Landmark Time Points Research Articles

Effectiveness of remdesivir in patients with COVID-19 and severe renal insufficiency: a nationwide cohort study in Japan

Background The effectiveness of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal insufficiency remains underexplored. Objectives To evaluate whether remdesivir reduces the risk of mortality or invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO) in this population. Methods This retrospective observational study utilising the COVID-19 Registry Japan (COVIREGI-JP) included noncritical patients with COVID-19 and severe renal insufficiency (defined as serum creatinine levels ≥3 mg/dL, on maintenance dialysis, or kidney transplant recipients) admitted to Japanese hospitals within 7 days of symptom onset between January 1, 2020 and May 8, 2023. Patients were classified into the remdesivir group if remdesivir was initiated within the first 2 days of admission. We estimated the multivariable-adjusted hazard ratio (HR) for mortality and initiation of IMV/ECMO using landmark analysis to address immortal time bias. Results Among the 1,449 patients included in the landmark analysis (median age, 74 years [interquartile range 62–84 years]; 992 [68.5%] were male), 272 initiated remdesivir within the first 2 days of admission. During the 28 days from the landmark timepoint, 19 (7.0%) and 136 (11.6%) patients in the remdesivir and control groups, respectively, had an outcome. The remdesivir group had a lower risk of mortality or IMV/ECMO initiation than the control group (adjusted HR, 0.44; 95% confidence interval, 0.23–0.83). Conclusions In noncritical patients with COVID-19 and severe renal insufficiency at admission, initiating remdesivir early after disease onset, within the first 2 days of admission, led to a lower risk of mortality or IMV/ECMO initiation, compared with non-initiation of remdesivir.

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial

BackgroundNivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited.MethodsATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician’s choice of SOX (oral S-1 [tegafur–gimeracil–oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints—centrally assessed progression-free survival (PFS) and overall survival (OS)—and landmark analyses of OS among patients alive using 3-year follow-up data.ResultsAt the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55–0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75–1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy.ConclusionThis 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer.Trial registrationNCT02746796

Longitudinal clinical performance of a novel tumor-naive minimal residual disease assay in patients with resected stage II and III colorectal cancer: A subset analysis from the GALAXY study in CIRCULATE-Japan.

3618 Background: The presence of circulating tumor DNA (ctDNA) can identify patients (pts) at higher risk of recurrence. Longitudinal surveillance of ctDNA may enable early identification of pts who are likely to relapse and presents a window of opportunity for early interventions to improve outcomes. A tumor-naïve plasma-only approach for minimal residual disease (MRD) assessment accelerates turnaround time, enabling rapid adjuvant chemotherapy (ACT) treatment decisions and ongoing molecular surveillance. Methods: Samples were collected from GALAXY in CIRCULATE-Japan and analyzed for postsurgical ctDNA detection at a landmark time point (LMT), 4 weeks after surgery in pathological stage II or III colorectal cancer (CRC). Initially, 80 pts meeting pre-specified eligibility criteria were randomly selected, with enrichment for recurrence to 50% while maintaining the stage II:III recurrent (R)/nonrecurrent (NR) ratio observed in GALAXY. Of those, 23 pts also had longitudinal plasma samples analyzed to date (including 17 false negative (FN) at LMT). Residual plasma samples were analyzed with the Tempus xM MRD assay (xM), a tumor-naïve MRD ctDNA assay that integrates methylation and genomic variant data to deliver a binary MRD call blinded to clinical outcomes. The methylation workflow detects fragments with CRC methylation signatures in differentially methylated regions. The variant classifier detects highly prevalent CRC variants. Longitudinal MRD+ status was defined as any MRD+ call after surgery or ACT; lead time as the time from first MRD+ call after definitive therapy to clinical recurrence. Results: Of the 80 pts, 70 [Stage II n= 29 (41%), Stage III n= 41 (59%)] were evaluable (36 R and 34 NR). At the LMT and with at least 1-year follow-up, 18/36 R pts had detectable ctDNA (MRD+) and 30/34 NR pts had undetectable ctDNA (MRD-), providing clinical sensitivity (CS) of 50% and specificity of 88%. Additional sensitivity analysis included 2 false positive pts who cleared ctDNA with ACT and provided CS 53% and specificity 94% at LMT. Longitudinal analysis of all FNs and ACT treated true positive (TP) pts improved CS from 50% at LMT to 90.9% (stage II 91.7%, stage III 90.5%) on surveillance. The mean lead time was 4.72 mos overall, 5.29 mos for pts treated with surgery alone. Additionally, xM MRD status at LMT strongly correlated with disease-free survival (DFS) with a hazard ratio (HR) of 5.09, superior to 12 week carcinoembryonic antigen (CEA) correlation with DFS, HR 2.63. Conclusions: xM is a novel tumor-naïve MRD assay that demonstrated remarkable clinical longitudinal performance, and can accurately predict clinical recurrence on surveillance. xM ctDNA status was a strong prognostic biomarker to DFS and superior to standard of care CEA.

