tbuckley/cabot-search huggingface dataset:
A new four-tiered grading scheme for postoperative prognostication in renal cell carcinoma with local recurrence.
Authors: Chang Lei, Le Qu, Linhui Wang, Jingping Ge, Wenquan Zhou
Journal: Journal of Clinical Oncology (2024)

e16524 Background: Renal cell carcinoma (RCC) patients suffering from local recurrence (LR) herald variable risk of second progression even after curative surgery for LR. Further risk stratification of these patients will facilitate selection of candidates for adjuvant immunotherapy. Here we evaluate the prognostic significance of tumor grade variation (GV) between the primary tumor (PT) and LR tumor in nonmetastatic RCC in the largest study to date. Methods: We reviewed Research of Multi-institution in East-China on Malignant and Benign Epithelial Renal Tumors (REMEMBER) database to identify ccRCC or pRCC patients who underwent surgery for LR. All pathology slides were centrally reviewed by three independent senior genitourinary pathologists and patients were assigned to groups based on GV as upgrading (WHO/ISUP Ⅰ/Ⅱ for PT grade and Ⅲ/Ⅳ for LR grade), downgrading (WHO/ISUP Ⅲ/Ⅳ for PT grade and Ⅰ/Ⅱ for LR grade), stable low-grade (WHO/ISUP Ⅰ/Ⅱ for both PT and LR grade) and stable high-grade groups (WHO/ISUP Ⅲ/Ⅳ for both PT and LR grade). To evaluate the predictive value of GV, four tumor grade measures (PT grade, LR grade, highest grade for the PT and LR, GV) were separately incorporated for model development. The primary end point was overall survival (OS), defined as the time from LR surgery to death from any cause or last follow-up. A multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 345 patients were identified 114 stable low-grade (33.1%), 56 downgrading (16.2%), 97 upgrading (28.1%), and 78 stable high-grade (22.6%). Median OS were highest among patients with stable low-grade (114 [stable low-grade] vs. 86 [Downgrading] vs. 59 [Upgrading] vs. 33 [Stable high-grade] months). Univariate analysis indicates that PT, LR and GV were significant correlated with poor OS (all P values &lt; 0.05). After separately constructing the PT grade model (#1) via LASSO cox regressions for predicting OS, LR grade model (#2), highest grade model (#3) and GV model (#4) were built by simply replacing the variable of PT grade, it turned out that GV model (#4) achieved the better discriminatory ability (AUC of model (#4) vs. model (#1), 0.812 vs. 0.743; model (#4) vs. model (#2), 0.812 vs. 0.788; model (#4) vs. model (#3), 0.812 vs. 0.762, all p values &lt; 0.05). Conclusions: This is the first study showing that GV is independently associated with clinical outcomes in patients with LR. Routine reporting of LR upgrading or downgrading in relation to the PT and assessment of GV can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression.
Effects of immune-enhancing nutrition on radical cystectomy outcomes: Primary results from the randomized phase III double-blind clinical trial (S1600).
Authors: Jill Hamilton-Reeves, Joseph M. Unger, Jeffrey Holzbeierlein, Danika Lew, James Ryan Mark, Siamak Daneshmand, Janet Baack Kukreja, Eugene K. Lee, William Tabayoyong, Dawn L. Hershman, Michael Jordan Fisch, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2024)

4501 Background: SWOG S1600 was a randomized, double-blind, phase III trial comparing the impact of consuming Specialized IMmunonutrition (SIM) to oral nutritional support (ONS) on postoperative complications following radical cystectomy (RC). SIM is fortified with nutrients: L-arginine; omega-3 fatty acids; and dietary nucleotides. Methods: Patients with bladder carcinoma planning to undergo RC were enrolled and randomized 1:1 to SIM vs. ONS. The primary endpoint was any (≥Grade I) postoperative complication assessed by the Clavien-Dindo (CD) scale at Day 30 after RC. Multivariable logistic regression was used, adjusted for the stratification factors: diversion type (neobladder vs. ileal conduit), prior neoadjuvant chemotherapy (any vs. none), and baseline nutrition status (well-nourished vs. moderate malnutrition). Additional outcomes included 90-day complications and high-grade (CD ≥Grade III) complications. Two-year progression-free survival (PFS) and overall survival (OS) were assessed; differences by arm were reported using Log-rank test statistics. Protocol-specified intention-to-treat (ITT) analyses based on all randomized patients and 1-sided alpha=.05 tests were performed. Results: Among N=203 enrolled patients (99 on SIM, 104 on ONS), median age was 68.8 years, 20% were female and 5% were Black. Five patients did not meet eligibility criteria (1 on SIM, 4 on ONS) but were included under the ITT design. Seventeen patients withdrew consent prior to their Day 30 assessment, and 8 patients were not assessed; thus, n=178 (90 on SIM, 88 on ONS) were evaluable at Day 30. The proportion of patients experiencing CD Grade ≥1 complications was 62.2% for SIM and 58.0% for ONS; in multivariable regression, there was no difference in Grade ≥1 complications by arm (OR=1.18, 95% CI, 0.64-2.18, 1-sided p=.71). There were no differences by arm in high-grade complications at Day 30, in any or high-grade complications at Day 90 or overall. To date, among all 203 patients, 17 on SIM and 26 on ONS have progressed or died, with 2-year PFS estimates of 77.2% and 68.3%, respectively (1-sided p=.16). Nine patients on SIM and 17 on ONS have died, with 2-year OS estimates of 87.4% and 78.2%, respectively (1-sided p=.07). Conclusions: There was no difference in any grade CD complications by type of nutritional supplement for patients with bladder cancer undergoing RC. Fewer patients on the SIM arm have progressed or died, although differences were not statistically significant; follow-up for survival will continue through 3-years after enrollment. Future work to understand the interaction of diet on cancers sensitive to immune modulation is needed. Clinical trial information: NCT03757949 .
