Subsequent Disease Progression Research Articles

Targeting Chemoresistance in Advanced Bladder Cancers with a Novel Adjuvant Strategy.

Advanced urinary bladder cancer is characterized by rapid progression and development of therapy resistance. About 30% of the patients are diagnosed with high-grade tumors (grade > T2a). A typical nonsurgical treatment is systemic chemotherapy using cisplatin (C) and gemcitabine (G). However, treatment failure and subsequent disease progression are common in treated patients, and adjuvant therapies are not significantly effective. The therapeutic potential of a molecular hybrid of ursolic acid (UA), a pentacyclic-triterpene conjugated to N-methyl piperazine (UA4), was tested on both naïve (WT) and gemcitabine-resistant (GemR) variants of two human invasive bladder cancer cell lines, 5637 and T24. UA4 killed 5637 (4 µmol/L), T24 (4 µmol/L) WT, and GemR cells in vitro at equal potency. Pretreatment with UA4 followed by G synergistically killed WT and GemR cells by >50% compared with G followed by UA4. Oral gavage of UA4 (100 mg/kg) inhibited WT and GemR tumor growth in athymic mice. UA4 + G was more effective against GemR tumors than either drug alone. Studies revealed cytotoxic autophagy as a mechanism of UA4 cytotoxicity. UA4 induced moderate apoptosis in T24 but not in 5637 cells. Mitochondrial integrity and function were most affected by UA4 because of high levels of reactive oxygen species, disruption of mitochondrial membrane, and cell cycle arrest. These effects were enhanced in the UA4 + G combination. UA4 was well-tolerated in mice, and oral gavage led to a serum level >1 µmol/L with no systemic toxicity. These results show the potential of UA4 as a nontoxic alternative treatment for high-grade bladder cancer.

Gut microbiome shifts in people with type 1 diabetes are associated with glycaemic control: an INNODIA study.

The gut microbiome is implicated in the disease process leading to clinical type 1 diabetes, but less is known about potential changes in the gut microbiome after the diagnosis of type 1 diabetes and implications in glucose homeostasis. We aimed to analyse potential associations between the gut microbiome composition and clinical and laboratory data during a 2 year follow-up of people with newly diagnosed type 1 diabetes, recruited to the Innovative approaches to understanding and arresting type 1 diabetes (INNODIA) study. In addition, we analysed the microbiome composition in initially unaffected family members, who progressed to clinical type 1 diabetes during or after their follow-up for 4 years. We characterised the gut microbiome composition of 98 individuals with newly diagnosed type 1 diabetes (ND cohort) and 194 autoantibody-positive unaffected family members (UFM cohort), representing a subgroup of the INNODIA Natural History Study, using metagenomic sequencing. Participants from the ND cohort attended study visits within 6 weeks from the diagnosis and 3, 6, 12 and 24 months later for stool sample collection and laboratory tests (HbA1c, C-peptide, diabetes-associated autoantibodies). Participants from the UFM cohort were assessed at baseline and 6, 12, 18, 24 and 36 months later. We observed a longitudinal increase in 21 bacterial species in the ND cohort but not in the UFM cohort. The relative abundance of Faecalibacterium prausnitzii was inversely associated with the HbA1c levels at diagnosis (p=0.0019). The rate of the subsequent disease progression in the ND cohort, as assessed by change in HbA1c, C-peptide levels and insulin dose, was associated with the abundance of several bacterial species. Individuals with rapid decrease in C-peptide levels in the ND cohort had the lowest gut microbiome diversity. Nineteen individuals who were diagnosed with type 1 diabetes in the UFM cohort had increased abundance of Sutterella sp. KLE1602 compared with the undiagnosed UFM individuals (p=1.2 × 10-4). Our data revealed associations between the gut microbiome composition and the disease progression in individuals with recent-onset type 1 diabetes. Future mechanistic studies as well as animal studies and human trials are needed to further validate the significance and causality of these associations.

METRADS-P vs. RECIST/PCWG criteria to detect disease progression in metastatic castration-resistant prostate cancer (mCRPC).

