bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined alternating sunitinib and bevacizumab in the management of advanced renal cell carcinoma: A phase I/II trial.
Authors: Bazarbashi Shouki , Alzahrani Ahmed M , Aljubran Ali H , Elshenawy Mahmoud Abdelsatar , Mostafa Gad Ahmed , Maraiki Fatma , Alzannan Noura , Elhassan Tusneem , Badran Ahmed Ali 
Published: March 2023

665 Background: Tyrosine kinase inhibitors remain a corner stone in the management of metastatic clear cell renal cell carcinoma (RCC). The intermittent schedule of sunitinib with 4 weeks on/2 weeks off could result in a rebound angiogenesis and tumor progression in the 2 weeks rest period. We propose the use of bevacizumab to alternate with sunitinib to attain continuous anti-angiogenesis during sunitinib therapy. Methods: This was a phase I/II design. Patients advanced clear cell RCC were recruited. Sunitinib was given as 50 mg daily on 4 weeks on/2 weeks off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. Bevacizumab starting dose was 5 mg/kg and the dose was escalated to 10 mg if no dose limiting toxicity. Primary endpoints were response rate and progression-free survival. Results: Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose limiting toxicity was found on the 5 mg dose level of bevacizumab. One patient achieved complete response and 12 achieved partial response for a response rate of 52%. At a median follow up was 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median progression-free survival was 16.5 months (95% CI 4.1-28.8), and the median overall survival was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity. The commonest grade 3 or 4 toxicity was thrombocytopenia and lymphopenia each occurring at a rate of 32%, followed by hypertension at a rate of 28% followed by fatigue at a rate of 24%. Conclusions: Continuous angiogenesis blockade by adding bevacizumab to sunitinib 4 weeks on and 2 weeks break regimen in advanced RCC produce significant anti-tumor activity with manageable increased toxicity. Clinical trial information: NCT02919371 .
Adjuvant immunotherapy in renal cell carcinoma: A systematic review and meta-analysis of randomized clinical trials.
Authors: Huang Emily , Riveros Carlos , Ranganathan Sanjana , Klaassen Zachary , Rini Brian I. , Wallis Christopher J.D. , Satkunasivam Raj 
Published: March 2023

671 Background: There has been interest in adjuvant immune checkpoint inhibition (ICI) following surgical resection in patients with high-risk renal cell carcinoma (RCC) given high recurrence rates and approvals of ICI in metastatic RCC. The primary objective of this analysis was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with RCC. Methods: This systematic review was performed according to the PRISMA guidelines. The protocol was registered in PROSPERO (CRD42022361599). We searched PubMed, EMBASE, and relevant conference proceedings to identify phase III randomized controlled trials (RCTs) comparing adjuvant ICI versus placebo/observation. The primary outcome of interest was DFS. Results: Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2=64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (HR 0.85, 95% CI 0.69-1.04), there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) or sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). Conclusions: The evidence base to date regarding ICI as adjuvant therapy in RCC is mixed – conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PDL1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.
Impact of number of treatment lines following first-line (1L) immuno-oncology (IO) combination on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Lemelin Audreylie , Ernst Matthew Scott , Wells Connor , Navani Vishal , McGregor Bradley Alexander , Wong Shirley S. , Pal Sumanta Monty , Basappa Naveen S. , Kapoor Anil , Lee Jae-Lyun , Donskov Frede , Li Haoran , Yuasa Takeshi , Chang Rose , Huynh Lynn , Nguyen Catherine , Holub Ashley , Clear Louise , Duh Mei Sheng , Heng Daniel Yick Chin 
Published: March 2023

