tbuckley/cabot-search huggingface dataset:
Real-world outcomes of patients with operable renal cell carcinoma from the German translational cancer research consortium (DKTK) network.
Authors: Viktor Grünwald, Christian Thomas, Maria De Santis, Christian Gratzke, Felix Chun, Rene Mager, Margitta Retz, Gunhild Von Amsberg, Philipp Ivanyi, Bolenz Christian, Hubert Kübler, Boris A. Hadaschik, Svenja Hahn, Ian Erhard, Bastian Reiter, Martin Lablans, Janne Vehreschild, Daniel Brucker, Daniel Maier
Journal: Journal of Clinical Oncology (2024)

394 Background: Nephrectomy and risk-adapted adjuvant pembrolizumab are standard treatments in localized renal cell carcinoma (RCC). Risk of recurrence from clinical trials is utilized to council patients. However, recurrence and survival in real-world practice may differ. We report real-world outcome data of patients with RCC from the German Cancer Consortium’s Clinical Communication Platform, a federated data warehouse infrastructure for oncological real-world evidence. Methods: Adult patients from routine care and nephron sparing surgery (NSS) or nephrectomy (Nx) for non-metastatic RCC between 2013-2022 at tertiary German cancer centers were retrospectively analyzed. Clear cell (cc), papillary (p) or NOS histologies were eligible. Kaplan-Meier-analyses were conducted stratified by pathological stage for DFS (Disease-Free-Survival) and OS (overall Survival). Results: 1,291 patients received NSS/Nx. 1,271 (98.5%) were R0/1. Median follow-up: 37.8 mo. (IQR 13.08; 65,74). 754 patients had ccRCC with a mean age of 63.5 y (SD: 12.1), 40% were female. 221 had pRCC, mean age was 62.1 (SD 12.6) and 36.8% were female. 165 had NOS, mean age was 63.3 (SD 12.4) and 36.8% were female. 151 patients had other histologies. Survival outcomes are reported in table 1. Conclusions: Morphologic RCC types and T-stages inform on recurrence and prognosis. Our study advises on real-world recurrence and survival rates in patients with different RCC types, which may be used to counsel patients with regards to adjuvant therapy in the clinic. A major limitation is the retrospective nature of the analysis. [Table: see text]
Tumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial.
Authors: Nourhan El Ahmar, Sayed Matar, Opeyemi Jegede, Yasmin Nabil Laimon, Varunika Savla, Aseman Bagheri Sheshdeh, Thomas Denize, Razan Assaad Mohanna, Toni K. Choueiri, Paul J. Catalano, David A. Braun, Naomi B. Haas, Hans J. Hammers, Mehmet Asim Bilen, Mark N. Stein, Jeffrey A. Sosman, Catherine J. Wu, David F. McDermott, Michael B. Atkins, Sabina Signoretti
Journal: Journal of Clinical Oncology (2024)

448 Background: There is evidence that intratumoral myeloid cell infiltration can modulate response to immune checkpoint inhibitors in some tumor types, but its role in ccRCC remains unclear. Here, we investigated the role of tumor-infiltrating CD163-positive macrophages as a determinant of clinical outcome to anti-PD-1 therapy in patients (pts) with advanced ccRCC treated with first-line nivolumab therapy as part of the HCRN GU16-260 clinical trial. Methods: Primary tumor tissues from pts with ccRCC (n= 67) were analyzed by multiparametric immunofluorescence (IF). Image analysis algorithms were used to assess the density of CD163-positive cells (dCD163) in tumor areas with high CD8+ T cell-infiltrates. In addition, dCD163 was also assessed in randomly selected tumor areas. Log-transformed densities were correlated with objective response rate (ORR) and progression-free survival (PFS) using Cox proportional hazards and binary logistic (modeling odds of attaining objective response) regression analysis, respectively. Alpha level was set a priori at 5% (2-sided). The functional form of CD163 for the PFS endpoint was obtained using a smoothed martingale residual plot. Results: Analysis of dCD163, assessed in high-CD8+ cell tumor areas and measured as a continuous variable, showed a positive association with ORR (OR= 2.21, p= 0.002) and PFS (HR= 0.77, p= 0.028). However, visual inspection of the dCD163 functional form plot for PFS revealed a threshold effect at the raw (log-transformed) value of 262.5 (5.6) cell/mm 2 . Similar to the entire cohort, in patients with dCD163 below this threshold (n= 54), dCD163 was positively associated with PFS (HR= 0.61, p&lt;.001). In contrast, in patients with dCD163 above this threshold (n=13), results suggested the presence of a negative association between dCD163 and PFS (HR= 1.36, p= 0.726). Of note, similar findings were obtained by analyzing dCD163 assessed in random tumor areas. Conclusions: Levels of tumor-infiltrating CD163-positive macrophages are associated with improved clinical outcomes to first-line nivolumab in pts with advanced ccRCC up to a density threshold, above which an association with poor outcomes is noted. Further investigations into the role of tumor-infiltrating myeloid cells in predicting outcomes to anti-PD-1-based therapies are ongoing. Clinical trial information: NCT05403541 .
SWOG S2210: A phase II study of neoadjuvant carboplatin for localized, high-risk prostate cancer with germline <i>BRCA1/2</i> mutations.
Authors: Heather H. Cheng, Samuel Callis, Daniel W. Lin, Evan Y. Yu, Tanya B. Dorff, Adam McLain Kase, Catherine Tangen, Daniel P. Petrylak, Seth P. Lerner
Journal: Journal of Clinical Oncology (2024)

