tbuckley/cabot-search huggingface dataset:
Real-world efficacy and toxicity of ipilimumab and nivolumab as first line treatment of metastatic renal cell carcinoma (mRCC) in a subpopulation of elderly and poor performance status patients.
Authors: Ana-Alicia Beltran-Bless, Noa Shani Shrem, Sunita Ghosh, Camilla Tajzler, Lori Wood, Christian K. Kollmannsberger, Naveen S. Basappa, Jeffrey Graham, Nazanin Fallah-rad, Daniel Yick Chin Heng, Denis Soulieres, Aly-Khan A. Lalani, Rodney H. Breau, Antonio Finelli, Simon Tanguay, Bimal Bhindi, Georg A. Bjarnason, Frederic Pouliot, Christina M. Canil
Journal: Journal of Clinical Oncology (2024)

367 Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) and response rates compared to sunitinib in the pivotal Checkmate 214 trial of intermediate/poor risk mRCC. A subgroup analysis showed no significant difference in OS for ipi/nivo in pts 65 to 75 years old (yo), as well as pts &gt;75 yo. In another subgroup analysis, Karnofsky performance status (KPS) &lt;70 was associated with worse median OS compared with pts with KPS ≥ 70. We evaluated efficacy and toxicity of ipi/nivo in an older and frailer population in a real-world cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N=378) treated with ipi/nivo as first line treatment from the Canadian Kidney Cancer Information System (CKCis) database from January 2011 to March 2022. Median follow-up was 14.3 m (range 0 to 87.6). A comparison was made between outcomes and toxicity in pts ≥ versus (vs) &lt;70 yo, ≥ vs &lt;75 yo, KPS &lt; vs ≥70, and ≥70 yo with KPS &lt;70 vs &lt;70 yo with KPS &gt;70. Toxicity was graded as per CTCAE v4.03 or any toxicity that resulted in a dose/schedule change. OS, progression free survival (PFS) and time to treatment failure (TTF) were calculated by Kaplan-Meier analysis. Log rank tests were used for comparison between groups. Multivariate analysis was done including IMDC for all outcomes. Results: Median OS was worse in older patients at 30.0 m in pts ≥ 70 yo vs 45.4 m in pts &lt; 70 yo (p=0.060), and 19.0 m in the pts ≥ 75 yo vs 45.5 m in pts &lt; 75 yo (p=0.003) despite similar disease control rates and toxicity. Median PFS was similar in younger and older pts: &lt; vs ≥ 70 yo (p=0.560) and &lt; vs ≥ 75 yo (p=0.296). Median TTF was comparable in &lt; 70 yo and ≥ 70 yo (p=0.106) and &lt; 75 and ≥ 75 yo groups (p-value=0.733). Median OS, PFS and TTF were comparable in pts KPS &lt; 70 vs pts KPS ≥ 70 and in pts ≥70 yo with KPS &lt; 70 vs pts &lt; 70 yo with KPS &gt;70. Adjusted and unadjusted analysis showed no difference in OS and PFS between groups. Conclusions: Use of ipi/nivo in mRCC in older patients was associated with inferior OS, while decreased performance status had equivalent OS. Both groups had equivalent TTF and PD without higher toxicity. We believe that ipi/nivo is a reasonable treatment option for older and low performance status patients. [Table: see text]
Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C
Authors: Edouard L. Fu, Juan-Jesus Carrero, Yingying Sang, Marie Evans, Junichi Ishigami, Lesley A. Inker, Morgan E. Grams, Andrew S. Levey, Josef Coresh, Shoshana H. Ballew
Journal: Annals of Internal Medicine (2024)

The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults.
Differential mutation profiles between benign and cancerous urothelium in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Hiroko Miyagi, Joshua Linscott, Billie Gould, Prithvi Murthy, Pan Du, Shidong Jia, Roger Li
Journal: Journal of Clinical Oncology (2024)

