bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Updated results from a phase 2 trial.
Authors: Lee Chung-Han , Fitzgerald Kelly N. , Voss Martin H , Carlo Maria Isabel , Knezevic Andrea , Peralta Laura , Chen Ying-Bei , Zucker Mark , Lefkowitz Robert A , Reznik Eduard , Shah Neil J. , Owens Colette Ngozi , McHugh Deaglan Joseph , Aggen David H , Laccetti Andrew Leonard , Kotecha Ritesh R , Feldman Darren R. , Motzer Robert J. 
Published: June 2023

4537 Background: Identification of effective systemic therapy for non-clear cell renal cell carcinoma (RCC) remains a unmet need. We reported a two arm, phase 2 trial of cabozantinib plus nivolumab (CaboNivo) that showed promising efficacy in the treatment arm comprised primarily of papillary and unclassified histology. (Lee, JCO, 40: 2022). Herein, we report updated results with extended follow up. Methods: Patients had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given for both arms. Arm 1 was comprised of papillary, unclassified, or translocation associated RCC; and Arm 2 had chromophobe RCC (closed early for lack of efficacy). The primary endpoint was objective response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Arm 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Correlative analyses by next generation sequencing were performed and will be presented. Results: A total of 40 patients were treated in Arm 1 (data cutoff: Dec 13, 2022). Median follow up time was 34 months (range 20, 51). Twenty-six patients (65%) were previously untreated, and 14 (35%) had 1 prior treatment line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR is 48% (95% CI 31.5–63.9). Median PFS is 13 months (95% CI: 7, 16). Progression-free survival is 51% (95% CI: 34, 65) at 12 months and 23% (95% CI: 11, 37) at 24 months. Median OS is 28 months (95% CI: 23, 43). Overall survival is 70% (95% CI: 53, 82) at 18 months and 44% (95% CI: 28, 60) at 36 months. PFS and OS were similar for previously treated and untreated patients. For responders, median DOR was 17 months (95% CI: 10, 36). Adverse effects of any grade were experienced by 35 patients (88%); grade 3/4 adverse events were experienced by 22 patients (55%). Grade 3/4 AST and ALT elevations were 18% and 23% respectively. Other common grade 3/4 adverse events were hypertension (5, 13%) and pain (4, 10%). Study therapy was discontinued in 9 patients (28%) for toxicity. Conclusions: Updated results with extended follow-up highlight efficacy and safety for CaboNivo in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies. Clinical trial information: NCT03635892 . [Table: see text]
Immunoglobulin as a predictive biomarker for the efficacy of immune checkpoint inhibitor combined with VEGF-TKI in metastatic renal cell carcinoma.
Authors: Cui Honglei , Wu Jie , Qu Wang , Hu Linjun , Zhou Ai-Ping , Shou Jian-Zhong 
Published: June 2023

4543 Background: The combination of immune checkpoint inhibitor (ICI) and vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) is recommended as the first-line treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). However, no effective serum biomarker has been used to predict the therapy response and potential benefits. Abnormal content and changes of immunoglobulin (IG) in serum or cancer tissue may indicate cancer progression and impact the prognosis. We examined the content of serum IG and analyzed the alteration after treatment to assess the efficacy of ICI and VEGF-TKI. Methods: Eighty-four patients with metastatic ccRCC were enrolled in this study. The total serum IG level was determined as the sum of IgA, IgG, and IgM. The data of baseline level and alteration of IG after 3-mo treatment was complete in 72 ccRCC patients. These patients were then divided into two groups based on alteration in their IG levels: the IG-increased group and the IG-decreased group. This study aimed to investigate the correlation between the baseline level of immunoglobulin (IG), changes in its content after 3-mo of treatment, and clinical outcomes. Results: Eighty-four patients were retrospectively enrolled with a median follow-up of 17.3 months (2.5-45.1). The objective response rate (ORR) was 41.67%, and the median overall survival (OS) was 31 months in our cohort. The baseline level of IG was not associated with ORR or OS. However, dynamic alteration in IG level after 3-mo treatment had a significant impact on ORR and OS in ccRCC patients. The ORR was 2.7% in the IG-increased group and 80.0% in the IG-decreased group. The OS was 21.0 months (95% CI 14.0–NA) in the IG-increased group and 48.0 months (28·0–NA) in the IG decreased-group (Hazard ratio [HR] 4.59, p=0·003). Conclusions: The change of serum IG level after 3-mo treatment served as an effective predictor of drug response and the prognosis for metastatic ccRCC patients. Value of serum IG needs to be validated in multi-centers and the mechanism of it should be further investigated.
