tbuckley/cabot-search huggingface dataset:
Implementing precision oncology in renal cell carcinoma (RCC): Prospective identification of clinical, tissue-based, and circulating factors to refine outcome prediction and support therapeutic choices (SIGNS-RCC TRIAL).
Authors: Ilaria Zampiva, Emanuela Fantinel, Veronica Mollica, Sara Elena Rebuzzi, Davide Bimbatti, Francesca Bertolotti, Matteo Brunelli, Stefano Manduca, Pierpaolo Marchetti, Andrea Marchetti, Jessica Menis, Guido Martignoni, Cecilia Nasso, Michela Piacentini, Francesco Pierantoni, Matteo Rosellini, Giuseppe Verlato, Roberta Vesentini, Michele Milella, Anna Caliò
Journal: Journal of Clinical Oncology (2025)

TPS617 Background: At diagnosis, 55% of RCC are localized, and 25% are locally advanced/metastatic (aRCC); an additional 30% develop metastases during follow-up. Prognosis is highly variable in both resectable and advanced disease. All patients’ stratification tools are based on clinical risk scores. For resected patients, only pembrolizumab has demonstrated OS benefit in the adjuvant setting. For metastatic disease, first-line combos (IO-IO and IO-TKI) have dramatically improved outcomes in intermediate/poor-risk patients but have shown no additional OS benefit over TKI in good-risk patients. Methods: We designed a multicentric trial to identify novel prognostic/predictive biomarkers to refine current therapeutic algorithms for systemic therapy in both early-stage and aRCC in three different cohorts of patients. Cohort (A) includes patients who underwent radical surgery for RCC (resected, rRCC). Cohort (B) is a retrospective cohort that reclutes aRCC treated with VEGFR TKI monotherapy in I line. The prospective cohort (C) enrolls aRCC patients who are candidate to receive current I-line IO-TKI combos. In the first part, we will correlate patient- and tumor-related factors with the risk of recurrence after surgery for rRCC and progression-free survival and overall survival for aRCC. Tissue-based signatures will be obtained using IHC (PD-L1 expression, tumor immune microenvironment - TiME - composition), an NGS custom panel (mutational profiling), and FISH (for recurrent RCC alterations, such as 9p loss). Multiplex IHC and RNA-ISH will assess cytokine production by specific TiME components. Correlations between the obtained signatures and clinical outcomes will be calculated. In cohort C, the prognostic role of circulating factors (serum cytokine levels and mononuclear cell subpopulations, focusing on MDSC and TReg) will also be evaluated in addition to clinical and tissue-based factors. Blood samples will be collected before and during I-line treatment at pre-planned timepoints. Biomarkers will be quantitatively analyzed to evaluate their relationship with outcomes. Enrollment is ongoing.
Updated results from a phase I/II study of CBP-1018, a bi-ligand–drug conjugate (Bi-XDC) as late line therapy for patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Kaiwen Li, Jianming Guo, Hongqian Guo, Qi Zhang, Hang Huang, Liyan Zhou, Junyong Dai, Jimin Chen, Lu Yang, Xudong Yao, Robert Huang, Mo Xu, Jing Zhang, en-Tzu Tang, Yehui Shi, Hai Huang
Journal: Journal of Clinical Oncology (2025)

161 Background: Patients (Pts) with mCRPC have a poor prognosis with limited treatment options, particularly those who have progressed after novel hormonal agents (NHA) and chemotherapy. CBP-1018 has demonstrated a well-tolerated safety profile based on 112 pts and preliminary efficacy in mCRPC at RP2D of 0.14mg/kg as shown in 2024ASCO and 2024ESMO. Here we report the updated safety data of 120 pts and efficacy at ≥0.14mg/kg including pts treated with prior 2 nd generation androgen receptor pathway inhibitor (ARPI) and taxane from the Phase I/II study. Methods: In this study, pts with progressive mCRPC after standard of care regardless of the number of prior therapies were enrolled. Response evaluation was undertaken per PCWG3 and RECIST v1.1. Primary endpoints were ORR, rPFS and safety. Results: As of cutoff date of 31-Aug 2024, a total of 120 pts were enrolled. 8.3% (10/120) of pts experienced treatment related adverse event (TRAE) leading to dose reduction and 4.2% (5/120) had TRAE leading to discontinuation. The AEs were consistent with the known safety profile, with the most common ≥G3 TRAE primarily being hematologic, which were transient and easily manageable. Typical common AEs seen with ADC were rarely observed; only 1 pt experienced treatment related visual acuity reduction and 11.7% (14/120) of pts experienced peripheral neuropathy. All of these TRAEs were G1. 