bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A).
Authors: Atkins Michael B. , Jegede Opeyemi , McDermott David F. , Haas Naomi B. , Bilen Mehmet Asim , Stein Mark N. , Sosman Jeffrey A. , Plimack Elizabeth R. , Alter Robert S. , Ornstein Moshe Chaim , Hurwitz Michael E. , Peace David J. , Einstein David Johnson , Catalano Paul J. , Hammers Hans J. , Regan Meredith M. 
Published: March 2023

604 Background: Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Toxicity from therapy can also persist after cessation. TFS with and without toxicity can characterize survival time. Significant TFS was reported for CheckMate 067 trial in pts with metastatic melanoma (Regan et al JITC 2021) and CheckMate 214 trial for pts with aRCC (Regan et al CCR 2021), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16 260 trial, which was designed to reduce toxicity and to cap immunotherapy duration (Atkins et al JCO 2022). Methods: Data were analyzed from 128 patients (pts) with clear-cell aRCC treated with first-line nivolumab (NIVO) monotherapy for up to 2 years. As part of the protocol, salvage nivolumab/ipilimumab (NIVO/IPI) for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (28% of pts). TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, estimated from 36-month (mo) mean times. The time on treatment or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured. Results: At 36 mos from enrollment, 68.3% of pts were alive: 96.8% of IMDC favorable-risk (FAV) pts and 56.6% of those with intermediate/poor-risk (I/P), respectively. The 36-mo mean time on protocol therapy was 11.5 mos (16.0 mos for FAV pts and 9.6 mos for I/P pts). The 36-mo mean TFS for the whole population was 9.4 mos. For FAV pts the mean TFS was 12.9 mos, of which TFS with grade 3+ TRAEs was 1.5 mos. For I/P pts, the mean TFS was 8.0 mos, of which TFS with grade 3+ TRAEs was 1.0 mos. At 36 mos, 65.6% of FAV pts and 27.1% of I/P pts were alive and second-line treatment-free. Conclusions: NIVO monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve pts with aRCC and results in substantial TFS and toxicity-free TFS. TFS was particularly noted in pts with FAV disease, further supporting the use of an immunotherapy-only regimen in this population. Clinical trial information: NCT03117309 . [Table: see text]
Evaluation of eligibility criteria in contemporary renal cell carcinoma based on ASCO-FCR recommendations.
Authors: Prajapati Sweta R. , Feng Matthew I. , Castro Daniela V. , Lee Kyle O. , Chan Elyse H. , Sehgal Ishaan , Patel Jalen , O'Dell Anna , Zengin Zeynep Busra , Li Xiaochen , Chehrazi-Raffle Alex , Dizman Nazli , Tripathi Abhishek , Rock Adam , Liu Sandy , Mercier Benjamin D. , Meza Luis A , Philip Errol James , Dorff Tanya B. , Pal Sumanta Monty 
Published: March 2023

612 Background: A consensus statement from the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FCR) collaboration highlights the importance of expanding eligibility criteria in cancer trials to more accurately reflect the real-world population (Kim et al., Clin Cancer Res 2021). We sought to characterize use of overly restrictive eligibility criteria in renal cell carcinoma (RCC) trials in the context of ASCO-FCR recommendations. Methods: Studies containing the MeSH terms “(metastatic OR advanced OR stage IV or unresectable) AND (kidney cancer OR renal cell carcinoma OR renal cell cancer)” from June 30, 2012 to June 30, 2022 were identified on the ClinicalTrials.gov platform. Our search query’s inclusion criteria identified international studies examining adult patients aged ≥ 18 in phase I-III trials. Exclusion criteria comprised pan-cancer studies, trials involving localized treatments, radiation therapy, and prognostic tools. Descriptive statistics were used to characterize the frequency of restrictive eligibility criteria across studies, while Fisher’s exact test or chi-square test were utilized to determine the association between treatment type and exclusion criteria. Results: The content of 423 RCC trials were analyzed, of which 112 (26.5%) had adequate data available. 48 (42.9%), 44 (39.3%) and 18 (16.1%) studies examined combination therapy, targeted therapy, and immunotherapy, respectively. The presence of HIV positivity, HBV/HCV positivity, brain metastases, and concurrent malignancies accounted for the most frequently cited exclusionary criteria, seen in 83/112 (74.1%), 60/112 (53.6%), 37/112 (33.0%), and 9/112 (8.0%) studies respectively. Differences in the use of HIV positivity (p<0.001) and HBV/HCV positivity (p<0.001) as eligibility criteria were observed across classes of therapy (see Table). Conclusions: A significant proportion of RCC studies utilize overly restrictive eligibility criteria as highlighted by the ASCO-FCR joint statement. Appropriate broadening of eligibility criteria to incorporate patient populations mirroring a real-world setting will provide more useful data going forward. [Table: see text]
Estimated cost of adverse event (AE) management for patients (pts) with metastatic renal cell carcinoma (mRCC) treated with a VEGFR TKI.
Authors: Yorio Jeffrey Thomas , Asnis-Alibozek Aviva G. , Kasturi Vijay , Hutson Thomas E. 
Published: March 2023

