tbuckley/cabot-search huggingface dataset:
Treatment (Rx) trends and attrition with lines of therapy in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Vinay Mathew Thomas, Yeonjung Jo, Nishita Tripathi, Soumyajit Roy, Beverly Chigarira, Emre Dal, Georges Gebrael, Chadi Hage Chehade, Nicolas Sayegh, Gliceida Galarza Fortuna, Richard Ji, Patrick Campbell, Haoran Li, Neeraj Agarwal, Sumati Gupta, Umang Swami
Journal: Journal of Clinical Oncology (2024)

562 Background: The Rx landscape of aUC has evolved significantly with the approval of novel therapeutic agents. However, even with the advent of new therapeutic options, aUC remains a lethal malignancy with poor outcomes. Here, we use a large real-world database to describe Rx trends and attrition in pts with aUC. Methods: Patient data was extracted from the Flatiron Health EHR-derived deidentified database. Inclusion criteria: pts with histological diagnosis of metastatic or aUC between 1/1/11-1/10/2023 and Rx receipt at participating site. Pts receiving Rx for two or more cancers were excluded. Rx were grouped into categories based on NCCN approved regimens. Rx in each line (L) of therapy were summarized using frequency and percentages. All the analysis was done using R version 4.2.3. Results: Of the identified 12,157 pts in the dataset, 8,660 had Rx information and 7,260 were included in the analysis based on eligibility criteria. Details of each line of therapy are presented in the table. Of all pts receiving 1L, only 37% receive 2L and only 12% receive 3L of therapies. Carboplatin containing regimen were most commonly used in 1L followed by PD-1/L1 therapies. PD-1/L1 therapies were most commonly used regimens in 2L and 3L. Over time, there has been a steady decline in the overall use of platinum-based regimens, and since 2015 an increase in uptake of PD-1/L1 agents has been observed. The use of novel therapeutic agents, such as enfortumab vedotin (EV), erdafitinib, and sacituzumab govitecan (SG), has increased since 2019, especially in the 2L and 3L of therapy. Conclusions: Approximately two-thirds of aUC patients don’t receive 2L or beyond systemic therapy. Majority of real-world patients (61%) did not receive cisplatin-based regimens and instead received carboplatin or PD- 1/L1i based therapies. These data warrant the need for more effective and tolerable Rx in front-line setting. [Table: see text]
Association of microbial metabolism of tryptophan with resistance to immune checkpoint (ICB) therapy in renal cell cancer (RCC).
Authors: Shahla Bari, Brandon J. Manley, Jameel Muzaffar, Humaira Sarfraz, Andrew J. Armstrong, Nizar M. Tannir, Daniel J. George, Jose Conejo-Garcia
Journal: Journal of Clinical Oncology (2024)

452 Background: Metastatic RCC has a poor prognosis. Despite improvement in treatment outcomes with ICB and targeted therapy, many patients fail to respond to first line therapy and durable responses remain elusive. The tryptophan metabolite kynurenine, an agonist of the immunosuppressive aryl hydrocarbon receptor (AhR), is associated with resistance to ICB. However, IDO (Indole 2,3 dioxygenase) blockers which inhibit tryptophan metabolism to kynurenine failed to show benefit in clinical trials, suggesting the presence of alternate AhR activation. We hypothesize that microbial metabolism of tryptophan to indole metabolites may be associated with AhR activation and ICB resistance. Methods: We prospectively collected paired stool and blood samples of treatment naïve metastatic RCC patients, treated with ICB +/- Tyrosine kinase inhibitors (TKI) at treatment initiation and at time of first response assessment (12+/-3 weeks). We evaluated stool metagenomics and untargeted stool and plasma metabolomics among responders (R) and non-responders (NR). We focused on kynurenine/tryptophan and indoles/tryptophan ratio to evaluate differential host and microbial metabolism of tryptophan. A responder was classified as progression free survival (PFS) greater than 6 months. We also performed global metabolomics on tumor and plasma of germ-free (GF) &amp; specific pathogen free (SPF) mice to identify microbial &amp; host metabolites. Results: Among 120 patients accrued, baseline paired samples were analyzed from 99 patients, 39 were treated with combination ICB, while 60 patients were treated with ICB + TKI. Median follow up was 15 months. 65% of patients had PFS &gt; 6 months. Using unpaired t test comparing baseline relative abundance of metabolites between R vs NR - plasma Kynurenine/tryptophan ratio was significantly higher in NR vs R, at baseline and at 3 months (baseline-0.042 vs 0.01, p=0.01, 3 months-0.058 vs 0.02, p=0.02). Microbial metabolites of Tryptophan -Indole pyruvic acid (IPA), Indole carboxylic acid (IcA), and Indole acetaldehyde (IAAld) were differentially associated with ICB resistance and was significantly higher in NR (IcA: 8.0 vs 5.2, p=0.03; IPA: 82.4 vs 64.9, p=0.01; IAAld: 78.7 vs 64.6, p=0.03). We also noted differential enrichment of microbial KEGG enzymes associated with IPA, IAAld and IcA production in the stool of NR patients compared to R. Microbial origin of these metablites was confirmed by its absence in tumor of GF mice. Conclusions: This is first study in metastatic RCC which shows the association of indoles (microbial metabolites of tryptophan) with resistance to ICB. These indoles are known to be potent AhR agonists and are associated with immunosuppression suggesting that microbial metabolism of tryptophan may represent a novel pathway for ICB resistance in RCC patients.
