bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II randomized double blind trial of axitinib (Axi) +/- PF-04518600, an OX40 antibody (PFOX) after PD1/PDL1 antibody (IO) therapy (Tx) in metastatic renal cell carcinoma (mRCC).
Authors: Sadeghi Sarmad , Parikh Rahul Atul , Tsao-Wei Denice D. , Groshen Susan G. , Li Ming , Appleman Leonard Joseph , Tagawa Scott T. , Nanus David M. , Molina Ana M. , Kefauver Cheryl , Ornstein Moshe Chaim , Rini Brian I. , Dreicer Robert , Quinn David I. , Lara Primo "Lucky" N. 
Published: June 2022

4529 Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T cells. PFOX is an agonist for OX40. We hypothesized that PFOX + the VEGFR inhibitor Axi would improve outcomes vs. Axi in patients (pts) with mRCC after IO Tx. Methods: Pts with predominantly clear cell mRCC were stratified for MSKCC risk groups then randomized 1:1 to Axi 5mg po bid plus PFOX 0.3mg/kg iv (Arm 1) or placebo (PL) iv (Arm 2) on Day 1 of a 2-week cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) per RECIST v1.1, and safety/tolerability. A prespecified interim analysis (IA) tested PFS at a 1-sided P < 0.02 when ≥ 33 events were observed. Results: Between February 2018 and October 2021 a total of 59 pts were randomly assigned and treated with Axi+PFOX (N = 29) or Axi+PL (N = 30). Pt and disease characteristics are summarized in the table. As of October 2021, 38 PFS events had occurred, 19 on each arm. The IA rejected the hypothesis of added efficacy for PFOX with a p of 0.0089. Subsequently the study was closed to new accrual. At a median follow up of 13.4 mo, median PFS was 13.1 (6-15.8) months (mo) for Arm 1 and 8.5 (5.5-11) mo for Arm 2 (HR = 0.85 [95% CI: 0.45-1.60] p = 0.61). After adjusting by MSKCC risk group and prior lines of Tx, HR = 0.74 [95% CI: 0.38-1.46] p = 0.39. Median OS was not reached (adjusted HR = 0.71 [95% CI: 0.24-2.12] p = 0.54). ORR Arm 1: 31% PR, 52% SD, 14% PD, and Arm 2: 37% PR, 50% SD, 13% PD. Median DOR 9.1 (3.3-23.9) mo for Arm 1, and 7.5 (1.8-32.7) mo. for Arm 2. Rates of any grade Tx related adverse events (TRAEs; 93% vs 100%), including grade 3 or 4 TRAEs (66% vs 47%), in Arm 1 and Arm 2, respectively. 4 pts discontinued Tx due to TRAE, 3 in Arm 1 (1 grade 3 hypertension, 1 grade 2 stroke, 1 grade 3 bullous dermatitis) and 1 in Arm 2 (grade 4 ALT elevation). The most common TRAEs were diarrhea 52%, hypertension 52%, fatigue 41%, nausea 41% for Arm 1 and hypertension 67%, diarrhea 53%, fatigue 50% for Arm 2. Conclusions: In IO-pretreated mRCC pts, Axi + PFOX did not improve outcomes compared to Axi alone. Clinical trial information: NCT03092856. [Table: see text]
Impact of steroid use among patients with renal cell carcinoma (RCC) who develop immune-related adverse events (irAE).