TPS354 Background: Carriers of germline pathogenic variants or mutations in BRCA2 and BRCA1 (referred to here as gBRCA1/2m) are enriched in metastatic prostate cancer (PrCa), and now have FDA-approved options for PARP inhibitors in late-stage disease. The NCCN guidelines recommends germline genetic testing for PrCa patients with metastatic, node positive and high risk localized prostate cancer. Prior studies have shown that gBRCA1/2m carriers with PrCa are more likely to have high-risk disease (6,7) and to develop lethal disease even after curative intent treatment (8,9). In other gBRCA1/2m-related cancers (breast, ovarian and pancreas), platinum-based regimens are part of neoadjuvant and front-line metastatic therapy options. Carboplatin is a well-tolerated, widely available and inexpensive DNA-damaging alkylating agent that is familiar to oncologists. The study hypothesis is that 4 cycles of neoadjuvant carboplatin, followed by radical prostatectomy for patients with localized high/very high risk PrCa and g BRCA1/2m will result in a meaningful pathologic complete response (pCR) rate. Methods: S2210 is a single-arm, open label study of 12 wks neoadjuvant carboplatin (4 cycles of AUC 5 every 21 days), followed by radical prostatectomy. Key eligibility criteria include people with high/very high-risk disease: cT3a or Grade Group 4-5 PrCa and/or PSA&gt;20 ng/mL, have no evidence of distant metastases by conventional imaging (PSMA-PET-detected mets permitted if conventional imaging is negative and surgeon deems PSMA-detected sites resectable), who are candidates for radical prostatectomy and carboplatin, and have documented evidence of gBRCA1/2m through testing in a CLIA-certified lab. ADT prior to registration is permitted but must be discontinued on study. The study hypothesis is that the study treatment will result in ³30% rate of pathologic complete response (pCR, primary endpoint). A two-stage design will be used such that if ³1 of first 20 eligible patients achieves pCR, 20 further evaluable patients will be enrolled. This design has a significance level of 4.7%, and a power of 99%. Secondary endpoints include biochemical recurrence-free (at 2-, 3-, 5-yrs), metastasis-free and overall survival. Translational/correlative studies include analysis of 2nd allele inactivation in tumor, HRD signature, and ctDNA signature for monitoring of recurrence. S2210 was activated in August 2023. Clinical trial information: NCT05806515 .
Oral cyclophosphamide (Cyc) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A retrospective cohort from a tertiary public cancer center in Brazil.
Authors: Yumi Ricucci Shinkado, Diana Del Cisne Pineda Labanda, Gabriel Berlingieri Polho, Gustavo Alves Contado, Nathália de Souza Del Rey Crusoé, Vivian Horita, João Carlos Resende Martins, Guilherme Fialho de Freitas, David Queiroz Borges Muniz, Jose Mauricio Mota
Journal: Journal of Clinical Oncology (2024)

