tbuckley/cabot-search huggingface dataset:
FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors.
Authors: Glenn J. Hanna, Douglas Adkins, Jacob Stephen Thomas, Justine Yang Bruce, Manish R. Patel, Guru P. Sonpavde, Jason Timothy Henry, Nawal Bendris, Zijing Zhang, Amitava Mitra, Amaya Gasco Hernandez, Andrew Saunders, Stephen Dale
Journal: Journal of Clinical Oncology (2024)

TPS4607 Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant ( HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Methods: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Clinical trial information: NCT06026410 .
Comparative outcomes of radical nephroureterectomy and kidney-sparing surgery in the treatment of high-grade upper tract urothelial carcinoma.
Authors: Kyle Moore, Helen Gao, Jennifer Delgado, Anirudh Kulkarni, Benjamin Lichtbroun, Kevin J. Chua, John Pfail, Arnav Srivastava, Vignesh T. Packiam, David Golombos, Thomas L Jang, Saum Ghodoussipour
Journal: Journal of Clinical Oncology (2024)

e16609 Background: Patients with upper tract urothelial carcinoma (UTUC) can be managed via radical nephroureterectomy (RNU) or kidney-sparing surgery (KSS) depending on pathology and patient characteristics. Unfortunately, UTUC is a rare disease lacking high-level evidence regarding clinical and oncologic outcomes after management. This study compares outcomes of RNU to KSS for high-grade (HG) UTUC. Methods: We retrospectively reviewed all patients with &gt;1 year follow-up treated for HG UTUC at our institution from 2015-2021. Oncologic and clinical outcomes were recorded. Procedure burden was analyzed as total procedures under anesthesia, anesthesia time, days hospitalized, and estimated cost of care. Results: We identified 17 patients treated with KSS and 46 with RNU. There was no significant difference in 5-year overall survival, 3-year metastasis-free survival, or 3-year recurrence-free survival with KSS compared to RNU (Table). The average change in GFR was 17.9 ± 18.3 mL/min/1.73 m² and 24.8 ± 21.0 mL/min/1.73 m² for patients who underwent KSS and RNU, respectively (p = 0.33). Renal function was preserved (GFR decline &lt;10 mL/min/1.73 m²) 2 years after surgery in 100.0% of patients who had KSS compared to 97.1% of patients who had RNU (p = 0.081). Patients who had KSS experienced a higher total number of procedures but fewer perioperative complications than those who had RNU with 3.4 ± 1.7 procedures vs 2.1 ± 1.7 procedures, respectively (p = 0.016), and 0% vs 41% of patients experiencing complications, respectively (p = 0.0098). Total anesthesia time and days hospitalized for KSS were similar to RNU at 400 ± 218 minutes vs 474 ± 185 minutes (p = 0.26) and 5.5 ± 4.3 days vs 6.8 ± 4.6 days, respectively (p = 0.36). Patients with KSS experienced a lesser in network but similar out of network cost of care to RNU patients at $7881 ± $4438 vs $10799 ± $4539 (p = 0.020) and $22159 ± $12401 vs $24523 ± $11282, respectively (p = 0.46). Conclusions: There were similar oncologic and clinical outcomes in HG UTUC patients treated with KSS or RNU. Patients treated with KSS endured a greater procedural load than patients who had RNU but at a reduced in network cost and with fewer complications. Larger datasets are needed to further evaluate outcomes and treatment burdens of RNU vs KSS as HG UTUC treatment. [Table: see text]
The prognostic significance of venous tumor thrombus grading for patients with renal cell carcinoma.
Authors: Silun Ge, Le Qu, Linhui Wang, Jingping Ge
Journal: Journal of Clinical Oncology (2024)

