bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing progression to subsequent lines of therapy in metastatic renal cell carcinoma (mRCC) after nivolumab plus ipilimumab (Nivo+Ipi): Results from the International mRCC Database Consortium (IMDC).
Authors: Lemelin Audreylie , Takemura Kosuke , Ernst Matthew Scott , Wells J Connor , Donskov Frede , Porta Camillo , de Velasco Guillermo , Davis Ian D. , Wood Lori , Pal Sumanta Kumar , Hansen Aaron Richard , Kollmannsberger Christian K. , Bjarnason Georg A. , Tran Ben , Li Haoran , Kanesvaran Ravindran , Powles Thomas , McKay Rana R. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: June 2023

4538

Background: Treatment patterns and number of lines of therapy for patients with mRCC are not well characterized in the era of immunoncology-based combinations. We aimed to quantify the attrition rates by line of therapy and to examine predictors of receiving second-line (2L) treatment. Methods: Using the IMDC, patients with mRCC who received first-line (1L) Nivo+Ipi were included. Clinical and pathologic characteristics and outcomes were extracted. Chi-square tests were used to compare categorical variables between patients who received 2L and those who did not. A logistic regression model was used to assess predictors of 2L therapy initiation in eligible patients. Results: 995 patients treated with 1L Nivo+Ipi were identified, of whom 704 stopped 1L and were thus eligible for 2L therapy. Reasons for stopping 1L included progressive disease (PD) in 39.5%, toxicity in 25.0%, death in 4.3%, complete response in 1.6% and other in 29.7%. Among 2L eligible patients, 410 (58.2%) received 2L whereas 294 (41.8%) did not. Patients who stopped 1L for PD were more likely to initiate 2L than those who stopped for other reasons (81.7% vs 43.0%, p <0.001). Patients who received 2L were more likely to have clear-cell histology (75.1 vs 62.9%, p=0.02), bone metastases (39.8 vs 29.6%, p=0.01), and only one site of metastases (18.3 vs 10.5%, p=0.01) and less likely to be poor risk by IMDC criteria (27.1 vs 34.4%, p=0.03). After adjusting for IMDC criteria, no predictors of receiving 2L therapy remained significant. The overall response rate to 1L therapy was lower in patients who received 2L than in those who did not: 18.5% (76/366) and 33.7% (99/245), respectively (p<0.001). Among 258 patients who stopped 2L, 145 (56.2%, overall 20.6%) started third-line (3L) therapy. Of the 98 patients who stopped 3L, 52 (53.1%, overall 7.4%) started fourth-line therapy. Conclusions: In our study, we found that over half of eligible patients received the subsequent line of therapy. We were unable to identify predictors of 2L therapy initiation. Attrition rates between lines of therapy have important implications for patient counseling, cost analyses, and clinical trial design. [Table: see text]
Disease-free survival in operated patients with nmRCC using machine learning.
Authors: Margue Gaëlle , Ferrer Loïc , Etchepare Guillaume , Bigot Pierre , Bensalah Karim , Mejean Arnaud , Roupret Morgan , Doumerc Nicolas , Ingels Alexandre , Boissier Romain , Pignot Geraldine , Parier Bastien , Paparel Philippe , Waeckel Thibaut , Colin Thierry , Bernhard Jean-Christophe
Published: June 2023

4539

Background: In patients operated for a non-metastatic renal cell carcinoma (nmRCC), risk evaluation of disease recurrence enables the therapeutic strategy to be adapted after surgery. Usual risk group stratification does not fully exploit the power of machine learning (ML) applied to multimodal data. We developed a ML model capable of calculating the risk of recurrence after surgery for nmRCC patients. Methods: A multicentric cohort of patients undergoing surgery between May 2000 and January 2020 for a nmRCC (pT any, N any, M0) was analyzed from data collected prospectively in the French research network on kidney cancer UroCCR (ClinicalTrials.gov: NCT03293563). Using clinical, biological, histological and radiological features, we developed a signature of patient-specific DFS. Participating medical centers were randomly assigned to training or validation cohorts with a 2:1 ratio of patients. The ML signature managed missing data using multiple imputation based on gradient boosted trees and chained equations. Several ML models were trained in a repeated 5x10-fold cross-validation procedure to optimize the integrated Area Under the ROC Curve (iAUC) between 0.5- and 5-years following surgery. The performance of the selected ML signature was then evaluated on the validation cohort and compared with usual risk scores. Results: 3354 patients were randomly assigned to a training cohort (n=2239 from 10 centers) and a validation cohort (n=1115 from 13 centers). Our risk score achieved an iAUC of 0.81 (0.76, 0.85) on the validation cohort and significantly outperformed the GRANT ( p <0.001), SSIGN ( p =0.03), and UISS ( p <0.001) risk scores. The Leibovich-2018 score was only defined in 51% of the patients, due to incomplete data. Permutation-based feature importance and Shapley values were used to estimate the contribution of each feature. The stratification of patients into four risk groups achieved an iAUC of 0.78 (0.74, 0.83) on the validation cohort. 190 (17%) patients were stratified in the low-risk group, with an actual 5-year DFS higher than 98% and no death observed within this horizon window. 188 (17%) patients were stratified in the high-risk group, with an actual 5-year DFS of 48%. Conclusions: The machine learning model estimating individual disease recurrence risk outperformed the predictive performances of usual risk scores while handling incomplete data in predictors. This could help in identifying patients for whom surveillance could be reduced and those who could be candidates for adjuvant therapies. [Table: see text]
Response to immune checkpoint inhibitor (ICI) rechallenge in patients with metastatic renal cell carcinoma who progressed on prior ICI: A systematic review and meta-analysis.
Authors: Gupta Garima , Yan Donglin , Myint Zin
Published: June 2023