Oncologic outcomes of neoadjuvant chemotherapy and lymph node dissection with partial cystectomy for muscle-invasive bladder cancer.
Authors: Ryan Michael Antar, Vincent Eric Xu, Olivia French Gordon, Christian Mark Farag, Sarah Azari, Michael Joseph Whalen
Journal: Journal of Clinical Oncology (2024)

698 Background: Partial cystectomy (PC) offers potential benefits for select patients with muscle-invasive bladder cancer (MIBC). However, the oncologic efficacy of PC may be compromised due to the underutilization of standard-of-care modalities, such as neoadjuvant chemotherapy (NAC) and pelvic lymphadenectomy (PLND). We aimed to assess factors influencing the incorporation of NAC and PLND with PC and evaluate their impact on overall survival (OS). Methods: We identified patients with cT2-4N0M0 BCa who underwent PC between 2004 and 2019 using the National Cancer Database (NCDB). The primary endpoint was OS. Kaplan-Meier analysis compared OS between PC patients who did and did not receive NAC. Multivariate Cox Proportional Hazards (CPH) model assessed the impact of age, sex, race, insurance, income, Charlson-Deyo Index (CDI), clinical T-stage, facility type, histology, surgical margins, NAC, PLND adequacy (≥10 LN yield), and adjuvant radiation treatment on OS. Multivariate logistic regressions were performed to examine predictors of NAC and PLND receipt in PC patients. Results: Of 2,832 patients included, 231 (8.1%) patients received multi-agent NAC with PC and had improved median OS compared to those who did not (115.0 vs. 87.4 months, p&lt;0.001). This finding persisted in the adjusted CPH model, where private insurance, NAC, and PLND significantly improved OS, especially when PLND yielded ≥10LN. Conversely, age &gt;80, CDI &gt;2, cT3-4, positive margins, and adjuvant radiation all increased adjusted mortality risk. After controlling for clinicopathologic variables, females were less likely to receive PLND (OR=0.634, p&lt;0.001), while NAC was more likely administered to PC patients diagnosed from 2015-2019 (OR=2.177, p=0.022). PC patients who received NAC were more likely to have PLND performed as part of their treatment regimen (OR=2.189, p&lt;0.001). Additionally, patients treated at academic centers were more likely to have NAC administered and PLND performed (OR=1.745, p=0.003; OR=2.465, p&lt;0.001, respectively). Conclusions: Despite guidelines, there is an insufficient utilization of NAC and PLND when performing PC. Our analysis underscores the significant OS benefit of these recommended treatments as part of MIBC care. Importantly, we highlight a gradual increase in NAC and PLND receipt in recent years, centered largely at academic facilities. Notably, gender disparities exist in PLND receipt, emphasizing the need for further investigation. [Table: see text]
A systematic review: Are the findings of indirect treatment comparisons (ITCs) in metastatic hormone-sensitive prostate cancer (mHSPC) consistent?