76 pts were enrolled at ≥0.14mg/kg dose level (0.14mg/kg N=69; 0.16mg/kg N=7). 68.4% (52/76) with ECOG 1. 17.1% (13/76) had liver metastases and 15.8% (12/76) had lung metastases. Additionally, 67.1% (51/76) had received at least one prior taxane and at least one 2 nd generation ARPI, while 53.9% (41/76) had received ≥ 2 prior 2nd generation ARPIs. 21.1% (16/76) had received prior PARP inhibitors. Among 25 pts with target lesion (≥0.14mg/kg), ORR was 20% and DCR was 88.0%. Target lesion reduction was observed in 60% of pts. In the subset of 15 pts with prior taxane and 2 nd generation ARPI treated pts with target lesion (0.14mg/kg), ORR was 20% and DCR was 80%. Among 69 pts (0.14mg/kg), median radiographic progression-free survival (rPFS) has not yet been reached; 7-month rPFS rate was approximately 70%, and 12-month rPFS rate was about 60%. Among the 48 pts with prior taxane and 2 nd generation ARPI treated (0.14mg/kg), 7-month rPFS rate was around 66%. Conclusions: CBP-1018 shows potential as a viable therapeutic option for heavily treated mCRPC pts based on the superior rPFS and anti-tumor activity, warranting further evaluation in later phase III trials. Clinical trial information: NCT04928612 .
Patient characteristics and overall survival with lutetium (Lu <sup>177</sup> ) vipivotide tetraxetan ( <sup>177</sup> Lu-PSMA-617): A real-world analysis of early adopters.
Authors: Daniel J. George, Neal D. Shore, Jennifer Nguyen, Jeetvan Patel, Amrita Sawhney, Barinder Kang, Chi-Chang Chen, Magdaliz Gorritz, Xiao X. Wei
Journal: Journal of Clinical Oncology (2025)

63 Background: 177 Lu-PSMA-617, a prostate-specific membrane antigen (PSMA)-targeting radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC), received FDA approval in March 2022 for the treatment of adult patients with PSMA-positive mCRPC who have received both an androgen receptor pathway inhibitor (ARPI) and a taxane-based chemotherapy. Outside of clinical trials, limited real-world evidence evaluating the effectiveness of 177 Lu-PSMA-617 has been reported. The aim of the current study was to evaluate patient characteristics and overall survival (OS) among patients diagnosed with mCRPC who were treated with 177 Lu-PSMA-617 within a large-scale real-world cohort. Methods: This retrospective, observational study used the IQVIA PharMetrics Plus claims data from July 1, 2013 to December 31, 2023, and linked social determinants of health data as well as mortality data to obtain month and year of death. Adult men with mCRPC who had received 177 Lu-PSMA-617 were included (first receipt of 177 Lu-PSMA-617 = index date). Patient demographics and characteristics were evaluated descriptively; patient demographics were reported on the index date and clinical characteristics were evaluated over the 12 months prior to index date. OS was measured from the start of the first 177 Lu-PSMA-617 treatment until death or end of available follow-up, and assessed using Kaplan–Meier analysis. Results: A total of 643 patients were included in the analysis; median age was 69 years. Treatment for the majority of patients (490/643 [76.2%]) was managed by oncologists (169 [26.3%] of which had specialty in radiation oncology). White patients (292 [72.8%]) made up the largest part of the patient population followed by Black (37 [9.2%]), Hispanic (23 [5.7%]), and Asian (8 [2.0%]). Most patients had multiple comorbidities with either one (226/643 [35.1%]) or two (224/643 [34.8%]) sites of metastasis. Most patients experienced bone metastases (581/643 [90.4%]); 284/643 (44.2%) also experienced visceral metastases of which the liver was the most common site (78/643 [12.1%]). The median OS from start of 177 Lu-PSMA-617 therapy was 15.3 months (95% confidence interval [CI]: 14.6–16.3); a total of 137/643 (21.3%) patients died. OS was analyzed in different patient subgroups and no major differences were observed by metastatic site, number of metastatic sites, race, or age. Conclusions: To our knowledge, this is the first large-scale study reporting OS with 177 Lu-PSMA-617 in clinical practice. OS observed with 177 Lu-PSMA-617 in this study (median: 15.3 months) was consistent with results from the VISION Phase III clinical trial (median: 15.3 months; NCT03511664). Furthermore, 177 Lu-PSMA-617 demonstrated similar survival across different patient subgroups.