e16520 Background: Venous tumor thrombus (VTT) is observed in 4−10% of newly diagnosed RCC patients, and a successful radical nephrectomy and thrombectomy provides considerable palliation to a proportion of nonmetastatic RCC patients with VTT. However, the reported postsurgical survival varies significantly with the 5‐year overall survival (OS) rate ranging from 37.0 to 71.0%. Hence, accurate risk factors are critically needed for these patients. Here we evaluate the prognostic significance of VTT grading for these patients. Methods: The final evaluable dataset enrolled 706 consecutively nonmetastatic ccRCC patients who underwent radical nephrectomy and thrombectomy, including 304 in the Training cohort from the Eastern China Renal Cancer Collaborative Group, 320 in the China‐Validation cohort and 82 in the Poland‐Validation cohort. All pathological specimens were centrally reviewed by three genitourinary pathologists blinded to clinical information. Univariable and multivariable Cox regression analyses were performed to identify independent predictors associated with survival outcomes. Results: To comprehensively evaluate the potential of VTT in risk assessment, multiple characteristics of VTT were incorporated, including VTT height, consistency and the pathological nuclear grading of VTT (VTT grading), which has not been studied yet. Although higher pathological grading of primary tumor (PT) and VTT were both significantly correlated with dismal prognosis, only VTT grading remained as an independent predictive factor for OS and DFS after multivariable Cox regression. Furthermore, VTT grading showed superiority in risk assessment compared with PT grading and other variables by c‐index analysis (OS: 0.663 vs. 0.501–0.610, 0.667 vs. 0.544–0.651, and 0.719 vs. 0.511–0.700 for Training, China‐Validation, and Poland‐Validation cohorts, respectively; DFS: 0.664 vs. 0.501–0.606, and 0.672 vs. 0.530–0.640 for Training, and China‐Validation cohorts, respectively), which was confirmed by the receiver operating characteristic (ROC) analysis (OS: area under the curve [AUC] 0.764 vs. 0.650–0.664, 0.684 vs. 0.650–0.667, and 0.814 vs. 0.641–0.711 for Training, China‐Validation, and Poland‐Validation cohorts, respectively; DFS: AUC 0.753 vs. 0.648–0.651, and 0.704 vs. 0.601–0.665 for Training, and China‐Validation cohorts, respectively). Conclusions: VTT grading displayed superior accuracy and discriminatory ability in predicting survival risk for nonmetastatic ccRCC patients with VTT. Assessing VTT grading in routine pathology reports may provide further information for stratification of patient risk.
Noninvasive early detection and recurrence monitoring for non-muscle-invasive bladder cancer via urine tumor DNA.
Authors: Junlong Wu, Huanqing Cheng, Huina Wang, Libin Chen, Lei Liu, Shanbo Cao, Feng Lou, Ding-Wei Ye
Journal: Journal of Clinical Oncology (2024)

e16586 Background: Traditional methods for the detection and surveillance of non-muscle-invasive bladder cancer (NMIBC) were generally invasive, costly, and not effective for early-stage, low-grade, and minimal residual disease (MRD) tumors. Whether urine tumor DNA could be used to early detect urothelial carcinoma and monitor MRD with high sensitivity should be explored. Methods: We conducted a perspective study to determine the performance of utLIFE-UC (our previously reported urine tumor DNA multidimensional bioinformatic predictor) in early detection and recurrence monitoring of NMIBC (Trial No. ChiCTR2300072635). We prospectively recruited 49 patients initially diagnosed with NMIBC. Urine samples were collected prior to transurethral resection of bladder tumor (TURBT) and repeat TURBT (Re-TURBT) if needed. Postsurgical samples were collected every 3-6 months when patients underwent routine cystoscopy. The utLIFE-UC score &gt; 60 indicates a positive clinical significance. Results: Overall, utLIFE-UC could discriminate NMIBC with high sensitivities of 91.8% (45/49), both in different T stages (Ta, 84.0%; T1, 100%; P = 0.110) and grades (low-grade, 88.2%; high-grade, 93.3%; P = 0.613). Twenty patients underwent Re-TURBT, of whom 8 cases had residual tumor. The utLIFE-UC correctly diagnosed 8 of 8 (100%) patients with residual tumor. In addition, the assay showed a high NPV of 100%, implying that it may aid in avoiding Re-TURBT in patients predicted to have no residual tumor. Notably, utLIFE-UC score before Re-TURBT in patients with multiple tumors (MT) was markedly increased than that of patients with single tumor (ST) (P = 0.028). MRD-positive rate in MT patients was 100%, whereas 50% of ST patients were MRD-negative. During follow-up, recurrence status of 27 patients was collected, and 18.5% (5/27) of them recurred. The median follow-up time was 211 days (range 39 to 326 days). For patients receiving Re-TURBT, all the tumors with MRD-negative results before Re-TURBT, had no recurrence, further supporting the possible unnecessity of Re-TURBT in this population. The prognostic value of postsurgical utLIFE-UC results in NMIBC was explored. MRD-positive patients showed a worse recurrence-free survival than MRD-negative ones (median 200 days vs unreached; P = 0.001). However, it was not observed the correlation between prognosis and clinical features, including age, sex, tumor number, T stage, and grade. Compared to clinical confirmed recurrence, utLIFE-UC could predict recurrence with a median lead time of 100 days (range 17 to 140 days; P = 0.056). Conclusions: TheutLIFE-UC assay for early diagnosis, MRD detection and surveillance in NMIBC is a noninvasive and effective approach, which may contribute to reducing the burden of cystoscopy and invasive examination. Clinical trial information: ChiCTR2300072635 .
Single-center retrospective analysis of safety and efficacy of dose-reduced enfortumab vedotin (EV) in frail patients with metastatic urothelial carcinoma (mUC).
Authors: Wilbur Song, Yu Tao, Jingqin Luo, Bruce J. Roth, Melissa Andrea Reimers
Journal: Journal of Clinical Oncology (2024)

