHP due to locoregional progression events with T-DM1+P prior to surgery. T-DM1+P was associated with fewer grade ≥3 AEs but increased treatment discontinuation. Clinical trial information: NCT02131064. [Table: see text]
Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: An interim safety analysis.
Authors: Tombal Bertrand F. , Loriot Yohann , Saad Fred , McDermott Raymond S. , Elliott Tony , Rodriguez-Vida Alejo , Nole Franco , Fournier Beatrice , Collette Laurence , Gillessen Silke
Published: May 2019

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Background: Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of metastatic castration resistant prostate cancer (mCRPC). The ERA223 trial (NCT02043678) was recently unblinded following the report of a significant increase in the fracture rates when abiraterone is combined with Ra223. Hence, FDA and EMA advised against this combination. The question whether mandated use of bone protecting agents (BPA), zoledronic acid or denosumab, would have mitigated the fracture risk and whether this risk also exists in the enzalutamide/Ra223 combination is presently unknown. Methods: The phase III EORTC-1333-GUCG/PEACEIII (NCT02194842) trial compares enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients (https://www.eortc.org/research_field/clinical-detail/1333/). After the unblinding of ERA223, the trial was amended (v4.0, April 19, 2018) to mandate that all patients must start a BPA. We report the fracture rate in the safety population of 146 treated patients as of 28/01/2019. Results: Overall, 54.2% of the patients in the enza/Ra223 arm and 51.4% of the enza arm did not receive BPA; 18.0% in the enza/Ra223 arm and 27.0% in the enza arm did not use BPA at randomization, but started during protocol treatment according to the v4.0 amendment. 27.8% and 21.6% respectively, received BPA as of randomization. In total, 45.8% of enza/Ra223 patients and 48.6% of enza only patients receive bone protection on treatment. The fracture rate is reported in the table. Conclusions: There is a 13% risk of fracture with enzalutamide in asymptomatic mCRPC, in line with previous reports. This risk is significantly increased to 33% when Ra223 is added to enzalutamide. Strikingly, the risk is almost abolished by mandatory continuous administration of BPA starting at least 6 weeks before the first injection of Ra223, thus emphasizing the importance of treating mCRPC patients with BPA. Clinical trial information: NCT02194842. [Table: see text]
Diagnostic performance of 18F-DCFPyL in the OSPREY Trial: A prospective phase 2/3 multicenter study of 18F-DCFPyL PET/CT imaging in patients (Pts) with known or suspected metastatic prostate cancer (mPC).
Authors: Morris Michael J. , Durack Jeremy C. , Alva Ajjai Shivaram , Vargas Hebert Alberto , Piert Morand , Pachynski Russell Kent , Pouliot Frederic , Beauregard Jean-Mathieu , Preston Mark A. , Choudhury Atish Dipankar , Saperstein Lawrence , Carroll Peter , Rowe Steven P. , Pienta Kenneth J. , Lin Tess , Wong Vivien , Nichols Melissa , Jensen Jessica Donato , Siegel Barry A.
Published: May 2019

5012

Background: Accurate detection of prostate cancer is imperative to patient management, yet standard imaging methods perform poorly in accurately detecting mPC. 18F-DCFPyL is a novel PET imaging agent that selectively binds to prostate-specific membrane antigen, a recognized target for prostate cancer. OSPREY was a prospective, multicenter study in pts with either newly diagnosed high-risk prostate cancer (cohort A), or known or suspected mPC (cohort B). Here we focus on Cohort B. Methods: 117 men planned for biopsy of recurrent or mPC received 18F-DCFPyL. Pts underwent image-guided biopsy. Sensitivity, positive predictive value (PPV), and safety of 18F-DCFPyL PET/CT were the key endpoints for Cohort B. 18F-DCFPyL PET/CT scans were evaluated by three independent, blinded central readers; and results were compared to histopathology as the truth standard. Results: The sensitivity and PPV of 18F-DCFPyL PET/CT as compared to histopathology ranged from 92.9-98.6% (lower bound of 95% CI: 84.0-91.6%) and 81.2-87.8%, respectively. Diagnostic performance by anatomic location showed high sensitivity and high PPV in all sites of disease (Table). Only two (1.7%) cohort B pts experienced ≥1 drug-related AE (dysgeusia and generalized rash), both were mild (Grade 1) in severity. Conclusions: 18F-DCFPyL PET/CT was well tolerated and demonstrated high sensitivity and PPV in accurately detecting nodal, bone, and visceral/soft tissue metastases. A positive 18F-DCFPyL PET/CT scan is highly likely to represent pathologically proven distant disease, demonstrating the potential of 18F-DCFPyL as a PET imaging agent to favorably influence treatment planning. Clinical trial information: NCT02981368. [Table: see text]
Association of noninvasive, radiographic measurement of prostate-specific membrane antigen (PSMA) expression with response to PSMA-targeted radionuclide therapy (TRT).
Authors: Vlachostergios Panagiotis J. , Niaz Muhammad Junaid , Mosallaie Seyed Ali , Christos Paul J. , Hackett Amy , Osborne Joseph R. , Jhanwar Yuliya , Gracey Lauren , Molina Ana M. , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: May 2019

