bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of KDR mutations on efficacy of immune checkpoint inhibitors in patients with bladder cancer.
Authors: Dai Honghai , Zhang Qin , Tan Yuan , Duan Qianqian
Published: June 2023

4521

Background: KDR (kinase insert domain receptor) is the most important VEGF (vascular endothelial growth factor) receptor that mediates the signaling transduction initiated by the VEGF ligands. VEGF signaling can activate angiogenesis which plays a crucial role in tumor growth, metastasis, and treatment response. Here we explore the relationship between KDR mutation and its efficacy of immune checkpoint inhibitors (ICIs) in patients with bladder cancer. Methods: To explore the association between KDR mutations and the efficacy of ICIs in bladder cancer patients, we collected clinical and mutation data of 215 patients who received ICIs (PD-(L)1 and/or CTLA-4 inhibitors) from MSKCC cohort. Gene expression data and WES mutation data of 413 samples in the TCGA database were obtained from the UCSC Xena for analysis of the differences of potential biological mechanisms between KDR-mutant and KDR-wildtype tumors. TMB was calculated as the total number of somatic non-synonymous mutations per megabase. CIBERSORT was applied to infer 22 immune cell type proportions in TCGA advanced bladder cancers. Results: In MSKCC cohort, we observed 5.6% (12/215) samples had KDR mutation. Survival analysis showed that KDR-mutant patients had longer overall survival (OS) than that of wildtype patients (hazard ratio (HR) = 0.27, 95% CI: 0.07-1.09, logrank test P = 0.048); median OS (not reached versus 15 months). Then we compared the TMB between KDR-mutant and KDR-wildtype tumors, the results showed that KDR-mutant group had higher TMB in MSKCC cohort (median [IQR]: 17.58 [11.64–47.81] versus 7.90 [4.92–14.76], P=0.002) and TCGA cohort (median [IQR]: 10.69 [5.87–19.85] versus 4.60 [2.52–8.08], P=0.001). Analysis of 22 immune cell subsets in the TCGA advanced bladder cancers, B cells naive, plasma cells and macrophages M1 were significantly abundant in KDR-mutant tumors (all P <0.05). Conclusions: In ICI-treated bladder cancers, KDR mutation is associated with prolonged OS, higher TMB and activated antitumor immunity, which suggests that KDR mutation may serve as a potential biomarker to guide ICI therapy in bladder cancer.
Determinants of resistance to nivolumab (nivo) monotherapy investigated through genomic and transcriptomic analysis of renal cell carcinoma (RCC) tumors from the HCRN GU16-260 study.
Authors: Braun David A. , Street Kelly , Jegede Opeyemi , Ruthen Neil , Hugaboom Miya , Schindler Nicholas R , McDermott David F. , Plimack Elizabeth R. , Sosman Jeffrey A. , Haas Naomi B. , Hurwitz Michael E. , Hammers Hans J. , Signoretti Sabina , Atkins Michael B. , Wu Catherine J.
Published: June 2023