5070 Background: Radiographic Progression-free survival (rPFS) derived from Computer Tomography (CT) and Bone Scan (BS) using Prostate Cancer Working Group (PCWG) criteria is utilized as an intermediate clinical endpoint for overall survival (OS) benefit in mCRPC. Whole Body MRI (WBMRI) is emerging as a potentially superior response biomarker, allowing a more accurate assessment of bone marrow and soft tissue disease. We have now compared the performance of previously reported WBMRI criteria (MET-RADS-P) with PCWG criteria as a response biomarker for mCRPC, and this with overall survival (OS). Methods: We retrospectively analysed imaging data from mCRPC patients that 1) discontinued therapy based on PCWG criteria; 2) had contemporaneous WBMRI, CT, and BS at time-points according to PCWG. Soft tissue lesions were classified according to RECIST1.1 both on CT and WBMRI; bone lesions were classified on BS using PCWG criteria as non-PD (non-progressive disease), PD-U (PD unknown) & PD (progressive disease) and on WBMRI using MET-RADS-P as non–PD (subclassified as partial response-PR & stable disease-SD) & PD, for each imaging time-point. We calculated % agreement between MET-RADS-P and PCWG across all time-points. Median PFS as per PCWG (rPFS) and METRADS-P (mPFS) and median OS according to METRADS-P response at 12 weeks was estimated by Kaplan Meier. Results: 100 cases (91 subjects received 100 lines of treatment, 100 baseline imaging & 216 follow-up imaging assessments). For soft tissue disease, RECIST 1.1 and WBMRI assessments were concordant at 201 of 216 time-points (93.1%); the discordance was related to superior detection of local disease and liver metastases on WBMRI. Bone metastases assessments showed agreement in 37.5% time-points, with details as follows (% over BS category): 1) Negative BS (13 time-points): WBMRI 69.2% negative, 15.4% PR, 15.4% as PD; 2) Non-PD BS (154 time-points): WBMRI non-PD 51% (34.4% PR, 17.5% SD), 48.1% PD; 3) PD-U BS (40 time-points): WBMRI PD 90%; Non-PD 10% (1pt FLARE & 3pt with subsequent concordant PD). At time of PD-U, 30 out of 40 pt (75%) discontinued treatment due to RECIST PD (24/40) & clinical progression (6/40). 4) PD confirmatory BS (9 time-points) : WBMRI 100%PD. Median rPFS by PCWG was 4.9 months (m) (95%CI: 3.8-5.7); the median mPFS by MET-RADS-P was 2.8 months (2.6-3.9), with overall progression rate of 70% and 94% respectively. Non-PD by WBMRI at 12-weeks associated with longer OS when compared with PD by MRI (median OS: 17.9m (14.2-22.6) vs 14.4m (9.6-17.0) (crude log-rank test 0.0059). Conclusions: Regarding soft-tissue disease, MET-RADS-P detects progression earlier than RECIST in 4.2% time-points, while for bone metastases it detects progression earlier than PCWG at 51.9% of timepoints. WBMRI can better classify BS non-PD patients in PR, SD and PD. Response evaluation based on WBMRI is a prognostic factor in mCRPC.

Outcomes following long-term response to immune checkpoint inhibitors in patients with advanced melanoma.

9520 Background: Immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4 can achieve durable responses. Historically, therapies in advanced malignancies were considered palliative, however long-term results from ICI melanoma studies suggest cure may be possible for some patients (pts). Despite clinical trial data, little is known about the risk, character, and clinical outcome of late recurrences after ICI. Methods: ICI treated pts with advanced melanoma who had a long-term disease control, defined as not requiring a subsequent line of systemic therapy within 3 years, were retrospectively identified at 11 centres. Those who had progressive disease managed with local therapies were included if no new systemic therapy was commenced within the 3 years. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 567 pts were identified, with a median follow up of 7 years since start of therapy. At ICI commencement, 41% and 17% had M1c or M1d disease respectively, 26% had an elevated LDH, 33% were BRAF mutant and 24% had received prior therapy. The ICIs received were anti-PD-1 +/- an investigational agent (59.3%), anti-PD-1 plus anti-CTLA-4 (35.8%), or an anti-CTLA-4 (5%). The median duration of therapy was 18 months, with 31% of pts stopping due to toxicity. 63 pts (11.1%) had oligo-progression within 3 years from ICI start. 53 pts (9.3%) had progression after 3 years, with median time to progression of 16.3 months. Subsequent late progression was more common in those who had oligo-progression within 3 years of treatment compared to those who had not (14/63, 22% vs 39/504, 7.7%, P<0.001). The risk of late progression was lower in those who achieved a complete response (CR) compared to those without a CR (23/369, 6.2% vs 30/198, 15.2%, P<0.001). The landmark 5 year PFS was 95% compared to 89% in those with or without a CR respectively. Duration of therapy, treatment cessation due to toxicity, or corticosteroid use were not associated with the risk of late progression. Most late progression occurred within year 3 to 5 (38/53, 72%). 15 pts who progressed after 3 years were managed with local therapy alone. In progressors retreated with PD-1 alone as the next subsequent therapy, 14 of 26 (54%) responded (7 CR, 7 PR). In the total cohort, there were 31 (5.5%) deaths, 7 (1.2%) from melanoma. Of the pts with a CR, 14 (3.7%) died, only 1 (0.3%) from melanoma. Of the 53 pts who progressed after 3 years, 10 (19%) died, 7 (13%) from melanoma. Conclusions: In this population of pts with advanced melanoma with long term disease control from ICI, the risk of subsequent disease progression and death was low (1.2%). Predictors for late progression after 3 years were a non-CR best response and prior progression within 3 years. This and other data suggest a significant proportion of long-term ICI responders are likely cured, and may inform frequency and duration of follow up.