e16556 Background: EV is a Nectin-4 directed ADC with activity in mUC. EV monotherapy increased PFS and OS compared to salvage chemotherapy in pretreated mUC. EV + pembrolizumab increased PFS and OS compared to chemotherapy as first-line therapy and is being explored in the perioperative setting. Thus, EV will likely have an increasingly prominent role in the management of UC. However, EV is given until disease progression and has significant toxicities, especially for elderly or frail patients. Other than the initial dose escalation, no studies have reported the efficacy or safety of starting EV at a dose lower than the approved dose of 1.25 mg/kg. Methods: We performed a single-center retrospective analysis of patients treated with EV from 1/1/2020 to 12/25/2023. Data were collected by chart review including labs, imaging, and clinical documentation. Grades of toxicity were assigned based on CTCAE v5.0 criteria with available data. Radiographic response was determined by the investigator. We evaluated outcomes including ORR, PFS, OS, and EV-associated AEs, and compared these between patients who received 0.75 mg/kg (“low-dose”) and patients who received higher doses (“standard-dose”). Given the small sample size, we present only descriptive statistics. Results: We analyzed data from 18 patients treated with standard-dose EV and from 9 patients treated with low-dose EV. The low-dose group, compared with the standard-dose group, had a similar number of females (33% vs 44%) and non-whites (33% vs 28%), and higher median age at first EV dose (81 vs 68). The low-dose group had a lower rate of prior curative intent surgery (55% vs 78%) and upper tract disease (11% vs 50%), and fewer prior lines of treatment in the palliative setting (median 1 vs 2). In the low-dose group, ORR was 78% with CR in 33%. With a median follow up of 15.9 months, median PFS and median OS from EV initiation were not estimable. In the standard-dose group, ORR was 78% with CR in 28%. With a median follow up of 28.2 months, median PFS was 8.9 months and median OS was 24.1 months. The low-dose group had similar or lower grades of EV-associated AEs (Table). Conclusions: Patients treated with low-dose EV 0.75 mg/kg had similar responses compared to historical controls and a same-institution cohort of patients treated with standard-dose EV, with lower rates of GI toxicities, rash, and peripheral neuropathy. Findings are limited by small sample size, retrospective nature, and differences in baseline characteristics. Low-dose EV in elderly or frail patients with baseline comorbidities warrants prospective study. [Table: see text]
Tumor immune microenvironment analysis and MRI results of a phase II trial investigating tislelizumab (T) in the neoadjuvant treatment of high-risk upper tract urothelial carcinoma (UTUC).
Authors: Jiwei Huang, Xinyun Cai, Cheoklong Ng, Yuansheng Luo, Zaoyu Wang, Wen Kong, Jin Zhang, Yonghui Chen, Guangyu Wu, Haige Chen, Wei Xue
Journal: Journal of Clinical Oncology (2024)