673 Background: Across the world, treatment of patients with mRCC is heterogeneous with different access to treatment sequences and number of lines of therapy (LOTs) employed. For instance, patients receiving first line (1L) nivolumab+ipilimumab (NIVO+IPI) may be offered second-line (2L) and third line (3L) vascular endothelial growth factor receptor targeted kinase inhibitor (VEGFR-TKI), whereas patients receiving 1L pembrolizumab or avelumab in combination with axitinib (IO+AXI) may only receive one subsequent VEGFR-TKI in 2L. We aimed to examine whether these different treatment strategies impact overall survival (OS). Methods: Adult mRCC patients who received at least three LOTs starting with 1L NIVO+IPI or at least two LOTs starting with 1L IO+AXI from the International Metastatic RCC Database Consortium (IMDC) centers were included. Kaplan-Meier analyses were used to estimate median OS (time from 1L to death). Results were stratified by 1L IMDC prognostic risk. Results: Among 128 patients who received at least three LOTs starting with 1L NIVO+IPI (median age 61 years, 77% White, 77% male, 37% from the US), 14% had favorable, 61% had intermediate, and 26% had poor IMDC risk. The most common 2L treatments following 1L NIVO+IPI were sunitinib (38%), cabozantinib (27%), and pazopanib (20%). Among 104 patients who received at least two LOTs starting with 1L IO+AXI (median age 62 years, 75% White, 67% male, 38% from the US), 28% had favorable, 48% had intermediate, and 25% had poor IMDC risk. The most common 2L treatments following 1L IO+AXI were cabozantinib (57%) and sunitinib (10%). Median OS are presented in the table, which suggested no difference in survival for patients who received at least two LOTs starting with 1L IO+AXI compared to patients who received at least three LOTs starting with 1L NIVO+IPI. Conclusions: Treatment for patients with mRCC varies depending on the 1L regimen chosen and by country. Our results demonstrate that, even with potential guaranteed time bias and IMDC imbalances, there is no statistically significant difference in OS for patients who received at least three LOTs starting with 1L NIVO+IPI and patients who received at least two LOTs starting with 1L IO+AXI, suggesting that selecting effective treatments in 1L resulting in fewer LOTs may have similar clinical outcomes as multiple LOTs. [Table: see text]
Adjuvant pembrolizumab (pembro) for renal cell carcinoma (RCC) across UCLA Integrated Staging System (UISS) risk groups and disease stage: Subgroup analyses from the KEYNOTE-564 study.
Authors: Choueiri Toni K. , Tomczak Piotr , Park Se Hoon , Venugopal Balaji , Ferguson Tom , Symeonides Stefan N. , Hajek Jaroslav , Chang Yen-Hwa , Lee Jae-Lyun , Sarwar Naveed , Thiery-Vuillemin Antoine , Gross-Goupil Marine , Mahave Mauricio , Haas Naomi B. , Sawrycki Piotr , Zhang Tian , Xu Lei , Imai Kentaro , Poehlein Christian Heinrich , Powles Thomas 
Published: March 2023