Genomic determinants of progression-free survival after second line of therapy (PFS-2) for patients on immunotherapy-based combination therapies for advanced clear cell renal cell carcinoma.
Authors: Fitzgerald Kelly N. , Kotecha Ritesh R , Knezevic Andrea , Shapnik Natalie , Aggen David H , Carlo Maria Isabel , Shah Neil J. , Voss Martin H , Feldman Darren R. , Motzer Robert J. , Lee Chung-Han 
Published: June 2023

4545 Background: The role of somatic genomic mutations in predicting outcomes in clear cell renal cell carcinoma (ccRCC) is poorly defined. Both ipilimumab/nivolumab (IO/IO) and several combinations of VEGFR-targeted tyrosine kinase inhibitor (TKI/IO) are preferred first-line treatment options for metastatic ccRCC. The impact of somatic mutations on PFS-2 for IO combination therapies was evaluated in this retrospective analysis. Methods: One-hundred forty-one patients with ccRCC had sequencing with MSK-IMPACT and initiated 1st line combination IO at Memorial Sloan Kettering (MSK) Cancer Center between 1/1/2014 and 12/30/2020. Treatment groups are defined as IO/IO (n=76) and TKI/IO (n=65). PFS-2 is defined as time from start of 1st line to progression on next therapy, or death, and is estimated using Kaplan-Meier method. PFS-2 association with each mutation was assessed via log-rank test and a model-based approach. Restricted mean survival time (RMST) up to 48 months was calculated for PFS-2 and modeled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of effect among treatment groups, an interaction test between somatic mutation and treatment group is performed in the model. Results: VHL, PBRM1, SETD2, mTOR pathway, BAP1, and TP53 were the most common somatic mutations. Only BAP1 was significantly associated with PFS-2: median PFS-2 was 44 months for patients without BAP1 mutation and 17 months for patients with BAP1 mutation (log-rank p=0.006). After adjusting for IMDC risk group, 48 month RMST for PFS-2 was 13 months lower in patients with BAP1 mutation. An interaction test performed in the RMST model showed no significant variation in the treatment effect of IO/IO or TKI/IO based on the presence or absence of BAP1 mutation (p=0.97), although sample size limits power to detect differences. Results for other somatic mutations are shown. Conclusions: PFS-2 was significantly inferior for ccRCC patients with somatic BAP1 mutation treated with IO-based therapy. Interaction test did not suggest a significant advantage for IO/IO or TKI/IO for mutation-present or -absent groups. Clinical stratification remains key for selecting TKI/IO or IO/IO for patients. [Table: see text]
Adjuvant everolimus in patients (Pts) with localized non-clear cell renal cell carcinoma (RCC): Subgroup analysis from the Everest trial (SWOG S0931).