4524

Background: Nivo monotherapy demonstrated anti-tumor activity in treatment-naïve RCC in Part A of HCRN GU16-260 across all IMDC groups and in multiple histologies. Patient tumor samples were collected to characterize the tumor-immune microenvironmental determinants of effective anti-tumor immunity with nivo. Methods: Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded tissue collected within one year prior to nivo. For single-cell RNA-sequencing (scRNA-seq), eligible patients (pts) with any RCC histology underwent tumor biopsy prior to and/or at resistance to nivo monotherapy. Gene expression signatures discovered through scRNA-seq were used to interrogate previously published bulk transcriptomic data of nivo in the treatment-refractory setting. Results: WES analysis (n = 96 tumors) identified recurrent focal amplifications within chromosome 11q13 (amp11q13), which was observed in 6 of 18 (33.3%) of tumors from pts with progressive disease (PD) compared to 0 of 20 (0%) of tumors from pts with complete or partial response (CR/PR; p = 0.005). amp11q13 was associated with worse progression free survival (PFS; p = 0.008) and overall survival (OS; p = 0.010). ScRNA-seq was performed on tumors from 17 pts (8 with baseline only, 7 with progression only, and 2 with paired baseline and progression samples) across 7 trial sites. Trajectory inference analysis of tumor-infiltrating T cells revealed a bifurcating structure, starting with naïve T cells and ending either in terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells. Surprisingly, the SLAMF7+ T cell population expressed high levels of cytotoxic genes (including GZMA, GZMB, GNLY) and markers of tissue residency ( ZNF683/HOBIT and ITGAE/CD103). Of the 14 pts with at least 100 sequenced tumor-infiltrating T cells, the presence of a higher percentage of SLAMF7+ CD8+ T cells (relative to total T cells) was associated with primary resistance to nivo (mean percentage in PD [n = 4] pts 32.7%; stable disease [n = 4] pts, 9.1%; CR/PR [n = 6] pts, 2.2%; p = 0.019 for CR/PR vs PD). Of 172 pre-treatment tumors from the nivo arms of the CheckMate-009/010/025 trials that we analyzed by bulk RNA-seq, a signature score derived using genes expressed in the SLAMF7+ CD8+ T cell trajectory branch was enriched in pts with PD compared to CR/PR as best response (p = 0.032). Conclusions: Bulk genomic and single-cell transcriptomic analyses uncovered somatic alterations (amp11q13) and infiltrating T cell populations ( SLAMF7+ CD8+) associated with resistance to frontline nivo monotherapy in a phase II study in RCC. Additional independent and functional validation studies are in progress.
Health-related quality of life (HRQoL) of risk-based patient subgroups with advanced renal cell cancer (aRCC) treated with nivolumab plus cabozantinib (NIVO+CABO) vs sunitinib (SUN) in the CheckMate 9ER trial.
Authors: Cella David , Choueiri Toni K. , Blum Steven I. , Ejzykowicz Flavia , Wallace Joel , Zhang Joshua , Simsek Burcin , Ivanescu Cristina , Motzer Robert J.
Published: June 2023

4527

Background: In CheckMate 9ER, NIVO+CABO improved or maintained HRQoL vs SUN in previously untreated aRCC. We report an exploratory analysis of HRQoL in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk-based subgroups treated with NIVO+CABO vs SUN in CheckMate 9ER (minimum follow-up, 36.5 mo). Methods: Subgroups were stratified by IMDC categories of favorable (F) risk (score = 0) or intermediate/poor (I/P) risk (score = 1–6) at randomization. HRQoL was evaluated using Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI-19). Changes from baseline (BL) through wk 151 were analyzed using mixed-model repeated measures (MMRM). Bother due to treatment side effects (FKSI-19 item GP5) was assessed using a generalized estimating equations model (response dichotomized as minimal [“not at all” or “a little bit”] vs notable [“somewhat,” “quite a bit,” or “very much”]). Cox proportional hazards (CPH) modeling was used to evaluate time to confirmed deterioration (TTCD). Results: Differences in least square means (LSM) for FKSI-19 scores through wk 151 indicated HRQoL benefit in the NIVO+CABO arm over the SUN arm for I/P-risk patients (n = 505) but not for F-risk patients (n = 146). In the I/P-risk subgroup, longitudinal analysis of FKSI-19 total scores indicated that HRQoL improved through wk 151 in the NIVO+CABO arm but decreased from BL in the SUN arm. HRQoL declined from BL through wk 151 in F-risk patients in the NIVO+CABO and SUN arms. Patients were less likely to be bothered by side effects of NIVO+CABO vs SUN regardless of risk (I/P-risk odds ratio [OR], 0.50; 95% CI, 0.34–0.75; F-risk OR, 0.51; 95% CI, 0.28–0.91). TTCD analysis of FKSI-19 scores of the I/P-risk subgroup indicated that the NIVO+CABO arm had lower deterioration risk than the SUN arm. For the F-risk subgroup, risk based on FKSI-19 total scores was similar for both treatment arms. Conclusions: Compared with SUN, NIVO+CABO improved or maintained HRQoL in I/P-risk patients and had less side effect bother in all subgroups. There were no significant differences between treatment arms for F-risk patients. Clinical trial information: NCT03141177 . [Table: see text]
CASSIOPE: A prospective noninterventional study of cabozantinib treatment following prior vascular endothelial growth factor (VEGF) -targeted therapy in patients with advanced renal cell carcinoma (aRCC).
Authors: Staehler Michael D. , Bigot Pierre , Barthelemy Philippe , Hamberg Paul , Suárez Cristina , Eymard Jean-Christophe , Gajate Pablo , Perrot Valérie , Qvick Bryan , Dutailly Pascale , Procopio Giuseppe
Published: June 2023

