tbuckley/cabot-search huggingface dataset:
Impact of renal function eligibility criteria in clinical trials and real-world survival outcomes among patients with metastatic renal cell carcinoma.
Authors: Benjamin Miron, Xiaoliang Wang, Jill S. Hasler, Trevor Joseph Royce, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2024)

407 Background: Registration trials in metastatic renal cell carcinoma (mRCC) establishing the efficacy of first-line (1L) combination regimens employed strict renal function eligibility criteria (NCT02853331, NCT02811861, NCT03141177, NCT02231749); however, pharmacokinetics and safety of immune checkpoint inhibitors and anti-vascular endothelial growth factor therapies have been shown to be similar regardless of baseline renal function. Therefore, we aim to evaluate the impact of renal function eligibility criteria used in previous trials on real world outcomes. Methods: Data from the US nationwide Flatiron Health electronic health record-derived de-identified database included adult patients (pts) with mRCC who received any 1L systemic treatment on or after 4/16/2018 (first FDA combination regimen approval), had hemoglobin level ≥9 g/dL and ECOG performance status (ECOG) 0-1 at 1L. Renal function eligibility criteria at 1L (-60 days to +7 days) include serum creatinine (≤1.5 vs &gt;1.5 x ULN), eGFR (≥30 vs &lt;30 ml/min/1.73m 2 ) and calculated CrCl (≥40 vs &lt;40 ml/min) based on registration trial protocols. Outcomes include real world progression free survival (rwPFS), time to next treatment (rwTTNT), and overall survival (rwOS) from 1L. Inverse probability of treatment weighted (IPTW) Kaplan Meier methods and Cox proportional hazard models with multiple imputation were applied. Results: Of 2038 pts in this cohort, 1390 (68.2%) met all criteria for renal function (included), 140 (6.9%) met at least one criteria (relaxed), 46 (2.3%) met none (excluded), and 462 (22.7%) had unknown renal function. Compared to included pts, excluded pts were more likely to be older (median age: 74 vs 66), female (35% vs 27%), have recurrent disease (61% vs 53%), less likely to have ECOG 0 (24% vs 40%) and favorable IMDC risk (9% vs 14%). Excluded pts are also more likely to be Non-Latinx Black (13% vs 6%) and have lowest SES quintile (22% vs 15%) compared to included pts. Although, after weighting included pts had higher median rwPFS of 9.3 (95% CI 8.4 - 10.1) vs 6.9 (95% CI 3.7 - 9.9), rwTTNT 12.0 (95% CI 11.0 - 13.1) vs 9.1 (95% CI 5.5 - 16.4) and rwOS 38.5 mo (95% CI 35.9 - 44.5) vs 19.3 mo (95% CI 16.6 - 41.8) compared to relaxed/excluded pts, none of the hazard ratios (HRs) were statistically significant after multiple imputation (Table). Conclusions: In this real world study, we found that although only 68.2% of patients met all renal function eligibility criteria, survival outcomes were not different across pts groups. This suggests that mRCC patients with reduced renal function may benefit similarly to 1L treatment and should not be excluded from clinical trials. [Table: see text]
Impact of combined novel hormonal agents on testosterone levels of patients with prostate cancer undergoing treatment with leuprorelin.
Authors: Dr. Paulo Sergio Lages, Daniel Vargas Pivato de Almeida, Paulo Gustavo Bergerot, Michelle Barbosa, Luciana Lages, Igor Alexandre Protzner Morbeck, Guilherme Augusto Zulli
Journal: Journal of Clinical Oncology (2024)