A nation-wide medical record database study: Value of hepatitisB surface antigen loss in chronic hepatitisB patients in Japan.

HepatitisB surface antigen (HBsAg) seroclearance is considered to be one of the best surrogate endpoints of functional cure for hepatitisB virus (HBV) infection. However, evidence regarding the relationship between achieving HBsAg seroclearance or a low baseline HBsAg level, and long-term clinical outcomes in Japanese patients with chronic HBV infection remains to be confirmed in a real-world setting. A retrospective observational cohort study was performed with an electronic medical record database, including data from 230 hospitals across Japan. Chronic HBV infection was defined as two consecutive, positive HBsAg laboratory measurements for HBV infection. The date of the second positive was used as a baseline to identify subsequent HBsAg seroclearance and liver disease progression. In the database, 2523 patients with chronic HBV infection were identified as the chronic hepatitisB (CHB) cohort. Among the CHB cohort with an average observational period of 5.19±3.87years, 202 patients (8%) achieved HBsAg seroclearance after baseline. They had a lower risk of developing hepatocellular carcinoma (HCC) (adjusted hazard ratio [aHR] 0.206, p<0.01) and cirrhosis (aHR 0.361, p<0.01). When the CHB cohort was stratified into two groups based on baseline HBsAg levels (<100IU/mL and ≥100IU/mL), patients with a lower baseline level of HBsAg (<100IU/mL) had a lower risk of developing liver disease (HCC aHR 0.600, p<0.01; cirrhosis aHR 0.618, p<0.05). These results confirm the clinical significance of HBsAg seroclearance and low HBsAg level at baseline with respect to long-term outcomes of patients with CHB in the Japanese population.

Abstract PO1-05-13: Drop-out rates from line to line of treatment in metastatic breast cancer (MBC): Results from the Austrian AGMT_MBC-Registry

Abstract Background: In metastatic breast cancer (MBC) continuous treatment with sequentially administered cancer drugs is the standard of care. Lines of treatment (LoT) consisting of single drugs or drug combinations are usually administered until disease progression or unacceptable toxicity. To provide as many patients as possible access to the most effective therapies, the “best treatment first” strategy has been established as a subset of patients will be lost from LoT to LoT. To investigate drop-out rates in all subsequent LoT, high-quality real-world data are needed. Here, we present data from the Austrian Study Group of Medical Tumor Therapy (AGMT) MBC-Registry, a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. Patients and methods: Patients with known hormone-receptor (HR) and HER2 status, available survival data and at least one LoT were included. Therapies administered between diagnosis or disease progression and subsequent disease progression were counted as one LoT. All types of antitumor drugs (endocrine therapy, targeted therapy, chemotherapy, immunotherapy) were considered. Results: As of 16-May-2023, 2,484 patients were included in the registry. Out of 2,044 evaluable patients, 1,330 (65.1%) were HR+/HER2-, 251 (12.3%) were HR+/HER2+, 146 (7.1%) were HR-/HER2+ and 317 (15.5%) were triple-negative, respectively. The median number of treatment-lines in the overall cohort was 3 (range 1-14; 95%CI 3-3). In patients with HR+/HER2-, HR+/HER2+, HR-/HER2+ and triple-negative tumors the median LoT were 3 (range 1-14; 95%CI 3-4), 4 (range 1-13; 95%CI 3-4), 3 (range 1-10; 95%CI 3-4) and 2 (range 1-9; 95%CI 2-3), respectively. Overall, 641 patients were still on treatment at data cut off. The estimated percentage of patients being treated in each LoT and the corresponding drop-out rates from 1st- to 5th-line are provided in Table 1. Conclusion: Relevant drop-out rates even in the early treatment lines support a “best treatment first” strategy. An accelerated investigation of promising cancer drugs in early treatment lines in patients with MBC is warranted. Drop-out-Rate 1st-line 2nd-line 3rd-line 4th-line 5th-line All n 2044 1281 869 558 344 Drop-out-Rate / 23.8% 24.8% 30.9% 34.0% HR+/HER2- n 1,330 854 586 380 244 Drop-out-Rate / 19.6% 23.0% 29.6% 30.7% HR+/HER2+ n 251 157 109 72 48 Drop-out-Rate / 23.4% 20.4% 25.0% 28.4% HR-/HER2+ n 146 78 59 37 24 Drop-out-Rate / 36.6% 16.9% 36.2% 33.3% Triple-negative n 317 192 115 69 28 Drop-out-Rate / 34.0% 38.2% 39.5% 57.6% Citation Format: Simon Gampenrieder, Gabriel Rinnerthaler, Angelika Pichler, Walter Herz, Andreas Petzer, Clemens Dormann, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Drop-out rates from line to line of treatment in metastatic breast cancer (MBC): Results from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-13.