A multicenter phase II study of modified FOLFIRINOX for first-line treatment for advanced urachal cancer (ULTMA; KCSG GU20-03).
Authors: Jae-Lyun Lee, Inkeun Park, Shinkyo Yoon, Sang Joon Shin, Seong-Hoon Shin, Kwonoh Park, Jung Hoon Kim, Hyo Jin Lee
Journal: Journal of Clinical Oncology (2024)

4510 Background: Systemic therapy is used for advanced urachal cancer that is not amenable to surgery. However, due to the low incidence of this disease, prospective clinical trials have not been conducted and there is no established standard of care. 5-FU, oxaliplatin, and irinotecan have synergistic mechanisms of action, do not overlap in major side effects, and all have the potential to be effective in urachal cancer. The ongoing ULTIMA trial (NCT04611724) is evaluating the efficacy and safety of modified FOLFIRINOX in patients with advanced urachal cancer. Methods: Patients with recurrent or metastatic urachal cancer with measurable lesions received modified FOLFIRINOX (Oxaliplatin 85 mg/m 2 over 2 hours, Irinotecan 150 mg/m 2 over 1.5 hours, Leucovorin 400 mg/m 2 over 2 hours and 5-FU 2400 mg/m 2 over 46 hours) with prophylactic pegteograstim 6 mg SC on day 3 Q2W till 12 cycles (or until progression or unacceptable toxicities). Response evaluation was done every 6 weeks. The primary endpoint is an ORR. The secondary objectives include PFS, OS and incidence of febrile neutropenia. Simon’s minimax two-stage design was employed to test null hypothesis P0=17% and P1=36%, with alpha of 5% and beta of 20%. The primary endpoint was met at the first stage and we decided to report the results. Results: From April 2021 to November 2023, 21 patients with advanced urachal cancer were enrolled in 5 cancer centers. A median age was 50 (28-68) and 15 were male. Lung was the most frequent site of metastasis (47.6%) followed by lymph node (38.1%) and peritoneal seeding (33.3%). As of December 2023, 18 patients discontinued treatment. A total of 235 cycles were administered with a median of 12 (6-12) cycles per patient. Two patients achieved CR and 11 patients PR with an ORR of 61.9%; the study met the primary endpoint in the first stage. With a median FU duration of 15.2 months, the median PFS was 9.3 months (95% CI, 6.6~12.0) and estimated median OS was 26.4 months (95% CI, 14.7-38.1). The treatment was tolerable and have no unexpected adverse events. Grade 3 adverse events included neutropenia (4.8%), anemia (9.5%), thrombocytopenia (4.8%) and diarrhea (4.8%). There were neither febrile neutropenia nor grade 4 adverse events. Conclusions: The first prospective ULTIMA study showed encouraging ORR and PFS in patients with advanced urachal cancer. The regimen is well tolerated without febrile neutropenia with prophylactic pegteograstim. Further analysis of efficacy will be presented. Clinical trial information: NCT04611724 .
Characterizing genomic alterations in patients with metastatic urothelial carcinoma (mUC) treated with enfortumab-vedotin (EV) with a focus on 1q23.3.