Authors: Gulati Shuchi , Tangen Catherine , Ryan Christopher W. , Vaishampayan Ulka N. , Shuch Brian M. , Barata Pedro C. , Pruthi Deepak K , Bergerot Cristiane Decat , Tripathi Abhishek , Thompson Ian M , Lara Primo N , Pal Sumanta Kumar 
Published: June 2023

4546 Background: In S0931, adjuvant treatment with the mTOR inhibitor everolimus respectively yielded disease-free survival (DFS) and overall survival (OS) hazard ratios (HR) of 0.85 (95% CI 0.71-1.00) and 0.90 (95% CI 0.71-1.13) in pts with resected, localized RCC. Previously, everolimus had been shown to be active in chromophobe RCC (chRCC; Tannir et al Eur Urol 2016) and papillary RCC (papRCC; Escudier et al Eur J Cancer 2016). We sought to evaluate the efficacy of everolimus within these non-clear cell subsets of EVEREST. Methods: 1545 adult pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to 54 weeks of everolimus 10 mg PO daily or placebo within 12 weeks of radical or partial nephrectomy. Exploratory analyses of RFS and OS chromophobe and papillary subgroups were performed. Results: A total of 99 eligible pts had chRCC; 109 had papRCC (16 type I; 37 type II; 56 NOS). Median follow-up is 6.3 years. Pt characteristics were balanced between the 2 arms in each histological group. Thirty-four (34%) pts in the chRCC subgroup and 50 (46%) pts in the papRCC subgroup had very high-risk disease. Fewer pts completed all 54 weeks of everolimus in each subgroup compared to placebo (49% vs. 74% in the ChRCC subgroup and 46% vs. 71% in the papillary subgroup). DFS and OS for each subgroup are shown. Conclusions: Non-clear cell histology accounted for a considerable proportion (~13%) of S0931 pts. The estimated everolimus HRs for DFS and OS in the chRCC subset are consistent with the overall trial result, but those same modest HRs were not seen in papRCC, in contrast to prior reports of mTOR inhibitor activity in this subtype. Although inferences are limited by sample size and wide CIs, this is the largest experience in chRCC or papRCC among any adjuvant trials presented to date. Clinical trial information: NCT01120249 . [Table: see text]
Association of neutrophil to eosinophil ratio (NER) with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line (1L) immune checkpoint inhibitors (ICI) –based regimens.
Authors: Eid Marc , Labaki Chris , Semaan Karl , Saliby Renee Maria , Saad Eddy , Shah Valisha , Choueiri Toni K. 
Published: June 2023

4557 Background: ICI-based regimens (ICI + ICI or ICI + VEGF targeted therapy [VEGF-TT]) represent current standard of care systemic therapies for the management of patients with mRCC. Robust biomarkers capable of predicting the therapeutic efficacy and safety of such regimens are still lacking. Eosinophils have been shown to play an important role in the response to immunotherapy. While recent investigations in RCC evaluated NER as a biomarker of poor response to immunotherapy, they did not fully account for the impact of different lines of therapy and the therapeutic classes of ICI-based regimens. We aimed to comprehensively evaluate the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI regimens. Methods: We retrospectively reviewed data from patients with mRCC treated with first line ICI-based regimens (dual ICI or ICI + VEGF-TT) at Dana-Farber Cancer Institute. Clinicodemographic information was collected, including tumor histology, ECOG performance status, IMDC risk score. We examined NER at baseline and at 6, 12, and 24 weeks while patients were still receiving treatment. The primary endpoint was overall survival (OS). Time to treatment failure (TTF) was a secondary endpoint. The association of NER with OS and TTF was evaluated using Cox regression models, adjusted for age, gender, BMI, histology, IMDC risk score and autoimmune disease. Results: Overall, 156 patients were included in the current analysis, with a median age of 61 years (IQR: 54-67). 60 patients received dual ICI therapy, while 96 were treated with ICI + VEGF-TT combinations. In the ICI+ICI group, a higher NER at baseline, 6 and 12 weeks was associated with worse OS. In the ICI + VEGF group, a higher NER only at 6 weeks appeared to be associated with worse OS. No association between NER and TTF was found. Conclusions: To our knowledge, this is the first study to investigate, across therapeutic classes, the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI-based regimens. Higher NER was linked to poor survival outcomes, especially in patients receiving dual ICI therapy. Future translational studies are needed to clarify these findings. [Table: see text]
Germline mutations in hereditary renal cell carcinoma (RCC) genes among 32,240 patients with all cancer types.