4529

Background: Cabozantinib is a tyrosine kinase inhibitor approved as monotherapy for aRCC in the USA, and as first-line therapy for patients with intermediate or poor risk aRCC, or after previous VEGF-targeted therapy in Europe. In the METEOR trial, a substantial proportion of patients required cabozantinib dose modifications. We report a real-world study of cabozantinib use for aRCC. Methods: CASSIOPE was a non-interventional prospective cohort study (conducted Apr 2018–May 2022; NCT03419572). Enrollment spanned 11 European countries (91 sites) where cabozantinib is marketed for aRCC. Patients had aRCC and had received ≥ 1 prior VEGF-targeted therapy (excluding cabozantinib). Decision to initiate cabozantinib was made prior to enrolment. The primary endpoint was cabozantinib usage (dose interruptions, reductions or discontinuations due to AEs) in the second- (2L) or later- (≥ 3L) line settings. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and tolerability. Data were analyzed descriptively for patients with safety follow-up after ≥ 1 cabozantinib dose. Results: In total, 679 patients were included (73.0% male; median [range] age 67.0 [29–93] yrs; 85.7% clear-cell aRCC; 80.3% prior nephrectomy). Median (range) observation period was similar for 2L (n = 335; 8.51 [0.2–15.4] mo) and ≥ 3L cabozantinib (n = 343; 9.26 [0.0–15.0] mo). Usage data are shown. For the overall population, ORR (95% CI) and median (95% CI) PFS according to local assessment were 21.9% (17.5%–26.9%) and 7.8 (6.3–8.7) mo for 2L cabozantinib, and 38.0% (32.7%–43.5%) and 8.7 (7.6–9.6) mo for ≥ 3L cabozantinib. Median OS (95% CI) was 13.0 (12.6–not calculated [NC]) mo for 2L, and 17.1 (13.8–NC) mo for ≥ 3L cabozantinib. Most patients (90.4%) reported treatment-related AEs (Grade 1, 71.1%; Grade 2, 70.3% of patients), most commonly any grade diarrhea (52.4%), palmar-plantar erythrodysesthesia syndrome (27.2%), decreased appetite (25.5%), hypertension (21.9%), asthenia (21.6%), fatigue (20.5%) and nausea (20.3%). Conclusions: In this real-world study, tolerability of ≥ 2L cabozantinib was consistent with the METEOR trial safety profile: cabozantinib dose modifications due to AEs were common, but discontinuation rates due to AEs were substantially less frequent. Cabozantinib activity was maintained across lines. Clinical trial information: NCT03419572 . [Table: see text]
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]
Final results from SAUL, a single-arm international real-world study of atezolizumab (atezo) in 1004 patients (pts) with pretreated locally advanced/metastatic urinary tract carcinoma (UTC).
Authors: Sternberg Cora N. , Loriot Yohann , Choy Ernest , Castellano Daniel , Lopez-Rios Moreno Fernando , Banna Giuseppe Luigi , De Giorgi Ugo , Masini Cristina , Bamias Aristotelis , Garcia del Muro Xavier , Duran Ignacio , Powles Thomas , Gamulin Marija , Zengerling Friedemann , Geczi Lajos , Gedye Craig , Huddart Robert A , Kandula Geetha , Skamnioti Pari , Merseburger Axel S.
Published: June 2023

