tbuckley/cabot-search huggingface dataset:
Matched tissue and circulating tumor DNA (ctDNA) analysis in renal cell carcinoma (RCC): Results from a multimodal real-world database.
Authors: Rana R. McKay, Chinmay Jani, Eli Tran, Adam J Hockenberry, Ellen B. Jaeger, Nabil Husni, Melissa Conrad Stoppler, Jacob Mercer, Sumanta Kumar Pal, Neeraj Agarwal, Toni K. CHOUEIRI, Brent S. Rose, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2024)

4533 Background: Next generation sequencing (NGS) of ctDNA can complement tissue NGS and is a non-invasive test that can be conducted serially, with the potential to enhance assessment of spatial and temporal molecular tumor heterogeneity. Here, we investigated mutations in RCC patients from ctDNA and matched tissue genomic profiling. Methods: From the Tempus multimodal database, we retrospectively analyzed de-identified NGS data from patients (pts) with RCC that had dual tissue (Tempus xT, 648 genes) and ctDNA testing (Tempus xF, 105 genes). Pts with matched samples (collected +/- 90 days of one another) were included. Clinical characteristics and select pathogenic somatic short variants (PSSV) and copy number variants [(amplifications and deletions, two copy number losses (CNL)] were evaluated. Concordance analyses were restricted to the 105 genes tested on the ctDNA panel and further restricted to short variants, with the exception of amplifications and CNL detected by both xF and xT. Results: Among all pts (n=393), the median age was 61 years and 71% were male. Median time from tissue to blood collection was 21 days (IQR, 7, 39). 67% (n=265) and 68% (n=266) had metastatic disease at the time of tissue and blood collection, respectively. The most common tissue sites were kidney (49%, n=189), bone (11%, n=43), lung (9%, n=34), lymph node (8%, n=29), liver (6%, n=23), and brain/CNS (4%, n=17). Genes harboring the most common PSSV in tissue included VHL (59% n=232), PBRM1 (31%, n=123), SETD2 (23%, n=91), and TP53 (14%, n=54). Genes with common PSSV in ctDNA included TP53 (23%, n=91), VHL (18%, n=69), BAP1 (6%, n=23), and PBRM1 (5%, n=21). The combination of tissue and ctDNA testing increased detection of mutations (Table). There was higher concordance between somatic alterations in select genes among patients with metastases. Conclusions: This analysis shows that ctDNA profiling is complementary to tissue based NGS in RCC and can increase the detection of mutations. Concordance between ctDNA and tissue profiling increased in individuals with metastatic disease. Future research is warranted to understand how longitudinal ctDNA analysis can define biomarkers of response and resistance at the mutation and ctDNA fraction levels. [Table: see text]
Examination of irAE and treatment discontinuation irAE in patients with RCC with T effector phenotype.
Authors: Catherine Fahey, Anupama Reddy, Kristin Kathleen Ancell, Kerry Roe Schaffer, Brian I. Rini, Katy Beckermann
Journal: Journal of Clinical Oncology (2024)

4549 Background: The standard of care for renal cell carcinoma (RCC) is physician-choice of dual immunotherapy with ipilimumab/nivolumab (IO/IO) or a combination a VEGF inhibitor with immunotherapy (VEGF/IO). The IMmotion 151 trial identified gene expression signatures that differentiate likelihood of response to IO/IO (cluster 4 and 5 – T effector) versus VEGF/IO (cluster 1 and 2 - Angiogenic). Given that the T effector RNA-seq signature consists of higher expression of genes associated with inflammation, we hypothesized that patients with the T effector phenotype would have higher rates of immune-related adverse events (irAE) on IO-based therapy. Methods: Patients with metastatic RCC treated with systemic IO-based therapy had RNA sequencing completed on the primary tumor or metastatic site. Charts of patients who had a T effector RNA-seq signature were manually curated to identify development of irAE by reading the most recent clinic note and searching ‘steroids’, ‘irAE’, ‘rash’, ‘thyroid’. Hits from searches were investigated by manual chart review. Results: 118 patients underwent RNA sequencing and 105 passed quality control. Nineteen patients (18%) were assigned the T effector phenotype. Of the 17 metastatic patients, twelve of these patients received at least one dose of IO/IO in the first or second line of therapy, five were treated with VEGF/IO Among patients treated with IO/IO, 8 developed any grade irAE (66%; 41% grade 3+), 5 (41%) required steroid treatment, 5 (41%) required hospitalization, and 4 (33%) discontinued treatment due to irAE. Grade 3 toxicities in this group included colitis, adrenal insufficiency, and hypophysitis. Of the 5 patients treated with VEGF/IO, 3 developed any grade irAE (60%; 20% grade 3+), none were treated with steroids, and none were hospitalized. The grade 3 toxicity in this group was adrenal insufficiency. Conclusions: Patients with a T effector RNA-seq signature had higher rates ofirAE than historic controls when treated with IO/IO leading to high rates of steroid use and treatment discontinuation. VEGF/IO-treated patients with the T effector RNA-seq signature had similar rates of irAE to historic controls. The ongoing OPTIC clinical will expand on these results by studying treatment assignment in a prospective manner.