e16582 Background: Although PD-1/L1 checkpoint inhibitors have shown promising efficacy results in the neoadjuvant treatment of urothelial carcinoma, part of patients may have disease progression during the treatment. Up to now, there is no definitive biomarker to predict the response of neoadjuvant immunotherapy. We have formerly reported the preliminary results of T, a PD-1 checkpoint inhibitor, in the neoadjuvant treatment of UTUC. Herein, we report the tumor immune microenvironment analysis and contrast-enhanced MRI results to explore possible pathological and radiological characteristics in correlation with treatment response. Methods: Patients were given T 200mg IV every 3 weeks for at most 4 cycles followed by surgery (radical nephroureterectomy, ureteral resection or endoscopic ablation). The primary endpoint was pCR rate (ypT0N0). The secondary endpoints included pathological response rate (≤ypT1N0), objective response rate and safety. Contrast-enhanced MRI examination was performed before the third dose and another before the surgery and the apparent diffusion coefficient(ADC) was calculated. The infiltrating immune cells pattern within tumor microenvironment was analyzed using multiplexed immunofluorescence (mIF) staining on pretreatment samples. Results: Between Mar 2021 and Sep 2022, 16 patients were enrolled. 4 patients (25%) patients achieved pCR and 7 patients (43.8%) were re-staged as ≤ypT1N0 at specimens. Best of response was cPR in 6 patients, cSD in 7 patients and cPD in 3 patients. The density of PD-L1+CD68+ cells in the stromal region was significantly higher in cPR patients compared to cSD or cPD patients before neoadjuvant treatment (p=0.002). Additionally, the density of PD-1+CD8+ cells in the stromal region of cPR patients was also higher, although the significance was borderline (p=0.065). The average value of ADC showed no statistically significant difference between cPR patients and cSD or cPD patients (p=0.997). However, a significant higher entropy of ADC was found in cPR patients compared with cSD or cPD patients (p=0.002). Conclusions: The elevated ADC entropy on MRI and the enrichment of PD-L1+CD68+ cells within tumor microenvironment before treatment were observed in cPR patients. Both characteristics might help to identify UTUC patients who can benefit from neoadjuvant immune therapy. Clinical trial information: NCT04672330 .
In-hospital outcomes of acute pulmonary embolism admissions in individuals with genitourinary cancers: Insights from a national population study in the United States.
Authors: David Joseph Benjamin, Arash Rezazadeh, Irfan Shafi, Omid Yazdanpanah
Journal: Journal of Clinical Oncology (2024)

e16581 Background: Management of acute pulmonary embolism (PE) in patients with genitourinary (GU) malignancies is usually challenging. It is usually associated with adverse outcomes and can significantly contribute to morbidity and mortality and detrimentally impacts quality of life among cancer patients. There has been scarce previous national population study on patients with PE and GU malignancies. Here, we studied the rate of readmissions and mortality for patients admitted for PE with GU cancers in the U.S. and its burden on health care system. Methods: Utilizing the Nationwide Readmissions Database (NRD), we conducted a retrospective cohort study on patients admitted with PE and segregated the individuals with GU cancers (GUC) including renal cell carcinoma (RCC), urothelial Carcinoma (UC), prostate cancer (PCa), testicular cancer (TC), and penile cancer (Pen Ca) between 2016 and 2019 across the United States. We used multivariable logistic regression to determine the predictors of unplanned readmissions within 30 days and mortality. Results: A total of 402,054 patients hospitalized with PE and 44,373 (11%) were readmitted within the next 30 days. Mean length of stay was 4.64 days (95% CI 4.62-4.65). Total charge for index hospitalization was $51,409 (95% CI 51,174-51,643). A total of 8,998 patients were found to have GU cancers. Following baseline comorbidities were associated with highest risk of readmission: Atrial fibrillation, proximal and caval deep vein thrombosis, obesity, hypertension, smoking, and diabetes mellites ( P &lt;0.001). Among GUC, rate of readmission was highest for UC (P&lt;0.01; OR 2.49, 95% CI 1.76 - 3.5) as shown in the table. Risk of in hospital mortality was also highest for UC (P&lt;0.01; OR 2.40, 95% CI 1.39-4.14) followed by RCC (P&lt;0.01; OR 2.06, 95% CI 1.62-2.5). Conclusions: There was higher risk of readmission and mortality for patients with GU malignancies who were hospitalized for PE. UC was the leading GU cancer for rate of readmission and mortality. These readmissions were lengthy and costly for the health care system. This study suggests that more aggressive intervention might be needed in this population to prevent readmission and mortality. [Table: see text]
Effect of patient-derived tumor-like cell clusters on personalized medicine of patients with non-muscle invasive bladder cancer.
Authors: Jianzhong Xi, Shenyi Yin, Yang He, Buqing Ye
Journal: Journal of Clinical Oncology (2024)