4547

Background: Several immune checkpoint inhibitor (ICI)-based combination regimens are standard-of-care for first-line treatment of metastatic renal cell carcinoma (mRCC). These include dual ICI and ICI-tyrosine kinase inhibitor (TKI) combinations. While single-agent ICI is recommended as subsequent-line therapy for ICI-naïve patients, there is limited knowledge regarding efficacy of rechallenging with a different ICI or using different ICI combinations in patients who have progressed on prior ICI therapy. This is a clinically critical question as most mRCC patients would have already received ICI therapy at progression. The aim of this study is to address the above by performing a systematic review and meta-analysis. Methods: PubMed, Cochrane Library and Web of Science were systematically searched to identify studies of later-line ICI rechallenge after progression on any previous ICI in mRCC patients from database inception to December 31st, 2022. Patients who had progressed on prior ICI and rechallenged with ICI as single agent/dual/TKI combination as any subsequent line of therapy in both retrospective and prospective studies were included. Exclusion criteria were phase I or any phase studies combining ICI with unapproved drugs, case reports and case series. We calculated the pooled objective response rate (ORR) and disease control rate (DCR) using mixed effects model treating individual studies as a random effect. We further stratified studies into prospective and retrospective and performed subgroup analyses. Results: A total of 11 studies, 6 prospective and 5 retrospective with a total of 603 patients were initially identified. Out of the 6 prospective studies, 3 had an adaptive design of using salvage ipilimumab/nivolumab in patients who had either progressed or had stable disease as the best overall response on nivolumab monotherapy. These studies were excluded as they did not meet our inclusion criteria. A total of 8 studies with 400 patients were included in the final analysis. The ORR was 28% (95% CI, 0.27-0.36) and the DCR was 70% (95% CI, 0.47-0.85) with no significant differences between prospective and retrospective studies. Our ORR is higher than an earlier meta-analysis reporting an ORR of 14% with salvage ipilimumab/nivolumab after previous treatment with ICI. Conclusions: This meta-analysis demonstrates a modest ORR and an impressive DCR. Therefore, it provides strong clinical rationale to consider rechallenging with ICI-based therapy for later-line treatment of mRCC patients who have progressed on prior ICI. [Table: see text]
Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.
Authors: Silva Carolina Alves Costa , Fidelle Marine , Birebent Roxanne , Dalban Cécile , Zoppi Silvia , Reni Anna , Rauber Conrad , Lahmar Imran , Mallard de La Varende Anne-Laure , Rioux-Leclercq Nathalie , Sautès-Fridman Catherine , Meylan Maxime , Vano Yann-Alexandre , Beusenlick Benoit , Chouaib Salem , Tantot Florence , Escudier Bernard , Zitvogel Laurence , Derosa Lisa , Albiges Laurence
Published: June 2023

4548

Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if >median and low if <median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p<.0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p<.0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-centered interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .
Association of host immune signatures with response to immunotherapy-based regimens in patients with metastatic renal cell carcinoma (mRCC).
Authors: Saad Eddy , Labaki Chris , Saliby Renee Maria , Song Li , Bakouny Ziad , Pan Wenting , Wall McKenzy , Lee Gwo-Shu Mary , Braun David A. , Liu Xiaole Shirley , Choueiri Toni K.
Published: June 2023

4550

Background: Treatment options for mRCC have evolved to include VEGF targeted therapies (VEGF-TT), immune checkpoint inhibitors (ICIs), or combinations of both. The interaction between the tumor and its immune microenvironment has been shown to influence clinical outcomes in patients treated with immunotherapy-based regimens. The aim of this study was to characterize the T-cell and B-cell immune repertoires in patients with mRCC treated with VEGF-TT, ICI or a combination of both, and evaluate their associations with clinical outcomes. Methods: We identified patients with mRCC at Dana-Farber Cancer Institute treated with VEGF-TT, ICI or both, and for whom tumor and/or blood samples were available. Bulk RNA-sequencing (RNA-seq) and T-cell receptor sequencing (TCR-seq) were performed on peripheral blood mononuclear cells (PBMCs), collected before and during therapy. Bulk RNA-seq was additionally performed on available pre-treatment primary tumor samples. Immunoglobulin heavy chain (IgH) isotypes were inferred from bulk RNA-seq data using TRUST4. Parameters of the T-cell and B-cell repertoires were evaluated in responders vs. non-responders to systemic therapies, and between pre- and on-treatment samples within patient subgroups. Results: In total, blood (PBMC) samples from 386 patients were available across all treatment cohorts. Following quality-control, TCR-seq and RNA-seq data were available for 367 and 134 patient samples, respectively. Responders to ICI-based regimens (ICI or VEGF-TT+ICI) presented a trend towards an increased baseline (pre-treatment) TCR clonality as compared to non-responders (p=0.06), corresponding to a less polyclonal T cell repertoire in responders at baseline. No significant changes in clonality were seen between pre- and on-treatment samples among responders to ICI regimens (p=0.14), as opposed to non-responders where a significant increase was identified (p=0.001). The analysis of IgH isotypes in baseline blood samples showed higher fraction of IgG1 in responders (vs. non-responders) to ICI regimens (p=0.01). This was further confirmed in the analysis of IgH isotypes inferred from tumor samples (p=0.04). No significant differences in IgH isotype fractions were identified between responders and non-responders to VEGF-TT. Conclusions: We were successfully able to characterize T-cell receptor and IgH repertoires in a large cohort of patients with mRCC and evaluate their associations with ICI response. Our results show that baseline TCR clonality and IgG1 antibody fraction are associated with the response to ICI regimens, suggesting a potential role for immune biomarker development.
Role of cytoreductive nephrectomy (CN) in metastatic clear cell renal cell carcinoma (mccRCC) in the era of immunotherapy (IO): An analysis of the National Cancer Database (NCDB).
Authors: Bou Zerdan Maroun , Wong Roger , Goldberg Hanan , Basnet Alina
Published: June 2023