5013

Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorporated PSMA imaging, but have not selected patients for treatment based upon imaging results and performed an analysis examining the relationship between imaging and response. Methods: Men with mCRPC had either planar radiolabeled J591 imaging (111In-J591 and/or 177Lu-J591) or 68Ga-PSMA11 PET/CT. Visual scores were assigned based upon PSMA uptake in tumors compared to liver uptake and scored on a 0-4 scale. Imaging scores were associated with PSA decline (≥30%, ≥50%) using Cox regression analysis. As several studies were dose-escalation in nature with prior demonstration of dose-response, we controlled for dose administered. Results: 216 men with metastatic CRPC, median PSA 72.45ng/dl, were treated with PSMA-TRT as follows: 177Lu-J591 (n=136), 177Lu-PSMA-617 (n=38), Lu-J591 + Lu-PSMA-617 combination (n=6), 225Ac-J591 (n=7), 90Y-J591 (n=29). 116 (53.7%) pts received low dose and 100 (46.3%) high dose as previously defined in the individual studies. 55 (25.5%) pts had low PSMA expression by imaging (VS 0-1) whereas 161 (74.5%) had high PSMA (VS 2-4). High PSMA expression was associated with more frequent PSA decline (≥30%: 39.2 vs 17.9% p=0.003; ≥50%: 27.5 vs 8.9% p=0.004). When controlling for dose level, this association remained significant for low (≥30%: 25 vs 8.6% p=0.04) and high doses of radionuclide therapy (≥50%: 34.9 vs 9.5% p=0.02). 13 (6%) pts with no PSMA uptake (VS=0) had PSA declines. Conclusions: This is the first study to formally analyze response to PSMA-TRT by PSMA imaging expression in an unselected patient population. The level of PSMA expression measured by imaging is associated with the chance of response. However, a subset of patients without any significant PSMA uptake on imaging did demonstrate response to PSMA-TRT, indicating that imaging cannot exclude all patients that might benefit. Clinical trial information: NCT03545165, NCT03276572, NCT03042468, NCT02552394.
Prospective head-to-head comparative phase 3 study between 18F-fluciclovine and 68Ga-PSMA-11 PET/CT in patients with early biochemical recurrence of prostate cancer.
Authors: Calais Jeremie , Ceci Francesco , Eiber Matthias , Bach-Gansmo Tore , Nanni Cristina , Savir-Baruch Bital , Hofman Michael , Hope Tom , Rischpler Christoph , Elashoff David , Grogan Tristan , Dahlbom Magnus , Slavik Roger , Gartmann Jeannine , Reiter Robert Evan , Rettig Matthew , Jadvar Hossein , Fendler Wolfgang P , Czernin Johannes
Published: May 2019

5014

Background: This is a prospective single-center, single-arm, head-to-head phase 3 study of paired 18F-fluciclovine (FACBC) and 68Ga-PSMA-11 (PSMA) PET/CT scans for localizing early biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) (NCT02940262). Methods: Fifty consecutive patients with BCR and prostate specific antigen (PSA) levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were included. All patients underwent FACBC and PSMA PET/CT scans within ≤15 days. PET/CT scans were each interpreted by 3 independent blinded expert readers not involved in study design and data acquisition. Region consensus interpretation (T,N,M1a,M1b,M1c) was generated based on majority rule in cases of reader disagreement (2 vs 1). PET/CT scans were considered as positive if any region was rated as positive. Detection rates per-patient and per-region served as primary study endpoint. Results: Median time interval between the 2 scans was 6 days (range 1-15). Median PSA level at the time of imaging was 0.50 ng/ml (mean 0.63; range 0.2-2.0 ng/ml). The detection rates were significantly lower with FACBC than with PSMA PET/CT per-patient (26% vs 56%; p = 0.003) and per-region for pelvic nodes (N) (8% vs 30%; p = 0.003) or any extra-pelvic lesions (M) (0% vs 16%; p = 0.008). Reader agreement for PSMA PET/CT image interpretations was significantly higher than for FACBC PET/CT (0.67 vs 0.20; p = 0.015). Conclusions: In patients with BCR and low serum PSA levels after RP, PSMA PET/CT demonstrates higher detection rates and superior reader agreement when compared with FACBC PET/CT. Therefore, PSMA PET/CT should be the imaging modality of choice in patients with early BCR. Clinical trial information: NCT03515577.
Outcomes of men with recurrent M0 prostate cancer who defer androgen deprivation therapy until metastasis.
Authors: Marshall Catherine Handy , Fu Wei , Wang Hao , Trock Bruce J. , Eisenberger Mario A.
Published: May 2019