Abstract PO2-20-01: The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062)

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-01.

Are the Radiological and Molecular Features of Pediatric Medulloblastomas Valuable Prognostic Indicators? A 10-Year Retrospective Review in the Middle East

Medulloblastomas are the most common malignant brain tumors in the pediatric population. Based on the idea that tumors with identical radio-genomic features should behave similarly, the four molecular subtypes are now widely accepted as a guide for the management and prognosis. The radiological features of medulloblastomas can predict the molecular subtype; thus, anticipating the subsequent disease progression. However, this has not been evaluated comprehensively. We aim to thoroughly study the association between the molecular subtypes and radiological features of medulloblastomas. Moreover, we aim to investigate the efficacy of this correlation with the use of progression-free survival (PFS) and five-year survival rates. A retrospective analysis was conducted for all histopathological confirmed medulloblastomas in pediatric patients (<16 years old) that were operated on in Kuwait over the past ten years (n=44). The radiological, histological, and molecular characteristics were justifiably evaluated and analyzed in our sample. The overall progression-free survival after one year was noticed among 27 cases (≈44%) and the non-specific five-year survival was seen in 31 cases (≈70%) after a five-year follow-up. SHH and WNT had the best outcomes, while group 3 showed the worst outcomes. Our findings did not support the association between most of the typical MRI characteristics and survival rate. We further established that SHH and WNT biological types have a better prognosis. There was no association observed between the radiographic features, specifically the location, and the molecular subtype.

Stage IV Triple-negative breast cancer with brain and visceral metastasis has a complete response to sacituzumab govitecan: A Case Report

Background: Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of cancer, characterized by its high propensity for metastasis. Patients who experience the development of brain metastases (BMs) and visceral metastasis face a challenging prognosis, as effective systemic treatment options for this specific condition are limited. Case presentation: This case report describes the journey of a 42-year-old female patient diagnosed with left-sided triple-negative breast cancer with metastasis to the lymph nodes, bone, and brain. The patient underwent a combination of chemotherapy, immunotherapy, and targeted therapy, showing an initial response but subsequent disease progression. Multiple treatment modalities, including surgery, radiotherapy, including stereotactic radiotherapy, were employed to manage the metastases. The patient experienced complications such as anemia and hypocalcemia and received supportive care. Serial imaging, including positron emission tomography and MRI, were utilized for monitoring treatment response and disease progression documented. Conclusion: The findings of this case report provide support for considering sacituzumab govitecan as a potential treatment option for recurrent and even BRCA-mutant triple-negative breast cancer (TNBC). Notably, sacituzumab govitecan demonstrated high activity in the presence of active bone and brain metastases.

A real-world study of treatment sequences and second-line clinical outcomes in patients with HER2-positive metastatic breast cancer in US community practice.

Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and ado-trastuzumab emtansine (T-DM1) or the more recently approved trastuzumab deruxtecan (T-DXd) in second-line (2L). Contemporary data on treatment sequencing and real-world effectiveness is limited. This study aims to report 2L treatments and outcomes among HER2 + mBC patients in the United States (US). HER2 + mBC patients initiating 2L treatment (index date) between January 2014 and February 2021 were identified from the Syapse Learning Health Network (LHN) database. Summary statistics for patient characteristics, treatment received, reasons for 2L discontinuation and time to 2L-clinical outcomes are reported. Of the 312 patients initiating 2L treatment, had a median age of 59years (interquartile range [IQR], 50-66) at the start of 2L. The majority were white (69%) and had de novo mBC (62%). Top three 2L regimens included T-DM1 ± endocrine therapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Around 88% discontinued 2L and 63% received subsequent treatment. Median time-to-next-treatment was 10.6months (95% CI, 8.8-13.3) and real-world progression-free-survival was 7.9months (95% CI, 7.0-9.9). Among 274 patients who discontinued 2L, 47% discontinued due to progression and 17% because of intolerance/toxicity, respectively. This real-world US study showed that approximately two-thirds of 2L patients received subsequent therapy and disease progression was the most common reason for 2L discontinuation highlighting the need for timely 2L treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression.

Abstract 3762: 11,000-plex aptamer based proteomics of bladder cancer urine for the discovery of novel disease biomarkers

Abstract In search of more accurate, non-invasive biomarkers of bladder cancer (BC), a comprehensive aptamer-based screen of urine proteins was conducted using urine samples from a BC cohort, followed by systems biology analyses. Following an initial 1317-plex screen, an extended 11,000 plex aptamer-based proteomic screen is in progress. Based on the initial screen, 30 urine proteins were next ELISA validated in an independent cohort of 68 subjects, and the results are shown in Table 1. Of 21 urine proteins that discriminated BC from urology clinic controls (UC), urine D-dimer displayed the highest ROC AUC value (0.96) and sensitivity (95%) (Table 1). Furthermore, 9 urine proteins significantly discriminated more advanced BC (T1-T4) from earlier stages (Ta-Tis), with IL-8 and MMP-12 being the best performers. Urine MMP12 exhibited the highest specificity of 80% at fixed sensitivity for identifying advanced BC. Systems biology analysis implicated molecular functions related to extracellular matrix, collagen, integrin, heparin and transmembrane tyrosine kinase signaling in BC susceptibility, with HNF4A and NFKB1 emerging as key molecular regulators. STEM analysis of the dysregulated pathways implicated a functional role for the immune system, complement and interleukins in BC disease progression. Urine C2, D-dimer, and Elastase were additionally ELISA validated in a second BC cohort of Chinese ethnicity. Thus, comprehensive proteomics and independent ELISA validation have uncovered novel urine biomarkers for initial BC diagnosis and subsequent disease progression, that warrant further head to head comparison with current diagnostic tests. Citation Format: Chandra Mohan, Kamala Vanarsa, Jessica Castillo, Long Wang, Yair Lotan. 11,000-plex aptamer based proteomics of bladder cancer urine for the discovery of novel disease biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3762.

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

BackgroundUnderstanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies.MethodsWe conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action.ResultsOur bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC.ConclusionsOur data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

Factors predictive of primary resistance (PrimRes) to immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial cancer (mUC).

703 Background: Response rates to ICIs in pts with mUC remain modest at around 20% and there are no reliable biomarkers to select pts most likely to respond to ICI. It is an unmet need to define factors associated with PrimRes (progressive disease (PD) clinically and/or radiologically after at least 2 cycles of ICI) to spare pts from unnecessary treatment and the associated physical and financial toxicity. PrimRes to ICI has not been well defined in mUC pts and we sought to study predictive factors in our real-world cohort. Methods: We retrospectively reviewed 335 pts at the Cleveland Clinic who received ≥ 2 cycles or at least 6 weeks of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Pt characteristics such as age, sex, race, BMI, primary site (bladder vs upper tract UC (UTUC)), and antibiotic (Abx) use before or after start of ICI and pre-treatment platelet to lymphocyte (PLR) ratios (divided into quartiles) were collected. PrimRes was defined as pts who had clinical and/or radiologic PD or death from disease within 14 weeks (time period of 1st assessment with imaging) of ICI initiation. Pts with PrimRes were compared to rest (responders, stable disease and subsequent PD). Multivariate cox regression models were used to identify factors associated with PrimRes. Results: Of the 335 pts, 129 (38.5%) pts had PrimRes based on our criteria. Median age was 73 yrs (35-95). PLR quartiles were clarified as (&lt;149, 149-207, 207-308, ≥308). In our multivariate regression model, we found that pts with PLR ≥308 had a significantly higher chance of PrimRes compared to those with PLR &lt;149 (Hazard Ratio (HR): 2.49; 95% CI: 1.22-5.15; p = 0.0133). Being underweight (BMI &lt; 18.5) was associated with significantly higher rates of PrimRes than normal weight pts (HR: 6.91; 95% CI: 1.55-48.81; p = 0.0211). Abx use within 60 days post ICI start (HR: 2.29; 95% CI: 1.38-3.83; p = 0.0015) and UTUC (HR: 0.46; 95% CI: 0.25-0.83; p = 0.0099) were associated with PrimRes to ICI. Conclusions: In our large cohort of pts with mUC receiving ICI, we report that PLR ≥308, BMI &lt; 18.5, use of Abx within 60 days post- ICI, and UTUC were associated with development of PrimRes to ICI. Ongoing genomic and immune correlates from tissues collected from our cohort will help us better understand the mechanisms of PrimRes to ICI. Validation and harmonization with more datasets and prospective studies can inform future steps towards patient-directed approaches. [Table: see text]