Inferring PDL-1 status from H&amp;E images using digital pathology to identify patients responsive to anti-PD(L)-1 immuno-oncology therapy for bladder cancer trials.
Authors: Albert Juan Ramon, Brandon Ginley, Madhawa Saranadasa, Chaitanya Parmar, Neil Beeharry, Shibu Thomas, Bolan Linghu, Joel Greshock, Kristopher Standish
Journal: Journal of Clinical Oncology (2024)

4579 Background: Programmed death ligand-1 (PDL-1) expression has been established as a biomarker for response to immune checkpoint inhibitors in bladder cancer. Targeted therapies that inhibit the PDL-1 pathway improve therapeutic response, but immunohistochemistry (IHC) testing is required to assess PDL-1 expression. In order to ease identification of patients who have high potential to respond to anti-PD(L)-1 therapies, we explore the use of a computer vision algorithm to infer PDL-1 expression from patients routine H&amp;E images. Methods: We pretrained a Foundational Model on ~55k unlabeled WSIs from various sources (multiple scanners, hospitals, diseases, tissues..). We then finetuned it on a train set (n=1546) of PDL-1 labeled H&amp;E images to infer expression. Labels were defined as PDL1-High or PDL1-Low based on the most sensible threshold for the various included antibodies (e.g., TPS&gt;=10% on 22C3 antibody, CPS&gt;=1% on 28-8 antibody, etc..). We applied this model to WSIs from 1) a holdout split (n=388) and 2) an independent dataset (n=93) to evaluate the performance at inferring PDL1-High vs. PDL1-Low, quantified by the Area Under ROC Curve (AUC). We then applied the model to a third dataset (n=27) containing WSIs from bladder cancer patients taken prior to start of anti-PD(L)-1 treatment (i.e., pembrolizumab) and evaluated treatment response (quantified by overall survival) for the two stratified groups based on the model outputs (PDL1-High vs. PDL1-Low). Results were compared to patients stratified based on IHC pathology readouts (i.e., TPS&gt;=10% vs. TPS&lt;10%). Results: For PD-L1 status inference, the model achieved AUC=0.82 and AUC=0.8 on holdout and independent datasets respectively. The table below shows survival analysis results upon pembrolizumab treatment (n=27) when stratifying patients based on the algorithm (AI-based PDL1-High vs. PDL1-Low) compared to IHC-based stratification. Note that the survival probability for PDL1-High patients is higher than PDL1-Low patients. Conclusions: We developed a computer vision algorithm to infer PDL-1 expression from routine H&amp;E images. The algorithm shows strong performance at classifying PDL-1 status and proficiency in inferring outcomes to anti-PD(L)-1 therapy in a small bladder cancer data set. This tool represents a novel, rapid means to assess whether a patient may respond to anti-PD(L)-1 therapies from common H&amp;E-stained images and has the potential to guide patient care decisions in clinic. [Table: see text]
Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.