Authors: Carlo Maria Isabel , Schroeder Andrew , Mukherjee Semanti , Kemel Yelena , Kotecha Ritesh R , Lee Chung-Han , Shah Neil J. , Feldman Darren R. , Liu Ying L , Walsh Michael Francis , Latham Alicia , Voss Martin H , Chen Ying-Bei , Stadler Zsofia Kinga , Mandelker Diana , Offit Kenneth , Motzer Robert J. 
Published: June 2023

4559 Background: Germline pathogenic variants (PVs) in VHL, FH, BAP1 and others cause hereditary syndromes with increased risk of renal cell carcinoma (RCC). Defining the clinical spectrum of these syndromes has been limited by ascertainment bias and their relative rarity. Using a large population of cancer patients who underwent germline and somatic tumor testing, we analyzed the landscape of germline PVs in RCC genes in individuals with all cancer types. Methods: We identified patients with germline PVs in RCC genes ( VHL, FH, SDHB, MET, FLCN, BAP1) in the MSK-IMPACT cohort, an institutional protocol of patients who had somatic and germline sequencing. The MITF E318K variant was analyzed separately given its uncertain role in RCC risk. Objectives were to determine whether patients met clinical criteria for their respective hereditary syndromes, analyze biallelic inactivation in all tumor types, and explore underrecognized cancer associations. Fisher test was used to compare frequency of variants to population. Results: Of 32,240 patients who consented to germline results, 55% were female; most common cancer types were breast (n=3600), pancreas (n=3554), prostate (n=3427), with 1166 (3.6%) with RCC. 110 (0.34%) had a germline variant in a RCC syndrome gene ( BAP1=26, SDHB=24, FH=24, FLCN=19, VHL=16, MET=1). Of 110 germline positive, 56% met clinical criteria for their hereditary syndrome, and 40% had RCC. For VHL, FH, SDHB and MET, a high proportion of patients met criteria for their hereditary syndromes, but this was much less for FLCN (Birt-Hogg-Dubé) and BAP1. Biallelic inactivation in the tumor, supporting causality, was very high except in FLCN. Possible novel cancer associations were liver cancer in BAP1 (n=5;19%) and colon cancer in FLCN (n=4;17%). Additionally, 114 patients had the MITF E318K variant; which was not enriched in RCC cases (only 1 RCC) compared to other cancers or population control (odds ratio 0.45; p-value = 0.16, 95% confidence interval: 0.1 -1.2). Conclusions: Germline analysis in a large pan-cancer cohort identifies a high prevalence of patients with hereditary RCC syndromes, variability in clinical phenotype and suggestion of novel cancer associations. The low number of MITF E318K variant carriers in RCC cases calls into question its role in RCC risk and warrants further study. [Table: see text]
Patient priorities and expectations of systemic therapy in metastatic renal cell carcinoma.
Authors: Battle Dena , Vaishampayan Ulka N. , Msaouel Pavlos , Pal Sumanta Kumar , Zhang Tian , Staehler Michael D. 
Published: June 2023

4560 Background: As treatment options for metastatic Renal Cell Carcinoma (RCC) have increased in number, selecting therapy has become more complicated. When prioritizing agents today, guidelines recommend selection based primarily on risk classification, as well as consideration of efficacy data, patient characteristics, quality of life, cost, and patient preference. Understanding how patients prioritize treatment selection and define treatment success is crucial to improving patient/provider communication and to improving future drug development. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure) and was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Those who agreed to participate were surveyed for demographics (age, gender, race, income, country) and clinical characteristics (date of the diagnosis, disease stage, treatment history). Descriptive statistics summarized the survey data. Results: 399 out of 1,062 patients surveyed had metastatic disease. 80% of patients were receiving or had received systemic therapy, 20% of patients had not yet received systemic therapy. 52% were female and 48% were male, with a median age of 57 years (range 28-86). Patients identified as white (89%) and living in the United States (86%). 69% of patients reported that they did not know their IMDC or risk status, 10% were favorable risk, 11% were intermediate risk and 10% were poor risk. When asked to select the most important outcome for treatment selection on a rank-choice scale from 1 to 8, the chance to eliminate all evidence of disease (complete response) scored highest (6.6), followed by durability of response (5.1), improved quality of life (5.0), rapid reduction of tumors (4.9), ability to go off therapy (4.2), low risk of toxicity (4.0) and reduction of tumor symptoms (4.0). Patients ranked low cost as the least important factor in selecting treatment (2.3). 70% of patients defined “long-term" response to therapy as five years or longer, and over a quarter of patients (26%) defined long-term response as 10 years or longer. When asked to define treatment success, patients rank radiological reduction in tumor size (83%) as the most important factor, followed by stable disease (67%), improved quality of life (48%) and the ability to return back to work (22%). The lowest ranked choice was “I just trust my doctor” (17%). Conclusions: Most patients are not familiar with their risk classification and may not realize the significance of this factor in treatment selection. Patients rank complete response as the most important outcome/desire when considering treatment options. Cost is the least important factor for patients in selecting treatment. Patient perceptions of long-term response to therapy may differ from provider perceptions. More research is needed to improve patient/provider communication in the therapy selection process.