Phase 1b/2 study of combination <sup>177</sup> Lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC.
Authors: Eric Jonasch, Elshad Hasanov, Lesley Flynt, Rebecca Slack Tidwell, Hyunsoo Hwang, Roserika Brooks, Lauren Michelle Wood, Travis Solley, Dahlia Mack, Yuko Yamamura, Aradhana M. Venkatesan
Journal: Journal of Clinical Oncology (2025)

TPS614 Background: Complete response (CR) is a rare event in advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for first-line treatment of ccRCC, demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, CR is only 9%. Drugs that could synergize with T cell anti-tumor activity can improve CR rates. Radiation-induced DNA damage to activate the cGAS-STING pathway is a promising mechanism. 177 Lu-girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9, expressed in &gt;90% ccRCC, to deliver targeted radiation to cancer with minimal damage to surrounding healthy cells. As a single agent in metastatic ccRCC, 177 Lu-girentuximab was safe and effective in stabilizing disease in 57% of patients. We hypothesize 177 Lu-girentuximab-induced DNA damage will potentiate the STING pathway, synergizing with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells and achieve higher CR rates. Methods: Up to 100 patients with treatment naive, biopsy-proven ccRCC with adequate organ/marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta (0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177 Lu-girentuximab 1480 MBq/m 2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18 F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics, and proteomics studies. Clinical trial information: NCT05663710 .
Evaluation of MIR-371A-3P for clinical implementation in a CLIA-certified laboratory.
Authors: Melis Gür, Kshitij Pandit, John T. Lafin, Cinzia Scarpini, Armon Amini, Bendu Konneh, Jeffrey Howard, Thomas Gerald, Michelle Nuno, Jin Piao, Nicholas Coleman, Lindsay Frazier, Matthew Murray, Sarah Murray, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2025)

648 Background: MicroRNAs (mi-RNAs) have emerged as promising biomarkers for the detection of viable germ cell tumors (GCT). Our previous work in a research lab demonstrated optimal performance with positive results that had Cq values less than 28, an indeterminate range between 28-35 and negative results greater than 35. In this study, we assessed performance characteristics of miR-371a-3p in a CLIA certified lab at UCSD. Methods: Due to workflows, equipment and scaling, several modifications were required from our original research protocol. Ultimately, serum samples from 53 cases and 139 controls were analyzed using qPCR for miR-371a-3p in the CLIA lab. Initial runs and re-runs were conducted for the indeterminate samples. Metrics used for calculation of performance were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC) and Youden’s index. Results: We used two analytic pipelines for classifying positive and negative Cq values: 1) a binary cutoff of 26.9 and, 2) an indeterminate range of 25.6 to 31.5. Using the binary cutoff, a sensitivity of 86%, specificity of 98%, PPV of 94%, NPV of 95%, AUC of 0.94 and Youden index of 0.85 was observed. In contrast, initial runs on the indeterminate ranges yielded a sensitivity of 95%, specificity of 99%, PPV of 97%, NPV of 98%, AUC of 0.97 and Youden index of 0.94. However, 36% (51 of 139) controls fell into the indeterminate range. Re-runs on these samples demonstrated similar findings. Conclusions: Our data demonstrated that there are likely lab specific, protocol specific and disease-state specific analytics and thresholding for circulating miR-371a-3p testing. These factors will need to be carefully considered while moving towards clinical implementation.
Assess the journey: Characterizing muscle-invasive bladder cancer patients who receive neoadjuvant therapy and do not proceed with cystectomy.