4552

Background: The role of CN remains questionable after the well intentioned two large prospective trials, SURTIME AND CARMENA, failed to show the benefit of CN for mccRCC, with Sunitinib as standard of care. Methods: We identified stage IV mccRCC only patients (pts) who received IO with or without surgery in the NCDB 2004-2018. Overall survival (OS) was calculated among three groups of IO alone (group (gr)1), IO followed by CN (gr2), CN followed by IO (gr3). Cox models compared OS by treatment group after adjusting for sociodemographic, health, and facility variables. Results: From 615,519 renal cancer cases, 2,903 met our criteria. 6.96% of ccRCC had sarcomatoid histology. Pts in the gr 2 and gr 3 had 63%, 95% CI [0.265-0.510] and 46%, 95% CI [0.487- 0.594], P= 0.001, risk reduction in mortality compared to IO alone. Black race compared to white race, education attainment quartile < 6.3% compared to > 17.6%, uninsured pts compared to privately insured, and pts treated at community cancer center compared to academic center had an increased mortality risk by 16%, 95% CI [0.980-1.387] (P= 0.083), 26%, 95% CI [1.054-1.511] (P= 0.011), 30%, 95% CI [1.003-1.683] (P= 0.047), 44%, 95% CI [1.161-1.779] (P= 0.001) respectively. Median income quartiles ranging > 63k, had 25% reduction in mortality over income quartiles < 40k, 95% CI [0.630-0.902] (P= 0.002). Regardless of the sequence of CN, partial nephrectomy was minimally used. Pts with brain and liver metastasis had a 48% (P= 0.063) and a 79% (P= 0.001) chance of increased risk of mortality. Conclusions: Pts receiving CN regardless of sequence with IO did better than IO alone in this national registry-based adjusted analysis for mccRCC. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification of pts was not done however Charlson-Deyo Comorbidity Index, visceral/brain metastasis were accounted for in OS analysis. Limitations inherited in the retrospective nature of this study are lack of randomization and pts’ and physicians’ choice. We believe the role of CN does warrant prospective validation in the era of IO for stage IV ccRCC. OS at 2 and 5 yrs for all three groups, with respective 95% CI. [Table: see text]
Gender disparities in metastatic RCC therapies and outcomes.
Authors: Gordon Olivia French , Nadjafi Romtin , Xu Vincent , Drouaud Arthur , Whalen Michael Joseph , Wang Yifeng
Published: June 2023

4565

Background: The incidence of metastatic renal cell carcinoma (mRCC) is rising globally in both males and females. Previous studies have shown that females with mRCC experience better overall survival (OS) when compared to males. In the era of immunotherapy (IM) as part of standard of care, gender-based outcome disparities are unclear. In this study, we identify gender-specific trends in treatment regimen and OS. Methods: The National Cancer Database (NCDB) was queried from 2004 to 2019 for a retrospective cohort analysis of mRCC patients. 51,596 males and 25,528 females were reviewed. The primary endpoints were OS and predictors of receipt of IM. Kaplan-Meier (KM) analysis was used to assess gender-based OS and compare OS in patients who received or did not receive CN or IM. Binomial logistic regression was performed to examine gender as a predictor of treatment received. Cox proportional hazards model assessed the impact of age, gender, sites of metastases, Charleson-Deyo comorbidity classification, insurance type, treatment facility, year of diagnosis, CN, and IM on OS. Results: In KM analyses, females had lower median OS compared to males (7.200 months vs 8.940 months, p<0.001). Higher median OS was found in patients who received IM (21.3 vs 7.6 months; p<0.001) and CN (22.1 vs 5.13 months; p<0.001). Logistic regression demonstrated that females were less likely to receive IM after controlling for the variables listed above (OR 0.839 (95% CI: 0.787 - 0.894), p<0.001). Cox regression demonstrated that when adjusting for clinicopathologic variables and treatment regimen, female gender independently conferred a statistically significant negative impact on OS (HR = 1.039 (95% CI: 1.015-1.063), p=0.001). Conclusions: While CN remains an efficacious treatment option, advances in IM have led to targeted therapies that improve OS in mRCC patients. We demonstrate that a gender-based discrepancy in mRCC survival persists. In contrast to previous literature, our analysis found worse OS as well as an underutilization of IM in female mRCC patients. Moreover, females with mRCC have increased mortality even when accounting for IM. Therefore, further investigation is needed to elucidate the causes of survival discrepancy in the modern era of mRCC treatment. [Table: see text]
Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study.
Authors: Sheng Xinan , Zhou Li , Yang Kaiwei , Zhang Shun , Xu Huayan , Yan Xieqiao , Li Siming , Li Juan , Cui Chuanliang , Chi Zhihong , Si Lu , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Bai Xue , He Zhisong , Guo Hongqian , Guo Jun
Published: June 2023