675 Background: Differentiating passenger and driver mutations of oncogenesis is essential in understanding disease biology and developing biomarkers that use genomic mutations for diagnosis or prognostication. Accumulating research shows normal urothelium harbors many mutations commonly reported in molecular profiling of urothelial carcinoma. This is especially true of NMIBC. Here, genetic profiling of the mutational landscape of pathologic NMIBC tumors (pNMIBC) was performed and compared to matched pathologically benign urothelial tissue (pBT) to determine the frequency of passenger mutations. Methods: From a prospective observational cohort, 9 patients with high-risk NMIBC and pBT on repeat TURBT were identified. Somatic mutational profiles of the index tumor (pNMIBC) and subsequent pBT of each patient was performed via PredicineWES+ whole exome sequencing. Somatic variants were identified using the Predicine DeepSea in-house algorithm as previously described. Briefly, non-synonymous variants are captured and probabilistically annotated as germline vs. somatic in comparison with matched germline PBMC WES+ sequencing. NS somatic mutations observed in pBT were compared to those in pNMIBC to evaluate for putative passenger versus driver mutations. Results: A median of 236 mutations (IQR:100-732) were detected for pNMIBC compared to 37 (IQR: 5-80) in the pBT group (p=0.018). The number of genes with likely somatic mutations in pNMIBC only, both samples, and pBT only, were 2239, 500, and 1, respectively. The most frequently mutated genes in pNMIBC tissue samples were ARID1, TERT, CREBBP, LMTK3 and NCOR1. Notably, both pBT and pNMIBC tissue shared mutations in commonly reported bladder cancer genes such as ARID1A, ERBB2, ATM, ERCC2 and CKDN2A. Somatic mutations in FGFR3, LMTK3, NCOR1, AKAP9, COL11A2, CRYBG3, KMT2A, MCM3AP, PHF3, VPS13A and ZNF28 were present solely in pNMIBC tissue, whereas OVGP1 mutation was exclusive to pBT. Analysis of the functional impact of mutations in genes that are mutated in both benign tissue and pNMIBC offers a deeper understanding of the evolution of bladder cancer via field cancerization. Conclusions: Analysis of the mutational profile of pBT and pNMIBC revealed differential patterns of somatic mutations. Many expected gene mutations were detected in pNMIBC, but surprisingly 18% of all mutated genes were shared between tumor and pathologically benign samples. The fact that only one somatically mutated gene was exclusive to pBT signifies excellent censoring of variants by the DeepSea algorithm. In summary, these preliminary findings suggest that common gene mutations in NMIBC are frequently observed as passenger mutations. This underscores the potential significance of tissue-informed biomarkers tailored to an individual's mutational profile, which may outperform panel assays.
Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: Preliminary results from the phase 1 TROPION-PanTumor01 study.
Authors: Aaron Lisberg, Alexandra Drakaki, Funda Meric-Bernstam, Omar Alhalabi, Takahiro Kojima, Manabu Kato, Alexander I. Spira, Mohamad Adham Salkeni, Rebecca Heist, Xin Gao, Manali A. Bhave, Gunnar Klauss, Hayato Sakaki, Yasuyuki Kakurai, TAKAHIRO KOGAWA
Journal: Journal of Clinical Oncology (2024)

603 Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has shown encouraging antitumor activity and a manageable safety profile in patients (pts) with solid tumors. We report preliminary results in pts with advanced/metastatic (a/m) urothelial cancer from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable a/m urothelial cancer treated with ≥1 prior line of therapy received intravenous Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR; CR + PR + stable disease) per RECIST 1.1 by BICR. This is the first data disclosure from this cohort in an ongoing expansion cohort study. Results: At data cutoff (May 18, 2023), 18 pts had received Dato-DXd. Median follow-up was 9.1 (range 5–17) months; 6 (33.3%) pts were receiving ongoing treatment. Median age was 63.5 (range 46–79) yrs. Pts were heavily pretreated, 15 (83.3%) had received ≥3 prior regimens. All pts received prior immunotherapy, 17 (94.4%) prior platinum-based chemotherapy, and 4 (22.2%) prior taxanes. Treatment-emergent adverse events (TEAEs) occurred in 100% (any grade [gr]) and 44.4% (gr ≥3) of pts, and drug-related TEAEs occurred in 94.4% (any gr) and 16.7% (gr ≥3) of pts. No drug-related serious AEs were reported, and no TEAEs associated with death were observed. Any gr TEAEs associated with reduction, interruption, and discontinuation of treatment were reported in 11.1%, 33.3%, and 5.6% of pts, respectively (Table). Adjudicated drug-related interstitial lung disease (gr 2) occurred in 1 (5.6%) pt. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 1 pt achieved a CR and 4 achieved a PR. DCR was 77.8% (95% CI 52.4–93.6). Clinical evaluation of this cohort is ongoing and updated results will be presented. Conclusions: In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . [Table: see text]
Real-world (rw) treatment patterns, sequencing, and outcomes in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) receiving avelumab first-line maintenance (1LM) in the US.
Authors: Helen H. Moon, Mairead Kearney, Seyed Hamidreza Mahmoudpour, Chiemeka Ike, Valerie A. Morris, Andrew Rava, Sonia Kim, Haiyan Sun, Marley Boyd, Gabriel Gomez Rey
Journal: Journal of Clinical Oncology (2024)