679 Background: Adjuvant pembro prolonged disease-free survival (DFS) for patients (pts) with RCC at increased risk of recurrence after nephrectomy in the phase 3 KEYNOTE-564 study (NCT03142334). This post hoc exploratory analysis evaluated efficacy of adjuvant pembro in pt subgroups based on UISS and disease stage. Methods: Pts with histologically confirmed clear cell RCC (pT2, Grade [G] 4 or sarcomatoid, N0, M0; pT3 or pT4, any G, N0, M0; any pT, any G, N+, M0; or M1 NED) were randomly assigned 1:1 to receive pembro 200 mg IV or placebo (pbo) every 3 weeks for ≤17 cycles (~1 y). DFS was assessed by investigator. UISS risk groups were derived retrospectively from TNM stage, Fuhrman nuclear grade, and ECOG PS. UISS groups were intermediate risk (pT2, G4, N0, M0; pT3, G1, N0, M0; or pT3, G2-4, N0, M0, ECOG 0), high risk (pT3, G2-4, N0, M0, ECOG PS 1; pT4, any G, N0, M0; or N1, M0), or M1 NED. Other subgroups were evaluated based on disease stage. Results: Baseline characteristics were balanced within subgroups. Median follow-up was 30.1 mo (range 20.8-47.5). Of 994 enrolled pts, most had UISS intermediate risk (n = 732, 73.6%; pembro n = 359; pbo n = 373); 195 pts (19.6%; pembro n = 100; pbo n = 95) had UISS high risk, and 58 pts (5.8%; pembro and pbo n = 29 each) had M1 NED. In the UISS intermediate risk group, the hazard ratio (HR) for DFS was 0.65 (95% CI, 0.48-0.88; 24-mo rates, pembro: 81.5%, pbo: 72.4%). In the UISS high-risk group, HR for DFS was 0.77 (95% CI, 0.49-1.20; 24-mo rates, pembro: 65.0%, pbo: 55.9%). In the M1 NED group, HR for DFS was 0.28 (95% CI, 0.12-0.66; 24-mo rates, pembro: 78.4%, pbo: 37.9%). DFS by disease stage is in the Table. Conclusions: Consistent with the results of the intention-to-treat (ITT) population, adjuvant pembro prolonged DFS compared with pbo for all subgroups. Results of this exploratory analysis further support the use of adjuvant pembro after nephrectomy as standard of care for pts with RCC at increased risk of recurrence. Clinical trial information: NCT03142334 . [Table: see text]
Phase II multi-center study of sintilimab in combination with axitinib in patients with advanced fumarate hydratase-deficient renal cell carcinoma.
Authors: Zhang Xingming , Liu Haoyang , Zhang Yaowen , Zhao Junjie , Chen Yuntian , Sun Guangxi , Sheng Xinan , Wang Yongquan , Gong Kan , Liu Xiaodong , Huang Rui , Wei Qiang , Li Xiang , Liu Jiyan , Shen Pengfei , Chen Ni , Yao Jin , Liu Zhenhua , Zeng Hao 
Published: March 2023

685 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly aggressive cancer mainly caused by germline or somatic aberrant of FH gene. Unfortunately, there are no standard treatment. Here we report the preliminary results of a phase II study investigating the efficacy and safety of sintilimab in combination with axitinib in patients with FH-RCC. Methods: Patients were treated at mutli-center in hospitals of the republic of China. Eligibility criteria included age ≥ 18 years and newly diagnosed as FH-RCC by FH immunohistochemistry and next-generation sequencing or multiplex ligation-dependent probe amplification. Patients received sintilimab (intravenous injection, every 3 week) in combination with axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary end point was objective response rate (ORR; RECIST v1.1). This study is registered with ClinicalTrials.gov, NCT04387500. Results: Between July 2021 and October 2022, 21 patients were enrolled. At this preliminary analysis (data cutoff, October, 2022), median follow-up was 9 months (0.9-15.2 months). Nineteen patients were available for efficacy assessment. Confirmed complete response rate was 15.8% (3/19), ORR was 63.1% (12/19). Disease-controlled rate (DCR) was 89.4% (17/19). The median of progression-free survival (PFS) was not reached, with a high 12-month PFS rate of 72.3%. All grade and ≥ 3 treatment-emergent adverse events occurred in 95% (20/21) and 23.8% (5/21), respectively. Conclusions: Sintilimab in combination with Axitinib had a manageable safety profile and achieved a promising tumor response rate in patients with advanced FH-RCC. The trial is an ongoing study, with a total of planned 41 patients from 8 sites. The study start date was June 2, 2021. Clinical trial information: NCT04387500 .
The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma.
Authors: Dai Jindong , Hu Xu , Zhang Haoran , Zhang Yaowen , Zhang Xingming , Sun Guangxi , Zeng Hao , Shen Pengfei , Liu Zhenhua 
Published: March 2023