Authors: Neal D. Shore, Alicia K. Morgans, Noman Paracha, Sarah Hodgkinson, Christian Eichinger, Craig Millar, Stephanie Chen, Martin Boegemann
Journal: Journal of Clinical Oncology (2024)

324 Background: Multiple treatment options exist for mHSPC, including androgen receptor-axis-targeted (ARAT) therapies with or without docetaxel (DOC). Many ITCs have been published that compare efficacy and safety of treatment alternatives in mHSPC that have not been directly compared in head-to-head clinical trials. We assessed the methodology and findings of previously published ITCs, focusing on outcomes related to triple therapy with darolutamide (DARO) + androgen deprivation therapy (ADT) + DOC from the ARASENS clinical trial. Methods: We performed systematic literature review searches in MEDLINE, Embase and Cochrane databases to identify ITCs published from 1946 to May 2023 (PROSPERO, CRD42023429478). We focused on reporting ITCs that included ARASENS trial data and treatment versus treatment comparisons. Results: We included 12 ITCs across 17 publications. There was variation across the ITCs in the number of trials included (range: 2–10), and the statistical method used (frequentist or Bayesian network meta-analyses, random or fixed effects). Furthermore, reporting of treatment effect modifiers, network inconsistency/heterogeneity, and subgroup analysis was inconsistent across studies. Despite methodological differences, ITCs were consistent in showing a significant benefit in overall survival (OS) with DARO triple therapy compared with ADT (4 ITCs), and with DOC+ADT (7 ITCs; in line with ARASENS trial results). DARO triple therapy demonstrated a numerical benefit in OS compared with doublet (ARAT+ADT) and with other triple therapies (abiraterone acetate+prednisone [AAP] or enzalutamide [ENZ]+DOC+ADT) (Table 1). DARO triple therapy was consistently ranked highest, above other ARAT double and triple therapies, on OS across 9 ITCs. The risk of grade ≥3 adverse events (AEs) were numerically greater with DARO triplet therapy compared with ARAT doublets (6 ITCs). Available ITC evidence comparing AEs across triple therapies showed numerically fewer AEs for DARO compared with AAP (2 ITCs). Conclusions: Despite variability in their methodology, ITCs were consistent in showing OS benefit and highest ranking with DARO triple therapy, above the other ARAT therapies, and in reporting fewer AEs for DARO compared with AAP. As the number of mHSPC publications grows, so too does the need for standardizing ITC methodology to ensure robustness of findings and to optimize treatment decision-making. [Table: see text]
Updated results from AVENANCE: Real-world effectiveness of avelumab first-line maintenance (1LM) in patients (pts) with advanced urothelial carcinoma (aUC) and analysis of subsequent treatment.
Authors: Philippe Barthelemy, Yohann Loriot, Constance Thibault, Marine Gross-Goupil, Jean Christophe Eymard, Eric Voog, Christine Abraham Jaillon, Sylvestre Le Moulec, Matthieu Chasseray, Aurélien Gobert, Benjamin Auberger, Caroline Viala, Mathilde Cabart, Eyad Kazan, Veronique Lorgis, Werner Hilgers, Constant Josse, Prisca Lambert, Marie-Noelle Solbes, Aude Flechon
Journal: Journal of Clinical Oncology (2024)

561 Background: Avelumab 1LM is the standard of care for aUC that has not progressed with 1L platinum-based chemotherapy based on level 1 evidence from the JAVELIN Bladder 100 phase 3 trial. Previous results from AVENANCE showed the effectiveness and safety of avelumab 1LM in a real-world population with aUC in France. We report updated data and analyses by subsequent (next-line) treatment. Methods: AVENANCE (NCT04822350) is a noninterventional, ambispective study. Eligible pts had aUC that had not progressed with 1L platinum-based chemotherapy and previous, ongoing, or planned avelumab 1LM treatment. The primary endpoint is overall survival (OS). Data reported are preliminary, and analysis is ongoing. Results: 594 pts were analyzed. At data cutoff (May 31, 2023), median follow-up was 24.2 mo (range, 0.6-43.7); 142 pts (23.9%) remained on avelumab. Median duration of avelumab treatment was 5.6 mo (95% CI, 4.9-6.9). Reasons for discontinuation were disease progression in 330 (73.2%), adverse event in 50 (11.1%), death in 42 (9.3%), and other reasons in 29 (6.4%) pts. 314 pts (52.9%) received subsequent treatment after avelumab: chemotherapy in 238 (75.8%), antibody-drug conjugate (ADC) in 52 (16.6%; enfortumab vedotin, 46 [14.6%]; other, 6 [1.9%]), immunotherapy in 12 (3.8%), and other in 12 (3.8%). Characteristics of pts who received ADC or chemotherapy are shown (Table). In the overall population, median OS from start of avelumab 1LM was 21.1 mo (95% CI, 17.3-23.8), and 1- and 2-y OS rates (95% CI) were 66.58% (62.57%-70.26%) and 45.41% (40.89%-49.82%), respectively. In pts who received subsequent ADC or chemotherapy, median OS (95% CI) from start of avelumab 1LM was 31.3 mo (22.2-not estimable) and 14.0 mo (13.2-15.6), 1-y OS rates (95% CI) were 85.93% (72.72%-93.04%) and 61.68% (55.13%-67.56%), and 2-y OS rates were 66.90% (49.85%-79.29%) and 25.43% (19.17%-32.14%), respectively. Conclusions: Updated results from the AVENANCE study confirm the effectiveness of avelumab 1LM in a real-world population. In pts with subsequent treatment (≈70% of pts who discontinued), a contemporary sequence of ADC after 1L platinum-based chemotherapy and avelumab 1LM treatment showed encouraging OS. Clinical trial information: NCT04822350 . [Table: see text]
Characteristics of patients (pts) with muscle-invasive urothelial carcinoma (MIUC) who received adjuvant nivolumab (NIVO) or adjuvant platinum-based chemotherapy (CHEMO) in the real-world (RW) setting.