Authors: Zang Peter , Resnick Karen , Larsen Travis , Ye Shirley , Choi April , Yu Xiao , Brady Kevin , Tulpule Varsha , D'souza Anishka , In Gino Kim 
Published: June 2022

4530 Background: Immune checkpoint inhibitor (ICI) therapy has become a standard therapy in the treatment of advanced renal cell carcinomas (RCC). This has led to a proportional increase in the frequency of immune related adverse events (irAE), however. While increasing evidence suggests that irAE may be correlated with benefit from ICI, the impact of steroids to mitigate irAE’s remains unclear. Methods: We analyzed records of patients with RCC treated with an ICI at the USC Norris Comprehensive Cancer Center, Keck Hospital of USC, and LAC+USC Hospital from 2015-2021. Statistical analysis was performed using R. The Kaplan-Meier model was used to calculate progression free survival (PFS) and overall survival (OS). A log-rank test was used to determine if differences in PFS/OS were statistically significant. Results: Out of a total 841 cancer patients treated with ICI, 107 RCC patients were identified. The median age was 60 (range 20-91). The two most common represented ethnicities were 48 Hispanic/Latino (44.9%) and 37 Caucasian (34.6%). The patient population include 64 male patients (59.8%) versus 43 female patients (40.2%). Most had metastatic disease (74.8%) versus local disease (25.2%), and most patients (80.4%) received ICI therapy as initial therapy. Only 6 patients (5.6%) were given combination ICI therapy. The three most common systems affected by irAE were endocrine (18.7%), dermatologic (16.8%), and renal (14.0%). Of the irAE that occurred, 21.5% were categorized as CTCAE grade III or higher. The median PFS of the irAE group was 51.8 months (95% CI 10.0 – 51.8) versus 11.2 months (95% CI 2.7 – 13.8) in the no irAE group. The median OS of the irAE group was 55.0 months (95% CI 23.9 – 55.0) versus 15.6 months (95% CI 13.5 – 23.5). The occurrence of irAE was associated with both statistically significantly increased PFS (p = 0.02) and OS (p = 0.007). The median PFS of patients receiving steroids to treat irAE was 6.5 months (95% CI 3.9 – 9.2) compared to 12.5 months (95% CI 10.4 – 12.5) in the group with irAE who did not receive steroids. The use of steroids was associated with statistically significant worse PFS (p = 0.04) and worse OS but not at statistical significance (p = 0.2). Conclusions: The occurrence of irAE was associated with improved PFS and OS in RCC patients treated with ICI. Furthermore, the use of steroids among patients with irAE was associated with worsened PFS, but not OS. Although steroids should still be used as clinically indicated for the management of irAE, clinicians should be judicious as they may blunt tumor response to ICI treatment.
The prognostic value of peripheral blood inflammatory indices early variation in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (Δ-Meet-URO analysis).
Authors: Rebuzzi Sara Elena , Signori Alessio , Buti Sebastiano , Banna Giuseppe Luigi L. , Stellato Marco , Santini Daniele , Basso Umberto , De Giorgi Ugo , Chiellino Silvia , Salfi Alessia , Zucali Paolo Andrea , Masini Cristina , Naglieri Emanuele , Procopio Giuseppe , Milella Michele , Boccardo Francesco , Fratino Lucia , Pipitone Stefania , Porta Camillo , Fornarini Giuseppe ,   Meet-URO: Italian Network For Research In Urologic-Oncology
Published: June 2022

4534 Background: Immunotherapy has improved the treatment landscape of mRCC pts and identifying biomarkers for patients’ selection is clinically needed. Inflammatory indices from peripheral blood showed a prognostic value in different tumors and therapies, including immunotherapy. These biomarkers are inexpensive and readily available in clinical practice. We aimed to assess the prognostic role of the dynamic evaluation of these indices in immunotherapy-naïve pretreated mRCC pts. Methods: The Meet-URO 15 multicentric retrospective study enrolled 571 pretreated mRCC pts receiving nivolumab. The Δ-Meet-URO was a secondary analysis on the early variation through the first four cycles of therapy compared with baseline (difference, delta - Δ) of white blood cells, platelets and inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, platelets x NLR), their comparison with baseline values and correlation with treatment response, overall (OS) and progression-free survival (PFS). The baseline and Δ cut-offs were identified by ROC curves for OS. Results: The analysis was performed on 422 mRCC pts (74% of the entire cohort). Patients with ΔNeutrophils < 730 at 2nd, 3rd and 4th cycles were more responders ( p < 0.001, p = 0.003 and p < 0.001) with longer mPFS (11 vs 6.1 months, p = 0.033) and mOS (46.9 vs 20.8 months, p = 0.046) compared to ΔNeutrophils ≥ 730. There was a significant interaction between baseline and ΔNeutrophils on PFS ( p = 0.047). Pts with baseline neutrophils ≥ 4330/mm3 had longer mPFS when ΔNeutrophils < 730 ( p = 0.002), whilst no difference was observed in those pts with baseline neutrophils < 4330/mm3 according to ΔNeutrophils ( p = 0.46). Similar non-significant trends were observed in mOS. Patients with ΔNLR < 0.5 at 3rd and 4th cycles were more responders ( p = 0.004 and p = 0.001, respectively) with doubled mPFS (12.1 vs 6.4 months, p = 0.007) and mOS (46.9 vs 21.7 months, p = 0.062) compared to ΔNLR ≥ 0.5. No significant interaction between baseline NLR and ΔNLR was observed in PFS and OS, suggesting a similar association between ΔNLR and PFS or OS, regardless of the baseline NLR cut-off of 3.2. The multivariable analyses confirmed all these results. Conclusions: The early assessment of NLR and neutrophils variations during immunotherapy for mRCC pts is a promising, affordable and non-invasive prognostic tool. Prospective and external validation analyses are warranted.