95 Background: Novel hormonal agents (NHA) are part of the management of prostate cancer (PCa) since from the high-risk localized disease throughout the disease continuum, while sustained androgen deprivation therapy (ADT), through the utilization of gonadotropin-releasing hormone (GnRH) agonists or antagonists, stands as the cornerstone of this combined treatment regimen. Although deeper and earlier PSA response rates were demonstrated with these combinations, there is a lack of information on the testosterone levels during the treatment with this doublet. In this retrospective real-world study, we meticulously analyzed data on testosterone tests obtained from a prominent Brazilian institution to comprehensively assess the clinical efficacy of leuprorelin either in monotherapy or in combinations on the management of PCa. Methods: We conducted a retrospective analysis by gathering data from the medical records of pts diagnosed with PCa who were undergoing treatment with leuprorelin alone or in combination with a novel hormonal agent (NHA). Descriptive statistics was assessed by medians and comparison between groups was assessed by chi-square test. This data collection spanned a nine-year period from 2014 to 2023. Results: A total of 1,744 tests were collected from 240 individual pts. Median baseline testosterone level was 373.9 ng/mL among those treated with leuprorelin monotherapy and 368 ng/mL for those receiving leuprorelin + NHA. Testosterone levels &lt; 50 ng/mL were achieved in 776/786 tests (98.7%) of pts receiving leuprorelin and 945/958 tests (98.6%) in pts receiving leuprorelin + NHA (p=0.9). Testosterone levels &lt; 20 ng/mL were found in 633/786 tests (80.5%) of pts receiving leuprorelin and 842/958 tests (87.9%) in pts receiving leuprorelin + NHA (p &lt; 0.0001). Conclusions: In this robust institutional database analysis, we demonstrated that leuprorelin demonstrated similar levels of testosterone suppression (&lt; 50 ng/mL) both in monotherapy or combined with NHA. However, when analyzing deeper testosterone suppression levels, the addition of NHA was associated with statistically significant difference in the rate of patients with testosterone &lt; 20 ng/mL. These results reinforce the importance of intense hormonal treatment in pts with PCa receiving leuprorelin.
Genomic mutations and homologous recombination deficiency (HRD) score in Japanese patients with metastatic hormone-sensitive prostate cancer (mHSPC): The impact of intraductal carcinoma of the prostate (IDC-P).
Authors: Masashi Kato, Akiyuki Yamamoto, Hideji Kawanishi, Yushi Naito, Shusuke Akamatsu, Toyonori Tsuzuki
Journal: Journal of Clinical Oncology (2024)

195 Background: Intraductal carcinoma of the prostate (IDC-P) is a significant prognostic factor associated with adverse clinical outcomes. A recent study has revealed significant associations between IDC-P and germline homologous recombination repair gene mutations (HRRm) and alterations in tumor suppressor genes. However, no study has investigated the association between IDC-P and gene mutations in a Japanese population. We evaluated the association between IDC-P in prostate core needle biopsies and gene mutations in metastatic hormone-sensitive prostate cancer (mHSPC) in a Japanese population. Methods: This study enrolled 102 mHSPC patients, classified as LATITUDE high-risk, diagnosed between 2018 and 2021 in Nagoya University and affiliated hospitals, all within three years of diagnosis, and with informed consent. Initial screening identified 106 patients with gene mutation data; four were excluded due to inadequate metastatic lesions or insufficient biopsy number. A single genitourinary pathologist assessed all biopsy slides according to 2019 ISUP grading system. Furthermore, the genetic analysis involved the examination of 108 genes using the Myriad myChoice HRD plus assay, alongside HRD (Homologous recombination deficiency) score analysis. Results: Our study achieved a 91% success rate in genomic testing. In total, 20 (19.6%) and 73 patients (71.6%) exhibited HRRm and molecular alterations in pathway other than HRR (MAOT-HRR), respectively. Notably, common HRRm included BRCA (n = 10; BRCA 1:2, BRCA 2:8) and CDK12 (n = 6) mutations, whereas common MAOT-HRR included FOXA1 (n = 30) and TP53 (n = 18) mutations. MAOT-HRR were more common in IDC-P positive patients (75.6% vs. 50%, p=0.06). PTEN and TP53 mutations were notably enriched in IDC-P positive patients (PTEN: 5.8% vs. 0%, TP53: 20.9% vs. 0%, p=0.06). Patients with IDC-P exhibited higher HRD scores (21.3 ± 8.8 vs. 16.6 ± 8.6, p = 0.06) compared to those without IDC-P, with CDK12 and BRCA mutations being more common in this group (CDK12: 7.0% vs 0%, BRCA: 10.5% vs 6.3%). In addition, the frequency of HRRm was slightly higher in patients with IDC-P compared to those without IDC-P (21% vs. 12.5%, p = 0.73). Finally, the frequency of genetic alterations (HRRm or MAOT-HRR) was significantly higher in patients with IDC-P positive patients (82.6% vs. 50%, p=0.0082). Conclusions: Among Japanese mHSPC patients, IDC-P demonstrates significant associations with an elevated incidence of genetic alterations and increased HRD score, emphasizing its potential clinical significance.
A phase 1, first-in-human, dose-escalation and expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma.
Authors: Gopa Iyer, Xin Gao, Drew W. Rasco, Matthew I. Milowsky, Benjamin Garmezy, Ildefonso I Rodriguez Rivera, Jennifer Tepper, Melissa Ann Moles, Evisa Gjini, Michaela Bowden, Michael L. Meyers, Joaquim Bellmunt, Matt D. Galsky
Journal: Journal of Clinical Oncology (2024)