Authors: Alex Chehrazi-Raffle, Bruce A. Feinberg, William S. John, Taavy A. Miller, Emily Bland, Sarah Gordon, Jalyna R. Laney, Andrew J. Klink, Hedyeh Ebrahimi, Miraj Y. Patel, Lisa Rosenblatt, Carmelo Alonso, Nisha Singh, Xin Yin
Journal: Journal of Clinical Oncology (2024)

565 Background: NIVO has shown promise as an adjuvant treatment for MIUC. In the CheckMate 274 trial, NIVO achieved a significant improvement in disease-free survival compared to placebo in MIUC pts at high risk of recurrence following radical surgery. However, it is unclear how treatment decisions are made in the RW setting and what factors drive providers in selecting either NIVO or CHEMO as adjuvant treatment. We compared the baseline demographic and clinical characteristics of pts with MIUC who received adjuvant NIVO to those who received adjuvant platinum-based CHEMO in the RW setting. Methods: This retrospective medical chart review included pts diagnosed with stage II-IIIB MIUC who initiated treatment with NIVO or CHEMO within 120 days of radical resection between 9/1/2021 and 11/25/2022. Treating oncologists from a US nationally representative network abstracted pts’ data from electronic medical charts. Pts’ demographic and clinical characteristics were assessed. Results: Age, sex, and race were similar across cohorts (Table). Pts who received adjuvant NIVO (n = 158) vs CHEMO (n = 88) were more likely to have ECOG-PS≥ 2 at treatment initiation (24.1% vs 17.1%; P = 0.02), and more likely to receive PD-L1 testing (Not tested: 36.1% vs. 47.7%; P &lt; 0.0001) and have PD-L1 expression levels ≥ 50% (13.9% vs 1.1%; P &lt; 0.0001). A higher proportion of pts who received NIVO vs CHEMO had diabetes with chronic complications (15.8% vs 5.7%; P = 0.02) and hypertension (20.9% vs 6.8%; P = 0.004), and were determined to be cisplatin-ineligible (41.8% vs 25%; P = 0.007), predominately based on creatinine clearance (&lt; 60 mL/min: 48.7% vs. 34.1%; P = 0.002) and poor PS (13.9% vs. 4.6%; P = 0.07); rheumatologic disease was less common among the NIVO cohort (1.9% vs 11.4%; P = 0.002). Conclusions: This RW analysis demonstrated that pts with MIUC who received adjuvant NIVO had greater baseline disease severity and comorbidities than those who received adjuvant CHEMO. These findings suggest that patient characteristics influence treatment selection of adjuvant therapy in this patient population, highlighting the need to adjust for baseline characteristics in future comparative analyses.[Table: see text]
Building a predictive model for outcomes with [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer using VISION data: Preliminary results.