Authors: Renee Maria Saliby, Karl Semaan, Ilana B. Epstein, Sonsoles Liria, Christopher Dall, Eddy Saad, Marc Eid, John Canniff, Lucia Kwak, Stephanie A. Berg, Charlene Mantia, Bradley Alexander McGregor, David A. Braun, Toni K. CHOUEIRI, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2024)

e16570 Background: EV has improved outcomes for patients with mUC whether used as monotherapy or in combination. Limited studies have explored EV's efficacy and toxicity using combined genomic data from multiple platforms. We explored the association of genomic alterations with clinical outcomes in patients with mUC receiving EV treated at a single institution. Methods: Clinical and genomic data from patients with mUC treated with EV at the Dana-Farber Cancer Institute was analyzed. Genomic data was obtained using the targeted Oncopanel platform. Overall survival (OS), progression-free survival (PFS), and toxicity-free survival (TFS) as well as objective response rate (ORR) and progressive disease (PD) as best response according to RECIST 1.1 criteria were studied. Patients were categorized based on genomic alterations employing log-rank tests and univariate Cox regression for OS, PFS, and TFS, and Fisher’s exact test for ORR and PD. Results: We identified 286 patients treated for advanced UC since the approval of EV in 2021, of whom 65 received EV monotherapy, had available genomic data and were included in our analysis. Two genomic regions, 1q23.3 and 9p21.3 were found of interest. 17% (N=11) exhibited gain or amplification at the 1q23.3 cytoband ( PVRL4 cytoband) while 35% (N=23) had a two-copy deletion or loss at 9p21.3 ( MTAP, CDKN2A/B cytoband). While none of the results were statistically significant, gain or amplification of 1q23.3 was associated with a trend towards worse OS (Table). ORR was 29% compared to 60% in those without, but this difference was not statistically significant (p.value = 0.62). Two-copy deletion or loss at 9p21.3 was associated with numerically longer OS (Table) ORR was 57% in patients with the alteration versus 50% in those without, and 9% versus 17% for PD, respectively. These differences also did not reach statistical significance (p.value = 0.46). Conclusions: Our study did not find significant correlations between specific somatic alterations and clinical outcomes in patients with metastatic UC treated with EV though limited by small sample size. The observed trends in alterations of 1q23.3 and 9p21.3 warrant further investigation in larger cohorts. [Table: see text]
Preliminary safety, pharmacokinetics and clinical activity of DFF332, an oral HIF2α inhibitor, as monotherapy in a phase 1 dose escalation study in patients with advanced clear cell renal cell carcinoma.
Authors: Sumanta Kumar Pal, Nizar M. Tannir, Peter Grell, Xin Gao, Ritesh R Kotecha, Joel Picus, Filippo G. De Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Laurence Albiges
Journal: Journal of Clinical Oncology (2024)

4513 Background: Targeting HIF2α inhibition has been proven to be an effective therapeutic option in patients (pts) with advanced clear cell renal cell carcinoma (ccRCC). DFF332, a small molecule inhibitor that selectively targets HIF2α transcriptional activity, has shown dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This is the first in human, Phase I/Ib, open-label, multicenter, study (CDFF332A12101, NCT04895748) of DFF332 in adult pts with advanced ccRCC. The study evaluated the safety, tolerability, antitumor activity, pharmacokinetics (PK) and pharmacodynamics of DFF332. Here we report the preliminary data of the dose escalation of DFF332 monotherapy, administered orally at 50 mg or 100 mg weekly (QW) or at 25 mg, 50 mg, 100 mg or 150 mg once daily (QD) in 28-day treatment cycles. Results: Between Nov 30, 2021 to Nov 15, 2023, 40 pts (male, 78%) with a median age of 62.5 (38-79) years received treatment with DFF332. All pts received ≥1 prior line of therapy. At data cutoff, 18 pts were continuing treatment, while the treatment was discontinued in 19 pts (48%) due to progressive disease, and in 3 pts (8%) based on the physician's decision. The median (range) duration of exposure was 12.1 (1.0-75.6) weeks. Overall, 37 pts (93%) reported ≥1 adverse event (AE) regardless of relationship to study drug. Most common AEs were fatigue (33%), anemia (30%), increased blood cholesterol, and constipation (each 15%). Treatment-related AEs (TRAEs) were reported in 24 pts (60%): anemia, increased blood cholesterol, fatigue (each 13%), and hypertriglyceridemia (10%) being the most common TRAEs. Grade 3 TRAEs were increased weight and hypertension (1 pt [2.5%] each). Hypertension was the only treatment-related serious AE reported in 1 pt. No grade 4 TRAEs and dose-limiting toxicities have been observed so far. None of the patients reported hypoxia. At cut-off, 18 pts (45%) had stable disease (SD) and two pts (5%) achieved partial response [PR] accounting to a disease control rate (complete response + PR + SD) of 50%. Preliminary PK results demonstrated fast oral absorption, slow elimination, and dose-proportional exposure. Conclusions: During this phase I study, the monotherapy of DFF332 has shown a promising safety profile across all doses and schedules. Additionally, there have been indications of clinical activity and a dose-proportional modulation of erythropoietin. Currently, we are conducting an ongoing analysis of the PK and biomarker data, which will be included in the presentation. Clinical trial information: NCT04895748 .
