bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC).
Authors: Shah Neil J. , Campbell Matthew T , Mao Shifeng S. , Ornstein Moshe Chaim , Haas Naomi B. , Gao Xin , Hammers Hans J. , Keshava-Prasad Holavanahalli , Yan Hongxia , Esquibel Vanessa , Geller Robert B. , Beckermann Katy 
Published: March 2023

666 Background: Activation of the GAS6/AXL pathway promotes tumor cell proliferation; high levels of GAS6 and AXL have been associated with drug resistance and decreased survival. Batiraxcept is an ultra-high affinity decoy protein that captures GAS6, preventing it from activating AXL signaling. Serum soluble AXL (sAXL)/GAS6 ratio correlates with response to batiraxcept in advanced ovarian cancer. Batiraxcept in combination with cabozantinib is being evaluated in patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) in this study. Prior studies of cabozantinib in similar pt populations have shown an overall response rate (ORR) ranging from 15 – 32.5% and progression-free survival (PFS) from 3.7-7.2 months (mo). Methods: Key eligibility criteria include previously treated ccRCC pts, excluding prior cabozantinib. Objectives were to determine the safety of batiraxcept plus cabozantinib 60 mg, the recommended phase 2 dose (RP2D), ORR, PFS, duration of response. Correlative endpoints included assessment of baseline serum sAXL/GAS6 with ORR and PFS. Results: In Phase 1b (P1b), 26 pts received at least one dose of batiraxcept with cabozantinib (16 pts - 15 mg/kg; 10 pts - 20 mg/kg). Median age was 60 (range 40-81), male 85% (n=22), IMDC intermediate/poor risk 77% (n=20). All pts received prior immuno-oncology (IO) therapy, 54% (n=14) also received VEGF-TKI; 85% (n=22) received 1 to 2 prior lines of therapy (range 1-6). Median follow-up time was 11.6 mo (range 3.7-18). The RP2D is 15 mg/kg. Related adverse events (AE) any grade and grade ≥ 3 were 100% and 39% (n=10), respectively. Cabozantinib dose reductions occurred in 54% (n=14). AEs of special interest were grade 1 or 2 infusion related reactions, 27% (n=7). Batiraxcept was discontinued due to disease progression 62% (n=16) or toxicity 12% (n=3). The table shows P1b efficacy, ORR of 42%, median PFS of 9.3 mo, and DCR of 84%. Twenty (77%) pts had high baseline sAXL/GAS6 levels; ORR was 55% (11/20) with mPFS of 9.3 mo, compared to 0% ORR and mPFS 6.4 mo in the low sAXL/GAS6 pts. Conclusions: Batiraxcept was well tolerated when combined with cabozantinib. No new safety signals were noted. Efficacy for the combination is encouraging compared to historical cabozantinib monotherapy data. Higher GAS6 levels were predictive for treatment response. The P2 accrual is complete and efficacy data are maturing. A P3 trial plans to evaluate the efficacy in ccRCC patients who have progressed on IO-based and VEGF-TKI therapies. Clinical trial information: NCT04300140 . [Table: see text]
A phase II study to evaluate the safety, pharmacodynamics and efficacy of entinostat in combination with nivolumab plus ipilimumab in patients with renal cell carcinoma previously treated with nivolumab plus ipilimumab or nivolumab alone.
Authors: Pili Roberto , Adra Nabil , Logan Theodore F. , Burney Heather , Atkins Michael B. 
Published: March 2023

668 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we opened a Phase II clinical study with the HDAC inhibitor entinostat and the immune check point inhibitors nivolumab (nivo) and ipilimumab (ipi) in clear cell RCC pts previously treated with nivo + ipi or nivo alone. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a dose de-escalation, two stage, phase II clinical trial with a safety lead-in. Due to a funder decision, enrollment was halted after completion of accrual to the safety lead in group. Pts received oral entinostat at a dose of 5 mg (dose level 1) or 3 mg (dose level 2) every 7 days, continuously, with nivo at a dose of 3 mg/kg mg IV every three weeks in combination with ipi at a dose of 1 mg/kg every 3 weeks X 4 doses. Then, nivo 480 mg was continued every 4 weeks. Results: A total of 12 pts with prior nivo+ipi or nivo treatments was enrolled. Dose level 1 (5 pts enrolled) was completed with the following DLTs: thrombocytopenia, nausea and vomiting, pneumonitis. Seven pts were enrolled on dose level 2 which was established as the recommended phase II dose. The most common treatment-related toxicities were fatigue, hypophosphatemia, neutropenia and thrombocytopenia. All were transient. Most of the pts had 2 or more prior treatments. Four pts achieved a partial response, with 3 out 4 pts previously treated with nivo alone (ORR 33%; 95% CI 9.9-65.1). The median PFS was 11.1 months (CI 1.3-26.4). We collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and nivo+ ipi is relatively well tolerated and may be active in pts with RCC. Clinical trial information: NCT03552380 .
Impact of pre-existing anemia and/or packed red blood cell transfusion prior to Radium-223 administration on oncologic outcomes.
Authors: Pierro Michael , Nelson Ariel Ann , Xie John , Jang Albert , Bylow Kathryn A. , Barata Pedro C. , Lawton Colleen Anne , Kilari Deepak 
Published: March 2023

