tbuckley/cabot-search huggingface dataset:
Clinical efficacy of enfortumab-pembrolizumab combination therapy in locally advanced/metastatic urothelial carcinoma (UC): A real-world experience.
Authors: Nikita Tripathi, Syed Arsalan Ahmed Naqvi, Tara Ballouz, Akshat Saxena, Arifa Bibi, Muhammad Ali Khan, Aneeta Channar, Irbaz Bin Riaz, Mark Tyson, Alan Haruo Bryce, Parminder Singh
Journal: Journal of Clinical Oncology (2024)

643 Background: The FDA approval of enfortumab (EV) and pembrolizumab (Pembro) combination therapy as a first-line treatment for cisplatin-ineligible patients with locally advanced/metastatic urothelial carcinoma (la/mUC) was based on the EV-103 trial. We aim to assess the clinical response rate of this combination therapy in our institution's patients with locally advanced and metastatic UC. Methods: This retrospective cohort study included 20 patients diagnosed with locally advanced/metastatic UC(la/mUC) who were treated with EV-Pembro combination for at least 2 cycles, from June 2022 to August 2023 at the Mayo Clinic. Patients who were treatment naïve or who progressed one or more lines of therapy were included in the study cohort. Main outcome of interest included imaging-based best overall response rate in terms of complete (CR) and partial (PR) response, stable disease (SD), and progressive disease (PD). Results: Out of 20 patients, the number of males and females were 16 (80%) and 4 (20%) respectively; the median age was 77 years (IQR: 51-92). 3 (15%) of patients had involvement of upper urinary tract disease along with bladder cancer. The common sites of visceral metastasis at the time of initial presentation include liver 2(10%), lung 6(30%) and lymph nodes12(60%). Common toxicities of this regimen included rash, pruritis, peripheral neuropathy, fatigue, transaminitis, dysgeusia, and diarrhea. The treatment was stopped in 10 (50%) patients due to completion of planned therapy (achieved CR or proceeded with resection of residual disease) (30%), 5 patients due to progression (50%), 1 patient due to therapy side effects (10%) and in 1 patient due to death (10%). The objective response was 45% (N =9); 5 (25%) had PR, and 4 (20%) had CR. A total of 2 (10%) had SD while 2 (10%) experienced PD. Histological correlation with clinical benefit is shown in the table. Conclusions: EV-Pembro combination therapy shows promising responses in patients who have progressed after previous lines of therapy, consistent with previously published data on EV 201 in small cohorts. However, ongoing expansion of this cohort and data from larger studies will help further elucidate survival benefits and their correlation with genetic testing. [Table: see text]
Single-center analysis on a real-world cohort of patients with metastatic urothelial carcinoma studied by NGS: Molecular landscape and efficacy of targeted therapies.
Authors: César Gutiérrez Pérez, Inmaculada Rodríguez Ledesma, María Pumares González, Miriam Vela Domínguez, Noelia Espinosa Cabria, María Liliana Cabrera Pinos, Laura Calvo Otero, Lina Marcela Valencia Cárdenas, Laura Viña Gopar, Carmen Blanco Abad, Benjamín Folgueira Hernández, María García Muñoz, Carlos García Girón, Enrique García Toro, Enrique Lastra Aras, Sandra López Peraita, Irene Ramos Reguera, Patricia Saiz López, Sofía de la Torre Lázaro, Guillermo Crespo Herrero
Journal: Journal of Clinical Oncology (2024)

661 Background: the median overall survival (OS) in metastatic urothelial carcinoma (mUC) treated with multiagent therapy is approximately 13 months (mo). Around 69% of these tumors harbor potential therapeutic targets. Real-world evidence on using Next Generation Sequencing (NGS) in mUC management is limited. Methods: we conducted a single-center analysis on a real-world cohort of patients (pts) with mUC. The study population included pts aged &gt;18 years with diagnosis of mUC studied by NGS at the moment of starting immunotherapy (enrollment period: 09/04/2019 – 03/25/2022). Median OS and median progression-free survival (PFS) were determined using Kaplan-Meier curves. Results: we included 43 pts. Median age at mUC diagnosis was 67 years; 38 (88.4%) pts were men; 38 (88.4%) pts were ECOG 0-1 at mUC diagnosis; one or more adverse prognostic factors (Bellmunt Risk