629 Background: Nearly all mRCC pts will be treated with one or more VEGFR TKI, alone or in combination with an immunotherapy (IO) or mTOR-inhibitor, during their therapeutic journey and may experience associated AEs. Evidence from the tivozanib (tivo) TIVO-3 trial suggests that median duration of clinically relevant VEGFR TKI class effect AEs is ≤90 days (range 14-90). Cost of AE management has not been clearly quantified to date. This study aimed to estimate how differences in TKI AE profile may impact treatment cost efficiency, particularly in later line (3L+) settings. Methods: iKnowMed EMR was used to identify mRCC pts from USON or Onmark Network, with matched 3rd party insurance claims, that initiated VEGFR TKI treatment between Jan 2015 and Mar 2021. First occurrence of each VEGFR TKI class effect AE was indexed, and associated costs for 90-day (longest median AE duration) follow-up was captured. To assess burden across different TKIs, average per-patient AE management cost was calculated using incidence data from trials supporting FDA approvals, and weight-adjusted to estimated number of commercially insured 3L/4L pts in a 1,000,000-member plan. Results: 5,958 mRCC pts were identified, of which 4,464 were on at least one TKI regimen. Among those, 1,777 experienced an index AE; 1,072 successfully matched to claims data [median 69 years (range 25-94); 55% ECOG PS 0/1; 69% male], accounting for 1,667 unique index AE cases. Most were on cabozantinib (cabo), axitinib (axi), or pazopanib; lenvatinib (len), sunitinib (sun), and sorafenib were also represented. >80% were TKI only, with the rest TKI+IO (18%) or TKI+mTOR (6%). AE costs largely originated from outpatient visits (range 38-77%), excluding renal failure (58% inpatient). Mean cost per AE ranged from $76 (proteinuria) to $1,687 (mucositis/stomatitis). Overall, estimated costs of managing VEGFR TKI class effect AEs in 3L/4L showed lowest resource burden with tivo, and highest with len+everolimus (len+ev; Table). Conclusions: Average VEGFR TKI AE management costs derived from real-world mRCC pts demonstrated differences in healthcare resource burden, with overall anticipated cost dependent on TKI regimen utilized. [Table: see text]
Evaluation of deep learning techniques (DL) in RNA sequencing data for the prediction of response to immune checkpoint inhibitors in patients with metastatic renal cell cancer m(RCC).
Authors: Alonso Paz Sandra , Duran Ignacio , Grande Enrique , Pinto Alvaro 
Published: March 2023

641 Background: Immune checkpoint inhibitors have become a cornerstone in the management of mRCC. However, to identify the most suitable patients for this treatment is an unmet medical need. We aimed to explore the utility of DL integrating clinical and molecular data to predict response to immunotherapy. Methods: We conducted a retrospective analysis using publicly available data from patients treated with nivolumab in the clinical trials Checkmate 009, 010 and 025. The primary objective was to assess the performance of different DL models (autoencoder and convolutional neural network (CNN)) predicting the PFS of these patients. With that scope, we followed several research lines including the creation of combined datasets with clinic and RNA sequencing and comparing the results of the DL models against the performance of traditional machine learning (ML) models. Finally, we came up with an interpretability analysis of those black-box models using LIME and SHAP values. Results: Clinical and transcriptomic data were available from 181 nivolumab-treated patients. Outcomes achieved confirmed that we can model the response for NIVOLUMAB using RNA sequencing data. (Table) However, DL models have not demonstrated to be significantly better than traditional ML methods when predicting response (p= 0.068). Deep autoencoder provided 68.9% accuracy, but the most accurate model was logistic regression classifier which achieved 86.4% of hit rate. Interpretability results revealed that most relevant genes for the decision making were related with the immune response and the regulation of kinases. Regarding interpretability, best results were achieved integrating both transcriptomic and clinical data (7 out of 10 DL and ML tested models achieved higher hit rates with combined data set. Logistic regression classifier improved its accuracy in 11%). Conclusions: The integration of clinical and molecular data could lead to more accurate predictions of outcome than any dataset by its own. However, further research is intended in the field of the DL analysis, as data codification and data structure could bias the results. The ongoing study ART (Artificial Intelligence in Renal Tumors) will address this issue prospectively. [Table: see text]
Cabozantinib in the elderly with metastatic renal cell carcinoma undergoing geriatric G8 screening test: A prospective multicenter observational study (ZEBRA/MEET-URO 9).
Authors: Basso Umberto , Buti Sebastiano , Verzoni Elena , Sorarù Mariella , Di Napoli Marilena , Fratino Lucia , Santini Daniele , Grillone Francesco , Chiuri Vincenzo Emanuele Emanuele , Carella Claudia , Atzori Francesco , Roviello Giandomenico , Sartori Donata , Maruzzo Marco , Pierantoni Francesco , Bersanelli Melissa , Ballestrin Melissa , De Toni Chiara , Mattana Alvise , Zagonel Vittorina 
Published: March 2023