605 Background: Avelumab 1LM is recommended in international guidelines for pts with la/mUC and disease control after 1L platinum-based chemotherapy (PBC). This study describes the treatment landscape after FDA approval of avelumab in June 2020 by examining pt characteristics, treatment patterns and sequencing, and rw outcomes in pts treated with avelumab 1LM. Methods: This noninterventional retrospective study identified pts with la/mUC who received avelumab 1LM in the US using data from Flatiron Health’s electronic health record database. Pts aged ≥18 y with ≥2 visits on/after Jan 1, 2011, diagnosed with la/mUC from Jan 1, 2019 - Dec 31, 2022, treated with 1L PBC followed by avelumab 1LM on/after Jul 1, 2020, ≤90 d after 1L PBC discontinuation, and with no disease progression ≤14 wk after 1L PBC were included. Treatment patterns in 1LM, second line (2L), and third line (3L) were assessed. Clinical outcomes, including rw progression-free survival (rwPFS), rw overall survival (rwOS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) from 1LM or 2L initiation, were assessed using Kaplan-Meier methods. Results: 214 avelumab 1LM-treated pts met eligibility criteria. Median age was 70 y; most pts were male (77%), White (66%), and had an ECOG of 0-1 (77%). Median follow-up from 1LM was 8.7 mo. Of 96 (45%) pts who received 2L treatment post avelumab 1LM, enfortumab vedotin (EV) monotherapy (55%) was most common, followed by carboplatin-based therapy (11%). Of 40 (42%) pts who received 3L treatment, EV monotherapy was most common (25%), followed by sacituzumab govitecan (20%). Median PFS and OS from start of avelumab 1LM was 5.1 (95% CI 4.1-7.0) and 23.8 (95% CI 18.2-NE) mo. Median TTNT from avelumab 1LM initiation was 7.0 (95% CI 5.6-8.6) mo. Of pts who received 2L EV, median rwPFS and rwOS from 2L initiation were 4.9 (95% CI 3.9-8.8) and 11.2 (95% CI 6.8-NE) mo. Further rw outcomes are presented in the Table. Conclusions: Clinical outcomes in this study are aligned with those of the JAVELIN Bladder 100 trial (NCT02603432), further supporting avelumab 1LM as a standard of care. With each additional line of therapy, substantial treatment attrition and less favorable clinical outcomes were observed. This study provides insights into the sequencing of treatments and management of pts with la/mUC after disease progression with avelumab 1LM in this rapidly evolving therapeutic landscape. The use of more effective upfront therapies may decrease the attrition rates. [Table: see text]
Avelumab first-line maintenance (1LM) in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) in the Czech Republic: Interim real-world results from a national reimbursement registry.
Authors: Anezka Zemankova, Hana Studentova, Bohuslav Melichar, Michal Eid, Alexandr Poprach, Jindrich Kopecky, Jan Spacek, Sarka Stuhlova, Jan Dvorak, Pavel Vlcek, Katerina Zychackova, Jana Katolicka, Tomas Blazek, David Vrana, Petra Majkova, Adam Cepa, Ondrej Fiala
Journal: Journal of Clinical Oncology (2024)