4566

Background: Disitamab vedotin has shown promising data across a spectrum of HER2 expression in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who progressed on chemotherapy. This study was conducted to evaluate the safety and efficacy of disitamab vedotin plus anti-PD-1 antibody in advanced urothelial carcinoma. Methods: This is an open-label, multicenter, phase 1b/2 trial to evaluate the safety and activity of RC48-ADC combined with toripalimab, a humanized immunoglobin G4 monoclonal antibody against PD-1 in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression assessed by the investigators, unacceptable toxicity, or voluntary withdrawal. The primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: Forty-one la/mUC patients were enrolled (22 males; median age 66 y [42-76]; 61% treatment-naïve). 54% of patients had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression IHC 2+ or 3+ was in 59% patients, and PD-L1 positive in 32%. No dose-limiting toxicity was observed and the recommended dose was RC48-ADC 2mg/kg plus toripalimab 3mg/kg every two weeks. By the cutoff date of 18 November 2022, the confirmed ORR was 73.2% (95%CI: 57.1, 85.8), including 9.8% CR. The ORR was 76.0% for treatment-naïve patients. In HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, the ORR was 83.3%, 64.3%, and 33.3%, respectively. The ORR was 61.5% and 78.6% in PD-L1 positive and negative subgroups. DCR was 90.2% (95% CI, 76.9–97.3), with a median progression-free survival (PFS) of 9.2 months (95%CI: 5.7-10.3) and 2-year overall survival (OS) rate of 63.2%. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST/ALT increase (68.3%), peripheral sensory neuropathy (61.0%), asthenia (61.0%), γ-glutamyl transferase increase (56.1%), hypertriglyceridemia (53.7%), and appetite decrease (51.2%). Grade 3 or greater TRAEs occurred in 43.9% of patients. Twenty-three patients (56.1%) had immune-related AEs (14.6% ≥ G3), including immune-related skin reactions, hyperglycemia, pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with la/mUC and a manageable safety profile. A phase 3 study is currently ongoing to compare the safety and efficacy of this regimen with standard of care. Clinical trial information: NCT04264936 .
Independent biomarkers predictive of outcomes with enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study.
Authors: Jindal Tanya , Zhang Li , Jiang Cindy , Kilari Deepak , Alhalabi Omar , Nizam Amanda , Basu Arnab , Bilen Mehmet Asim , Zakharia Yousef , Milowsky Matthew I. , Shah Sumit , Hoimes Christopher J. , Davis Nancy B. , Gupta Shilpa , Emamekhoo Hamid , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S
Published: June 2023

4573

Background: EV is used for treatment-refractory aUC with activity also noted in a frontline trial. Independent biomarkers associated with EV treatment outcomes are lacking. Methods: UNITE is a multi-site retrospective study of pts treated with EV and other agents. In this analysis we included pts treated with EV monotherapy and available next generation sequencing (NGS) data. Assessed biomarkers included genomic alterations (alts) in ≥5% of pts, tumor mutation burden (TMB) and PD-L1 expression. Pts were evaluable for observed response rate (ORR) if they had scans after ≥1 EV cycle. Biomarkers were evaluated individually in univariate analyses (UVA) and in separate multivariate analyses (MVA) which accounted for clinical variables. Progression-free survival (PFS) and overall survival (OS) from EV start were assessed using Kaplan Meier method and cox proportional hazard (cph) modeling. ORR was assessed using logistic regression. Results: Among 303 pts with NGS treated with EV monotherapy at 16 US sites, 207 had TMB and 146 had PD-L1 data. Median age was 70; 218 (72%) men, 262 (87%) White, 196 (66%) with pure urothelial histology, 212 (71%) with lower tract primary tumor, 204 (67%) had ≥2 prior therapies. ORR was 53% (140/264); mPFS was 6.0 mos, mOS was 13.1 mos. In UVA, longer OS was associated with higher Hgb, albumin and GFR (>30cc/min), lower neutrophil to lymphocyte ratio, older age, and absence of liver mets. MVA included these variables along with histology as covariates. In multivariate cph models, better outcomes were associated with alts in ERBB2, KDM6A and PIK3CA, while inferior outcomes with low TMB (<10 Mut/Mb) and high PD-L1 (CPS ≥ 10). Conclusions: MVA of this large, multi-site, retrospective cohort of aUC pts, identified several putative biomarkers independently associated with EV treatment outcomes. Longer OS was associated with ERBB2 and KDM6A alts, low PD-L1 and high TMB. Limitations include lack of central scan review, pt selection and confounding biases. These findings require external validation, while their underlying mechanisms merit translational study. [Table: see text]
EphrinB2 (B2) expression predicts poor response to PD1/L1 antibodies (Ab) in metastatic urothelial carcinoma (mUC).
Authors: Sadeghi Sarmad , Siddiqi Imran , Ashouri Karam , Tsao-Wei Denice D. , Cogan Jon P , Jackovich Alexandra , Chennapan Krithika , Freeman Dory , O'Toole Jillian , van Bokhoven Adrie , Torkko Kathleen , Gill Inderbir , Gill Parkash S. , Flaig Thomas W. , Sonpavde Guru P.
Published: June 2023