Performance characteristics of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies.

3009 Background: Plasma cell-free DNA (cfDNA) tests have emerged as a promising approach for cancer management. cfDNA methylome approaches are well-suited for molecular residual disease (MRD) detection. Here we present data using a tissue-agnostic, genome-wide methylome enrichment platform based on cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMEDIP-seq) in head and neck cancer (HNC) to predict relapse for purposes of guiding adjuvant therapy after completion of curative-intent treatment and to detect early relapse. Methods: The cohort is comprised of biobanked samples from individuals diagnosed with stage I-IVB human papillomavirus (HPV)-negative and HPV-positive HNC with longitudinal data collection and sampling. The full cohort includes 325 unique patients with 1,155 samples. Samples were split into distinct sets to train and test a classifier consisting of differentially methylated regions. Blood collection time points include at diagnosis, and approximately 3 (landmark), 12 and 24 months after curative intent treatment. 5-10 ng of cfDNA isolated from each plasma sample was used for cfMEDIP-seq. MRD signals were quantified from average normalized counts across informative methylated regions and binarized into a positive (above the threshold) and negative groups. Recurrence-free survival (RFS) was compared for patients who tested positive to those who tested negative at 3 months post-curative treatment (i.e., landmark timepoint) and longitudinally. Results: A total of 196 post-treatment samples from 80 unique patients [stage I (35%), II (15%), III (24%), IV (26%)] were analyzed and correlated with recurrence, in this interim training result. At the landmark timepoint, patients who tested positive showed significantly worse RFS than those who tested negative (Hazard ratio (HR) 9.69; 95% CI, 4.39-21.4, P<0.001). Incorporating serial longitudinal samples, recurrence-free survival was worse in patients who tested positive compared to those that tested negative (HR 14.52; 95% CI, 5.78-36.46, P<0.001). Conclusions: Interim analysis demonstrates that MRD detection with a tissue-agnostic, genome-wide methylome enrichment platform in HNC patients after curative intent treatment correlates strongly with RFS with hazard ratios consistent with tumor-informed assays previously described. Updated analyses from the cohort will be presented at the meeting.

Ultrasensitive circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection in early stage non-small cell lung cancer (NSCLC).

8078 Background: Translation of ctDNA MRD in NSCLC has been hampered by suboptimal sensitivity of 1st-generation assays. Here, we explore how improvements in analytical sensitivity can drive improved clinical sensitivity for MRD after surgery in NSCLC. Methods: To understand MRD kinetics, we analyzed longitudinal ctDNA in early stage NSCLC using data from the TRACERx study. Patient-specific mathematical models were generated to predict MRD levels at the postsurgical landmark and estimate the impact of an assay’s 95% limit of detection (LOD95) on clinical sensitivity. To test these predictions, tumor-informed ctDNA testing was performed using an SNV-based assay (CAPP-Seq) and a phased variant-based assay (PhasED-Seq, Foresight Diagnostics) on 269 samples from 46 patients. We also assessed MRD performance for predicting 1) patient outcomes at the landmark timepoint and 2) the effect of adjuvant treatment. Results: ctDNA MRD dynamics were assessed in 23 patients from TRACERx with ≥3 consecutive samples with detectable ctDNA without intervening therapy. MRD kinetics strongly correlated with exponential growth, with a median ctDNA doubling time of 51 days. Extrapolating MRD levels to the postsurgical landmark predicted that improving MRD assay LOD95 from 100 ppm (0.01%) to 1 ppm could increase clinical sensitivity by 2.1-fold. We then evaluated 46 NSCLC cases using two assays. The median LOD95 was 1 ppm for PhasED-Seq and 84 ppm for CAPP-Seq. Twelve cases were MRD+ by PhasED-Seq, all of whom recurred (100%), with MRD levels as low as 0.19 ppm. In contrast, 6 cases were MRD+ by the SNV-based approach, of whom 5 (83%) recurred. Accordingly, PhasED-Seq had a higher clinical sensitivity than the SNV-based method (12/18 [67%] vs. 5/18 [28%], P = 0.022). Kaplan Meier analysis for freedom from recurrence revealed significantly worse outcomes for patients with detectable MRD regardless of the method used; however, outcomes were better stratified using PhasED-Seq (HR 3.1 vs. 11.4). Patients who were MRD- after surgery by both assays had similar outcomes regardless of adjuvant therapy (chemotherapy and/or radiotherapy). However, MRD+ patients by PhasED-Seq receiving adjuvant therapy had significantly better outcomes than those who did not (HR 8.2, P = 0.00035). A similar benefit for adjuvant therapy was not observed with the SNV-based assay. Using PhasED-Seq, 80% (4/5) of MRD+ patients receiving adjuvant therapy cleared their MRD, compared to 0% (0/3) without adjuvant treatment. Conclusions: Ultrasensitive ctDNA detection improved the clinical sensitivity of MRD at key landmarks in early stage NSCLC. PhasED-Seq detected MRD at levels below 1 ppm and was associated with significantly better outcomes, revealing potential benefits of adjuvant therapy in MRD+ patients. This suggests that ultrasensitive MRD detection is promising for use in risk-adapted trials in early stage NSCLC.

Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions, MET exon skipping or de novo MET amplification.

Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC) with these mutations remains unknown. This prospective, non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions (ALK, ROS1, RET, and FGFR1), MET exon 14 skipping or de novo MET amplification. We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021- and 338-gene panels, respectively. Detectable MRD correlated with a significantly higher recurrence rate (P < 0.001), yielding positive predictive values of 100% and 90.9%, and negative predictive values of 82.4% and 86.4% at landmark and longitudinal time points, respectively. Patients with detectable MRD showed reduced disease-free survival (DFS) compared to those with undetectable MRD (P < 0.001). Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not (P = 0.05). To our knowledge, this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations. Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy’s effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25–8.8). Median survival time was 9.9 months (95% CI 9.2–10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889–9.328; 60 days, HR: 2.351, 95% CI 1.104–5.009; 90 days, HR: 2.416, 95% CI 1.232–4.739; and 120 days, HR: 2.521, 95% CI 1.357–4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Abstract PO2-04-10: Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials

Abstract Background: Alpelisib (ALP) is an α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor and degrader approved with fulvestrant (FUL) for patients (pts) with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) following progression on/after endocrine therapy-based treatment (tx). Toxicity limited ALP exposure in some pts in the SOLAR-1 and BYLieve studies. On-target effects of PI3K inhibitors, including hyperglycemia, rash, and diarrhea, are among the most common adverse events (AEs) associated with ALP. During SOLAR-1, median onset times were 15 and 13 days for grade ≥3 hyperglycemia and rash and 46 days for grade 2/3 diarrhea. ALP dose modification can help manage AEs. We report efficacy of ALP + FUL as second-line (2L) tx in pts who underwent ALP dose reduction (DR). Methods: Pts with PIK3CA mutations from SOLAR-1 and BYLieve, treated with ALP + FUL in 2L, were included. Landmark (LM) analyses were performed at 1, 2, 3, 4, 5, and 6 mo after tx initiation to evaluate the association between DR status (yes, no) with progression-free survival (PFS) and duration of tx (DoT), respectively. Pts with PFS or exposure time less than each LM time point were excluded from each LM analysis; pts were then grouped by DR (yes, no) before each LM time point. Median PFS and DoT were obtained using a modified Kaplan-Meier method. Alternatively, Cox regression analysis was used to assess the effect of DR on PFS and DoT, where 2 time-dependent variables were included separately in the model as a covariate: 1) DR status, and 2) DR groups (300 to 250 mg [1 DR] vs no DR, 300 to 250 to 200 mg [2 DR] vs no DR). Association between AEs and DR was evaluated descriptively. A matched analysis of AEs will be presented. Results: In all, the analysis included 212 pts in 2L: 77 from SOLAR-1, and 95 and 40 from BYLieve Cohorts A and C, respectively. Of these pts, 92 (43.4%) had no DR and 120 (56.6%) had DRs: 70 (58.3%) had 1 DR, 43 (35.8%) had 2, and 7 (5.8%) had other types of DR. 25 of 92 pts (27.2%) with no DR and 40 of 120 pts (33.3%) with DR had ≥12-mo exposure to ALP. Hazard ratios (HRs) for PFS and DoT in DR status for the LM analysis are shown (Table). HRs (95% CI) for PFS from the time-dependent covariate analyses were 1.28 (0.94-1.74) with DR status as the covariate, and 1.24 (0.88-1.76) and 1.21 (0.79-1.84) with DR group (1 DR vs no DR, 2 DR vs no DR) as the covariate, respectively; for DoT, these were 1.34 (1.00-1.79) for DR status, and 1.30 (0.93-1.80) and 1.30 (0.87-1.93) for DR group, respectively. During the treatment period, the incidence rate for grade ≥3 AEs was the highest for pts with 2 DR and lowest for those with no DR. Similarly, incidence of AEs leading to DR or tx discontinuation was higher in pts with 2 DR than 1 DR. The post-DR incidence rate for grade ≥3 AE was similar for pts with 2 DR or 1 DR. A matched analysis will assess the relationship between DR group and AE. Conclusions: In this pooled analysis, regardless of if/when DR occurred, PFS was similar and DoT may be sustained with ALP + FUL. ALP DR can potentially reduce AEs, which may allow pts to remain on tx. Using DR as an AE management strategy may enable pts with PIK3CA-mutated, HR+, HER2− ABC to optimize tx duration and clinical benefit of ALP in the 2L. Landmark Analyses of PFS and Tx Duration by DR Group (Yes vs No; Pooled FAS) Citation Format: Hope Rugo, Alessandra Gennari, Stephen Chia, Dejan Juric, Neil Vasan, Sherko Küemmel, Patrick Neven, Florence Lerebours, Manuel Ruíz - Borrego, Pedram Razavi, Jyotika Singh, Yogesh Chattar, Murat Akdere, Eva Ciruelos. Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials [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 PO2-04-10.