Advances in metabolic reprogramming of renal tubular epithelial cells in sepsis-associated acute kidney injury.

Sepsis-associated acute kidney injury presents as a critical condition characterized by prolonged hospital stays, elevated mortality rates, and an increased likelihood of transition to chronic kidney disease. Sepsis-associated acute kidney injury suppresses fatty acid oxidation and oxidative phosphorylation in the mitochondria of renal tubular epithelial cells, thus favoring a metabolic shift towards glycolysis for energy production. This shift acts as a protective mechanism for the kidneys. However, an extended reliance on glycolysis may contribute to tubular atrophy, fibrosis, and subsequent chronic kidney disease progression. Metabolic reprogramming interventions have emerged as prospective strategies to counteract sepsis-associated acute kidney injury by restoring normal metabolic function, offering potential therapeutic and preventive modalities. This review delves into the metabolic alterations of tubular epithelial cells associated with sepsis-associated acute kidney injury, stressing the importance of metabolic reprogramming for the immune response and the urgency of metabolic normalization. We present various intervention targets that could facilitate the recovery of oxidative phosphorylation-centric metabolism. These novel insights and strategies aim to transform the clinical prevention and treatment landscape of sepsis-associated acute kidney injury, with a focus on metabolic mechanisms. This investigation could provide valuable insights for clinicians aiming to enhance patient outcomes in the context of sepsis-associated acute kidney injury.

Canakinumab in combination with docetaxel compared with docetaxel alone for the treatment of advanced non-small cell lung cancer following platinum-based doublet chemotherapy and immunotherapy (CANOPY-2): A multicenter, randomized, double-blind, phase 3 trial

ObjectivesCanakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy. Materials and methodsCANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel. ResultsA total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2–12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5–13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76–1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3–4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm. ConclusionAdding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy.Clinical registration: NCT03626545.

Reinfusion of Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies Is Feasible with Sustained Responses