The prognostic role of nephrectomy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with immunotherapy according to the novel prognostic Meet-URO score: Subanalysis of the Meet-URO 15 study.
Authors: Rebuzzi Sara Elena , Signori Alessio , Banna Giuseppe Luigi L. , Buti Sebastiano , Rescigno Pasquale , Gemelli Maria , Panni Stefano , Massari Francesco , Sorarù Mariella , Santoni Matteo , Cortellini Alessio , Prati Veronica , Soto Parra Hector Josè , Atzori Francesco , Di Napoli Marilena , Caffo Orazio , Messina Marco , Morelli Franco , Prati Giuseppe , Fornarini Giuseppe ,   Meet-URO: Italian Network For Research In Urologic-Oncology
Published: June 2022

4535 Background: Most of mRCC pts with favorable and intermediate prognosis, according to the IMDC classification, are offered a nephrectomy. However, in the immunotherapy era, the role of nephrectomy is still unclear. In the Meet-URO 15 study we reported the higher prognostic accuracy of the Meet-URO score compared to the IMDC score, by the addition of the neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases to the IMDC score, identifying five categories with progressively worse prognosis. For this reason, we aimed to explore the prognostic impact of the previous nephrectomy (PN) on mRCC pts receiving immunotherapy and according to the Meet-URO score groups. Methods: The Meet-URO 15 study was a multicentric retrospective analysis on 571 pretreated mRCC pts receiving nivolumab. Univariable analysis of the correlation between PN and overall survival (OS) and multivariate analysis adjusted for IMDC score, therapy line, NLR and metastatic sites were performed. The interaction of PN with the Meet-URO prognostic groups was then evaluated. Results: 503/571 pts (88%) underwent PN. A reduced risk of death (HR = 0.44; 95% CI: 0.32-0.60; p< 0.001) and higher mOS and OS rate were observed in pts with PN than without (mOS: 36 vs 13 monhts; 1-year-OS 72% vs 52% and 2-year-OS 57% vs 24%, respectively). The reduced risk of death for pts who underwent PN was confirmed at the multivariate analysis (HR = 0.69; 95% CI: 0.49-0.97; p= 0.032). The percentage of pts receiving PN progressively reduced through the five Meet-URO prognostic groups (PN: group 1: 98%, group 2: 95%, group 3: 84%, group 4: 79%, group 5: 59%). No significant interaction was observed between the PN and Meet-URO score when all the five groups were considered ( p= 0.17). A significant interaction was observed when the Meet-URO groups 1,2 and 3 were taken together (HR = 0.40; 95% CI: 0.25-0.63; p< 0.001), highlighting the significant protective role of the PN on OS for these three groups. For the Meet-URO groups 4 and 5, the interaction was indeed not significant (HR = 0.81; 95% CI: 0.51-1.30; p= 0.39). Conclusions: PN has a favourable prognostic impact on pretreated mRCC pts receiving immunotherapy. This benefit may be limited to mRCC pts with more favorable diseases as belonging to Meet-URO prognostic groups 1, 2 and 3. Further analysis of the type of PN (i.e., radical vs cytoreductive) is ongoing and confirmatory prospective evaluations are warranted.
Real-world treatment patterns in von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC): Costs of tumor reduction procedures and their complications.