Authors: Jay Ogunkeye, Ruth E Belay, Eila C. Skinner
Journal: Journal of Clinical Oncology (2025)

746 Background: The standard treatment of muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), offering a 5-10% survival benefit and reducing recurrence by 35%. However, little is known about the patients who start NAC but do not proceed to RC. In the SWOG-8710 trial, 18% of patients did not undergo surgery after NAC. Platinum-based regimens, while generally well tolerated, sometimes cause severe side effects. With increasing NAC use and evolving treatment options, some patients start NAC without completing definitive treatment. This study aims characterize patients who do not proceed with RC, focusing on their NAC experience and alternative treatments. Methods: A retrospective analysis was performed on MIBC patients recommended for neoadjuvant therapy followed by RC between 2020-2023 by a single provider at Stanford Health Care. Eligible patients had clinically localized bladder cancer (cT2-T4N0) who initiated neoadjuvant therapy and were deemed surgical candidates. Patients who were not platinum-eligible received alternative therapies on clinical trials . Data were collected on patient demographics, comorbidities, functional status, renal and hematologic function, and NAC administration. Patients who underwent cystectomy were excluded. Results: A total of 90 patients with MIBC who had a treatment plan involving neoadjuvant therapy followed by RC between 2020-2023 were identified. 22% (20/90) of these patients did not undergo cystectomy. The median age was 76, 75% male, 75% white. 50% of patients had variant or non-urothelial carcinoma histology. 60% were cT2 at time of initial consult. The majority of patients (80%) received platinum-based NAC, with only 4 receiving alternative therapies. One patient died of a stroke before completing NAC. The reasons for not undergoing RC were declining additional treatment (30%) and inability to tolerate surgery due to toxicity from therapy (30%), followed by patient preference of radiation therapy (20%), and disease progression (10%). Two additional patients were taken to the operating room; however, surgery was aborted due to unresectable disease and anesthetic complications. Among those who did not undergo RC, 42% opted for surveillance, 37% received trimodal therapy (TMT), and 21% received additional immunotherapy. Conclusions: In this study, we were able to gain a better understanding of our patient cohort who started neoadjuvant therapy but did not proceed to cystectomy. Reasons for this decision included toxicity related to neoadjuvant therapy, personal desire to forgo surgery, or prioritization of bladder preservation. These findings highlight the need for future efforts aimed at trying to predict this patient population and further comparative analysis of outcomes between this cohort and those who underwent cystectomy.
Characterization, treatment and survival outcomes of penile cancer: Over a decade in a tertiary Mexican center.
Authors: Cristhel Cervin, Aaron Saenz, Mariana Perez Rosado, Maria Guadalupe Diaz Alvarado, Perla Perez, Jorge Aguirre, Mariana Madrid Morales
Journal: Journal of Clinical Oncology (2025)

5 Background: Penile cancer, as a rare disease worldwide, represents 4.1% of urological cancers in Mexico. Despite the need for multimodal treatments, delayed diagnoses and poor follow-up adherence impact survival outcomes. This study aims to characterize the patient population diagnosed with penile cancer at a tertiary center in Mexico and evaluate treatment and survival outcomes. Methods: This cross-sectional retrospective cohort study analyzed patients diagnosed with penile cancer at the medical oncology and urology services of Centro Médico Nacional 20 de Noviembre from January 2005 to January 2024. Statistical analyses included Kaplan-Meier survival analysis and subgroup analyses by age, surgical treatment type and radiotherapy. Results: Of the 54 patients analyzed, the median age was 64 years (34-84) with a median time symptoms to diagnosis of 12 months. Clinical stages at diagnosis were stage I (9.2%), II (40.7%), III (29.6%) and IV (20.3%). Human papillomavirus (HPV) was positive in 17 patients (31.4%), negative in 2 (3.7%) and undetermined in 35 (64.8%). HIV status was undetermined in 88.8% of cases. Additionally, 22 patients (40.7%) were smokers. Tumor anatomical locations were glans (64.8%), prepuce (25.9%), body of the penis (7.4%) and scrotum (1.8%). Histologically, all cases were squamous cell carcinoma. Most common sites of metastasis were lymph nodes (79.6%), lungs (7.4%) and liver (5.5%). Systemic therapy was administered to 38.8% and radiotherapy to 55.5% with a median overall survival of 44.8 months. Surgical treatment was required in most cases (88.8%), with total penectomy and bilateral inguinal dissection predominating in 21 patients (38.9%), followed by total penectomy alone in 8 (14.8%), partial penectomy with bilateral inguinal dissection in 6 (11.1%) and partial penectomy in 8 (14.8%). Tumor resection alone was performed in 5 (9%). Subgroup analysis based on age, surgical technique and radiotherapy indicated that overall survival was not significantly affected by age when comparing patients &lt;60 years to those &gt;60 years (p=0.1). However, patients undergoing partial penectomy had significantly higher survival rates (12 months vs 7 months; p=0.04), regardless of clinical stage. There was no significant difference in overall survival between patients who received radiotherapy and those who did not (p=0.7). Conclusions: Despite advanced stage at diagnosis, the results suggest that surgical intervention is associated with improved survival rates. However, neither age nor radiotherapy significantly impacted overall survival outcomes, likely due to the homogeneity of clinical stages and surgical approaches. These findings underscore the importance of early detection and comprehensive management strategies to improve survival in this patients.