Authors: Ken Herrmann, Andrei Gafita, Johann S. De Bono, A. Oliver Sartor, Kim N. Chi, Bernd J. Krause, Kambiz Rahbar, Scott T. Tagawa, Johannes Czernin, Ghassan El-Haddad, Connie Wong, Zhaojie Zhang, Celine Wilke, Osvaldo Mirante, Michael J. Morris, Karim Fizazi
Journal: Journal of Clinical Oncology (2024)

208 Background: 177 Lu-PSMA-617 is approved in adults with PSMA+ metastatic castration-resistant prostate cancer (mCRPC). This analysis of VISION data sought to build predictive models for clinical outcomes after 177 Lu-PSMA-617. Methods: In VISION, adults with PSMA+ mCRPC received 177 Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤6 cycles) plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, 29 baseline parameters were assessed for prognostic and predictive value on overall survival (OS), radiographic progression-free survival (rPFS) and PSA response (≥50% reduction; PSA50). Parameters associated with outcome regardless of treatment were prognostic, and those associated with outcome after treatment with 177 Lu-PSMA-617+SoC vs SoC were predictive. Cox proportional hazards (OS and rPFS) or logistic regression (PSA50) models were used in univariate analyses for parameter selection and to build statistical models. Here, univariate analyses are presented. Multiplicity was corrected by use of q values (α = 0.05). Results: Data from 831 adults were analyzed. In initial univariate analyses, 76%, 69% and 38% of parameters assessed were prognostic for OS, rPFS and PSA50, respectively; fewer were predictive of better outcomes after 177 Lu-PSMA-617+SoC vs SoC (subset shown). Conclusions: Baseline prognostic and predictive parameters were identified for OS, as well as for rPFS and PSA50, in adults with mCRPC in VISION receiving 177 Lu-PSMA-617+SoC or SoC alone. For clinical application, select parameters will be reassessed categorically, and multivariate predictive models will be developed using identified parameters and parameter shrinkage. [Table: see text]
Development and validation of a novel prognostic model for disease-specific survival in patients with non-metastatic small cell carcinoma of the bladder.
Authors: Leonidas Nikolaos Diamantopoulos, Daniel S Childs, Akeem Ronell Lewis, Fabrice Lucien, Spyridon P. Basourakos, Adam McLain Kase, Parminder Singh, Mark Tyson, Stephen A. Boorjian, Lance C. Pagliaro, Brian Addis Costello, Jacob Orme
Journal: Journal of Clinical Oncology (2024)

695 Background: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with limited data informing prognosis. We present a novel prognostic model for disease specific survival (DSS) for patients with non-metastatic (M0) SCCB, derived from the Surveillance, Epidemiology and End Results (SEER) database. Methods: The SEER database (18 registries/November 2020) was queried with the ICD-10 topography codes C67.0-C67.9 (bladder), and the morphologic code 8041 (SCCB). Eligible patients (adults, histologic confirmation, available follow-up/staging data, M0) were randomly divided into a training (TC) and a validation cohort (VC) (7:3 ratio). Variables significantly associated with DSS were identified with multivariate Cox regression and backwards stepwise conditional approach and inserted in the model. Points were assigned to each variable based on the formula: Probability of an event at time t=S 0 (t) exp(β 1 x 1 , β 2 x 2 ...) , (β = regression coefficients, x = observed covariate values, S0(t) = survival function). Cumulative risk points were assigned to each patient and three distinct risk categories for DSS were constructed. Harrel’s C-statistic with bootstrap resampling was used for internal (TC) and external (VC) validation. Model performance was compared to the AJCC 8 th edition (likelihood ratio test -LRT). Results: A total of 1039 patients were included (739 TC, 300 VC). No statistically significant differences in baseline characteristics/survival outcomes were identified between TC and VC. Age (years), T/N stage, radical cystectomy, chemotherapy, and radiation were significant variables inserted in the multivariate model (table). Patients were stratified to three risk groups (low, intermediate, high) based on the total cumulative risk points collected. Median DSS was NR (95%CI; NR, NR), 25 (95% CI; 18-32) and 9 months (95% CI; 7-11) for the low, intermediate, and high-risk category, log-rank p&lt;.001. Harrel's C-statistic for the model was 0.70 (95%CI;0.67-0.73) in the TC and 0.66 (95%CI; 0.61-0.71) in the VC. In comparison, C-statistic for the AJCC 8 th edition was 0.56 (95% CI; 0.52-0.59) and 0.53 (95% CI; 0.51 to 0.57), respectively. The LRT demonstrated superior performance of the model compared to AJCC (p&lt;.001). Conclusions: We present a novel prognostic model for DSS in patients with locoregional SCCB composed of variables readily available in daily practice, which may serve as a useful tool for individualized risk assessment of patients with this rare malignancy. Further validation in prospective studies/clinical trials is warranted. [Table: see text]