4569

Background: In the SAUL study (NCT02928406), clinical outcomes in a broad population were similar to findings from phase 3 trials of anti-PD-(L)1 in highly selected pts. We report the final analysis 4 y after enrolling the last pt. Methods: Eligible pts had locally advanced/metastatic urothelial or non-urothelial UTC that had progressed during or after 1–3 prior lines of therapy for advanced UTC (or within 12 months of [neo]adjuvant therapy). Unlike most phase 3 immunotherapy trials, pts with autoimmune disease (AID), ECOG PS 2, creatinine clearance (CrCl) ≥15–30 mL/min, and/or stable CNS metastases were eligible. Pts took atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS) and duration of response (DoR). Results: Among 997 treated pts, 10% had ECOG PS 2, 5% had CrCl <30 mL/min, 4% had a history of AID, and 7% had 2–3 prior lines of therapy. At data cutoff (Dec 20, 2022; median follow-up 55 mo), 78% of pts had died. Median treatment duration was 2.8 mo (range 0–62 mo; mean 9.5 mo), 96 pts (10%) took atezo for >3 y, and 68 (7%) for >4 y. Grade ≥3 adverse events (AEs) occurred in 51%; AEs led to atezo discontinuation in 8%. We show outcomes overall and in key subgroups. OS was >4 y in 136 pts (14%); 132 responders had OS >2 y. Conclusions: After 55 mo median follow-up, median OS was 8.6 mo and 3-y OS was 21% in a real-world population including important understudied subgroups. Long-term safety data continue to support the tolerability of atezo in pts with complex comorbidities. AESIs were not increased in pts typically considered to be at increased risk of immune-related AEs. OS was similar to trials in highly selected pts. Ongoing analyses are characterizing pts with exceptional long-term outcomes. Clinical trial information: NCT02928406 . [Table: see text]
Biomarkers of response to sacituzumab govitecan (SG) and efficacy after treatment with enfortumab vedotin (EV) in advanced urothelial carcinoma (aUC): Analysis of the UNITE study.
Authors: Jindal Tanya , Jiang Cindy , Alhalabi Omar , Bakaloudi Dimitra Rafailia , Talukder Rafee , Davidsohn Matthew , Nizam Amanda , Taylor Amy K , Nguyen Charles B , Kilari Deepak , Pywell Cameron , Davis Nancy B. , Emamekhoo Hamid , Sonpavde Guru P. , Gupta Shilpa , Bellmunt Joaquim , Grivas Petros , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S
Published: June 2023

4572

Background: SG is an antibody-drug conjugate (ADC) with accelerated FDA approval for aUC refractory to platinum-based chemotherapy and immune checkpoint inhibitor (ICI). SG activity following treatment with EV, the most commonly used ADC in the post-platinum/ICI setting, and biomarkers of response to SG are not well described. We hypothesized that SG would be active after EV in aUC. Methods: Patients (pts) treated with SG monotherapy who had next-generation sequencing (NGS), were identified in the retrospective UNITE study. Observed response rate (ORR) was determined for evaluable pts with scans after ≥1 SG cycle. All pts were assessed for baseline clinical characteristics, as well as molecular biomarkers including tumor mutational burden, somatic gene alterations (alt) in ≥ 10% of pts and presence of ≥1 DNA damage response (DDR) mutations. ORRs were compared with Chi-squared test. Kaplan Meier method and cox proportional hazard (cph) models were used to assess progression-free survival (PFS) and overall survival (OS) from SG start. Pt characteristics and molecular biomarkers were evaluated in univariate analyses (UVA), followed by evaluation of biomarkers in separate multivariate cph analyses (MVA), while accounting for clinical features. Results: Among 90 pts treated with SG at 9 US sites, 78 had NGS data. Median age at SG start was 68, 65 (72%) men, 73 (81%) Caucasian, 56 (62%) with pure urothelial histology, 60 (67%) primary bladder tumor and 67 (74%) ECOG PS 0/1. Most (n=84, 93%) received SG after EV, and 33 (37%) had ≥4 prior therapies for aUC. ORR with SG was 23% (15/66); 24% in pts with prior CR/PR/SD on EV and 14% after primary PD on EV. Median follow-up from SG start was 8.7 mos, PFS and OS were 3.5 mos and 7.1 mos. In pts with NGS, ORRs to SG were higher in MTAP altered pts (50% vs 19%; p = 0.05). In UVA, low neutrophil to lymphocyte ratio (NLR), high Hgb, no prior smoking history, < 3 prior therapies, as well as BRCA2 and DDR alts were associated with longer OS (p<0.05 for all). In MVA, pts with alt in either TP53 or MDM2 had longer OS. Conclusions: SG has notable activity after EV in heavily pretreated pts with aUC, with ORR consistent with SG phase 2 trial data in post-platinum/ICI only pts. We identified several clinical and genomic biomarkers, including TP53/MDM2 alt, that are potentially associated with improved outcomes with SG treatment. [Table: see text]
Evaluating the use of circulating tumor DNA (ctDNA) in patients with urothelial cancer in the context of FGFR-targeted therapy.
Authors: Schönlau Elena , Müller David Christian , Vandekerkhove Gillian , Murtha Andrew , Bacon Jack V.W. , Wells Connor , Rostin Kimia , Parimi Sunil , Noonan Krista , Basappa Naveen S. , Ko Jenny J. , Finch Daygen L. , Alimohamed Nimira S. , Bismar Tarek A. , Nappi Lucia , Annala Matti , Bernales Cecily Q. , Chi Kim N. , Wyatt Alexander William , Eigl Bernhard J.
Published: June 2023