4575

Background: B2 is a ligand for EphB4 which enhances tumor invasion, proliferation, survival and promotes angiogenesis. A prior analysis of TCGA data from 409 muscle invasive bladder cancer (MIBC) patients (pts) demonstrated that high (34%) B2 gene expression had poor survival vs. low (66%) expression (Hazard Ratio 0.7 p = 0.02). Our phase II trial of sEphB4-HSA (JCO PMID 35984996) which targets B2, in combination with pembrolizumab in previously treated mUC (N=70) demonstrated an objective response rate (ORR) of 37%. Among pts with high expression of B2, ORR was 52% with 24% complete response (CR). This retrospective study examined the ORR to PD1/L1 Ab in pts with mUC and its correlation with B2 mRNA expression. Methods: Pts with mUC who had received anti PD1/L1 Ab were eligible if they had radiographic response data and tumor tissue for B2 testing. Pts’ demographics and disease characteristics were abstracted. Radiographic images were reviewed using RECIST 1.1. Tumor specimens were analyzed for intensity of B2 expression using in-situ hybridization (ISH). Scores of 2-4 were considered High (Hi) and 0-1 were considered Low (Lo) expression. Standard descriptive statistics were used to summarize study results. Fisher’s exact test was used to test the association of ORR with B2 expression using SAS 9.4. Results: 120 (N) pts from University of Southern California (USC, n=49), Dana Farber (DFCI, n=55), and University of Colorado (UC, n=16) met were included. 88 pts were male (73%). Median age was 72. PD1/L1 Ab were administered in the post-platinum progressive disease (n=95, 79%) and first-line setting (n=25, 21%) and included pembrolizumab (n=88, 73%), atezolizumab (n=26, 22%) and nivolumab, avelumab, and durvalumab, 3%, 1%, and 1%, respectively. Objective response rate (ORR) defined as radiographic CR plus partial response (PR) were calculated and summarized. Among all pts (N=120), ORR was 20% (95% CI 13-28). 62% had B2 Hi expression with a response rate of 12%, and 38% had B2 Lo expression with a response rate of 33%, p=0.009). These proportions were similar for each institution. Conclusions: In addition to conferring poor prognosis in MIBC, B2 expression is associated with poor ORR to PD1/L1 Ab monotherapy in mUC. Given that the combination of B2 inhibition & pembrolizumab was more active in B2 expressing mUC, these data provide further rationale for investigating B2 as a mechanism of resistance to PD1/L1 ab, biomarker of response and a therapeutic target. [Table: see text]
Clinical utility of plasma ctDNA sequencing in metastatic urothelial carcinoma.
Authors: Helal Clara , Pobel Cedric , Bayle Arnaud , Vasseur Damien , Nicotra Claudio , Blanc-Durand Felix , Naoun Natacha , Bernard-Tessier Alice , Patrikidou Anna , Colomba Emeline , Flippot Ronan , Fuerea Alina , Auger Nathalie , Ngocamus Maud , Besse Benjamin , Lacroix Ludovic , Rouleau Etienne , Ponce Aix Santiago , Italiano Antoine , Loriot Yohann
Published: June 2023

4576

Background: Genomic stratification may help to improve the management of patients with metastatic urothelial cancer (mUC) given the recent identification of targetable molecular alterations in this disease. However, collecting tissue samples in mUC remains challenging. We assessed the clinical utility of plasma circulating tumor DNA (ctDNA) sequencing in mUC. Methods: mUC patients were prospectively enrolled in the STING trial (NCT04932525) whereby ctDNA was profiled using the FoundationOne Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESCAT tier leading to molecular-based treatment suggestions whenever it was possible. Results: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. Median time to assay results was 20 days. ctDNA abundance was correlated with number of prior lines and number of metastatic sites. ctDNA analysis reproduces the somatic genomic landscape reported by previous tissue-based cohorts. Concordance for serial tumor tissue was moderate (r=0.545 CI95: [0.121-0.801], p= 0.016). At least one actionable target was detected in 63 patients (45 %) with a total of 35 actionable alterations including TMB high (≥12 mutations/Mb) (N= 39, 21.1%), FGFR3 (N= 20, 10.8%) and HRD alterations (N= 14, 7.6%). The MTB recommended a matched therapy for 63 patients (45.0%). In total, 8 patients (5.7 %) were treated with an overall response rate of 50% (95%: 15.70-84.30) and a median PFS of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with lower progression-free survival in patients treated with immunotherapy. Conclusions: Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in mUC is a reliable and feasible approach to timely initiate genotype-matched therapies. Clinical trial information: NCT04932525 .
The effect of antibiotic (Abx) use on immune checkpoint inhibitor (ICI) efficacy in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Patgunarajah Ubenthira , Dawsey Scott , Pramod Nikhil , Maroli Kimberly , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Martin Allison , Nizam Amanda , Mian Omar Y. , Wei Wei , Diaz-Montero C. Marcela , Pavicic Paul G. , Nguyen Jane , Gupta Shilpa
Published: June 2023