Transcriptome analysis of cardiac endothelial cells after myocardial infarction reveals temporal changes and long-term deficits.

Endothelial cells (ECs) have essential roles in cardiac tissue repair after myocardial infarction (MI). To establish stage-specific and long-term effects of the ischemic injury on cardiac ECs, we analyzed their transcriptome at landmark time points after MI in mice. We found that early EC response at Day 2 post-MI centered on metabolic changes, acquisition of proinflammatory phenotypes, initiation of the S phase of cell cycle, and activation of stress-response pathways, followed by progression to mitosis (M/G2 phase) and acquisition of proangiogenic and mesenchymal properties during scar formation at Day 7. In contrast, genes involved in vascular physiology and maintenance of vascular tone were suppressed. Importantly, ECs did not return to pre-injury phenotypes after repair has been completed but maintained inflammatory, fibrotic and thrombotic characteristics and lost circadian rhythmicity. We discovered that the highest induced transcript is the mammalian-specific Sh2d5 gene that promoted migration and invasion of ECs through Rac1 GTPase. Our results revealed a synchronized, temporal activation of disease phenotypes, metabolic pathways, and proliferation in quiescent ECs after MI, indicating that precisely-timed interventions are necessary to optimize cardiac tissue repair and improve outcomes. Furthermore, long-term effects of acute ischemic injury on ECs may contribute to vascular dysfunction and development of heart failure.

Survival outcomes of surgical resection in perihilar cholangiocarcinoma in endemic area of O. Viverrini, Northeast Thailand

BackgroundPerihilar cholangiocarcinoma (pCCA) is an intractable malignancy and remains the most challenge for surgeon. This study aims to investigate survival outcomes and prognostic factors in pCCA patient. MethodsFrom October 2013 to December 2018, 240 consecutive patients with pCCA underwent surgical exploration were retrospectively reviewed. The clinicopathological parameters and surgical outcomes were extracted. Patients were divided into two groups: unresectable and resectable group. The restricted mean survival time between two groups were analyzed. Factors associated with overall survival in resectable group were explored with multivariable Cox regression analysis. ResultsOf the 240 patients, 201 (83.75%) were received surgical resection. The survival outcomes of resectable group were better than unresectable group significantly. The restricted mean survival time difference were 0.5 (95%CI 0.22–0.82) months, 1.8 (95%CI 1.15–2.49) months, 4.7 (95%CI 3.58–5.87) months, and 9.1 (95%CI 7.40–10.78) months at four landmark time points of 3, 6, 12 and 24 months, respectively. The incidence of major complications and 90-day mortality in resectable group were 35.82% and 11.44%, respectively. Multivariable analysis revealed that Bismuth type IV (HR:4.43, 95%CI 1.85–10.59), positive resection margin (HR:4.24, 95%CI 1.74–10.34), and lymph node metastasis (HR:2.29, 95%CI 1.04–4.99) were all independent predictors of long-term survival. For pM0, R0 and pN0 patients, the median survival time was better than pM0, R1 or pN1/2 patients and pM0, R1 and pN1/2 patients (32.4, 10.4 and 4.9 months, respectively; p < 0.001) ConclusionSurgical resection increased survival in pCCA. Bismuth type IV, positive resection margin and lymph node metastasis were independent factors for long-term survival.