4577

Background: Fibroblast growth factor receptor (FGFR) inhibitors (e.g., erdafitinib) are increasingly important in the management of FGFR-mutated urothelial carcinoma. FDA-approved archival tissue testing for specific FGFR alterations was implemented as a companion diagnostic for erdafitinib. However, longitudinal sequencing studies indicate variable tumor FGFR status over time, and erdafitinib resistance mechanisms in metastatic urothelial carcinoma (mUC) are underreported. This ongoing study aims to evaluate the accuracy of cell-free DNA (cfDNA) compared to archival tissue testing in mUC for FGFR alterations detection, and to evaluate genomic mechanisms of erdafitinib resistance in cfDNA at progression. Methods: Patients with progressing mUC who were undergoing archival tissue testing for FGFR1-3 mutations and/or fusions and who had blood samples drawn during the management of their metastatic disease were eligible. Plasma cfDNA and matched leukocyte DNA were subjected to deep targeted sequencing with a custom panel including UC-specific gene loci and all clinically approved hotspots in FGFR1+2 and all exons and introns of FGFR3. Results: As of January 2023, 109 patients from 6 sites were enrolled. Median age at diagnosis was 71, 33% had upper urinary tract primaries, and 76% were male. Tissue and cfDNA results for comparison were available for 69 patients to date. Actionable somatic FGFR alterations were found in the tissue of 15 patients (31%); the most common alteration was the FGFR3 p.S249C mutation (67%). 50 of the analyzed cfDNA samples had detectable somatic circulating tumor DNA (ctDNA) variant allele fraction of 0.5% (72%). Of those, 49 had an evaluable tissue test result. Analysis of this subset revealed high concordance (92%) between the two test methods. With the assumption that archival tissue testing is considered the ‘gold standard’, sensitivity is 93% and specificity is 91%. The four discordant results comprised one cfDNA test with undetectable FGFR3-TACC3 fusion, which was detected in tissue and three positive ctDNA test results in patients with FGFR wild-type tissue tests. In one case at erdafitinib progression, ctDNA revealed multiple subclonal populations with distinct FGFR3 gatekeeper mutations suggesting polyclonal resistance. Conclusions: This ongoing study suggests cfDNA is a valuable minimally invasive adjunct to tissue-based assays for the detection of FGFR alterations to identify patients for FGFR inhibitor therapy and to monitor for mechanisms of resistance.
Presence of CD8+ cytotoxic T-cells in proximity to tumor cells, TIM3, CTLA-4 and prognostic implications for muscle-invasive urothelial cancer.
Authors: Debatin Nicolaus F. , Plage Henning , Klatte Tobias , Elezkurtaj Sefer , Bruch Paul G. , De Santis Maria , Horst David , Marx Andreas H. , Fisch Margit , Slojewski Marcin , Kaczmarek Krystian , Ecke Thorsten , Hallmann Steffen , Koch Stefan , Adamini Nico , Lennartz Maximilian , Sauter Guido , Zecha Henrik , Schlomm Thorsten , Blessin Niclas C.
Published: June 2023