Background: Varnimcabtagene autoleucel, a CD19 directed CAR-T cell therapy with a 4-1BB co-stimulatory domain and a non-FMC63 based murine scFv (A3B1 binder), has demonstrated remarkable responses in relapsed/refractory B cell malignancies (RR BCM) in the IMAGINE study. Reinfusion of var-cel is an option to improve functional persistence for CD19+ relapsed disease. This abstract describes the clinical outcomes following reinfusion of var-cel in patients (pts) who relapsed after first infusion. Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible for IMAGINE study if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). The primary target dose was 1x10 6/kg CAR+ cells (B-ALL) and 5x10 6/kg CAR+ cells (B-NHL) (overall range 0.1x10 6 to 5x10 6) and was infused over 3 days (10%/30%/60% fractions). Primary objectives were overall response rate (ORR: CR + CRi in B-ALL and CR + PR in B-NHL) at day +90 after first infusion, and safety. Response was assessed as per NCCN (B-ALL) and IWG (B-NHL) criteria. Adverse events (AEs) were graded using CTCAE v5.0. CRS and ICANS were graded according to ASTCT criteria. Criteria for reinfusion was: 1) achieved response with subsequent disease progression and presence of CD19 positive malignant cells; 2) available second dose for retreatment from initial apheresis and manufacturing run; and 3) after primary endpoint at D+90. This abstract evaluates the outcomes at D+28 after var-cel reinfusion. Results: At data cut-off, 25 pts were enrolled (median age 31 yrs, range 3 - 66) with RR BCM (n=13 B-ALL; n=12 B-NHL). 24 pts received var-cel (1 withdrawal) with majority of infusions on Days 0, +3, +7. ORR was 91.7% at D+28 and 80.9% at D+90. Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR). Nine pts had relapsed disease (37.5%) with median PFS of 178 days (range 28-319). Of these 9 pts, 7 had CD19+ relapse (77.8%) and 2 (with B-ALL) had CD19- relapse. Four of these pts received second infusion at full dose (same as primary infusion) fractionated over 3 days (10%, 30%, 60%). For these 4 pts, duration of B cell aplasia after primary infusion was 90 days to NR (range); var-cel was detectable in 1 pt (n=1/4) at relapse; and median PFS was 166 days (range 90-275). Tumour burden at relapse was: Ph+ B-ALL (n=1) with 22% blasts (p210 BCR ABL transcript 36.7%); B-NHL (n=3) with TMTV range 7.5 to 277 ml and SPD range 660.5 to 8686 mm 2 (Table 1). PDL1 exhaustion marker was expressed in one B-NHL pt only. Salvage regimen in B-NHL pts was involved field radiotherapy (n=2); 1 B-NHL pt was reinfused without salvage treatment. B-ALL pt received Dasatinib, Inotuzumab and CNS prophylaxis. Preparative conditioning regimen for these 4 patients were: Fludarabine-Cyclophosphamide (n=1), with Rituximab (n=2) and Rituximab with Nivolumab (n=1). Post reinfusion, var-cel was not detected in 1 pt (B-ALL) however B cell aplasia was persistent. In B-NHL pts, Cmax range was 7222 to 31846 CAR+ copies / ug genomicDNA; Tmax was D+2 after reinfusion and duration of var-cel persistence was range 2 days to NR (Figure 1). Post reinfusion, no CRS (0%) or ICANS (0%) was reported. Hematotoxicity was the most common AE (100%) with neutropenia (G3+ 100%); anemia (G3+ 66.7%); and thrombocytopenia (G3+ 33.3%;). Hypogammaglobulinemia (IgG &amp;lt;4g/L) was seen in 2 pts (50%, new onset 1 pt). Time to first response after reinfusion was 28 days. The D+28 ORR for evaluable pts (n=2) was 100%. Median PFS after reinfusion is NR. Post reinfusion 1 pt (Ph+ B-ALL) died of disease progression at 313 days (50 days after reinfusion). The evaluable B-NHL pts are in remission. Conclusions: Reinfusion of varnimcabtagene autoleucel (IMN-003A) is feasible, safe and well tolerated. Preparative conditioning regimen for reinfusion needs personalization guided by CAR persistence, disease biology (CD20, PDL1 expression) and haematological reserve. After reinfusion, prolonged B cell aplasia was observed with 100% ORR at D+28 in evaluable pts. Var-cel was detected post reinfusion in B-NHL patients with sustained responses. Reinfusion may be considered in preference for some pts. The ideal preparative regimen and pt characteristics to guide reinfusion outcomes remains an area of research.

The features and management of acquired resistance to PD1-based therapy in metastatic melanoma

BackgroundAnti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown. MethodsPts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated. Results299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001). ConclusionsAcquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.

A Phase I Clinical Trial of Fully Human Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed or Refractory Lymphoid Malignancies