557 Background: Avelumab 1LM treatment is recommended by international guidelines as the standard of care for pts with la/mUC that has not progressed with 1L platinum-based chemotherapy (PBC) and has been approved in the EU since Jan 2021. In the Czech Republic, following EU approval, there is a requirement to provide real-world data for “highly innovative medicinal products” such as avelumab 1LM when reimbursement decisions are temporary. Obtaining reimbursement therefore requires the creation of a registry to collect real-world data. We report interim results from a retrospective analysis of a national reimbursement registry for avelumab 1LM in the Czech Republic. Methods: Registry data were collected by the Office of Health Insurance (KZP) for pts with la/mUC receiving avelumab 1LM in the Czech Republic between Oct 2021 and Jan 2023. The primary endpoint was overall survival (OS) from the start of avelumab 1LM (index date); secondary endpoints included progression-free survival (PFS) from the start of avelumab 1LM and safety. Descriptive statistics were used to analyze the data. OS and PFS were estimated using the Kaplan-Meier method. Results: 59 eligible pts with la/mUC were treated and documented. At data cutoff (Jan 3, 2023), median follow-up was 6.1 mo (range, 0-16.5). All pts were White; 43 were male and 16 were female. At the start of avelumab 1LM, median age was 71 y (range, 49-84) and 22 pts (37.3%) had visceral metastases. 1L PBC was cisplatin-based in 30 pts (50.8%), carboplatin-based in 24 (40.7%), and both (switched from cisplatin to carboplatin) in 5 (8.5%). Best response to 1L PBC was complete response in 5 pts (8.5%), partial response in 30 (50.8%), and stable disease in 24 (40.7%). Median time from the end of PBC to the start of avelumab was 4.1 wk (range, 1.0-44.0). Effectiveness data for avelumab 1LM are shown in the Table. OS and PFS data are immature, with only 14 pts (23.7%) having died or had disease progression at the time of analysis. 10 adverse events were reported in 9 pts (15.3%), including grade 3 infusion-related reaction (1 pt), grade 2 diarrhea (2 pts), and grade 2 nephritis, pneumonitis, and Addison disease (1 pt each). At last evaluation, 53 pts were alive, of whom 5 pts had started subsequent treatment. Conclusions: This is the first study of pts with la/mUC treated with avelumab 1LM in a real-world setting in the Czech Republic. These preliminary data agree with the results of the phase 3 JAVELIN Bladder 100 trial and other real-world studies, confirming the effectiveness and manageable safety profile of avelumab 1LM in la/mUC. Follow-up for OS is ongoing. [Table: see text]
Single institutional experience of neoadjuvant therapy prior to planned surgical resection for complex or locoregional renal cell carcinoma.
Authors: Dhruv Puri, Kit Yuen, Luke Wang, Margaret Meagher, Jonathan Afari, Mimi Nguyen, Julian Cortes, Mirha Mahmood, Mariam Mansour, Joshua Matian, Juan Javier-Desloges, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2024)

439 Background: Cytoreduction via systemic neoadjuvant therapy is an emerging investigational strategy in localized renal cell carcinoma (RCC). We analyzed our single institutional experience with neoadjuvant therapy. Methods: ingle institutional retrospective analysis of patients with T2-T3N0M0 RCC. Patients received confirmatory biopsy for clear cell histology prior to receipt of systemic therapy and underwent radical (RN) or partial nephrectomy (RN). Neoadjuvant therapy consisted of tyrosine kinase inhibitor (TKI) or Immuno-oncology (IO) therapy and/or combination (TKI-IO). Neoadjuvant therapy was given prior to planned partial nephrectomy for complex renal mass with imperative indications for nephron preservation and prior to planned radical nephrectomy in setting of locoregional disease with possible adjacent organ or great vessel involvement where multiorgan system resection was risked. Primary outcome was percentage cytoreduction comparing pre-treatment and post treatment mass size. Secondary outcome included partial response (PR) rate as per RECIST criteria, negative surgical margins, and lack of major 30-day complications (Clavien ≥3). Comparative analysis was conducted for outcomes between groups for overall survival (OS), cancer specific survival (CSS), and progression free survival utilizing Kaplan Meier Analyses (KMA). Results: A total of 50 patients (33 TKI, 17 IO + TKI-IO) were analyzed (median follow up 31.1 months). Overall PR and cytoreduction rates were 18.0% and 4.2%. No differences in tumor size were noted (7.7 vs. 10.4 cm, p= 0.08). There were no differences in % cytoreduction (12.2 vs. 11.8, p=0.13) and % PR (17.8% vs. 30.7%, p=0.73) between the groups. Overall, 18 patients and 30 patients underwent PN and RN, respectively. 30-day major complication rate was 28.0% and 20.5% was PSM rate. KMA revealed 3-year OS, CSS and PFS of 74%, 75%, and 14%. No differences were noted between TKI and IO/IO-combination groups for PFS (16.7% vs. 10.0%, p=0.45), CSS (70.9% vs. 93.3%, p=0.20), and OS (68.3% vs. 93.3%, p=0.06). Conclusions: Neoadjuvant therapy prior to surgery for complex and locoregional disease resulted in cytoreduction and was associated with acceptable safety, surgical quality, and short term oncological outcomes. Further investigation is requisite to delineate role of neoadjuvant therapy in localized RCC.
Blood-based liquid biopsy: A promising non-invasive test in diagnosis, surveillance, and prognosis of patients with upper tract urothelial carcinoma.
Authors: Alireza Ghoreifi, Stephanie Shishido, George Courcoubetis, Salmaan Sayeed, Amy Huang, Anne K. Schuckman, Monish Aron, Mihir Desai, Siamak Daneshmand, Inderbir Gill, Peter Kuhn, Jeremy Mason, Hooman Djaladat
Journal: Journal of Clinical Oncology (2024)