647 Background: Cabozantinib (CABO) is an oral tyrosine kinase inhibitor registered for the treatment of metastatic renal cell carcinoma (mRCC) for the first or subsequent lines. Tolerability in real world elderly patients is poorly documented. G8 is a short test for vulnerability gaining increased interest as a screening tool for trials in geriatric oncology. Methods: ZEBRA/MEET-URO 9 was a prospective multicenter study of safety and activity of CABO administered to pts ≥70 years with mRCC, either in the first or subsequent lines of treatment, until progression or unacceptable toxicity. All pts underwent G8 score at baseline, with a cut-off for vulnerability of 14 or below. Data on tolerability and activity were collected prospectively after signature of informed consent. Results: A total of 104 pts started CABO at 13 Italian Centers, 38,5% as first line. Median age was 75.8 yrs (range 70.2-87.4 yrs, 26 pts ≥80 yrs), 73.1% males. IMDC score was good 19.2%, intermediate 53.9%, poor 26.9%. Primary tumor had been removed in 82.7% of pts, histology was clear cell 78.8%, papillary 8.7%, chromophobe 5.8%, unclassified 6.7%. G8 score was ≤14 in 65.4% of pts. Up-front dose reduction of CABO was more frequent in pts with low G8 score (79.4 vs 41.7%, p=0.003), but eventually the majority of pts (91.4%) underwent dose reductions of CABO. After a median treatment of 6.4 months (0.5-26.1 months), 38.4% of pts developed G3-4 toxicities, 22.1% interrupted treatment due to adverse events, 2.8% (3 pts) died due to cardiovascular or thromboembolic events. Median PFS was 7.6 months (95% CI=5.8-12.6 months) in first line, 10.0 months (5.8-15.6) in second or further lines, median OS was 20.1 months (11.1-not reached) and 15.6 months (12.5-not reached), respectively. G8 score ≤14 did not correlate with rate of temporary interruptions >7 days, hospitalization, incidence of G3-5 toxicities, as well as with PFS. Pts with G8 score ≤14 had a trend for reduced OS, but difference was not statistically significant both in the first and further lines of treatment. Conclusions: Screening G8 test was positive in more than a half of pts, underlying the need for detailed geriatric assessment and increased clinical monitoring of such patients. A G8 score ≤14 correlated with up-front dose reduction of CABO but not with G3-5 toxicities probably due to the high rates of dose reductions in the whole cohort. Correlation between low G8 score and OS could not be demonstrated in this population.
Characterization of clinical outcomes among patients with advanced chromophobe renal cell carcinoma (ChRCC) treated with first-line immunotherapy (IO)-based regimens.
Authors: Labaki Chris , Bakouny Ziad , Wells J Connor , Takemura Kosuke , Saliby Renee Maria , Meza Luis A , Gebrael Georges , Porta Camillo , Lee Jae-Lyun , Basappa Naveen S. , De Velasco Guillermo , McKay Rana R. , Pal Sumanta Monty , Agarwal Neeraj , Donskov Frede , Braun David A. , Henske Elizabeth , Xie Wanling , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: March 2023