150 Background: Oral Cyc is an active treatment for mCRPC, although largely unused in current clinical practice due to the rise of more effective options and no evidence of survival benefit. Real-world data on its use in developing countries is still scarce. Methods: We reviewed our institutional database to identify mCRPC pts who received oral Cyc. Medical charts were analyzed to extract clinical data. PSA50 response was determined as the proportion of patients achieving a prostate specific antigen (PSA) declines ≥50%. Radiographic responses and progression were evaluated by Prostate Cancer Working Group 3. Survival estimates used the Kaplan-Meier method and correlations were made with the Chi-square test for categorical variables. Results: From January 2011 to January 2023, 287 pts received oral Cyc. Most patients (&gt;96%) received 100 mg once daily 3 weeks on/1 week off. Median age was 64.3 years (interquartile range [IQR] 35.8-85.3). 63.1% had metastatic de novo disease, 57.1% had Gleason ≥8, and 5.9% had visceral metastasis. 78.1% received two or more previous lines of treatment, and most pts (73.5%) had docetaxel previously. Any PSA decline was observed in 36.0%, and 15.0% had a PSA50 response. Median time for a PSA50 response was 2.7 months (IQR 1.3-3.8). Radiographic overall response rate was 24.2%. Median time on treatment was 2.53 months (IQR 0.40-51.9). Median time to PSA, clinical, or radiological progression among responders was 6.9 months (IQR 0.7-51.9), but 16.6% (n=7) had responses lasting for ≥12 months. Permanent treatment discontinuation due to toxicity occurred in 14.1%, and 8.0% were hospitalized due to adverse events. Table shows the association between baseline factors with PSA50 response. Correlative biomarker studies are ongoing and will be presented. Conclusions: Metronomic oral Cyc can benefit a small proportion of patients with mCRPC in a scenario of limited healthcare resources. [Table: see text]
Radiographic progression without PSA progression in metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective analysis from the ENZAMET trial (ANZUP 1304).
Authors: Ian D. Davis, Andrew James Martin, Robert Richard Zielinski, Alastair Thomson, Thean Hsiang Tan, Shahneen Sandhu, M. Neil Reaume, David William Pook, Francis Parnis, Scott A. North, Gavin M. Marx, John McCaffrey, Raymond S. McDermott, Andrisha Jade Inderjeeth, Lisa Horvath, Mark Frydenberg, Simon Chowdhury, Kim N. Chi, Martin R. Stockler, Christopher Sweeney
Journal: Journal of Clinical Oncology (2024)

151 Background: ENZAMET randomized 1125 participants with mHSPC to compare enzalutamide (ENZA) versus a standard non-steroidal anti-androgen (NSAA) and demonstrated superior progression-free survival and overall survival (PFS and OS) with ENZA. Radiographic progression in the absence of prior/concurrent PSA progression (rProg1st) is an emerging biomarker of poor clinical outcomes. We sought to determine the frequency of rProg1st, and correlate the impact of enzalutamide on transitions between disease states for the ENZAMET cohort. Methods: The ENZAMET dataset was analyzed using a multi-state Cox proportional hazards regression model that partitioned the clinical experience of participants (pts) into 4 states: (1) Evt-Free (event-free), (2) rProg1st (radiologic progression recorded without prior/concurrent evidence of confirmed PSA progression), (3) OtherProg (All Other type of clinical progression events (PSA and treatment switch, excluding death), (4) Death. Results: Radiographic progression was recorded in 388/1125 (34%) pts. Radiographic progression without confirmed prior/concurrent PSA progression per protocol was recorded in 114/1125 (10%) with similar proportions in those assigned ENZA 55/114 (48%) vs NSAA 59/114 (52%). Baseline characteristics of the 114 pts with rProg1st were similar to the other pts in ENZAMET, and were similar in the ENZA and NSAA groups (Table 1). Compared with NSAA, ENZA delayed both rProg1st (HR 0.66, 95%CI: 0.46 to 0.96, p=0.03) and OtherProg (HR 0.37, 95%CI: 0.31 to 0.44, p&lt;0.001). 5-year OS rates were 24% (95%CI: 18-34) in the rProg1st group versus 42% (95%CI: 38-47) in the OtherProg group. Of those who had not progressed (495/1125) with a median follow-up of 68 months, 8% had died of causes other than prostate cancer. As previously reported ENZA prolonged overall survival in the whole trial cohort (N=1125, HR 0·70, 95%CI 0·58 to 0·84, p&lt;0·0001). Conclusions: Participants who had radiographic progression without prior/concurrent PSA progression had worse overall survival whether assigned NSAA or enzalutamide. Enzalutamide reduced the hazards for, and delayed the times to, rProg1st and OtherProg. There were no baseline characteristics that helped identify these pts upfront; we plan molecular biological analyses to help identify this unique group earlier. Clinical trial information: NCT02446405 . [Table: see text]
COMBAT: A study of <sup>64</sup>Cu-SAR-BBN and <sup>67</sup>Cu-SAR-BBN for identification and treatment of GRPr-expressing metastatic castrate-resistant prostate cancer.
Authors: Luke T. Nordquist, Eva Lengyelova, Frankis Almaguel, Brandon Robert Mancini, Hong Song, Andrew J. Armstrong, Amado J. Zurita, Monique Anderson, Michelle Parker, Robert M. Miller, Andrei Iagaru
Journal: Journal of Clinical Oncology (2024)