Score) were identified in 33 (76.7%) pts; primary tumor site was lower tract in 36 (83.7%) pts. All pts were treated with platinum-based combinations (neoadyuvant, adyuvant or first line) and immunotherapy. Pathogenic alterations were found in 25 (58.1%) pts. In the group of 25 pts with pathogenic alterations, 17 pts progressed to immunotherapy and 7 pts of them received targeted therapies; 10 pts could not receive targeted therapies due to poor prognosis. In the group of 18 pts without pathogenic alterations, 11 pts progressed to immunotherapy and 8 pts of them received other chemotherapy options; 3 pts could not receive other chemotherapy options due to poor prognosis. The median OS (time since mUC diagnosis) among 25 pts with pathogenic alterations was 30.2 (CI 95%: 18.9-41.5) mo compared to 22.9 (CI 95%: 12-33.9) mo among 18 pts without pathogenic alterations, (p = 0.557). Focusing on the subgroup of 7 pts treated with targeted therapies (Table), we found an objective response rate (ORR) of 42.9%; the median PFS was 7.3 (CI 95%: 6.7-7.9) mo and the median OS (time since beginning targeted therapies) was 10.9 (CI 95%: 2.4-19.5) mo. Conclusions: We recommend that all pts with mUC undergo NGS at the time of diagnosis, given the high percent (58.1%) of pathogenic alterations in our real-world cohort and the efficacy in terms of ORR, PFS and OS in pts treated with targeted therapies. [Table: see text]
Phase I/II study of ipilimumab plus nivolumab (IPI-NIVO) combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma.
Authors: Rohit K. Jain, Yuanquan (Aaron) Yang, Juskaran Chadha, Jingsong Zhang, Sarah Raymond, Erika Oschmann, Trey Poehlman, Wenyi Fan, Youngchul Kim, Jasreman Dhillon, Jad Chahoud, Monica Sheila Chatwal, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2024)

TPS713 Background: Treatment options are suboptimal and limited for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Sacituzumab govitecan (SG) is a Trop-2 directed antibody-drug conjugate (ADC) coupled with SN-38 through a hydrolysable linker. In the phase II TROPHY-U-01 study, SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in mUC patients who progressed after platinum-based chemotherapy and immune checkpoint inhibitors (ICI), receiving accelerated approval by the US FDA. In CheckMate 032 study, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1+I3) every 3 weeks (Q3W) x 4 cycles followed by nivolumab monotherapy 3mg/kg Q2W showed promising activity post-platinum that led to the ongoing phase III trial in the first-line setting (NCT03036098). Given potential synergism between immunogenic cell death induced by ADC and ICI, we hypothesized that the combination of SG and IPI-NIVO would benefit patients with manageable toxicities. We designed this study to assess the safety and clinical activity of IPI-NIVO with SG as first-line therapy for cisplatin-ineligible mUC patients. Methods: This is an ongoing phase I/II, single arm, multicenter study for cisplatin-ineligible mUC. The Phase I portion enrolled 9 patients using a 3+3 design with safety and RP2D as primary endpoints. In this part, patients received fixed doses of IPI-NIVO (N1+I3) IV Q3Wx 4 cycles combined with SG (DL1 8 mg/kg or DL2 10mg/kg) IV on days 1, 8 Q3W x 4 cycles. This was followed by maintenance nivolumab 360 mg IV Q3W with SG on days 1, 8 Q3W. The RP2D of SG was determined as 8 mg/kg and combination was deemed safe and tolerable. ORR is the primary endpoint in the ongoing phase II portion of the study using Simon 2 stage design (n=34) with a futility interim analysis after 13 patients. The null hypothesis of ORR ≤ 38% will be tested with a desirable ORR of &gt;60% under a statistical power of 80% and a one-sided type I error rate of 5%. Thirteen of the 34 patients have been enrolled and the study has passed the predefined interim analysis for futility. We aim to continue accrual. Exploratory biomarker analyses will be conducted using tumor and blood samples collected during screening and at progression. Clinical trial (NCT04863885). Clinical trial information: NCT04863885 .
Performance of a tumor-informed molecular residual disease (MRD) assay in resected bladder cancer with mixed or pure variant histology: Analysis of a real-world multicenter cohort.