e16610 Background: Non-muscle invasive bladder cancer (NMIBC) has a high recurrence and progression rate, and the intravesical instillation chemotherapy drugs is diverse. To optimize patient prognosis, patient-derived tumor-like cell clusters (PTC) for drug testing seeks to identify an effective drug for individual patient. Methods: A prospective, single-center, parallel-group, randomized phase II clinical trial was conducted from December 2020 to December 2023 in Department of Urology of the Second Hospital of Tianjin Medical University (ClinicalTrials.gov: ChiCTR2000040996). This study enrolled a total of 120 patients who had been diagnosed as NMIBC. Patients who met the inclusion and exclusion criteria were randomly assigned to either the control group or the PTC drug-screening group. In the control group, chemotherapy drugs (gemcitabine, pirarubicin, epirubicin and hydroxycamptothecin) were selected for intravesical instillation according to the doctor's experience. In the PTC group, chemotherapy drugs were administered according to PTC drug screening results. Results: The PTC group was associated with significantly lower 1-year Relapse-Free Survival (RFS) rate (10.0 %; 95% CI, 2.4%-17.6%,) compared with the control (31.7%; 95% CI, 19.9%-43.4%), (HR=0.2264; 95% CI, 0.0845-0.6068; p = 0.0013). Similarly, the PTC group was associated with significantly lower 2-year RFS rate (18.3%; 95% CI, 8.5%-28.1%) compared with the control (48.3%; 95% CI, 35.7%-61.0%), (HR=0.3730; 95% CI, 0.1756-0.792; p = 0.0075). Conclusions: PTC drug screening significantly reduced the recurrence rate of postoperative NMIBC. Clinical trial information: ChiCTR2000040996 .
Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of the bladder: Post hoc analysis of two prospective studies.
Authors: Min Jung Kim, Sung Wook Cho, Sung Hee Lim, Se Hoon Park
Journal: Journal of Clinical Oncology (2024)

e16583 Background: Bladder preservation chemoradiotherapy (CRT) in patients with a clinical complete response (cCR) following cisplatin-based neoadjuvant chemotherapy (NAC) is a promising treatment strategy for muscle-invasive bladder urothelial carcinoma (MIBC). A combined analysis of raw data from two prospective phase II studies (Sung HH, Investig Clin Urol 2022; Kim H, Cancer Res Treat 2023) was performed to better evaluate the feasibility of selective bladder preservation CRT. Methods: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving NAC followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survival was defined as the date of commencing CRT. Results: Among 76 patients, 66 had a cCR following NAC. Sixty-four patients received gemcitabine/cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. Bladder preservation CRT following NAC was generally well-tolerated, with low urinary tract symptoms being the most common late complication. With a median follow-up of 64 months, recurrence was recorded in 43 patients (57%): intravesical only (n = 20), metastatic only (n = 16), and both (n = 7). In 27 patients with intravesical recurrence, transurethral resection and BCG treatment was given to 17 patients. Salvage cystectomy was performed in 10 patients. Median DFS was 46.3 (95% CI, 25.1-67.5) months, and the median MFS was not reached. Neither DFS nor MFS appeared to be affected by any of the baseline characteristics. However, DFS was significantly longer in patients with a cCR than in those without (HR, 0.465; 95% CI, 0.222-0.976). Conclusions: The strategy of NAC followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC. A standardized definition of cCR is needed to better assess disease status post-NAC.