67 Background: Radium-223 (Ra-223), a targeted alpha-emitting radiopharmaceutical approved for the treatment of metastatic prostate cancer (mPC), can cause myelosuppression. In the ALSYMPCA trial 30% of patients developed cytopenias, including 13% with grade 3/4 anemia. Therefore, it is recommended that only men with a hemoglobin ≥10 g/dL, platelet count ≥100,000/mm3, and ANC ≥1,500/mm3 be considered for Ra-223. Since the FDA approval of Ra-223 in 2013, several new treatments have been approved for men with mPC. With the changing therapeutic landscape, we anticipate more patients (pts) will have preexisting cytopenia prior to Ra-223 consideration. Hence, clinicians are increasingly likely to face the dilemma of whether it is safe and efficacious to administer Ra-223 in the setting of Hgb ≤10 with/without RBC transfusion support. Methods: We retrospectively identified pts with mPC treated with Ra-223, including a subset of men with Hgb <10g/dl at the Medical College of Wisconsin and Tulane Cancer Center from 2014 – 2019. Clinical data including demographics, prior cancer treatments, laboratory data, blood product transfusion data, and oncologic outcomes were collected. Survival was estimated using Kaplan-Meier method and statistical analysis was conducted using student’s t-test. Results: Sixty-two pts were identified. Median age at the time of Ra-223 was 75.3 years. Of these, nearly 20% (n=12) had a Hgb <10 g/dL and/or received RBC transfusions to meet “eligibility criteria” prior to beginning Ra-223 treatments. Compared to men who had Hgb >10g/dL, men with Hgb <10g/dL required more RBC transfusions both during and after Ra-223 treatment and had significantly worse oncologic outcomes. No patients experienced treatment delays of more than 1 week. There were no significant differences in the median number of treatments prior to Ra-223, median number of Ra-223 treatments received, platelet count nadir, or ANC nadir. Conclusions: Pre-existing Hgb < 10 g/dl and/or RBC transfusions prior to Ra-223 therapy is associated with worse oncologic outcomes in mPC, suggesting that the benefit of Ra-223 is limited in this subset. A larger sample size is needed to further validate our findings. Multivariable analysis is planned. [Table: see text]
Safety and tolerability of pembrolizumab/axitinib combination in metastatic renal cell carcinoma (mRCC): A multicentric prospective analysis (ProPAXI study).
Authors: Guida Annalisa , Maruzzo Marco , Lai Eleonora , Bimbatti Davide , Pierantoni Francesco , Dionese Michele , Fornarini Giuseppe , Zanardi Elisa , Murianni Veronica , Caserta Claudia , Mosillo Claudia , Calandrella Maria Letizia , Sirgiovanni Grazia , Calabro Fabio , Cerbone Linda , Caffo Orazio , Galli Luca , Bracarda Sergio 
Published: March 2023