654 Background: IO-based regimens have demonstrated substantial efficacy in the management of metastatic clear-cell RCC (mccRCC), where they currently represent the standard of care. ChRCC has a dismal prognosis in the metastatic setting. Recent clinical trials evaluating IO-based regimens across non-ccRCC subtypes identified a preliminary poor response in advanced ChRCC, but were limited by low sample sizes. We sought to comprehensively evaluate the outcomes of patients with ChRCC treated with IO-based regimens. Methods: Using real-world data from the International Metastatic RCC Database Consortium (IMDC), we conducted a retrospective analysis of patients with advanced ChRCC who received IO-based therapies, including dual IO therapy or IO + VEGF targeted therapy (VEGF-TT), in the first-line setting. The primary outcome was overall survival (OS). Secondary outcomes included time to treatment failure (TTF) and ORR. Cox proportional hazards models were used to adjust for age and IMDC risk groups as covariates. A logistic regression was used to determine the association between the odds of achieving a response and RCC subtype. Results: We identified 31 patients with advanced ChRCC and 856 patients with ccRCC treated with IO-based therapies in the first-line setting, with a median age of 61.5 years (IQR: 51.5-69.0). Compared to patients with ccRCC who received IO-based therapies as initial regimens, patients with ChRCC had a lower OS (median OS: 24.7 vs. 50.5 months, respectively; p<0.001) and a lower TTF (median TTF: 4.5 vs. 11.0 months, respectively; p<0.001). Among patients with an evaluable objective response, the ORR was lower among patients with advanced ChRCC, as opposed to those with ccRCC (ORR: 12.0 vs 47.1%, respectively; p<0.001). When evaluating first-line treatment with VEGF-TT monotherapy (sunitinib or pazopanib), no difference in outcomes was found between patients with ChRCC (n=122) and ccRCC (n=6,379) in relation to the primary endpoint of OS, while TTF and ORR suggested better outcomes for ccRCC (Table). Conclusions: In this real-world study, patients with metastatic ChRCC appear to display poor clinical outcomes even with IO-based regimens, as compared to ccRCC. The molecular determinants of poor response require further investigations. [Table: see text]
Improved health-related quality of life (HR-QOL) with use of an online mindfulness tool in patients with metastatic renal cell carcinoma (mRCC) receiving immunotherapy (IO).
Authors: Bergerot Cristiane Decat , Malhotra Jasnoor , Bergerot Paulo Gustavo , Philip Errol James , Castro Daniela V. , Govindarajan Ameish , Molina Lorena Nascimento Manrique , Fuzita William Hiromi , Azeredo Andressa Cardoso , Mota Augusto C. A. , Franca Marcos V S , Anjos Gabriel dos , Filho Romildo De Araujo Periera , de Souza Douglas Manfroi , Hsu Joann , Chawla Neal , Chehrazi-Raffle Alex , Saab Bechara , Carlson Linda E , Pal Sumanta Monty 
Published: March 2023

660 Background: Previous randomized studies have shown the benefit of interventions to increase mindfulness in multiple cancer types, including prostate cancer (Chambers et al JCO 2017), but limited data exists in mRCC. We sought to determine the effect of an app-based mindfulness intervention on anxiety, fear of cancer progression (FCR), fatigue and HR-QOL in this population. Methods: Eligible patients had mRCC, were receiving IO, had measurable symptoms of anxiety or FCR, had a smartphone with internet access and had not participated in a mindfulness program in the past 5 years. Patients were recruited in Brazil across 7 private centers and one academic center in the US. We evaluated the Mindfulness-Based Cancer Survivorship Journey, a program within the Am Mindfulness smartphone app (AmDTx). Patients used AmDTx for 20-30 minutes each day for a minimum of 4 days per week over a period of 4 weeks. Patients were assessed at baseline (T1) and at weeks 2 (T2), 4 (T3) and 12 (T4) using the PROMIS-Anxiety, FCR-7, Brief Fatigue Inventory (BFI), and Functional Assessment of Chronic Illness Therapy-General (FACT-G). RM-ANOVA was used to test the effect of time on symptoms and on HR-QOL. Results: A total of 41 patients were recruited; median age was 59 (range, 36-79) and patients were predominantly male (70%), white (61%), married (75%) and well educated (65% had at least a college degree). Most patients were receiving nivolumab/ipilimumab (44%), nivolumab (22%) or axitinib/pembrolizumab (9%). Symptoms of anxiety significantly decreased from 21.6 + 4.8 to 12.5 + 5.1 (P=0.001). Similar findings were found for FCR (MT1=21.4 to MT4=13.5, P=0.001) and fatigue (MT1=32.0 to MT4=19.4, P=0.001). Notably, HR-QOL increased from 81.1 + 13.4 to 92.7 + 14.9 (P=0.001). No significant differences were identified based on disease characteristics or type of therapy. Conclusions: The current study suggests that smartphone-based mindfulness intervention could improve HR-QOL and decreased FCR, anxiety and fatigue. This low-cost, easily accessible intervention may provide an important alternative to in-person psychosocial support for patients with mRCC and should be assessed in randomized trials in this disease. Funding: Kure It Cancer Research: 2020 Barry Hoeven Memorial Kidney Cancer Research Grant (PI: C D Bergerot).
C-reactive protein (CRP) as a predictive marker for outcomes with avelumab + axitinib (A + Ax) in patients with poor-risk advanced renal cell carcinoma (aRCC): Exploratory analysis from JAVELIN Renal 101.
Authors: Tomita Yoshihiko , Motzer Robert J. , Choueiri Toni K. , Rini Brian I. , Uemura Hirotsugu , Oya Mototsugu , Albiges Laurence , Fujii Yosuke , Umeyama Yoshiko , Huang Bo , Di Pietro Alessandra , Schmidinger Manuela 
Published: March 2023