Authors: Ajitha Kommalapati, George Laliotis, Jordan Rich, Shivaram Cumarasamy, Samuel Rivero, Shruti Sharma, Charuta C Palsuledesai, Meenakshi Malhotra, Matt D. Galsky, Adam ElNaggar, Minetta C. Liu, John P. Sfakianos, Charles Peyton, James Ferguson, Arnab Basu
Journal: Journal of Clinical Oncology (2024)

649 Background: Circulating tumor DNA (ctDNA)-based MRD assays can detect clinically occult disease with high sensitivity and specificity in patients with solid tumors. Previous trials that evaluated MRD testing in bladder cancer, such as ABACUS and IMVigor010, enrolled patients with a predominant urothelial carcinoma component. Given the known histological and molecular heterogeneity in urothelial carcinoma, we examined the prognostic value of a tumor-informed MRD assay in bladder cancer patients with mixed or pure variant histologies (M/VH). Methods: This retrospective study analyzed the results of post-cystectomy longitudinal ctDNA testing from a multi-institutional database of patients with urothelial carcinoma (n=205). A personalized, tumor-informed assay (Signatera, Natera, Inc.) was used for the detection and quantification of ctDNA. Patients with M/VH and at least 3 months of postoperative follow-up data on relevant demographic, clinical, pathologic, and NGS variables were eligible for inclusion. Time-dependent Cox regression analyses were performed for disease-free survival (DFS) based on ctDNA during the MRD window (&lt;12 weeks from surgery, N=29) and surveillance window (&gt;12 weeks post-surgery or post-AT, N=29). Multivariable regression was performed to adjust hazards for clinicopathologic factors predicting DFS. Results: Of the 205 patients, 46 (74% male, median age: 69 years) met the inclusion criteria for analysis. Whole exome sequencing of tumor tissue revealed that TP53 (45.7%), ARID1A (32.6%), and KDM6A (30.4%) were the top three genes with somatic mutations. Twenty-seven (59%) patients received neoadjuvant therapy, 37% of whom (10/27) also received adjuvant therapy. ctDNA-positivity during the MRD window and during surveillance was strongly associated with poor DFS (MRD window: HR=4.93, 95%CI: 1.77-20.77, p=0.03; surveillance: HR=28.3, 95% CI: 3.52-3660, p&lt;0.001). None of the serially ctDNA-negative patients (N=25) recurred, whereas 58.9% (10/17) of patients who were ctDNA-positive anytime post-surgery recurred at a median follow-up of 9 months from the date of surgery, range: 3.1-36.4 months). When adjusted for all other risk factors, ctDNA-positivity anytime post-surgery was the only significant predictor of recurrence (HR=55.26, 95%CI: 5.3-7648, p&lt;0.00001). Conclusions: Personalized, tumor-informed ctDNA testing can identify patients with mixed or variant histology bladder cancer who are at high risk of recurrence. Further studies are warranted to evaluate the potential benefit of ctDNA-guided adjuvant therapy in this patient population.
Evolving metastatic renal cell carcinoma (mRCC) treatment landscape in the post vascular endothelial growth factor (VEGF) and immune checkpoint inhibitor (IO) setting.
Authors: Neil J. Shah, Rituparna Bhattacharya, Ning Ning, Reshma Shinde, Jordana Schmier, Malinda Tan, Traci LeMasters, Murali Sundaram, Rodolfo F. Perini, Robert J. Motzer
Journal: Journal of Clinical Oncology (2024)

406 Background: IO and VEGF based therapies have transformed the front-line treatment paradigm for patients with mRCC. This study's objective is to describe treatment patterns and clinical outcomes among mRCC patients in the post IO and VEGF setting. Methods: Adult patients diagnosed with mRCC between Jan 2015 - Dec 2022 and received IO and VEGF (in combination or sequence) in the first three lines of therapy after mRCC diagnosis were identified from Optum’s de-identified Clinformatics® Data Mart Database, a large retrospective claims database. Index date was defined as the date of the first (index) treatment in the post IO and VEGF setting. Patients were required to have continuous enrollment of 6 months prior to index date. Patients were categorized into 3 cohorts based on lines of index treatment (2L, 3L, 4L). Treatment patterns were described and real world (rw) time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) were estimated by Kaplan Meier analysis. Results: A total of 664 patients were included (2L:186, 3L:429, 4L:49). 37% received IO and VEGF in combination prior to index line of therapy. Median age at mRCC diagnosis was 67.0 years, with 72.7% male and 68.1% White; 11.6% died and 7.4% disenrolled during index treatment. Post IO and VEGF, cabozantinib was the most used therapy across 3 cohorts (2L: 43.5%, 3L: 35.2%, 4L: 30.6%) (Table). Median rwToT and rwTTNT for 2L, 3L, and 4L cohorts were 4.4, 5.0, and 5.6 months and 10.7, 11.7, and 9.5 months, respectively. Median OS from mRCC diagnosis was similar across the 3 cohorts (2L: 41.6, 3L: 38.7, 4L: 40.6 months); median OS from index date decreased with advancement in LOT (2L: 20.6, 3L: 14.1, 4L: 10.3 months). Conclusions: Our study is one of the largest and comprehensive study giving a unique perspective into evolving treatment patterns and outcomes for mRCC patients in the post IO and VEGF setting. Post IO+VEGF, the most common treatments were tyrosine kinase inhibitor-based treatments, and the median ToT was less than 6 months. Hence, novel treatments are needed to improve clinical outcomes for mRCC patients in the post IO and VEGF setting. [Table: see text]
Estimating the impact of adjuvant treatment with nivolumab on long-term survivorship rates compared with surveillance: Analyses of disease-free survival (DFS) from the phase 3 CheckMate-274 trial.