<i>FGD1</i> splice variants as predictors of brain and bone metastatic organotropism in clear cell renal cell carcinoma.
Authors: Justin Miller, Alyssa N Obermayer, Mitchell T. Hayes, Roy Elias, Nirmish Singla, Michelle L. Churchman, George Daniel Grass, Ahmad A. Tarhini, Paola Ramos Echevarria, Alex C. Soupir, Youngchul Kim, Eric A. Singer, Sean Kern, Yousef Zakharia, Paul Vincent Viscuse, Patrick J. Hensley, Timothy I Shaw, Brandon J. Manley
Journal: Journal of Clinical Oncology (2025)

577 Background: Approximately 30% of patients with ccRCC present with metastatic disease (stage IV) and close to half of patients with stage III disease will recur during follow-up surveillance. Two of the most common and morbid sites of metastatic development are brain and bone metastasis. Existing treatment guidelines do not recommend routine brain or bone directed imaging during either initial staging or surveillance in the absence of clinical signs or symptoms. A group of recurrently altered aberrant splice variants in primary ccRCC tumors associated with metastatic progression have previously been identified. Our study aims to investigate metastatic organotropism of the FGD1 -splice variant ( FGD1 -SV) to refine risk stratification and therapeutic decision-making as cabozantinib is drug with activity at these disease sites. Methods: This study leveraged the ORIEN AVATAR network, a data-sharing alliance of 18 NCI-designated cancer centers, to evaluate the presence of FGD1 -SV in a cohort of 1,001 clear cell renal cell carcinoma (ccRCC) patients using bulk RNA-sequencing (RNA-seq). Samples with three or more FGD1 -SV reads were classified as positive. Clinical and survival data were collected, and Kaplan-Meier curves were generated. Odds ratios (ORs) evaluated the presence of FGD1 -SV on brain and bone metastases, while hazard ratios (HRs) assessed association with cabozantinib response. Of 1,037 RNA-seq samples, 84 were metastatic tumor specimens. The relationship between FGD1 -SV positivity and metastasis to common sites was assessed with Fisher's exact test. Results: Brain and bone metastases demonstrated the highest FGD1 -SV positivity (50% and 44%, respectively). A grouped comparison of brain and bone metastases versus all other common metastatic sites (adrenal, lymph node, pancreas, lung, and liver) revealed significant enrichment of FGD1 -SV in these metastases (OR 5.33, 95% CI [1.64 - 18.42], p=0.002). FGD1 -SV positivity in primary tumors was associated with greater risk of recurrence after surgical resection (p=0.0029). Furthermore, FGD1 -SV positive tumors were associated with poor survival when not treated with cabozantinib (HR 2.04, 95% CI [1.20 - 3.45], p=0.01). Conclusions: FGD1 -SV positivity is significantly associated with brain and bone metastatic organotropism in ccRCC. Our findings warrant prospective studies to validate these results and investigate the integration of FGD1 -SV into clinical decision-making, potentially guiding surveillance and therapeutic approaches in high-risk and metastatic patients.