670 Background: Analyses from the phase 3 JAVELIN Renal 101 trial (NCT02684006) suggested that CRP levels at baseline (BL) and early after treatment may predict outcomes with A + Ax in patients with aRCC. In addition, many patients with International Metastatic RCC Database Consortium (IMDC) poor risk who had prolonged progression-free survival (PFS) and overall survival (OS) were observed at the third interim analysis of OS. We analyzed the association between CRP levels and prolonged PFS/OS with A + Ax in patients with IMDC poor risk. Methods: CRP levels were assessed at screening and on day 1 of each 6-week cycle. Patients in the A + Ax arm with 3 or 4-6 IMDC risk factors were categorized into subgroups with CRP normal (BL CRP <10 mg/L), normalized (BL CRP ≥10 mg/L and ≥1 CRP value decreased to <10 mg/L during 6-week treatment), or non-normalized (CRP ≥10 mg/L at BL and during 6-week treatment). CRP levels were compared in patients with prolonged PFS/OS (PFS ≥24 months [mo] and OS ≥30 mo) or PFS <24 mo (any OS duration). Results: In the A + Ax arm (N=442), 44 and 29 patients had 3 or 4-6 IMDC risk factors, of whom 7 and 5 had prolonged PFS/OS, and 26 and 20 had PFS <24 mo, respectively (Table). Most patients with 3 or 4-6 risk factors with prolonged PFS/OS were in the normal or non-normalized CRP group, respectively. In patients with 3 risk factors with prolonged PFS/OS, CRP levels were generally low at BL and remained low for 24 mo. In patients with 4-6 risk factors with prolonged PFS/OS, CRP levels were high at BL and decreased markedly within 6 weeks, then maintained for 24 mo. Conclusions: In patients with poor-risk aRCC treated with A + Ax, a low CRP level at BL and during treatment or a rapid decrease in high CRP levels might predict favorable long-term outcomes, although CRP levels are unspecific and may increase/decrease with other diseases/comorbidities. Clinical trial information: NCT02684006 . [Table: see text]
Effects of baseline C-reactive protein on prognosis in patients with metastatic non-clear cell renal cell carcinoma treated with systemic therapy.
Authors: Mizuno Ryuichi , Yasumizu Yota , Tanaka Nobuyuki , Matsumoto Kazuhiro , Oya Mototsugu 
Published: March 2023

680 Background: With the induction of targeted agents and immune checkpoint inhibitors, treatment strategies for systemic treatment of metastatic renal cell carcinoma (mRCC) have been changed with improved survival. However, those agents were approved based on phase 3 study results designed for clear cell mRCC. For patients with non-clear cell mRCC, those drugs designed for clear cell mRCC have also been used because no validated systemic therapy exists. This retrospective study aimed to identify patients with non-clear cell mRCC who benefit from systemic therapy. Methods: A total of 255 patients with mRCC were reviewed (Institutional review board approval No 2013-0425). Among them, 41 patients who pathologically diagnosed as non-clear cell mRCC and received systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each variable on progression free survival (PFS) and overall survival (OS) were investigated. OS for patients with non-clear cell mRCC was further investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 33.9 months after first line treatment initiation, the median PFS was 3.3 and 19.7 months for non-clear cell and clear cell RCC, respectively (p<0.0001). The median OS was 20.9 and 50.1 months for non-clear cell and clear cell RCC, respectively (p<0.0001). For patients with non-clear cell RCC, univariate analyses revealed duration of first line treatment, baseline C-reactive protein, and International Metastatic RCC Database Consortium (IMDC) risk group (favorable vs intermediate/poor) were significantly correlated with OS, respectively. Multivariate analysis revealed that the duration of first line treatment (HR: 0.997, p=0.027) and the baseline C-reactive protein (HR:1.128, p=0.004) were independent predictors for longer OS in non-clear cell mRCC patients. Conclusions: Systemic therapy for non-clear cell mRCC patients resulted in relatively shorter PFS and OS. A shorter duration of first line treatment and elevated baseline C-reactive protein are correlated with longer OS.