4580

Background: Use of Abx may negatively affect outcomes with ICI, possibly due to negative impact on gut microbiota. We previously showed that in our real world cohort of 138 mUC pts, Abx use within 30 or 60 days (d) of ICI initiation did not impact overall survival (OS). We now report updated follow-up (fu) and results from our expanded cohort of 310 mUC pts who received ICI. Methods: We performed a retrospective analysis of adult pts with mUC treated at the Cleveland Clinic between 2015 and 2022 who received 2 or more cycles of ICI with pembrolizumab (P), atezolizumab (A) or avelumab (Av). Effect of Abx use within 30 and 60 (d) of ICI initiation was correlated with progression free survival (PFS) and OS. OS and PFS were estimated using Kaplan-Meier method and compared using log rank test. Results: Median age of pts was 71 years (41-90) and 75% pts were males. 224 pts (72.3%) received P, 82 (26.4%) A and 4 (1.3%) Av. Fluoroquinolones (31.1%), penicillins (29.6%) and cephalosporins (19.7%) were most commonly used Abx. With a median fu of 47 weeks (3.86- 325.3), median OS in pts who received Abx within 60 (d) prior to ICI was 11.79 months (mos) vs 14.55 mos in those who did not receive Abx (p=0.007) and median PFS was 3.68 mos vs 5.29 mos respectively (p=0.038). Median OS in pts who received Abx within 30 days prior ICI was 10.41 mos vs 14.46 mos in those who did not receive Abx (p=0.037). There was a non-significant trend for worse PFS in pts who received Abx within 30 (d) prior to ICI (3.06 mos vs 5.03 mos, p=0.238). There was no effect on OS or PFS with Abx use 30 or 60 (d) after ICI initiation. Conclusions: In our real-world cohort of mUC pts receiving ICI, Abx use 60 and 30 (d)prior to ICI initiation was associated with significant worse OS and worse PFS for the former group but Abx use after ICI initiation did not have an effect on OS or PFS. These findings have the potential to influence clinical practice, including a higher threshold for giving Abx to mUC pts starting ICI. Further prospective studies are warranted. [Table: see text]
Assessing tumor-infiltrating immune cells and outcomes with cisplatin- versus carboplatin-based treatment in advanced urothelial cancer (UC): Survival analysis of three platinum-treated UC cohorts.
Authors: Stawiski Konrad , Perera-Bel Júlia , Rodriguez-Vida Alejo , Rodero Núria Juanpere , Mouw Kent William , Bamias Aristotelis , Carvalho Filipe Lf , Bellmunt Joaquim
Published: June 2023

4583

Background: The association between tumor-infiltrating immune cells and the response to platinum-based chemotherapy (cisplatin vs carboplatin) in advanced urothelial cancer is not well characterized. We dissected the immune microenvironment of 3 large UC cohorts to define populations of immune cells associated with survival following carboplatin- or cisplatin-based chemotherapy. Methods: Two advanced UC cohorts – Hospital del Mar (HM; n = 55) and GREEK (n = 62) – treated with platinum-based chemotherapy were profiled using bulk RNA sequencing (RNA-seq) with tumor-infiltrating immune cells inferred using CIBERSORTx. Our findings were validated in a publicly available platinum-treated UC cohort (n = 93; Taber et al. Nat Comm 2020). Additionally, we assessed the impact of tumor-infiltrating immune cells in IMvigor210, an anti-PD-L1 treated cohort. Analysis was adjusted by tumor stage, and treatment regimen (cisplatin, carboplatin, atezolizumab) to determine associations between tumor-immune cell populations and overall survival (OS). Results: In platinum-treated patients, increased lymphoid cell infiltration was associated with improved OS. Specifically, the presence of naive and memory B-cells and CD4+ T cells was associated with prolonged OS (Table). Interestingly, infiltration of memory B-cells was associated with a better prognosis in patients treated with cisplatin (HR = 0.14) and detrimental in patients treated with carboplatin (HR = 249.53; difference p = 0.006). Additionally, macrophages (HR = 3.44; p = 0.027) and resting dendritic cell (HR = 41.47; p = 0.009) infiltration was associated with worse OS in patients treated with platinum therapy alone, but enrichment of pro-inflammatory M1 macrophages was associated with prolonged OS in patients treated with immunotherapy (p < 0.001). Conclusions: Immune cell infiltration is associated with differential outcomes to cisplatin- and carboplatin-based chemotherapy in advanced UC. Our findings suggest better OS in advanced UC treated with cisplatin in tumors enriched with memory B-cells compared to carboplatin treatment. [Table: see text]
Final analysis results from a multicenter clinical study of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy in patients with cT2-T4aN0M0 MIBC.
Authors: Lin Tianxin , Li Kaiwen , Fan Jinhai , Wang Shaogang , Yu Dexin , Xu Tao , Lyu Jiaju , Qin Tao , Liu Zheng , Wu Kaijie , Wang Jinyou , Wang Qi , Min Jie , Hu Zhiquan , Li Fan , Zhang Zhiqiang , Yu Luping , Ding Sentai , Huang Jian
Published: June 2023