Authors: Daniel M. Geynisman, Georgia Yates, Kateryna Chepynoga, Siguroli Teitsson, Murat Kurt, Miraj Y. Patel, Ronac Mamtani
Journal: Journal of Clinical Oncology (2024)

528 Background: Durable DFS and cure are the ultimate goals for the treatment of muscle invasive urothelial carcinoma (MIUC) with radical cystectomy. This analysis employed mixture cure models (MCMs) to estimate the underlying cure fraction among high-risk MIUC patients following radical resection in the Phase 3 CheckMate-274 study. Methods: MCMs were applied to patient-level DFS data from the trial (minimum follow-up: 31.6 months). Intention-to-treat (ITT) population and the subpopulation with tumor PD-L1 expression ≥1% were analyzed separately for nivolumab (NIVO) and placebo (PBO) arms. In MCMs, the patient populations were assumed to consist of two exclusive subgroups as cured and uncured. Cured subgroup was assumed to be free of disease recurrence and disease-related mortality risks. The uncured subgroup was at the risk of both disease recurrence and all-cause mortality. DFS for the cured subgroup was estimated using background mortality rates published by WHO matched to the trial’s demographic characteristics. DFS for the uncured subgroup was modelled using parametric distributions, which were characterized along with the cure fraction by maximum likelihood methods. Model selection was primarily based on clinical plausibility of estimated DFS for the uncured subgroup. Visual comparison of the fits from the MCMs to the reported DFS data from the trial and goodness-of-fit statistics also assisted model selection. Results: In the trial, 353 patients were treated with NIVO (mean age: 65.3; male: 75.1%; PD-L1≥1%: 39.7%) and 356 patients were in PBO control (mean age: 65.9; male: 77.2%; PD-L1≥1%: 39.9%). Selected models estimated almost all uncured patients to experience recurrence within 5 years. The estimated cure fraction in the ITT population ranged from 43.1%-45.1% in the NIVO arm (95% CI: 36.7%-51.6%), and 36.4%-37.0% in the PBO arm, (95% CI: 30.9%-43.0%) for clinically plausible models. Projected range of 10-year mean DFS for the ITT patients was 4.38-4.47 years in the NIVO arm and 3.61-3.64 years in the PBO arm. Estimated cure fractions in the PD-L1≥1% subpopulation ranged from 59.1%-61.0% in the NIVO arm (95% CI: 48.9%-72.0%), and 35.9%-36.9% in the PBO arm, (95% CI: 27.5%-45.9%). Projected range of 10-year mean DFS for the PD-L1≥1% subpopulation was 5.54-5.65 years in the NIVO arm and 3.54-3.57 years in the PBO arm. Conclusions: In the adjuvant treatment of MIUC, relative to radical resection only, systemic therapy with NIVO is associated with a 6-9 percentage points higher cure fraction in the ITT population. Tumor PD-L1≥1% expression was associated with higher cure fractions in the NIVO arm but had only negligible impact on the underlying cure fraction in the PBO arm. Clinical trial information: NCT02632409 .
First-line PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPi) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and meta-analysis.