TPS709 Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .
Impact of timing of immunotherapy and cytoreductive nephrectomy on outcomes in metastatic renal cell carcinoma: Results from the CKCis database.
Authors: Changsu Park, Sunita Ghosh, Feras Ayman Moria, Lori Wood, Georg A. Bjarnason, Bimal Bhindi, Daniel Yick Chin Heng, Vincent Castonguay, Frederic Pouliot, Christian K. Kollmannsberger, Dominick Bosse, Naveen S. Basappa, Antonio Finelli, Nazanin Fallah-rad, Rodney H. Breau, Aly-Khan A. Lalani, Simon Tanguay, Jeffrey Graham, Ramy R. Saleh
Journal: Journal of Clinical Oncology (2024)

416 Background: Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC but its role and timing are not well-understood in the era of immunotherapy. The primary objective of this study is to assess patient outcomes in patients who received ST only, CN followed by ST (CN-ST) and ST followed by CN (ST-CN). Methods: The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST for mRCC between January 2014 to June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression free survival (PFS), after adjusting for IMDC risk group. Complications of ST and CN for these cohorts were collected. Results: A total of 588 patients were included in this study. 331 patients received ST only, 215 patients received CN-ST and 42 patients received at least one dose of ST prior to CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST and metastatic sites are reported and globally well-balanced. OS analysis favoured patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13-0.68) and CN-ST (HR 0.68, CI 0.47-0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26-0.77) and CN-ST (HR 0.9, CI 0.68-1.17). The most common cause of ST delay or cessation was treatment toxicity, followed by progression of disease. The most common perioperative complication was bleeding, followed by infection. Conclusions: This study examined baseline features and outcomes associated with the use and timing of CN and ST using real world data through the CKCis database. Patients selected to receive CN after ST seem to have improved outcomes. There were no appreciable differences in ST toxicity or perioperative complications across groups. Limitations include the small number of patients in the CN-ST group and residual confounding and selection bias that may influence the outcomes in patients undergoing CN.
WUTSUP-02-II-Neo-Dis-Tis: Investigating the efficacy and safety of neoadjuvant tislelizumab plus disitamab vedotin with adjuvant tislelizumab in upper urinary tract carcinoma—A phase II multi-center study.
Authors: Yige Bao, Xinyang Liao, Peng Zhang, Hao Zeng, Jiyan Liu, Qiang Wei
Journal: Journal of Clinical Oncology (2024)

TPS718 Background: Upper tract urothelial carcinoma (UTUC) and urothelial bladder cancer (UBC) are frequently referred to as “disparate twins” despite their common tissue origin. They exhibit varying biological behaviors, prognostic outcomes, and responses to treatment. It is crucial to conduct dedicated clinical trials for UTUC as a separate entity rather than relying solely on UBC study results, giving that UTUC lags in evidence quantity and quality compared to UBC. Despite the superior outcomes of neoadjuvant treatment over adjuvant treatment in UBC trials, the currently available evidence for neoadjuvant therapy of UTUC remains limited in quantity and diversity, as the largest trial, POUT, is focused on adjuvant therapy. Additionally, the limited number of neoadjuvant trials for UTUC primarily utilize chemotherapy-based regimens, with little investigation into combination therapies. Of note, UTUC patients frequently have impaired renal functions, making a chemotherapy-independent approach a desirable alternative. On the other hand, given the short duration of neoadjuvant therapy, a combination therapy strategy appears to be necessary, especially with the increasing interest in immune therapy maintenance after surgery. Tislelizumab has demonstrated efficacy in patients with advanced or metastatic urothelial carcinoma. Disitamab Vedotin, a HER2-targeting antibody-drug conjugate (ADC), has demonstrated robust clinical efficacy in metastatic urothelial carcinoma patients with HER2 2+ or 3+ expression. Disitamab Vedotin in combination with PD-1 immunotherapy has shown remarkable results in locally advanced or metastatic urothelial carcinoma, regardless of HER2 expression, indicative of a synergistic effect between ADC and PD-1 immunotherapy. In this study, we aim to conduct a prospective phase II trial to investigate the efficacy and safety of neoadjuvant tislelizumab plus Disitamab Vedotin followed by adjuvant tislelizumab in patients with high-risk UTUC. Methods: This multi-center phase II trial aims to enroll 45 patients with histologically confirmed UTUC at clinical stage cT2-4N0M0 or cT1-4N1-2M0. Neoadjuvant therapy includes 4 cycles of Tislelizumab (200mg for each 3-week cycle) in combination with Disitamab Vedotin (2.0mg/kg for each 3-week cycle). Radical nephroureterectomy (including bladder cuff resection and regional lymph node dissection if indicated) will be performed if there is no obvious contraindication within 3-6 weeks after the final neoadjuvant therapy administration. Postoperative adjuvant treatment with 8 cycles of tislelizumab will be provided. The primary endpoint is pathological complete response rate. Secondary endpoints include overall survival, local recurrence free survival, distant metastasis free survival, FACT–G. Clinical trial information: ChiCTR2300067836 .
Predictive value of dynamic changes in ctDNA and baseline biomarkers with neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.
Authors: Matthew Nicholas Young, Bernadett Szabados, Zoe Assaf, Francesca Jackson-Spence, Elizabeth Nally, Connor Wells, Cristina Suárez, Daniel Castellano, Thomas Powles, Romain Banchereau
Journal: Journal of Clinical Oncology (2024)