686 Background: A subset of patients with metastatic clear cell renal cell carcinoma (ccRCC) might benefit from metastasectomy, while those with metastatic non-clear cell carcinoma (non-ccRCC) might be potential candidates for metastasectomy remains unclear. Methods: From the metastatic RCC database of West China Hospital, a total of 114 patients with confirmed metastatic non-ccRCC were identified. Patients were divided into groups by systemic therapy plus nephrectomy and metastasectomy or systemic therapy plus nephrectomy alone. Clinical outcomes included overall survival (OS) and progression-free survival (PFS). The potential factors predicting clinical benefits from cytoreductive surgery (including nephrectomy and metastasectomy) were also explored using Cox regression and Kaplan-Meier analyses. Results: 100 patients received nephrectomy alone and another 14 patients who underwent nephrectomy and metastasectomy were enrolled in the present study. In addition, total of 19 metastatic lesions were dissected among 14 patients. Compare to patients with systemic therapy plus nephrectomy alone, systemic therapy plus nephrectomy and metastasectomy could significantly improve the progression-free survival (PFS) (27.1 vs. 12.4 months, HR: 0.352, 95%CI: 0.108-1.143, p=0.046). For patients with synchronous metastasis, only systemic therapy plus nephrectomy alone showed an advantage in the PFS (HR: 0.363, 95%CI: 0.179-0.737, P=0.005) and OS (HR: 0.172, 95%CI: 0.080-0.371, P<0.001). And for patients with metachronous metastasis, systemic therapy plus nephrectomy and metastasectomy could improve the PFS (HR: 0.124, 95%CI: 0.016-0.956, P=0.045) and OS (HR: 0.250, 95%CI: 0.059-0.971, P=0.043). None of the patients had any serious (Clavien-Dindo Classification ≥III grade) perioperative complications. Conclusions: Metastasectomy could be one of the optional treatments for patients with metastatic non-ccRCC. For patients with synchronous metastases, only nephrectomy could improve prognosis; however, patients with metachronous metastases might get benefit from metastasectomy.
Impact of sarcomatoid features on treatment outcomes in metastatic clear cell renal cell carcinoma treated with first-line immunotherapy combinations.
Authors: Fitzgerald Kelly N. , Duzgol Cihan , Knezevic Andrea , Shapnik Natalie , Kotecha Ritesh R , Aggen David H , Carlo Maria Isabel , Shah Neil J. , Voss Martin H , Feldman Darren R. , Motzer Robert J. , Lee Chung-Han 
Published: March 2023

687 Background: The presence of sarcomatoid features in clear cell renal cell carcinoma (cRCC) has historically been associated with poor response to tyrosine kinase inhibitor (TKI) monotherapy and poor overall survival; however, immunotherapy (IO) combination therapies have shown more promise in treating this variant. Front-line anti-PD-1 based IO combinations used in ccRCC include ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted TKI with a PD-1 inhibitor (TKI/IO). Here, we compare progression-free survival after therapeutic 1st-line (PFS) and 2nd-line (PFS-2) in patients who received IO/IO vs TKI/IO combinations as 1st line treatment for metastatic ccRCC, and test whether the treatment effects differ based on the presence or absence of sarcomatoid dedifferentiation. Methods: A retrospective analysis was performed on patients with ccRCC initiating 1st line combination IO at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020. Patient cohorts were defined by 1st line treatment type: IO/IO or TKI/IO. PFS and PFS-2 were estimated using the Kaplan-Meier method. Restricted mean survival time (RMST) was calculated for PFS and PFS-2 in each 1st line treatment group and modelled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of treatment effect among subgroups, sarcomatoid features (presence/absence) is included in the models and an interaction test is performed. Results: Ninety patients (28 sarcomatoid) received 1st line IO/IO and 83 (17 sarcomatoid) received 1st line TKI/IO. Median PFS time is 6.8 months (95% CI: 4.5, 12.2) for IO/IO and 21 months (95% CI: 15, 25) for TKI/IO, p=0.009. After adjusting for IMDC risk, and after 48 months of follow-up, RMST for PFS was 10 months for IO/IO and 24 months for TKI/IO (p=0.02) and RMST for PFS-2 was 20 months for IO/IO and 23 months for TKI/IO (p=0.24). In the RMST model, the interaction between treatment group and presence or absence of sarcomatoid features is not significant for PFS (0.95) or PFS-2 (0.29). Conclusions: For ccRCC patients treated with 1st line IO/IO or TKI/IO, adjusted RMST for PFS was significantly longer for the TKI/IO group, but there was no statistically significant difference in adjusted RMST for PFS-2. Anti-PD-1-based therapy is an effective approach to treating ccRCC with sarcomatoid features. [Table: see text]
Outcomes of partial nephrectomy for non-metastatic cT2 renal tumors: Results from a Canadian multi-institutional collaborative.
Authors: Bansal Rahul K. , Cassim Raees , Sun Ryan , Mallick Ranjeeta , Finelli Antonio , Tanguay Simon , Drachenberg Darrel E , Pouliot Frederic , Lavallee Luke , So Alan I. , Rendon Ricardo A. , Wood Lori , Kapoor Anil , Lalani Aly-Khan A. , Basappa Naveen S. , Bhindi Bimal , Dean Lucas W. , Bjarnason Georg A. , Breau Rodney H. 
Published: March 2023