A multi-institution analysis of outcomes with first-line systemic therapy for 99 patients with metastatic chromophobe renal cell carcinoma.
Authors: Sahil D. Doshi, Nazli Dizman, Andrea Knezevic, Amina Touma, Reza Alaghehbandan, Yasser Ged, Moshe Chaim Ornstein, Andrew Warren Hahn, Pavlos Msaouel, Martin H Voss
Journal: Journal of Clinical Oncology (2024)

4512 Background: Chromophobe renal cell carcinoma (ChRCC) represents ~5-10% of all RCCs. Given its rarity, there is limited clinical trial data to guide systemic therapy for metastatic disease. Phase 2 trials have demonstrated that targeted agents inhibiting vascular endothelial growth factor receptor and mammalian target of rapamycin have similar efficacy in ChRCC compared to conventional RCC. However, immune checkpoint inhibitor (IO) containing regimens appear less efficacious compared to other RCC subtypes. Importantly, these efforts have all enrolled &lt; 30 ChRCC patients, and larger scale studies are needed. Methods: We conducted a retrospective study of patients with metastatic ChRCC seen at 3 academic centers. Baseline characteristics and treatment outcomes were obtained from EHR review. Patients were categorized into 4 treatment categories: 1) IO + targeted therapy doublets (e.g., lenvatinib plus pembrolizumab) 2) Pure IO monotherapy and doublets (e.g., ipilimumab plus nivolumab) 3) targeted therapy doublets (e.g., lenvatinib plus everolimus) and 4) targeted monotherapy (e.g., sunitinib). We calculated time to treatment failure (TTF) of first-line systemic therapy and overall survival (OS) by the Kaplan-Meier method. Median time-to-event was reported for each treatment category and categories compared with the log-rank test. Results: Ninety-nine patients with metastatic ChRCC treated with first-line systemic therapy were included; 62% were male, 44% had sarcomatoid features, and 33% had IMDC favorable risk. Outcomes with TTF and OS are summarized in the table below. Median TTF and 18-month OS rates were 5 months and 58% for the targeted monotherapy group, 15 months and 80% for the IO/targeted doublet group, 17 months and 65% for the targeted doublet group, and 7 months and 83% for the pure IO group. Treatment with any doublet containing a targeted agent compared to targeted monotherapy yielded a superior median TTF (15 vs 5 months, HR 0.48; 95% CI: 0.29, 0.80; p=0.005) and OS (56 vs 23 months, HR 0.56; 95% CI: 0.30, 1.04; p=0.07). Most treatment (64%) was discontinued due to progression; 25% due to toxicity. 11 patients had ongoing treatment at time of analysis. Conclusions: In this observational analysis, patients with targeted doublet regimens had a higher median TTF and OS compared to those receiving monotherapies. We continue to build on this dataset and plan to conduct progression free survival analysis. [Table: see text]
Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Shilpa Gupta, Yohan Loriot, Michiel Simon Van Der Heijden, Jens Bedke, Begoña Pérez Valderrama, Eiji Kikuchi, Aude Flechon, Daniel P. Petrylak, Maria De Santis, Matt D. Galsky, Jae-Lyun Lee, Umang Swami, Srikala S. Sridhar, Ugo De Giorgi, Phoebe Wright, Yi-Tsung Lu, Xuesong Guan, Ryan Dillon, Blanca Homet Moreno, Thomas Powles
Journal: Journal of Clinical Oncology (2024)

4502 Background: EV+P nearly doubled median progression-free survival and overall survival vs PBC in patients (pts) with previously untreated la/mUC in the phase 3 EV-302 trial. PROs are reported here. Methods: In EV-302 (NCT04223856) pts were randomized 1:1 to EV+P or PBC (gemcitabine with cisplatin or carboplatin). PRO assessments included the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), and the Brief Pain Inventory Short Form (BPI-SF) completed at baseline, weekly for 12 weeks (wks), then every 3 wks through survival follow-up, inclusive of the time post-progression. Time to pain progression (TTPP) and mean change from baseline in worst pain at wk 26 using the BPI-SF were prespecified analyses statistically tested using a gatekeeping strategy. Mean change from baseline through wk 26 and time to confirmed deterioration (TTCD) of EORTC-QLQ-C30 and BPI-SF domains were prespecified descriptive analyses. TTPP and TTCD were assessed using Kaplan-Meier methods. Results: Of 886 pts randomized, 731 (376 received EV+P; 355 PBC) completed baseline PRO questionnaires. Compliance rates differed between arms and remained &gt;70% through wk 29 for EV+P and through only wk 17 for PBC. Median TTPP was 14.2 months (mos) with EV+P and 10.0 mos with PBC (hazard ratio [HR]=0.92; 95% CI=0.72, 1.17; 2-sided p-value=0.48). The least squares (LS) mean reduction in worst pain at wk 26 was numerically greater with EV+P vs PBC (-0.61 vs -0.03, LS mean difference [95% CI]: -0.58 [-1.05, -0.11] [nominal 2-sided p-value=0.015]). Pts with moderate to severe pain at baseline who were treated with EV+P (n=128, 34%) had a meaningful (&gt;2 pt) improvement from baseline in BPI worst pain from wk 3 through 26. In EORTC QLQ-C30 Global Health Status/Quality of Life [GHS/QoL], EV+P demonstrated a transient worsening at wk 3 (-6.3) that returned to baseline from wks 4 through 26, while patients treated with PBC demonstrated deterioration from wk 1 through wk 17 (range -1.2 to -7.1) when scores returned to baseline. TTCD for EORTC QLQ-C30 GHS/QoL was 5.9 mos with EV+P vs 3.2 mos with PBC (HR = 0.98 [95% CI]: 0.79 – 1.2). Conclusions: Pts treated with EV+P have improved survival compared with PBC without detriment to quality of life and functioning, further supporting the value of EV+P for pts with la/mUC. Compliance, especially after progression, was lower than expected (particularly in the PBC arm) and may have impacted the results. Clinical trial information: NCT04223856 .
Prognostic analysis of disitamab vedotin combined with PD-1 inhibitor first-line treatment in advanced urothelial carcinoma: A propensity score analysis.
Authors: Yupeng Jiang, Chao Xu, Wen Zou, Minfeng Chen, Wei He, Yuan Li, Yeqian Feng, Songqing Fan, Lin Wu, Jingjing Wang
Journal: Journal of Clinical Oncology (2024)

e16565 Background: The combination of antibody-drug conjugates and PD-1 inhibitor has great prospects for first-line treatment of advanced urothelial carcinoma (UC). This real-world study explored the efficacy, safety, and prognostic biomarkers of disitamab vedotin (DV) combined with PD-1 inhibitor, and compared them with other first-line regimens without DV. Methods: Patients were enrolled retrospectively from July 2021 to December 2022 in two cancer centers. There were four first-line treatment regimens: DV (120-180mg) plus PD-1 inhibitor (Tislelizumab 200mg or Toripalimab 240mg) once every 3 weeks, chemotherapy (gemcitabine plus cisplatin/carboplatin) plus ICI, chemotherapy, and ICI. Then patients were classified into the DV group and No DV group. Treatment outcomes were compared between the two groups after 1:1 ratio PS matching adjusted for sex, PS score, stage, histological grade, and tumor location. In DV group, RNA-seq was used to analyze differential expressed genes (DEGs). Results: There are 63 patients enrolled with median age 68 years (44–90 years). The median follow-up time was 13 months (4–36 months). The 1-year overall survival and progression free survival (PFS) rates were 74.3% and 47%, respectively. There were 30 patients received DV plus ICI, 17 received chemotherapy plus ICI, 9 received chemotherapy, and 7 received ICI alone. PS score and first-line regimen containing DV are independent prognostic factors for PFS. After PS matching, there were 22 patients each in the DV group and No DV group. There were significant differences between the two groups in terms of objective response rate (81.8% vs.27.3%, p=0.003) and 1-year PFS rate (68.2% vs.33.5%, p=0.008) (Table). In safety, hematology and gastrointestinal toxicity were more likely to occur in the No DV group, while neurotoxicity and rash were more likely to occur in the DV group, and most of which were grade 1-2. In DV group, the top 5 most significantly DEGs between patients with long (&gt;6 months) and short PFS (≤6 months)were SCGB1A1, AKR1C1, FAM205C, ACP7 and NLGN4X, and which are enriched in the pathway of cytoplasmic translocation and the function of ribosome. Conclusions: The first-line regimen of DV plus PD-1 inhibitor for patients with advanced UC was more effective and safer than the regimen without DV. The pathway of cytoplasmic translocation and the function of ribosome may be highly correlated to the effectiveness of the regimen of ADC plus ICI. [Table: see text]