Authors: Sundaram Murali , Song Yan , Freimark Jonathan , Berman Richard , Nguyen Ha , Signorovitch James , Jonasch Eric 
Published: June 2022

4539 Background: VHL disease is an inherited condition associated with tumors in multiple organs; RCC may affect up to 70% of patients with VHL. Patients often need many tumor reduction procedures (TRP) to manage renal neoplasms. This study evaluated TRP treatment patterns, costs, and complications among patients with VHL-RCC. Methods: Using an algorithm based on VHL manifestations, patients with VHL were identified from the Optum Clinformatics claims database. Patients were then selected with a prior RCC diagnosis. Minimum continuous enrollment of 12 months before and 3 months after first observed RCC diagnosis was required. TRPs for RCC included nephrectomy, renal ablation, and cryotherapy. Time to first TRP from initial observed RCC diagnosis was estimated using Kaplan-Meier analysis. Mean hospitalization costs per TRP type were estimated. Costs associated with TRP complications were estimated via linear regression; the explanatory variable was the presence of a given complication. Short-term complications were evaluated for 4 weeks post-TRP; long-term ones were evaluated over 6 months. Renal function was evaluated using chronic kidney disease (CKD) stages before and after TRPs, using diagnosis codes and eGFR lab values. Results: 160 patients with VHL-RCC were identified; mean follow-up time was 34.1 months. 115 (71.8%) patients incurred ≥1 RCC TRP over their study period. 68.4% had a TRP in the first year after RCC diagnosis and 76.5% had TRPs by year 5. Of the 125 observed TRPs, 97 (77.6%) were nephrectomies and 28 (22.4%) were ablation/cryotherapy. The mean costs for nephrectomy were nominally higher vs. ablation/cryotherapy ($29,313 vs. $18,290). The most common short-term complications were respiratory related (20.8%) and vascular injury/anemia (13.6%). The most common long-term complications were CKD stage 1-5 (24.0%) and end-stage renal disease (chronic dialysis dependence) (4.0%). The most expensive complications were related to impaired renal function: acute renal failure ($21,013 over 4 weeks), CKD ($26,032 over 6 months) and end stage renal disease ($65,338 over 6 months). At baseline, the proportion of patients with a diagnosis of CKD ≥ stage 3 was similar between patients who had TRPs (n = 115) and those who did not have TRPs (n = 45): 24.3% and 24.4%, respectively. After the first TRP, the proportion of patients with CKD ≥ stage 3 increased from 24.3% to 41.7%. Conclusions: Patients with VHL-RCC incur a significant clinical and economic burden related to TRPs for managing their renal tumors. This is in addition to the burden that VHL-RCC patients incur from the management of other VHL tumors. This study underscores the need for novel effective therapies to prevent or delay the recurrence of VHL-related renal neoplasms to mitigate the burden of morbidity and long-term medical management related to VHL.
Preventing adverse events in patients with renal cell carcinoma treated with doublet immunotherapy using fecal microbiota transplantation (FMT): Initial results from perform a phase I study.
Authors: Fernandes Ricardo , Parvathy Seema Nair , Ernst D. Scott , Haeryfar Mansour , Burton Jeremy , Silverman Michael , Maleki Saman 
Published: June 2022

4553 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved with the advent of either dual immune checkpoint inhibition (ICI) or in combination with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor. Gut microbiota plays a central role in developing local and systemic immunity, with potential influence in controlling anti-tumor immune response in cancer patients treated with ICI. We hypothesize that FMT from healthy donors given before immunotherapy will establish a more resilient gut microbiota, reducing the treatment toxicity and improving response to therapy. PERFORM is an ongoing phase I study evaluating the safety of FMT and immunotherapy combination in first-line (1L) mRCC, and assessing whether FMT will prevent or mitigate immune-related adverse events (irAE). Methods: Eligible patients with untreated mRCC received a full dose and 2 supportive FMT procedures prior to the first 3 cycles of doublet ICI or in combination with VEGF-TKI. Primary endpoint is the feasibility and safety of combining FMT using intestinal bacteria existing in the stool of healthy donors with immunotherapy. Secondary endpoints include incidence of irAEs, objective response rate (ORR; RECIST v1.1), and changes in pts microbiome and immune profile post-FMT. We included a preliminary analysis of the first 10 patients. Results: 10 patients received FMT and doublet ICI therapy (10 ongoing). 8/10 (80%) patients were male. Median Age: 59.5 (53-71) years-old. Most common histology was clear cell RCC (90%) and all patients had an intermediate or poor-risk disease. 93.3% of planned FMT were administered. No dose-limiting toxicities due to FMT were observed. Median (range) follow-up was 5.5 (1–22) months. 4 patients (40%) discontinued treatment due to irAEs: colitis (n = 3), arthritis (n = 1). IrAEs were reported in 8 (80%) patients, including diarrhea (n = 6; 60%) and skin rash (n = 2, 20%). Grade 3/4 AEs were experienced by 6 (60%) patients, including colitis (n = 4, 40%). ORR was confirmed in 4/9 patients (44%; 95% CI, 30–60); 1 (11%) partial response. Microbiota and immune analysis data to be presented. Conclusions: The role of microbiome modification in preventing immune-related toxicities by adding FMT to ICI therapy was associated with a safety profile in unselected 1L mRCC and promising clinical efficacy data. Further prospective studies to examine the changes in the immune and microbiota profiles to determine biomarkers related to healthy outcomes/less frequent toxicities in patients receiving immunotherapy are warranted. Clinical trial information: NCT04163289.
Distinct outcomes in Hispanic/Latinx and non-Hispanic/Latinx patients with metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab plus nivolumab (ipi/nivo).