Authors: Muhammad Ali Khan, Syed Arsalan Ahmed Naqvi, Manal Imran, Aneeta Channar, Akshat Saxena, Ammad Raina, Kaneez Zahra Rubab Khakwani, Zaryab Bin Riaz, Adam McLain Kase, Mitchell R. Humphreys, Cassandra N. Moore, Jacob Orme, Daniel S Childs, Parminder Singh, Alan Haruo Bryce, Jeanne M. Palmer, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2024)

173 Background: The data for combining PARPi and ARPi in mCRPC have shown conflicting results. Here, we report a quantitative summary of benefits by clinically meaningful subgroups (HRR mutation status, BRCA mutation status) to guide the use of PARPi and ARPi combination in mCRPC setting. Methods: MEDLINE, EMBASE, and CENTRAL were systematically searched from each database’s inception through September 7, 2023. Phase III studies comparing PARPi + ARPi with ARPi + placebo in mCRPC were included. Radiographic progression-free survival (rPFS) and overall survival (OS) in patient subgroups based on HRR and BRCA mutation status were assessed. Hazard ratios for rPFS and OS with 95% CI were collected at the level of each trial, and a random-effects meta-analysis was conducted using an inverse variance approach. Subgroup differences were assessed and p-value of interaction &lt;0.1 was considered statistically significant. Results: The literature search identified 4976 studies from which 3 trials (11 references) – TALAPRO2, PROpel and MAGNITUDE met the inclusion criteria. A total of 2254 participants were eligible for analysis. PARPi + ARPi prolonged rPFS in patients with HRR mutations (HR: 0.55, 95%CI: 0.38-0.78) as well as in patients without HRR mutations (HR: 0.74, 95%CI: 0.63-0.88). There is no evidence of treatment interaction by HRR mutation status (p = 0.14). In patients harboring HRR mutations, improved rPFS was observed in those with BRCA mutations (HR: 0.28, 95%CI: 0.13-0.62) as well as those without BRCA mutations (HR: 0.72, 95%CI: 0.59-0.87). However, there is evidence that patients with BRCA mutations derived greater rPFS benefit as compared to patients without BRCA mutations (p =0.02). PARPi + ARPi showed no significant improvement in overall survival either in patients with HRR mutations (HR: 0.79, 95%CI: 0.59-1.05) or in patients without HRR mutations (HR: 0.92, 95%CI: 0.74-1.14). Conclusions: Genomic testing for HRR genes is mandatory to guide clinical decision making in mCRPC patients. Patients harboring BRCA mutations are most likely to derive clinically meaningful benefit from combination PARPi + ARPi treatment. [Table: see text]
Real world data on treatment of chromophobe renal cell carcinoma.
Authors: Dena Battle, Meghan Griffith, Pavlos Msaouel, Martin H Voss, Michael D. Staehler
Journal: Journal of Clinical Oncology (2024)

409 Background: Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma (RCC), accounting for 5%–7% of all RCCs. ChRCCs are generally viewed to have a favorable clinical outcome compared to clear cell RCC, yet up to 10% of patients with ChRCC will develop metastases. To date, there are no genomic biomarkers that predict post-surgical metastatic recurrence, and no standard of care exists for treating metastatic chRCC. We sought to better understand real world patient experiences in this underrepresented and understudied patient population. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure) and was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Those who agreed to participate were surveyed for demographics (age, gender, race, income, country) and clinical characteristics (date of the diagnosis, disease stage, treatment history). Out of 1,062 participants 121 patients self-identified with chRCC, 34 patients had metastatic disease, and 23 patients had received systemic therapy. Results: The majority of patients were from the United States (75%), median age was 49.7 years (range 19-74), 70 percent of patients identified as female, and 30 percent of patients identified as male. Stage distribution at initial diagnosis was stage 1 in 37.3%, 27.3% were stage 2 and stage 3 respectively, 8.3% were metastatic at diagnosis. 14% of patients reported having sarcomatoid dedifferentiation. 20 percent of patients (24) experienced recurrent metastatic disease after a median duration of 3.3 years (range 1-6). Of the 23 patients who received treatment, first line therapy consisted of TKI monotherapy (9), combination IO and TKI (7), combination IO/IO (4), mTOR mono-therapy (1), other therapies (2). Second and later line therapies were combination IO/IO (3), IO and TKI (9), Lenvatinib and everolimus (7), TKI monotherapy (5), mTOR monotherapy (5) and other therapies (5). Median duration of therapy was 43 months (range 2-196). The most used TKIs were cabozantinib and lenvatinib. In the metastatic setting, 4 patients reported being treated as part of a clinical trial, 9 patients reported that no one had ever talked to them about participating in a clinical trial. 6 patients said that no trials were being held at their treating center. Conclusions: Patients reported higher rates of recurrence than what is usually reported in ChRCC, however this could reflect sample bias as patients with more aggressive disease may be more likely to engage with patient communities. No standardized treatment for metastatic disease could be identified. Overall treatment duration was comparable to clear cell carcinoma. Very few patients had access to clinical trials. ChRCC-specific clinical trials and tailored treatment regimens are urgently needed.