688 Background: Pembrolizumab/axitinib (PAXI) combination is an approved option as first-line therapy of mRCC. The aim of this analysis is to evaluate safety profile of PAXI combo in the real-world experience in Italy. Methods: This is a prospective study including patients (pts) diagnosed with mRCC who received PAXI as first-line therapy in recruiting Italian Centers. Safety data about clinically significant adverse events (AEs), defined as AE requiring corticosteroids, hormone replacement, drug delay, discontinuation or dose reduction were collected. Results: Data from 122 pts treated from January 2021 to September 2022 have been analyzed. With a median follow-up of 10 mos (range 0.2 - 21) and treatment interruption in 35 pts (29%), at landmark 6-mos and 12-mos the treatment was ongoing in 76% (95%CI 0.67-0.83) and 66% of pts (95%CI 0.56-0.75) respectively. In 11% of pts a starting dose of Axi <5mg was reported (8% higher starting dose). 2% of pts experienced Axi dose titration while 37% of pts had a dose reduction. Pts completed a mean of 10 (1 - 31) cycles of Pembro. Toxicity led to treatment discontinuation in 20% (7/35) of cases. Clinically significant AEs occurred in 61% of pts (74), managed with corticosteroids use in 32% (24/74) of pts, hormone replacement (mainly levothyroxine) in 11% (8/74), drug delay in 64% (47/74), discontinuation in 41% (30/74) or dose reduction 18% (13/74). When required, the most used steroid was prednisone (48%) following by dexamethasone (22%), prednisolone (17%), methylprednisolone (13%). Grade 3-4 clinically significant AEs occurred in 25% (18) and 3% (2) of pts respectively, with hepatic injury 33% (6/18) and hypertension 17% (3/18) as the most common reported G3 events. The two G4 AEs reported were pancreatitis and hepatic injury. No treatment-related deaths emerged. In 20% of cases AE were related to Pembro and in 47% of cases to Axi, in 14% to both drugs. In 28% of pts (34/122) a second clinically significant AE occurred, requiring corticosteroids 27% (9/34), hormone replacement 9% (3/34), drug delay 59% (20/34), discontinuation 41% (14/34) or dose reduction 21% (7/34). Grade-3 clinically significant AEs occurred in 29%, with hepatic injury and hypertension (both 3 pts) as the most common events. No grade 4 AEs were reported. The second AE in 21% of cases was related to Pembro and in 59% of cases to Axi, in (9%) to both drugs. Conclusions: PAXI combination had a tolerable safety profile in mRCC, with few high-grade clinically significant AEs, no new toxicities were identified.
Adjuvant immunotherapy in renal cell carcinoma: A living systematic review and network meta-analysis (NMA).
Authors: Sipra Qurat Ul Ain Riaz , Riaz Irbaz Bin , Naqvi Syed Arsalan Ahmed , He Huan , Siddiqi Rabbia , Islam Mahnoor , Asghar Noureen , Ikram Waleed , Xu Wenxin (Vincent) , Singh Parminder , Ho Thai Huu , Bilen Mehmet Asim , Zakharia Yousef , Bryce Alan Haruo 
Published: March 2023

694 Background: The treatment landscape of localized renal cell carcinoma (RCC) is rapidly evolving. Recent trials have demonstrated contrasting efficacy with adjuvant immunotherapy. Therefore, we sought to assess the mixed treatment comparisons among different adjuvant treatment options using updated data from trials and quantified the absolute effect with these treatments stratified by risk categories. Methods: This living network meta-analysis was conducted using the living interactive evidence (LIvE) synthesis framework. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each risk category. Results: This NMA included eight RCTs with 8480 participants and seven unique treatment options. Pembrolizumab (pembro; rank 1) was associated with improved disease-free survival (DFS) when compared to atezolizumab (atezo; rank 6; hazard ratio: 0.68; 0.49;0.93), and nivolumab-ipilimumab (nivoipi; rank 5; 0.68; 0.48-0.97). However, no statistically significant difference was observed between pembro and atezo for overall survival (0.53; 0.28-1.01). Survival data for nivoIpi was not reported. No new statistically significant differences were observed since last update. The absolute benefit of atezo and nivoipi was minimal with higher T and N patients (Table). The results were similar with increasing Leibovich risk scores. Conclusions: Current evidence favors the use of a risk adapted approach when offering adjuvant immunotherapy. Adjuvant pembrolizumab remains a preferred treatment in patients with RCC who underwent nephrectomy. [Table: see text]
Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis.
Authors: Zakharia Yousef , Singer Eric A. , Acharyya Satwik , Garje Rohan , Joshi Monika , Peace David J. , Baladandayuthapani Veera , Laancette Claudia , Kryczek Ilona , Zou Weiping , Alva Ajjai Shivaram 
Published: March 2023

696 Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .
Creatinine to cystatin C ratio and mortality in renal cell carcinoma.
Authors: Schmeusser Benjamin , Ali Adil , Patil Dattatraya H , Midenberg Eric , Nabavizadeh Reza , Ogan Kenneth , Master Viraj A. 
Published: March 2023