Authors: Yasmin Nabil Laimon, Morgan Paul, Fatme Ghandour, Nourhan El Ahmar, Sayed Matar, Thomas Denize, Aseman Bagheri Sheshdeh, Varunika Savla, Razan Assaad Mohanna, Maxine Sun, Renee Maria Saliby, Eddy Saad, Marc Machaalani, David A. Braun, Dana T. Aftab, Wanling Xie, Toni K. CHOUEIRI, Sabina Signoretti
Journal: Journal of Clinical Oncology (2024)

4543 Background: High expression of the receptor tyrosine kinase AXL has been associated with resistance to targeted agents and anti-PD-1 therapy in multiple tumor types, including metastatic clear cell Renal Cell Carcinoma (mccRCC). Cabozantinib (cabo), a multitargeted tyrosine kinase inhibitor (TKI) active against VEGFR, MET, and AXL, is approved for the treatment of mccRCC, but no predictive biomarkers are available. Here, we analyzed tumor samples from the METEOR trial to assess whether AXL expression predicts improved clinical outcomes with cabo relative to everolimus (evero, mTOR inhibitor) in patients (pts) with mccRCC. Methods: Double immunohistochemistry staining for AXL and CD45/CD163 (immune cell/ macrophage markers) was performed on 278 pretreatment tumor tissues from the METEOR trial (cabo=147; evero=131). Image analysis algorithms were used to assess the % of AXL+ tumor cells (TC), % of AXL+ immune cells (IC), and combined % of AXL+ TC and IC (TC/IC). Optimal cutoffs, based on the minimum p-value approach, were determined at the 17 th , 30 th , and 22 nd percentile for TC, IC, and TC/IC, respectively. The association with progression-free survival (PFS) was assessed using Cox regression adjusted for IMDC risk groups, the presence of bone metastases, and the number of previous VEGFR TKI treatments. The association with objective response rate (ORR) (cabo arm only due to low response rate in evero arm) was reported descriptively. Results: We observed a strong correlation between % AXL+ TC and % AXL+ IC (Spearman correlation coefficient 0.85; p-value &lt;0.001). In the evero arm, high % AXL+ TC and high % AXL+ TC/IC were significantly associated with shorter PFS (median 1.9 vs. 4.1 months and 1.9 vs 4.2 months, respectively); a similar trend was observed for % AXL+ IC. In the cabo arm, % AXL+ TC, % AXL+ IC, and % AXL+ TC/IC were not associated with PFS or ORR (Table). The magnitude of increase in PFS for pts receiving cabo versus evero was larger in pts with high % AXL+ TC compared to pts with low % AXL+ TC (HR: 0.30 vs. 0.51, p-interaction=0.18) and in pts with high % AXL+ TC/IC compared to pts with low % AXL+ TC/IC (HR: 0.30 vs 0.53, p-interaction=0.12). Conclusions: Our finding that the improvement in outcome with cabo relative to evero is more evident in pts with high levels of AXL expression supports that the antitumor activity of cabo in mccRCC is mediated, in part, by AXL inhibition. Our work identifies AXL expression as a potential predictive biomarker for cabo-based therapies in mccRCC. [Table: see text]
SOGUG-Vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.
Authors: Guillermo de Velasco, Iciar García Carbonero, Urbano Anido, Juan Antonio Virizuela, Carlos Álvarez-Fernández, Francisco José Álvarez-Márquez, Marina Justo de la Peña, Rebeca Lozano, Pablo Gajate, Oscar Reig, Aina Iranzo, Eduardo Pujol
Journal: Journal of Clinical Oncology (2024)

4576 Background: Nivolumab (nivo) 1mg/kg plus ipilimumab (ipi) 3mg/kg achieved the highest ORR (42.4%) in refractory metastatic urothelial carcinoma (mUC) with a manageable safety profile. The addition of nivo and ipi subsequently to first-line chemotherapy (CT) could consolidate the clinical benefit. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of ipi 3 mg/kg and nivo 1 mg/kg (Q3W) for 4 cycles followed by nivo maintenance therapy (Q4W) in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line platinum-based CT (at least 4-6 cycles of CT). Autoimmune disease, immune deficiency, and symptomatic brain metastasis were excluded. The primary endpoint is Progression Free Survival (PFS) in intention-to-treat and PD-L1 populations. Secondary endpoints include: objective response rate (ORR), duration of response (DoR), overall survival (OS), overall survival from 1 st dose of CT (cOS), progression-free survival from 1 st dose of CT (cPFS), safety and translational biomarker analysis. Sample size was estimated using a Simon II stage design for 4-months PFS rate (H0= 40%; H1= 60; α= 0.05; β= 80%; attrition 10%), requiring 25 patients in the 1 st stage and up to 66 in total. Here we report the interim analysis for 1 st stage. Results: As of January 2024, the 1 st accrual stage was completed with 25 evaluable patients. Baseline characteristics are outlined in the table. With a median follow-up of 6.8 months (95% CI: 6.2-10.5), the 4-m PFS rate was 64% (95% CI: 47.7-85.9) and the median PFS was 4.3 months (95% CI: 3.2-NR). The median cPFS was 9.4 months (95% CI: 8-NR). The 6-m OS rate was 76.4% (95% CI: 60-97.2), while median cOS was 15.4 months (95% CI: 15.4-NR). The median duration of treatment was 2.6 months (95% CI: 2.1, 5.7). Nivo and ipi were permanently discontinued due to toxicity in 3 (12%) and 1 (4.2%) patients, respectively. Nivo doses were delayed in 8 (32%) patients and ipi in 3 (12%) for management of toxicity. Grade ≥3 toxicities were reported in 8 (32%) patients, being the most common: Immune-mediated hepatitis (8%), ALT/AST increased (8%) and diarrhea (8%). Conclusions: Maintenance treatment with nivo and ipi showed preliminary efficacy consolidating clinical benefit to CT with a manageable safety profile. The 4-m PFS rate surpassed the futility threshold in the interim analysis and the accrual in Stage II is underway. Final survival results are awaited. Clinical trial information: NCT05219435 . [Table: see text]
Association of ephrinB2 (B2) expression on overall survival (OS) and resistance to PD1/L1 inhibitors (inh) in metastatic urothelial carcinoma (mUC).