690 Background: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. Methods: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/- 1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. Results: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 2] vs 8.4 [IQR 2.4], p=0.05), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p<0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.9). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37), lower risk of distant metastasis (HR 0.36, 95%CI 0.15-0.88), better cancer specific survival (HR 0.56, 95%CI 0.18-1.78) and overall survival (HR 0.36, 95%CI 0.11-1.19) and as compared to RN. At 6 months and beyond after surgery, PN patients had less decline in eGFR than RN patients (-16.6 [SD 21.1] vs -24.4[SD 16.2], p=0.0002). Complications rates between PN and RN were (18% vs 9%, p=0.057). Conclusions: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with slightly higher risk of peri-operative complications, better preservation of renal function, and higher risk of local recurrence. The lower risk of distant metastasis and death was likely from residual confounding unaccounted for in the individual patient match. [Table: see text]
Predictive biomarkers for the oncolytic virus, JX-594, through the HIF-dependent interferon beta pathway in metastatic renal cell carcinoma.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Lee Namhee , Oh Keunhee , Ham Won Sik 
Published: March 2023

710 Background: Although combination approaches with an immunotherapy are established as the first-line setting in metastatic renal cell carcinoma (mRCC), immunotherapy are only efficacious for a subset of patients. Our group has been working on improving the benefit of immunotherapy using JX-594 (pexastimogene devacirepvec, Pexa-vec) in mRCC. The purpose of this study is to develop predictive biomarker for JX-594 in metastatic clear cell RCC (ccRCC). Methods: Using ccRCC cell lines representative of each four mutations (786-O (VHL mutation), Caki-2 (VHL and PBRM1 mutation), A-498 (VHL and SETD2 mutation), and 769-P (VHL and BAP1 mutation)), four cell line-derived xenograft (CDX) mouse models have been developed. 2-10x106 tumor cells were subcutaneously injected into the right flank of wild-type BALB/c nude mice. When tumors reached >50 mm3, mice were treated with either PBS or 1x107 plaque-forming units of JX-594 by intratumoral injection in day 0, 3, and 6. Interferon beta (IFN-β) expression were measured with qRT-PCR after the JX-594 treatment in 786-O CDX model. Results: All CDX models demonstrated significant decrease in tumor size by the JX-594 compared to control. Most rapid tumor growth was observed in BAP1-deficient xenografts while PBRM1-deficient xenografts demonstrated the slowest growth among four xenografts. The decrease of tumor volume by the JX-594 was most pronounced in BAP1-deficient tumors compared to VHL, PBRM1, and SETD2 mutation tumors. Even after adjusting the relative differences of tumor growth rate in each model, xenografts with BAP1 loss were still associated with significantly better response to JX-594. IFN-β expression significantly decreased in BAP1-deficient tumors compared to other tumors, while the expression level was recovered dramatically after JX-594. Conclusions: BAP1-deficient tumors demonstrated rapid tumor progression while they were most significantly reduced after JX-594. BAP1-deificient tumors had decreased levels of IFN-β expression while it was most dramatically recovered after JX-594, suggesting the mechanism of JX-594 through the HIF-dependent interferon beta induction. This is the first study to elucidate the potential of BAP1 as predictive biomarker for JX-594 and its underlying mechanisms.