534 Background: Circulating tumour DNA (ctDNA) is being explored in the neoadjuvant setting in multiple prospective trials. Dynamic changes may be a surrogate marker of pathological complete response. ABACUS was a multi-centre, single-arm phase II trial investigating two cycles of atezolizumab before cystectomy in patients with muscle-invasive urothelial cancer who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy (NCT02662309). Results of primary and secondary endpoints have been previously published. Here we perform exploratory biomarker analysis using different definitions of ctDNA response and assess correlation with tissue response at time of cystectomy in the ABACUS trial. We also assess how these definitions of response correlate with baseline biomarker expression. Methods: Patients with baseline PDL-1, CD8, TMB and sequential ctDNA measurements (baseline and at cystectomy) were included. ctDNA analysis was performed using the Signatera assay, PD-L1 positivity was defined as ≥5% of immune cell staining, TMB was assessed using the FoundationOne CDx assay and CD8 measurement was performed via immunohistochemistry analyses. Two definitions of ctDNA response were used—ctDNA clearance and a 50% reduction (or greater) in ctDNA variant allele frequency (VAF). Results were correlated with pathological complete response (pCR) rate at time of cystectomy and relapse-free survival. Results: The 2-yr DFS and OS rates in ABACUS were 68% and 77%, respectively (N=95). 40 patients had sequential DNA analysis. 43% (17/40) had pathological complete response and 20% (8/40) experienced relapse. 63% (25/40) patients were ctDNA+ at baseline, with 40% (10/25) having ctDNA response of 50% VAF reduction and 8% (3/40) achieving ctDNA clearance. 30% (3/10) of patients who had VAF reduction experienced relapse and 40% (4/10) achieved pCR. All patients with ctDNA clearance achieved pCR none relapsed. There was no association between VAF reduction of 50% and tissue response (pCR) (p=0.24). Additional analysis showed no association between a ctDNA reduction of 75% (rather than 50%) and pCR (p=0.24). Baseline PDL-1, TMB and not predictive of pathological complete response (p=0.18, p=0.77, p=0.10, respectively) or ctDNA response (p=0.54, p=0.77, p=0.74) to neoadjuvant atezolizumab. There was no difference in relapse rates between ctDNA/PD-L1+ve vs ctDNA+ve/PD-L1-ve patients (16% vs 16%, respectively). Conclusions: ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse. This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint. Combining immune tissue based biomarkers with ctDNA does not appear to improve biomarker accuracy.
CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: An updated multicenter real-world experience applying different CRP kinetics definitions.
Authors: Benedikt Hoeh, Cristina Cano Garcia, Severine Banek, Niklas Klümper, Alexander Cox, Joerg Ellinger, Philipp Schmucker, Oliver Hahn, Angelika Mattigk, Friedemann Zengerling, Philippe Becker, Kati Erdmann, Bjoern Buerk, Luka Flegar, Johannes Huber, Charis Kalogirou, Philip Zeuschner
Journal: Journal of Clinical Oncology (2024)

405 Background: Although biomarkers predicting therapy response in 1 st line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. To assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world 1 st line mRCC cohort. Methods: mRCC patients treated with IO-based 1 st line therapy within 5 years were retrospectively included in this multi-center study. According to Fukuda et al., patients were defined as ‘CRP flare-responder’, ’CRP responder’ and ‘non-CRP responder’; according to Ishihara et al., as ‘normal’, ‘normalized’ and ‘non-normalized’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalized patients had a significantly longer PFS and OS, compared to non-normalized group. Conclusions: Different early CRP kinetics may predict therapy response in 1 st line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.