677 Background: Blood-based liquid biopsy has emerged as a novel biomarker to improve the diagnosis and monitoring of urothelial tumors while enabling individualized risk stratification. The aim of this study was to assess the efficacy of these novel biomarkers in the diagnosis, surveillance, and prognosis of patients with primary upper tract urothelial carcinoma (UTUC). Methods: In this prospective study, peripheral blood samples were collected from patients with primary UTUC before surgery with curative intent and follow-up visits between May 2021 and September 2022. The samples were analyzed using the third-generation comprehensive high-definition single-cell assay (HDSCA3.0) to detect rare events, including circulating tumor cells (CTCs) and oncosomes, based on the immunofluorescent signals of DAPI (D), cytokeratin (CK), CD45/CD31 (CD), and vimentin (V). The findings of pre-surgery liquid biopsies were compared to the blood samples of normal donors (NDs) and matched follow-up liquid biopsy samples. The association between liquid biopsy findings and clinical data elements, including progression-free survival (PFS), was also assessed. Results: Twenty-eight patients with a median (range) age of 67.5 (43-88) years were included, of whom 21 had follow-up samples. Pathologic staging revealed 15 pT&lt;2 and 13 pT≥2 tumors, and most cases (23/28) were high-grade.Significant differences in specific rare analytes were detected in pre-op samples as compared to NDs. On the post- vs. pre-surgery matched analysis, a significant decrease was detected in total-, CK-, and CK|V oncosomes as well as D-, D|V-, and D|V|CD cells. Correlation between pre-surgery liquid biopsy findings and clinical data is shown in Table 1. With a median follow-up of 11 months, seven patients had disease recurrence. Survival analysis demonstrated that patients with greater than 1.95 preoperative CK|V oncosomes as well as those with greater than 4.18 D|CK|V cells had worse PFS compared to other patients ( p=0.02 and p=0.05, respectively). Conclusions: This study demonstrates promising initial evidence for biomarker role of CTCs and oncosomes in diagnosis and surveillance of patients with UTUC.[Table: see text]
Trends over time in the proportion of sequential treatment and overall survival in patients with metastatic urothelial carcinoma in real-world practice.
Authors: Shoma Yamamoto, MInoru Kato, Taisuke Matsue, Nao Yukimatsu, Yuji Takeyama, Taiyo Otoshi, Takeshi Yamasaki, Katsuyuki Kuratsukuri, Junji Uchida
Journal: Journal of Clinical Oncology (2024)

606 Background: New approaches involving immune checkpoint inhibitors (ICIs) and antibody-drug conjugates prolong overall survival (OS) in patients with metastatic urothelial carcinoma (mUC). However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve OS in patients with mUC over time remains unclear. In the present study, we investigated the OS trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. Methods: We retrospectively evaluated 195 patients who received platinum-based chemotherapy as a first line treatment. The patients were treated with chemotherapy, pembrolizumab, avelumab, or enfortumab vedotin (EV) sequentially and were divided into the following three groups: chemotherapy period (April 2009–June 2017; P1), pembrolizumab period (July 2017–December 2020; P2), and avelumab and EV period (January 2021–August 2022; P3) based on the regulatory approval. Data cutoff was set at July 31, 2023. Results: OS was prolonged over time by the new therapeutic agents, and median OS was 11, 25, not reached, and 35.5 months for patients who were treated with chemotherapy, pembrolizumab, avelumab, or EV, respectively. However, median OS was 14, 18 months, and not reached in P1, P2 and P3, respectively. Analysis by periods showed that OS was significantly longer in P2 than in P1 (HR = 0.62, 95% CI: 0.43–0.89, P = 0.009) and in P3 than in P1 (HR = 0.47, 95% CI: 0.28–0.78, P = 0.015). No difference was observed in OS between P2 and P3 (HR = 0.66, 95% CI: 0.36–1.20, P = 0.21). Overall, the proportion of patients who received ICIs increased over time, as indicated by the fact that 77 and 95 patients received ICIs (pembrolizumab or avelumab) in P2 and P3, respectively. However, the prevalence of the treatment with EV was only 24%, and 43% of patients who received pembrolizumab received best supportive care. Conclusions: This study showed an improvement in OS over time in patients with mUC in real-world practice and may indicate the importance of not missing the appropriate opportunity to receive sequential treatments.