4585

Background: To evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy for patients (pts) with clinical T2-T4aN0M0 (cT2-T4aN0M0) muscle-invasive bladder urothelial cancer (MIBC). At predefined interim analysis, the study has met the first stage aim. Here reported the results of the predefined final analysis. Methods: This phase II study enrolled pts tolerated with the cisplatin therapy. Eligible pts received tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m2 D2, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for four cycles. Radical cystectomy (RC) was performed within 6 weeks after last dose treatment. The primary end point was pathologic complete response (pCR, pT0N0M0). Secondary end points were pathologic downstaging (≤pT1N0M0) (pDS), EFS, OS and safety. Simon two-stage design was used. If >5 pts achieved pCR in the first stage (n=22), study would proceed to the second stage and enroll 33 additional pts. If >18 of 55 pts achieved pCR, we would deem the study to have met the primary endpoint. Results: At the data cut off time of 14th Dec 2022, 63 pts (38 cT2, 19 cT3, and 6 cT4a) have completed neoadjuvant therapy, with median age of 64 (48-75) years. The median relative dose intensity of tislelizumab, cisplatin and gemcitabine were 92.3%, 85.7% and 85.6%, respectively. At this time, 55 pts underwent RC and completed 30 days post-surgery follow-up. The median time from last dose to RC was 4.4 (range: 0.6-13.3) weeks. Eight pts refused RC. Among 55 efficacy evaluable pts, 27 (49.1% [90% CI, 37.4-60.9]) pts achieved pCR, while 41 (74.5% [95% CI, 61.0-85.3]) pDS. Pts with cT2 achieved 55.6% (20/36) pCR and 86.1% (31/36) pDS. Among 14 non-responders, 3 of them (1 cT2, 2 cT3) achieved pT0, but with pathologic N1. Clavien-Dindo grade ≥3 postoperative complications occurred in 7.9% pts. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (88.9%), nausea (77.8%), and vomiting (50.8%). Grade ≥3 neoadjuvant therapy related AEs occurred in 60.3% pts, which were hematologic toxicities (58.7%) in most. The frequently occurring immune-related AEs (irAEs) (>5%) included dizziness (14.3%), fatigue (12.7%), ASL/ALT increased (7.9%), rash (7.9%), pruritus (7.9%), and GGT increased (6.3%). Grade ≥3 irAEs occurred in 2 pts (pneumonia, n=1; cardiomyopathy, n=1). Conclusions: The study met its primary endpoint. Neoadjuvant tislelizumab combined with gemcitabine and cisplatin showed promising anti-tumor activity with high pCR and well tolerance in MIBC pts. Clinical trial information: ChiCTR2000037670 .
Open versus robotic-assisted radical cystectomies: A risk analysis.
Authors: Simhal Rishabh , Wang Kerith Ruoyao , Shah Yash , Simon Daniel P , Mark James Ryan , Shah Mihir S , Gomella Leonard G. , Chandrasekar Thenappan , Lallas Costas D.
Published: June 2023

4593

Background: Radical cystectomy (RC) is standard of care for muscle-invasive bladder cancer, but it comes with significant perioperative risk with half of patients experiencing major postoperative complications. Robot-assisted radical cystectomies (RARC) have aimed to decrease patient morbidity and have become increasingly adopted in North America. Currently, both open radical cystectomies (ORC) and RARC are frequently performed. To contribute to the existing literature using newly available data from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP), representing one of the most recent, largest multi-institutional studies, while uniquely accounting for a variety of factors including type of urinary diversion, cancer staging, and neoadjuvant chemotherapy. Methods: RC procedures performed between 2019-2020 were identified in NSQIP and the corresponding Cystectomy Targeted database. Cases in the ORC group were planned open procedures, and cases in the RARC group were robotic with intra- or extracorporeal diversions, including unplanned conversion to open cases for intention-to-treat. Chi-square and t-tests were performed to compare baseline demographics and operative parameters. Multivariate analysis was performed for outcomes including major complications, minor complications, and 30-day mortality, while adjusting for operative approach, medical comorbidities, functional status, age, race, sex, BMI, ASA-classification, preoperative labs, type of urinary diversion, pathological staging, prior pelvic surgery or radiation, need for preoperative transfusion, preoperative sepsis, emergent or elective surgery, and recent chemotherapy. Results: 4,022 RC cases were identified. Of these, 3,146 (78.2%) received planned ORC while 876 (21.8%) received RARC. Baseline demographics of the patients who received ORC versus RARC were largely similar, with no significant difference in age or medical comorbidities. RARC was associated with longer operative times and shorter hospital length of stay compared to ORC. On multivariate analysis, ORC was associated with a higher rate of 30-day mortality [OR 3.1; 95% CI 1.3-7.2; p=0.009], reintubation, cardiac arrest, superficial wound infection, bleeding requiring transfusion [OR 4.7; 95%CI 3.6 - 6.1; p<0.001], prolonged postoperative nasogastric tube use, rectal injury, and ureteral fistula or urine leak compared to RARC. Conclusions: In the NSQIP database, ORC is associated with higher rates of 30- day mortality and operative complications, most notably bleeding, compared to RARC. This study is unique in the size of the cohorts compared, the timeliness of the data (2019-2020), and the ability to control for factors, such as type of urinary diversion, pathological bladder cancer staging, and use of neoadjuvant chemotherapy.
Prognostic impact of PSA nadir (n) ≥0.1 ng/mL within 6 months (m) after completion of radiotherapy (RT) for localized prostate cancer (PCa): An individual patient-data (IPD) analysis of randomized trials from the ICECAP collaborative.
Authors: Ravi Praful , Kwak Lucia , Armstrong John , Beckendorf Veronique , Chin Joseph , D'Amico Anthony Victor , Dearnaley David P. , Denham James William , Di Stasi Savino Mauro , Gillessen Silke , Lukka Himanshu , Mottet Auselo Nicolas , Pommier Pascal , Seiferheld Wendy , Sydes Matthew R. , Tombal Bertrand F. , Zapatero Almudena , Regan Meredith M. , Xie Wanling , Sweeney Christopher
Published: June 2023