TPS247 Background: Metastatic castrate resistant prostate cancer (mCRPC) is an advanced and lethal form of prostate cancer. Prostate-specific membrane antigen (PSMA)-targeted theranostic agents, 68 Ga-PSMA-11 and 177 Lu-PSMA-617, have been approved by the FDA for patient selection and therapy for patients with mCRPC, respectively. Approximately 25% of patients with mCRPC show low or no PSMA expression. Consequently, these patients are unlikely to benefit from PSMA-targeted agents and represent a significant unmet need for both imaging and therapy. The Gastrin Releasing Peptide receptor (GRPr) is a transmembrane G-protein coupled receptor that is upregulated in many human cancers, including PC. A promising new theranostic pair, consisting of 64 Cu-SAR-BBN (imaging) and 67 Cu-SAR-BBN (therapy), targets the GRPr. This may offer a potential imaging and treatment option for patients with low or no PSMA expression. Methods: COMBAT is a multi-center, open-label, phase I/IIa dose-escalation and cohort expansion study of 64 Cu-SAR-BBN and 67 Cu-SAR-BBN administered to patients with mCRPC. Eligible patients will have progressive mCRPC, prior exposure to at least one androgen receptor pathway inhibitor, will be ineligible for 177 Lu-PSMA-617 therapy, and show a positive 64 Cu-SAR-BBN PET. This study is being conducted in 2 phases: a Dose Escalation Phase (n=up to 24) and a Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of safety of 64 Cu- and 67 Cu-SAR-BBN, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67 Cu-SAR-BBN. The 67 Cu-SAR-BBN dose levels investigated in the escalation phase include: 6 GBq (cohort 1, single dose with dosimetry assessment), 10 GBq (cohort 2, single dose), 14 GBq (cohort 3, single dose), and up to 28 GBq across two doses (cohort 4, two doses at MTD/MFD). Additional doses may be administered during the Dose Escalation Phase (maximum of 4 doses in each cohort). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67 Cu-SAR-BBN at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response, and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 1 is open for enrollment. Clinical trial information: NCT05633160 .
Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Authors: Michael Thomas Serzan, Opeyemi Jegede, Mehmet Asim Bilen, David A. Braun, David Johnson Einstein, Naomi B. Haas, Hans J. Hammers, Jennifer King, Karie Runcie, Jeffrey A. Sosman, Cora N. Sternberg, Yuanquan (Aaron) Yang, Toni K. Choueiri, Sabina Signoretti, Michael B. Atkins
Journal: Journal of Clinical Oncology (2024)

TPS492 Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC ( favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has &gt; 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR &gt; 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .
EORTC GUCG 2238 De-escalate: A pragmatic trial to revisit intermittent androgen-deprivation therapy in metastatic hormone-naïve prostate cancer in the era of new AR pathway inhibitors.
Authors: Guillaume Grisay, Fabio Turco, Anna Patrikidou, Enrique Gallardo Díaz, Raymond S. McDermott, Saskia Litiere, Beatrice Fournier, Silke Gillessen, Bertrand F. Tombal
Journal: Journal of Clinical Oncology (2024)

TPS232 Background: The development of androgen receptor pathway inhibitors (ARPI) - abiraterone acetate, apalutamide, darolutamide and enzalutamide - has profoundly reshaped the management of metastatic hormone naïve prostate cancer (mHNPC). Seven trials demonstrated that combining these drugs with androgen deprivation therapy (ADT) reduces the risk of death by 20-40%, delays further treatment, and improves health-related quality of life (HR-QoL). These trials, however, suffer from two critical limitations: treatment duration and patient selection. Treatment usually continues until biochemical, radiological, or clinical progression, sometimes many years after drug initiation, exposing patients to chronic side effects affecting their QoL. Furthermore, registration trials include those not representative of the general population. Several sub-analyses of the registration trials demonstrated that patients achieving a PSA ≤0.2 ng/ml have prolonged overall survival (OS). In this study, we hypothesized that patients reaching PSA ≤ 0.2 ng/ml may benefit from treatment interruption without compromising OS. Methods: The primary goal of this academic-led, open-label, multicenter, pragmatic, randomized phase III study is to investigate whether intermittent maximum androgen blockade (iMAB) can be safely administered to mHNPC patients who reached a PSA ≤ 0.2 ng/mL at 6-12 months of continuous treatment (cMAB), as compared to continuing cMAB. Recommendations for restart include increasing clinical or radiological progression or PSA to ≥ 50% of diagnostic PSA with a maximum of 5 ng/mL.This will be demonstrated through the following co-primary objectives: 1) The proportion of patients who do not need to restart their MAB within one year of interruption is not less than 70%. 2) OS using an iMAB regimen at three years is non-inferior to continuous treatment. Secondary objectives include toxicity comparisons, HR-QoL (physical functioning, role functioning and fatigue scales of EORTC QLQ-C30, sexual activity scale of EORTC QLQ PR25), and assessing the impact on treatment resources of using an intermittent schedule. The study will include 1600 patients treated by cMAB for mHNPC for 6-12 months presenting with a PSA ≤ 0.2 ng/mL. Patients may have received docetaxel and radiotherapy as part of standard treatment. The PRECIS-2 (Pragmatic-Explanatory Continuum Indicator Summary) will be used to evaluate the study as a pragmatic trial. Clinical trial information: NCT05974774 .