Authors: Sarmad Sadeghi, Nataliya Mar, Denice Tsao-Wei, Karam Ashouri, Imran Siddiqi, Jon P Cogan, Alexandra Jackovich, Dory Freeman, Jillian O'Toole, Thomas W. Flaig, parkash S. gill, Arash Rezazadeh, Guru P. Sonpavde, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2024)

4577 Background: B2 is a ligand for EphB4 (B4) which enhances tumor invasion, proliferation, survival and promotes angiogenesis. TCGA data (N= 409) bladder cancer patients (pts) showed B2 high expression (34%) had poor OS vs. low expression (66%) (Hazard Ratio- HR- 0.7 p=0.02). Our phase II trial of sEphB4-HSA, a B2 inhibitor, combined with pembrolizumab in pre-treated mUC (N=70) showed an objective response rate (ORR) of 37%. Pts with high B2 had 52% ORR with 24% complete response (CR) (JCO PMID 35984996). This retrospective study examined the OS and ORR to PD1/L1 inh in pts with mUC and its correlation with B2 expression. Methods: Pts with mUC who received PD1/L1 inh were eligible if they had radiographic response data and tumor tissue for B2 testing. Demographics and disease characteristics were abstracted. Radiographic was assessed using RECIST 1.1. Tumor specimens were analyzed for B2 expression using in-situ hybridization (ISH). Scores of 2-4 were marked High (Hi) and 0-1 Low (Lo). Descriptive statistics summarized the results. Cox Model, logrank and Fisher’s exact test were used for the association of B2 status with OS and ORR, respectively, using SAS 9.4. Results: 143 (N) pts from University of Southern California (USC, n = 49), Dana Farber (DFCI, n = 55), and University of California, Irvine (UCI, n = 39) were included. 101 pts were male (71%). Median age was 73. PD1/L1 inh included pembrolizumab (n = 111, 78%), atezolizumab (n = 25, 17%), nivolumab, avelumab, and durvalumab in 3%, 1%, and 1%, respectively. ORR defined as CR + partial response (PR) was 21% (95% CI 14%, 29%) (N = 136 evaluable). ORR was 12% vs 33% in B2 Hi vs Lo, p = 0.005. The median OS was 17.2 months (mo) (95% CI 13.5, 23.8) (N = 143). Median OS was 14.5 (95% CI 9.4, 21.0) mo vs 24.0 (95% CI 13.7, 60.8) mo for B2 Hi vs Lo, logrank p = 0.022 (HR 1.65 95% CI:1.07, 2.55 Wald p = 0.023). Conclusions: B2 Hi is associated with poor OS and poor ORR in PD1/L1 inh monotherapy treated mUC acting as a biomarker of disease outcome. These data suggest B2-B4 pathway to be a mechanism of resistance to PD1/L1 inh and a therapeutic target. [Table: see text]
Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).