Real-world response rates and clinical outcomes of patients treated with first-line (1L) platinum-based chemotherapy (PBC) in advanced urothelial cancer (aUC).
Authors: Moon Helen H , Aragon-Ching Jeanny B. , Thompson Allison , Abraham Anup , Vlahiotis Anna , Ike Chiemeka , Benjumea Darrin , Shao Anran , Sun Haiyan , Kearney Mairead , Gharibian Norbek , Hanson Sarah , Li Benjamin , Kirker Melissa , Grivas Petros 
Published: June 2023

4567 Background: Standard of care has been established as 1L PBC followed by avelumab 1L maintenance (1LM) in eligible pts based on the JAVELIN Bladder 100 trial (NCT02603432) which showed that avelumab 1LM significantly prolonged overall and progression-free survival (OS, PFS) in pts with aUC with no disease progression after 1L PBC. Contemporary and robust real-world (rw) data are limited in pts treated with 1L PBC; however, because response status to PBC determines avelumab 1LM eligibility, it is critical to understand rwR rates. This study aimed to assess current rwR rates and rw outcomes in pts treated with 1L PBC. It also sought to understand avelumab 1LM eligibility and its early utilization since FDA approval on June 30, 2020. Methods: A non-interventional, retrospective cohort study of pts with aUC in the US was conducted using data from Flatiron Health’s electronic health record database. Pts were included if they were diagnosed with aUC between Jan 1, 2017, and Sep 30, 2021, received 1L PBC, did not have a progression event and had an observed rwR (complete response [rwCR]/partial response [rwPR]) or stable disease (rwSD) during 1L. Pt characteristics and rw outcomes were described based on response type (rwCR/PR, rwSD); rwPFS and rwOS were measured from time of 1L PBC initiation using the Kaplan-Meier method. Results: 1,245 pts with aUC received 1L PBC and had rwR data available during study period. Of these, 80% (n=998) may have been eligible to receive avelumab 1LM (rwCR/PR: 60%, rwSD: 20%). Key characteristics and outcomes by rwR are summarized. During the study period that occurred after FDA approval of avelumab 1LM, 435 pts discontinued 1L PBC, 78% (n=339) of these pts had observed rwCR/PR/SD during 1L PBC, and 29% (n=97) of maintenance eligible pts received avelumab 1LM. Follow-up time for avelumab 1LM treated pts was short (median 7.5 months from initiation of 1LM) and outcomes were immature at the end of the study period. Conclusions: In this rw study, a large proportion of pts with aUC treated with 1L PBC had rwR or rwSD (≈80%) and may have been eligible for avelumab 1LM, which is the standard of care supported by international guidelines. RwR rate appears slightly higher compared to historic data, and may reflect better general patient care, as shown in recent large phase 3 trials (NCT02853305, NCT02516241, NCT02807636). Early uptake of avelumab 1LM was observed, and future studies with longer follow-up may demonstrate increased utilization and allow assessment of potential impact on outcomes. [Table: see text]