697 Background: Creatinine and cystatin C are routinely used to assess renal function. Given creatinine originates from skeletal muscle and cystatin C is produced by nucleated cells, a creatinine to cystatin C ratio (Cr/Cys-C) may positively correlate with muscle mass. Low Cr/Cys-C has also been associated with decreased overall survival (OS) in cancer, including in a combined cohort of genitourinary malignancies. Furthermore, elevated cystatin c has been associated with shorter OS and recurrence free survival (RFS) in renal cell carcinoma (RCC). Cr/Cys-C may be a simple and affordable tool to assist with patient-specific risk stratification. We assess the ability of Cr/Cys-C to predict OS and RFS in patients with RCC. Methods: Retrospective review of a prospectively maintained database identified patients that underwent partial or radical nephrectomy for RCC from 2018-2021. Included patients had preoperative creatinine and cystatin C and 1+ year of follow up. Cr/Cys-C associations with patient/tumor characteristics were determined by generalized chi-square or Fisher’s exact tests for categorical variables and Wilcoxon rank-sum test for continuous variables. Cr/Cys-C ability to predict OS and RFS was analyzed with Kaplan-Meier method and Cox hazards models. Statistical tests were two-sided with type I error set at 0.05. Results: 219 patients were identified. Median age was 64, with most being male (67%). 62% and 29% of patients were white and black, respectively. Median eGFR was 72mL/min/1.73m2. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). 55% were stage T3-T4, with 12% N1 and 16% M1 at time of surgery. 72% had clear cell histology. Low Cr/Cys-C was significantly associated with older age, males, Eastern Cooperative Oncology Group score ≥ 1, radical nephrectomy, T3-T4 stage, and metastasis. Kaplan-Meier curves showed low Cr/Cys-C association with decreased OS (p=0.0003) and RFS (p=0.0094). Cox regression analysis revealed lower Cr/Cys-C as independent predictor of decreased OS (binary HR=3.66, 95% CI 1.2-11.3, p=0.02; continuous HR=0.05, 95% 0.0-0.8, p=0.03) and RFS (binary HR=4.8, 95% CI 1.6-14.6, p=0.006; continuous HR=0.02, 95% 0.0-0.3, p=0.006;Table). Conclusions: Lower Cr/Cys-C may be associated with decreased OS and RFS in patients with RCC. [Table: see text]
Genomic alterations in metastatic renal cell carcinoma (mRCC): Impact on survival and clinical outcomes.
Authors: King Jennifer , Hassoun Rebecca , Althouse Sandra K. , Fausel Christopher A. , Schneider Bryan P. , Logan Theodore F. , Adra Nabil 
Published: March 2023

700 Background: Genomic alterations in RCC can serve as biomarkers for response to therapy. Wild type VHL has shown inferior response to VEGF inhibitors, while patients (pts) with mutated VHL have improved outcomes with immunotherapy (IO)/tyrosine kinase inhibitor (TKI) therapy. We describe the impact of genomic alterations on outcomes and response to front-line therapy. Methods: Pts with mRCC who underwent genomic sequencing between 2015-2022 at Indiana University and were treated with front-line therapy were included. Kaplan-Meier method was used to analyze progression free survival (mPFS) and overall survival (OS) using the log rank test to compare groups. Results: 141 pts were included. Median age was 58yrs (range, 24-81). Tumor histology was 68% clear cell, 10% papillary, 9% unclassified, 1% chromophobe, 1% poorly differentiated, and 9% other. 18% of pts had sarcomatoid features; 13% had rhabdoid. 47% pts had metastasis at diagnosis and 53% at relapse. Metastasis sites were lungs 60%, regional lymph nodes (LNs) 41%, bone 36%, distant LNs 21%, liver 17%, and brain 8%. IMDC risk was 18% good, 48% intermediate, 17% poor, and 17% unknown. Front-line therapy was IO/IO in 21%, IO/TKI in 18%, single-agent TKI in 29%, single-agent IO in 6%, and other in 26%. Genetic alterations included VHL in 50%, PBRM1 in 29%, SETD2 in 23%, BAP1 in 16%, and TP53 in 15%. Median follow-up was 2.74yrs (range 0.1-18.6). Overall mPFS with first line therapy was 1.2yrs (95%CI 0.9-1.5). 2-yr OS was 80% (95%CI: 71-86). For pts with a VHL mutation, mPFS was 1.4yrs (95% CI; 0.9-1.8) compared to 0.9yrs (0.5-1.4) for pts without (p=0.38). 2-yr OS for pts with a VHL mutation was 93% (95% CI: 82-97) vs. 68% (95%CI: 54-78) for pts without (p=0.01). No other mutations impacted overall mPFS or 2-yr OS. mPFS for pts treated with IO/IO was 0.6yrs (95%CI 0.3-0.9) vs. 0.9yrs (95%CI 0.5-1.4) for IO/TKI (p=0.09). 2-yr OS for pts treated with IO/IO was 70% (95% CI 44-85) compared to 94% (95% CI 65-99) for IO/TKI (p=0.29). For pts with SETD2 mutations treated with IO/IO, mPFS was 0.7yrs (95%CI 0.3-1.2) vs. 1.4yrs (95%CI 0.8-1.9) for IO/TKI (p=0.01). For pts with BAP1 mutations treated with IO/IO, mPFS was 0.4yrs (95%CI 0.2-1.2) vs. NE (95%CI 0.2-NE) for IO/TKI (p=0.04). The table outlines outcomes by genomic mutation and therapy. Conclusions: VHL mutation was associated with improved 2-yr OS. Pts with SETD2 and BAP1 mutations treated with IO/TKI had improved mPFS, though no differences in OS. [Table: see text]