4582

Background: Although it is well known that the quantity of specific immune cell types can provide prognostic information in bladder cancer, only little is known about the prognostic relevance of the localization of immune cells within the tumor microenvironment. Methods: To study the spatial interplay of different immune cell subpopulations and its prognostic role in bladder cancer, 2463 urothelial bladder carcinomas were immunostained with 21 antibodies (i.e., TIM-3, PD-L1, PD-1, CTLA4, CD3, CD8, CD4, FOXP3, CD20, CD68, CD163, CD11c, panCK, Ki67, CD31, Vimentin, HLA-DRa, Myosin-11, Desmoglein 3, PAX-8, and CDH16) using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for image analysis. Thus, Spatial immune parameters were compared with histopathological parameters and overall survival data. Results: The identification of more than 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. 32 immune parameters showed prognostic significance in univariate analyses of which 16 were independent from pT, pN, and histologic grade in muscle-invasive bladder cancer. The strongest association to clinical outcome was identified for intraepithelial CD8+ cytotoxic T-cells (AUC: 0.70) while stromal CD8+ cells were less relevant (AUC: 0.64, p=0.016). A favorable prognosis of inflamed cancers with high levels of “exhaustion markers” suggests that TIM3, PD-L1, PD-1, and CTLA-4 on inflammatory cells do not hinder anti-tumoral immune response in tumors rich of tumor infiltrating tumor cells. Conclusions: The density of intraepithelial CD8+ T-cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T-lymphocytes through direct cell-to-cell-contacts represents the “terminal end route” of anti-tumor immunity, the quantity of “tumor-cell adjacent CD8+ T-cells” may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway using conventional brightfield IHC in routine pathology as the CD8 labelling index.
Genome-wide aneuploidy detected in circulating cell-free DNA of patients with metastatic urothelial cancer as a predictive biomarker of response to pembrolizumab.
Authors: Salhi Youssra , Rijnders Maud , Mendelaar Pauline , de Weert Vania , Beaufort Corine , Head R , Westgeest Hans M. , Voortman Jens , Aarts Maureen J.B. , Martens John W.M. , Van Der Veldt Astrid Aplonia Maria , De Wit Ronald , Wilting Saskia M , Robbrecht Debbie
Published: June 2023

4584

Background: Pembrolizumab is the standard of care second-line treatment of metastatic urothelial cancer patients. However, success rates are low and there is risk for significant toxicity. Therefore, reliable biomarkers to select patients who will or will not benefit from pembrolizumab are urgently needed. An earlier study showed that a high aneuploidy score (i.e. Z-score ≥ 5) at baseline in cell free DNA (cfDNA), based on the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), associated with poor response to pembrolizumab. However, a low aneuploidy score (Z-score < 5) at baseline was not discriminative. The aim of this study was to evaluate early during treatment (after the first cycle pembrolizumab), whether the cfDNA based mFast-SeqS aneuploidy scores can discriminate patients with expected benefit from therapy from those who will not benefit. Methods: The mFast-SeqS to assess aneuploidy was performed on blood samples collected from 74 patients with metastatic urothelial cancer (mUC) at baseline and after cycle 1 of pembrolizumab. Responders were defined as patients with stable disease (SD) or partial/complete response (PR, CR) according to RECIST v1.1. and continued treatment beyond 6 months from initiation of pembrolizumab. Non-responders did not fulfil these criteria. Results: Paired samples were available in 60 out of 74 patients. At baseline 25% (n=15) of patients had a high aneuploidy score and 75% (n=45) had a low aneuploidy score. Two patients (13%) with a high baseline score were responders and 13 (87%) were non-responders. In all responders, there was a marked decrease in aneuploidy score after one cycle of pembrolizumab (p=0.005), irrespective of their baseline score. About half of patients (47%) with a low baseline score were non-responders and in those patients there was a significant increase of the aneuploidy score post cycle 1, when compared to the responders (p=0.039). Conclusions: The aneuploidy score based on mFast-SeqS may stratify mUC patients for expected lack of benefit early during treatment (after 1 cycle) with second line pembrolizumab, providing an opportunity to switch treatment and to spare patients from potential unnecessary toxicity. Clinical trial information: NCT03263039 .