Background: Chimeric antigen receptor (CAR) T-cells have revolutionized the standard of care for numerous lymphoid malignancies but continue to present challenges related to toxicity, long-term efficacy, cost, and accessibility. Novel CAR-T cell constructs hold promise for improving desired outcomes. CD19 CAR-T cells with fully humanized chimeric antigen receptors have demonstrated excellent preclinical activity and the potential for lower rates of cytokine release syndrome (CRS) and severe immune effector associated neurotoxicity syndrome (ICANS). To evaluate safety, we conducted a phase 1 clinical trial evaluating fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain against relapsed or refractory (R/R) CD19-positive lymphoid malignancies, utilizing a single lymphodepletion regimen and local CAR-T cell manufacturing using the Prodigy® Device. Methods: We designed a parallel-group phase I trial with two clinical groups. Group A enrolled subjects with relapsed and refractory CD19+ lymphomas and chronic lymphocytic leukemia (CLL), while Group B comprised patients with acute lymphoblastic leukemia/lymphoma (ALL). The primary endpoint was safety and toxicity assessment, along with the identification of the recommended phase 2 dose in each clinical group. Secondary endpoints included efficacy evaluation. Dose escalation in each group followed a “3 + 3” phase I study design, with three dose levels: 5e5 CAR-T cells/kg, 1e6 CAR-T cells/kg, and 2e6 CAR-T cells/kg. Lymphodepletion consisted of cyclophosphamide 60mg/kg on day -6 and Fludarabine 25mg/m2/day on days -5 to -3. Dose-limiting toxicities included prolonged CRS grade 3 or higher, ICANS grade ≥ 3, and grade ≥ 3 non hematologic toxicities with the exception of self-limited (&amp;lt;7 days) laboratory abnormalities without associated symptoms or clinical consequences. Results: As of 7/1/2023, a total of 13 patients were enrolled in Group A (NHL), and two patients were enrolled in Group B (B-ALL). Three patients in Group A withdrew consent or were withdrawn at the investigator's discretion due to new comorbid conditions before cell collection. Additionally, three patients were unable to receive CAR-T cell infusions due to disease progression, including two with Burkitt lymphoma. Among the remaining patients, 7 in NHL and 2 in B-ALL, received CART cells. The average age was 59 (range: 40-73), and 2 patients were female. In the NHL group, diseases treated included CLL (3), mantle cell lymphoma (2), follicular lymphoma (1), and Waldenstrom's (1). The median number of prior treatments was 4 (range: 3-10). CAR-T cell product manufacturing was successful in all patients to achieve the target dose, with a mean transduction efficiency of 43.8% (29.7% - 54.6%). One potential dose-limiting toxicity, nodular regenerative hyperplasia of the liver, considered possibly related to CAR-T cells, was observed in the NHL group at the 1e6 cells/kg dose level, leading to an expansion of this dose level. Other observed toxicities were as expected and manageable. Six patients experienced CRS, with grades 1-2 in the NHL group. Both patients in the B-ALL arm experienced CRS, one grade 1 and one grade e, with observed severity congruent with known disease burden before receiving CAR-T cells. Two cases of CRS required no intervention, while the remaining cases received tocilizumab (n=4), steroids (n=2), and/or anakinra (n1). There were three occurrences of ICANS, two in Group A and one in Group B. Treatments included corticosteroids (n=3) and anakinra (n=2). Among the 7 NHL patients evaluable for response, 2 achieved complete remission (follicular, mantel cell), three had a partial response (CLL), and one exhibited stable disease (Waldenstrom's). Two NHL patients (CLL and Mantel Cell) had subsequent disease progression. One B-ALL patient evaluable for response achieved a CR but experienced disease progression at one year and subsequently died. Discussion: In this parallel-group phase 1 study, fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain were successfully manufactured in all patients undergoing leukapheresis. Human CAR-T cells demonstrated preliminary safety and clinical activity in the setting of heavily pre-treated patients with R/R B cell malignancies. A platform of point-of-care manufacture permits access to novel CAR-T cell products, and may facilitate the development of novel immune effector cell products.

Low level of tonic interferon signalling is associated with enhanced susceptibility to SARS-CoV-2 variants of concern in human lung organoids

ABSTRACT There is tremendous heterogeneity in the severity of COVID-19 disease in the human population, and the mechanisms governing the development of severe disease remain incompletely understood. The emergence of SARS-CoV-2 variants of concern (VOC) Delta (B.1.617.2) and Omicron (B.1.1.529) further compounded this heterogeneity. Virus replication and host cell damage in the distal lung is often associated with severe clinical disease, making this an important site to consider when evaluating pathogenicity of SARS-CoV-2 VOCs. Using distal human lung organoids (hLOs) derived from multiple human donors, we compared the fitness and pathogenicity of SARS-CoV-2 VOC Delta and Omicron, along with an ancestral clade B variant D614G, and evaluated donor-dependent differences in susceptibility to infection. We observed substantial attenuation of Omicron in hLOs and demonstrated enhanced susceptibility to Omicron and D614G replication in hLOs from one donor. Transcriptomic analysis revealed that increased susceptibility to SARS-CoV-2 infection in these hLOs was associated with reduced tonic interferon signaling activity at baseline. We show that hLOs can be used to model heterogeneity of SARS-CoV-2 pathogenesis in humans, and propose that variability in tonic interferon signaling set point may impact susceptibility to SARS-CoV-2 VOCs and subsequent COVID-19 disease progression.

Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial

Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma. TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete. Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5-34·8), 39 (36%, 90% CI 28-44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24-40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3-4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia. In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy. Bristol Myers Squibb.