5016

Background: Optimal timing and criteria for implementation of androgen deprivation therapy (ADT) in men with relapsed M0 prostate cancer (PCa) remains undefined. Early ADT induces the non-metastatic castration resistant PCa (nmCRPC) clinical state. FDA approved apalutamide (SPARTAN) and enzalutamide (PROSPER) for nmCRPC based on prolongation of metastasis free survival (MFS) which is now considered a valid endpoint for drug approval. Because overall survival (OS) in PCa is usually long and long-term ADT is associated with irreversible adverse events and high costs, we sought to evaluate OS and other outcomes of men with relapsed PCa and ADT deferred until metastasis. Methods: Retrospective review of 2,636 men who had radical prostatectomy (RP) between 1981-2017 and developed biochemically recurrent PCa from a single-institution. Patients who received ADT prior to metastasis were excluded. Kaplan-Meier survival estimates of MFS and OS were defined from RP to event or censor. Multivariable Cox proportional hazards regression was used to identify prognostic factors. Results: 1,686 men treated with deferred ADT until metastasis or censored metastasis-free were eligible. Medians: follow up 10 years (IQR5-16), age 60 years, PSADT 33 months, Gleason < 7 (24%), Gleason 7 (55%), Gleason > 7 (21%). 688 (41%) received salvage radiotherapy. Median MFS and OS were 21 and 22 years, respectively (Table). In multivariable models, age (HR 1.06, 95% CI 1.04-1.1), Gleason < 8 vs ≥8 (HR 0.4; 0.3-0.5) , RP stage (organ confined vs not 0.6; 0.5-0.8), PSADT (0.995, 0.993-0.997) and salvage RT (0.88; 0.81, 0.96) were associated with OS. Conclusions: Deferred ADT in relapsing M0 patients is associated with long OS measured from time of local treatment, comparable to OS with salvage ADT in contemporary experience. Drug approval trials in nmCRPC should focus on patients at high risk for metastasis and death prior to ADT, and determine standardized criteria for initiation of ADT. Prolongation of MFS in nmCRPC requires further validation and may not necessarily reflect a net OS benefit. [Table: see text]
Age-related efficacy and safety of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in subgroups of patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Post hoc analysis of SPARTAN.
Authors: Graff Julie Nicole , Smith Matthew Raymond , Saad Fred , Hadaschik Boris A. , Uemura Hiroji , Lee Ji Youl , Mainwaring Paul N. , Olmos David , Oudard Stephane , Londhe Anil , Bhaumik Amitabha , Rooney Oliver Brendan , Lopez-Gitlitz Angela , Small Eric Jay
Published: May 2019

5024

Background: SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC and PSA doubling time ≤ 10 mo, showed that, compared with PBO, addition of APA to ongoing ADT treatment (tx) prolonged metastasis-free survival (MFS) by > 2 y, reduced the risk of symptomatic progression by 55%, and increased second progression-free survival (PFS2), which is the time from randomization to disease progression on first subsequent anticancer tx, or death. The impact of APA in terms of benefit and safety profile was evaluated in pts aged < 65, 65-74, and ≥ 75 y. Methods: Pts with nmCRPC were randomized 2:1 to APA (240 mg QD) or PBO; ADT was continuous. APA effect was analyzed by Cox models and Kaplan-Meier methods across age subgroups. Results: Baseline characteristics among age groups were similar, although ECOG PS 1 vs 0 increased with age. MFS benefit with APA was highly significant for all age subgroups (Table). In pts ≥ 75 y, MFS risk with APA vs PBO was reduced by 59%; MFS risk was reduced by 86% and 76% for pts < 65 and 65-74 y, respectively. Risk of PFS2 with APA vs PBO was reduced across all age subgroups. PFS2 in pts < 65, 65-74, and ≥ 75 y: HR, 0.09 (p < 0.0001); HR, 0.56 (p = 0.0343); HR, 0.59 (p = 0.0092), respectively. Risk of symptomatic progression was lessened with APA vs PBO for all age subgroups (Table). There was a similar increase in incidence of tx-emergent adverse events (TEAE) with age in both tx arms that remained higher with APA. Incidence of grade 3/4 TEAE (≥ 75 vs < 65 y): APA, 50% vs 37%; PBO, 37% vs 28%. Conclusions: Pts in all age subgroups with high-risk nmCRPC had significant improvement in MFS with APA + ongoing ADT. The safety profile of APA was similar across age subgroups. Clinical trial information: NCT01946204. [Table: see text]