5002

Background: RT + androgen deprivation therapy (ADT) is a standard of care in treatment of intermediate- and high-risk localized PCa. Identification of early surrogate measures for long-term outcome measures such as PCa-specific survival (PCSS), metastasis-free survival (MFS) and overall survival (OS) could expedite development of new systemic therapies added to RT/ADT while potentially identifying patients (pts) for therapy (de)escalation. Methods: IPD from the RT+/-ADT trials in the ICECAP repository with evaluable PSA follow-up were eligible for inclusion. Pts were grouped based on their trial-allocated treatment: RT alone, RT+stADT (short-term ADT: 3-6m), RT+ltADT (long-term ADT: 18-36m). PSAn was defined as the lowest PSA recorded within 6m after RT completion. A 12m landmark analysis for PCSS, MFS and OS was performed to account for guarantee-time bias. Multivariable Cox proportional hazards regression was used to estimate associations of PSAn < or ≥0.1ng/mL with MFS and OS, and a multivariable Fine and Gray distribution used for PCSS to account for competing risk of non-PCa deaths. Models were adjusted for age, ECOG performance status, clinical T stage, Gleason score and PSA at randomization. Results: 10,415 pts from 16 RCTs were included: 2629 (25%) allocated to RT, 6033 (58%) to RT+stADT, and 1753 (17%) to RT+ltADT. Median follow-up was 10.1years (yrs). 2339 (98%), 4756 (84%) and 1258 (77%) of patients allocated to RT, RT+stADT and RT+ltADT respectively achieved a PSAn ≥0.1ng/mL within 6m after RT completion. After adjustment, PSAn ≥0.1ng/mL was associated with poorer PCSS, MFS and OS in pts allocated to RT+stADT (PCSS hazard ratio [HR] = 1.97 [95% CI 1.52-2.92], MFS HR = 1.27 [1.12-1.44], OS HR = 1.26 [1.11-1.44]) and RT+ltADT (PCSS HR = 1.97 [1.11-3.49], MFS HR = 1.58 [1.27-1.96], OS HR = 1.59 [1.27-1.99]). A weaker association was noted in pts allocated to RT (PCSS HR = 1.82 [0.51-6.49], MFS HR = 2.23 [1.20-4.14], OS HR = 1.72 [0.97-3.05]). Table shows 5-yr MFS, 10-yr PCSS and 10-yr OS based on PSAn within 6m after RT completion. Conclusions: PSAn ≥0.1ng/mL within 6 mths after RT completion was strongly prognostic for PCSS, MFS and OS in pts receiving RT+ADT for localized PCa in this IPD analysis of > 10,000 patients. This could be used as an early signal-seeking endpoint in trials evaluating novel systemic therapies with RT + ADT and to help identify pts for therapy (de)escalation trials. [Table: see text]
Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status.
Authors: Olmos David , Lorente David , Alameda Daniel , Cattrini Carlo , Romero-Laorden Nuria , Lozano Rebeca , Lopez-Casas Pedro P. , Capone Camille , Vanden Broecke Anne Marie , Trevisan Marco , Van Sanden Suzy , Jürgens Alexandra , Herrera-Imbroda Bernardo , Castro Elena
Published: June 2023

5003

Background: Understanding of the association between HRR mutations and outcomes in mCRPC pts is limited. This analysis investigated the prevalence and outcomes of pts with/out HRR mutations (somatic and/or germline), stratified as BRCA, non-BRCA, or HRR non-BRCA, who initiated 1L mCRPC treatment with novel hormonal therapy (NHT) or taxane. Methods: Eligible pts from PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620), and PROSABI (NCT02787837) studies underwent paired somatic/germline DNA analyses using a custom NGS panel that included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B, and RAD54L. Those with pathogenic (likely) mutations in ≥1 allele of ≥1 gene were considered deficient (HRR). rPFS, PFS2, and OS were reported for BRCA, non-BRCA, and HRR non-BRCA subgroups; associations between mutations and outcomes were assessed using inverse probability weighted Cox models, which balanced the baseline (BL) characteristics between subgroups. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p values are presented. Results: Of 729 pts, 223 (30.6%) were HRR, including 96 (13.2%) BRCA. 60.4% of pts were treated with NHT and 39.6% with taxane in 1L; 80.7% received at least second-line treatment. Median age at BL was 72.2 years, 63.5% had Gleason >7, 53.1% had ECOG ≥1, and 13.3% presented with visceral metastases. BL characteristics after adjustment were similar (standard mean difference: <0.1 in HRR and maximum 0.11 for all pts). BRCA pts had significantly worse rPFS, PFS2, and OS than non-BRCA pts; BRCA pts also had significantly worse PFS2 and OS than HRR non-BRCA pts. There were no significant differences between the outcomes of somatic and germline BRCA pts. Conclusions: BRCA pts, regardless of somatic/germline origin, had significantly worse rPFS, PFS2, and OS than the total non-BRCA population and significantly worse PFS2 and OS than non-BRCA pts in the HRR subgroup. It is crucial to screen early for HRR mutations, particularly in BRCA1/2, to begin timely, targeted mCRPC treatment and improve prognosis.[Table: see text]