Authors: Ali Sana , Leong Sally , Meza Luis A , Dizman Nazli , Zengin Zeynep Busra , Kim Tane , Pak Youngju , Onyshchenko Mykola , Pal Sumanta K. , Chehrazi-Raffle Alex 
Published: June 2022

4554 Background: Subgroup analyses have reported differences in clinical outcomes by ethnicity in patients (pts) receiving immune checkpoint inhibitors (Cheng et al Ann Oncol 2019; Peravali et al World J Clin Oncol 2021). We sought to compare real-world outcomes between Hispanic/Latinx and non-Hispanic/Latinx mRCC pts treated with first-line ipi/nivo within a safety-net healthcare system and at a tertiary care center in Southern California. Methods: We performed a retrospective analysis of mRCC pts who received ipi/nivo within the Los Angeles County Department of Health Services (a safety-net healthcare system) and the City of Hope Comprehensive Cancer Center (a tertiary oncology center) between Jan 1, 2015 and Dec 31, 2021. Pts were identified using institutional databases and clinical data were compiled from electronic health records. Pts with pathologic diagnosis of stage IV mRCC, age > 18 years and receipt of ipi/nivo as first-line therapy were included. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. Results: Of 96 pts, 67 (70%) were male, 90 (94%) had clear-cell histology, and 89 (93%) had intermediate/poor IMDC risk. Forty-two pts (44%) were Hispanic/Latinx while the remainder were non-Hispanic/Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (52%) and 46 (48%) pts received their care at a tertiary care center and within a safety-net healthcare system, respectively. Median age, IMDC risk classification, BMI, and number of comorbidities were similar between both groups. Pooled analysis by ethnicity revealed significantly shorter PFS in Hispanic/Latinx vs non-Hispanic/Latinx pts (HR 1.60, 95% CI 1.04-2.48, p = 0.03). At 12 months, 19% of Hispanic/Latinx pts (95% CI, 9-32) and 35% of non-Hispanic/Latinx pts (95% CI, 23-48) were alive and progression-free. There was no difference in PFS between pts at the safety-net hospital system vs tertiary care center (HR 1.32, 95% CI 0.87-2.02, p = 0.19). Conclusions: Our real-world analysis of mRCC pts demonstrated poorer outcomes with ipi/nivo in Hispanic/Latinx pts. We are currently interrogating multiple social determinants of health that may contribute to these concerning disparities.
A robust, trial-agnostic gene signature for response to tyrosine kinase inhibition in ccRRCC.
Authors: Khaleel Sari Safaa , Liu Minwei , Kuo Fengshen , Kotecha Ritesh , Lee Chung-Han , Voss Martin H , Motzer Robert J. , Hakimi A. Ari , Reznik Eduard 
Published: June 2022

4558 Background: Combination systemic therapies (ST) including immunotherapy (IO) and Tyrosine Kinase Inhibitors (TKI) have become the standard of care for management of metastatic clear cell carcinoma (ccRCC). Several expression (GE) signatures have been reported to predict TKI response with the aim of identifying the optimal ST regimen (IO/IO or IO/TKI) per patient. However, these gene signatures were developed and evaluated using data from individual trials with clinically distinct patient cohorts, fundamentally impeding their general application to diverse and heterogeneous patient populations. We therefore sought to identify genes consistently and directly associated with progression-free survival (PFS) with TKI ST across several trials. Methods: We applied a stratified, weighted concordance model to identify genes consistently demonstrating statistically significant association with PFS in the sunitinib TKI arm in four large randomized controlled trials (RCTs) of ST in ST-naïve ccRCC patients: COMPARZ (Motzer et al, 2013), Checkmate 214 (Motzer et al, 2018), IMmotion 151 (Rini et al, 2019), and Javelin 101 (Motzer et al, 2019). Concordant genes with Benjamini-Hochberg adjusted p-value (pAdj) ≤ 0.01 were selected. Of these, genes significantly associated with PFS on Cox proportional hazard regression (pAdj ≤ 0.05) in at least 3 of the 4 datasets were selected. Ontologic process and pathway enrichment analyses (OPPEA) against several ontologic databases were peformed using Metascape (Zhou et al, 2019). Results: We identified 2,794 statistically significant genes demonstrating concordant association with PFS across all 4 datasets (1087 patients); 71 genes were significantly associated with PFS on univariate post-hoc analysis in ≥3 of the datasets. OPPEA of these results identified significant enrichment in genes associated with cell cycle, cell division, and VEGFA-VEGFR2 pathways (Table 1). Although 5 genes in our set overlapped with published angiogenesis GES, the majority of these genes constitute entirely novel transcriptomic correlates of response to sunitinib. Conclusions: We developed a robust meta-gene signature consisting of genes directly and consistently associated with TKI response using data from several clinical trials. This gene signature is readily applicable to heterogeneous patient populations treated with anti-VEGF therapies. [Table: see text]