Authors: Jacob Peter Zaemes, Miya Hugaboom, Valisha Shah, Naomi B. Haas, David F. McDermott, Opeyemi Jegede, Mehmet Asim Bilen, Mark N. Stein, Jeffrey A. Sosman, Robert S. Alter, Elizabeth R. Plimack, Michael E. Hurwitz, Catherine J. Wu, David Johnson Einstein, Hans J. Hammers, Sabina Signoretti, Destiny West, Thomas Denize, Michael B. Atkins, David A. Braun
Journal: Journal of Clinical Oncology (2024)

4546 Background: Seven molecular subsets of ccRCC have been proposed: 1: Angiogenic/Stromal; 2: Angiogenic; 3: Complement/Ω-oxidation; 4: T-effector/Proliferative; 5: Proliferative; 6: Stromal/Proliferative; and 7: snoRNA (Motzer et al. Can Cell 2020). In an analysis of IMmotion 151, which compared 1L atezolizumab/bevacizumab to sunitinib, combination immune checkpoint blockade (ICB) and anti-VEGF therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in clusters (CLs) 4 and 5, increased PFS in CL 7, and decreased OS in CL 2 (Motzer Can Cell 2020, Motzer JAMA Onc 2022). CL 4 was also associated with higher PFS and objective response rate (ORR) in &gt;1L nivo compared to everolimus in an analysis of CheckMate-025 (Denize CCR 2022). To date, outcomes have not been compared among accRCC subtypes in pts who received 1L pure ICB. Methods: In HCRN GU16-260-Cohort A, pts with accRCC received 1L nivo monotherapy until progressive disease (PD), unacceptable toxicity, or completion of 96 weeks of therapy. Pre-treatment FFPE tumor samples were obtained. A machine learning model (random forest) was trained on annotated transcriptomic data from bulk RNA-seq and used to classify tumors that passed quality control into one of the 7 molecular subtypes. Results: 70 tumor samples contained adequate RNA quality and were classified as outlined in the table. IMDC rates and ORR (40%) for the RNAseq population closely matched those of the whole study (Atkins JCO 2022). No tumors were classified in CL 7 and only 3 in CL 5. Tumors in each IMDC group contained a mix of subtypes. The highest ORR occurred in CL 4 (6/10, 60.0%); CL 4 median PFS was 15.2 months and 1-year PFS was 60%. ORR was also high in CLs 1 and 3 at 52.4% and 40.0%, respectively and lowest in CL 2 (12.5%). PD as best response (5/10, 50.0%) and short PFS (5.1 months) were seen in CL 6. Conclusions: Consistent with prior analyses with combination ICB + anti-VEGF and &gt;1L ICB, CL 4 was associated with robust 1L ICB monotherapy antitumor efficacy. Surprisingly, ORR was also high in CLs 1 and 3. In this small dataset, transcriptomic signatures enriched for but did not fully predict ORR. Future prospective trials are needed to identify more discriminative biomarkers of efficacy for pure ICB therapy.[Table: see text]
A pilot study of tazemetostat and pembrolizumab in advanced urothelial carcinoma (ETCTN 10183).
Authors: Maha H. A. Hussain, Masha Kocherginsky, Parminder Singh, Winston Tan, Zin Myint, Di (Maria) Jiang, Elizabeth Marie Wulff-Burchfield, Yangruijue Ma, Elad Sharon, Richard Piekarz, Joshua J Meeks, David James VanderWeele
Journal: Journal of Clinical Oncology (2024)

4574 Background: Mutations of COMPASS-related proteins KMT2D, KMT2C, and KDM6A are observed in 66% of advanced urothelial carcinomas (UC). In vivo, the administration of tazemetostat, an enzymatic EZH2 inhibitor (EZH2i), reduced tumor burden and enhanced the immune response in animal models of UC. We hypothesized that tazemetostat might improve response to immunotherapy in advanced UC. Methods: ETCTN 10183 (NCT03854474) is a multicenter pilot study evaluating the safety and efficacy of tazemetostat 800 mg BID+ pembrolizumab 200 mg given every three weeks for up to two years in patients (pts) with platinum-refractory (Arm A) or cisplatin/chemo-ineligible advanced UC (Arm B). The primary objective was to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives included safety, response rate, and progression-free survival. Translational objectives included determining tumor mutational burden in COMPASS-related genes, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: There were no dose-limiting toxicities in the safety lead-in phase (n=6 pts), and the RP2D for tazemetostat was established at 800 mg BID. Baseline characteristics for Arm A N=12, Arm B N=13: 72% males; 96% white, 4% Black; 88% ECOG PS 0-1; 88% had bladder primary, 20% Stage III, 72% stage IV; 80% had visceral or bone metastases. The median number of cycles was 5 in Arm A (range 1-35) and 4 in Arm B (range 2-12). Treatment related G3/4 adverse events (AEs) were observed in 8 patients, most common were anemia and lymphopenia (n=2 each). Treatment related G1/2 AEs included nausea (n=6); skin and subcutaneous tissue disorders (n=3); anemia, lymphopenia, and thrombocytopenia (n=2 each). Among evaluable patients (n=10 in each arm), partial response rate was: Arm A 30%, Arm B 20%; stable disease: Arm A 30%, Arm B 30%; and progressive disease: Arm A 30%, Arm B 20%. 8 pts were on study treatment for ≥ 9 cycles (5 in Arm A, 3 in Arm B). All pts are off protocol treatment. Median progression-free survival was 3.06 (95% CI: 1.38-7.75) months for Arm A and 3.02 (95%CI: 2.4-5.65) for Arm B. Conclusions: Tazemetostat 800 mg BID and pembrolizumab combination is feasible and well-tolerated in patients with advanced UC. In this pilot study, improvement in efficacy relative to historical controls of pembrolizumab alone appears to be modest. Response in tumors with COMPASS-related mutations and EZH2 activity will be evaluated. Clinical trial information: NCT03854474 .