MRD assay to evaluate recurrence and response via a tumor informed assessment: MARIA-Colorectal Cancer Observational trial.

TPS242 Background: The detection of ctDNA in patients with colorectal cancer (CRC) is emerging as a potential biomarker to identify patients at high risk of relapse, assess treatment response and monitor for recurrence. Solid tumors are currently monitored by imaging studies, tumor markers and clinical symptoms and recent studies suggest tumor-informed molecular residual disease (MRD) testing may outperform these current methods and may serve as a prognostic biomarker to aid in the identification of patients at high risk of relapse (Reinert et al, 2019; Christensen et al, 2019; Coombes et al, 2019). Recent studies have demonstrated that tumor-informed MRD testing can detect relapse prior to detection with imaging in CRC and while interventional trials are needed, this may provide an opportunity for therapeutic intervention (Reinert et al, 2019; Kotani et al, 2023). This study utilizes the Invitae Personalized MonitoringTM (PCM) test, a highly sensitive tumor-informed MRD test (Zhao et al, 2023), to monitor early stage CRC patients. Methods: MARIA is a multi-site, prospective, observational trial in the United States of 200 newly diagnosed patients with early stage (high risk stage II, stage III and stage IV oligometastases) CRC undergoing curative intent treatment. Formalin fixed paraffin embedded (FFPE) tissue from the biopsy or surgical specimen is utilized to create the PCM test. Tumor tissue and a matched normal blood sample will undergo whole exome sequencing to identify 18-50 unique tumor variants to create a patient specific panel (PSP) for ctDNA analysis. Participants are asked to provide serial plasma specimens for ctDNA analysis at baseline, post surgical landmark and surveillance time points. A clinical report will be provided to the ordering physician. Physicians will be asked to complete a case report form for each participant when the first result is reported and every 6 months. The primary endpoint is to evaluate the correlation between the PCM test result at the landmark timepoint and the patient’s 24 month recurrence risk. Secondary endpoints include evaluating the impact on patient outcomes attributable to MRD result-based changes to treatment or clinical management, correlating between the PCM result at the baseline time point and patient recurrence risk and outcomes and investigating the lead time of PCM positivity over clinical/imaging based evidence of recurrence. Active enrollment started in March, 2022. Clinical trial information: NCT05219734 .

Predicting recurrence using a tumor-uninformed ctDNA assay detecting MRD in patients with resected stage II or III colorectal cancer: Subset analysis from the GALAXY study in CIRCULATE-Japan.

21 Background: The presence of circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who are at risk of recurrence and aid with postsurgical risk stratification. ~80% of stage II and only 50% of stage III colorectal cancer (CRC) patients are cured by surgery alone. A tumor-uninformed plasma-only approach for MRD assessment accelerates the turnaround time, enabling rapid adjuvant chemotherapy (ACT) treatment decision making, optimizing the impact on patient outcomes. Methods: A subset of samples from GALAXY, an observational arm of the CIRCULATE-Japan study (UMIN000039205), were analyzed for postsurgical ctDNA detection at a landmark time point (LMT) defined as 4 weeks after curative surgery in pathological stage II or III CRC patients. In a prospective lead-in to clinical validation, 80 patients meeting pre-specified eligibility criteria were randomly selected with enrichment for recurrence to 50% while maintaining the stage II:III recurrent (R)/nonrecurrent (NR) ratio to that observed in GALAXY. Residual plasma samples were analyzed with the Tempus xM assay (xM), a tumor-uninformed ctDNA MRD assay that integrates methylation and genomic variant MRD classifiers to deliver a binary MRD call. All calls were blinded to clinical outcomes. The methylation-based classifier detects fragments with CRC methylation signatures in differentially methylated regions trained by sequencing CRC and presumed-healthy samples on a 6Mbp panel. The variant-based MRD classifier detects highly prevalent CRC variants. Artifacts, CHIP, and germline variant filtering algorithms were also applied. Results: Of the 80 patients (pts), 70 [Stage II n= 29 (41%), Stage III n= 41 (59%)] were evaluable (36 R and 34 NR). At the LMT and with at least 1-year follow-up, 18/36 R pts had detectable ctDNA (xM MRD+) and 30/34 NR pts had undetectable ctDNA (xM MRD-), providing a sensitivity of 50% and specificity of 88%. Additionally, xM MRD+/- status strongly correlated with disease-free survival (DFS) with a hazard ratio (HR) of 5.09, adjusted to account for a 24% recurrence rate in GALAXY. In an updated, ongoing longitudinal analysis of the 4 false positive pts, 2 were Stage III, MRD+ from both the methylation and genomic classifiers, received ACT, and have likely cleared their ctDNA without any sign of clinical recurrence. An adjusted sensitivity and specificity analysis resulted in xM clinical performance of 53% (20/38 R) and 94% (30/32 NR), respectively. Conclusions: xM is a novel tumor-uninformed assay that demonstrated remarkable performance to detect clinical recurrence at a LMT, and a clinically meaningful correlation with DFS. A larger clinical validation study including longitudinal analysis, correlation with ACT, and outcomes from the GALAXY study is currently underway.

Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4 year (yr) follow-up of CheckMate 649.

306 Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated, advanced non-HER2+ GC/GEJC/EAC, leading to approvals in many countries. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy at 2 and 3-yr follow-ups. We present 4-yr follow-up results for NIVO + chemo vs chemo from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. HER2+ patients (pts) were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were randomized to NIVO + chemo or chemo. At the 48-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table) OS benefit with NIVO + chemo was observed in most prespecified subgroups. Objective response rates (ORR) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). In the exploratory analysis of OS by response at the 18-week landmark timepoint, there were numerically more pts achieving response with NIVO + chemo vs chemo, and median OS (95% CI) with NIVO + chemo was numerically longer in responders vs non-responders both in pts with PD-L1 CPS ≥ 5 (20.5 [17.5–25.0] vs 14.0 [11.6–15.7]) and all randomized pts (19.4 [17.5–21.7] vs 13.1 [11.6–14.4]). No new safety signals were identified, consistent with the 3-yr follow-up. Conclusions: NIVO + chemo is the first PD-1 inhibitor/chemo combination to demonstrate long-term efficacy and acceptable safety after 4 yrs of follow up in previously untreated advanced GC/GEJC/EAC. These results are consistent with earlier follow-ups, further supporting NIVO + chemo as a standard 1L treatment in these pts. Clinical trial information: NCT02872116 .[Table: see text]

Late CMV Disease after Hematopoietic Cell Transplantation: Significance of Post-Transplant Cyclophosphamide, Steroid Treatment and CMV Viral Load

Introduction: Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT), and are widely used worldwide. However, both strategies are associated with late-onset CMV disease. The goal of this study was to determine the period of risk, clinical manifestations, risk factors for initial and recurrent late CMV disease at key landmark time points, and its impact on mortality. Patients and Methods: We retrospectively analyzed CMV seropositive allogeneic HCT recipients transplanted between 2001 and 2017 who survived more than 100 days post HCT. All patients underwent PCR monitoring and PET before day 100 and for patients deemed at high risk for late CMV complications continuation of PCR monitoring and PET was recommended. Data were collected via medical record review of CMV disease and viremia, PET, transplant variables such as lymphopenia, corticosteroid use, donor type, stem cell source, type of underlying disease, and outcomes for 2 years post-transplantation. Cumulative incidence curves and Cox proportional hazards models were used to evaluate time to event and risk factors for late CMV disease and mortality. Results: Among 2155 day 100 survivors, 166 episodes of late CMV disease were observed in 144 (6.7%, 95% CI 5.7%-7.8%) patients. Most of the cases were diagnosed between day 100 and 1 year (126 cases), 40 episodes occurred within the second year (1.6% 95%CI 1.2%-2.3%) post HCT (Figure 1). CMV gastrointestinal (GI) disease (3.4%, 95% CI 2.7%-4.2%) was the most common manifestation of late CMV disease, followed by CMV pneumonia (2.9%, 95% CI 2.2%-3.7%), occurring at a median of 196 days after HCT for first GI disease episode (range 104-685) and 211 days (range 105-574) for first late pneumonia. Twenty-nine patients (10.5%, 95% CI 7%-14.7%) developed recurrent CMV disease. Most recurrences involved the same anatomical site as the first episode with a median of 126 days (range 52-444) after the initial event. Five patients developed a third episode, with a median of 145 (range 85-350) days after their second episode. Prolonged CMV surveillance was recommended in 1787 (83%) cases. High risk patients included: cord blood recipients , in vivo T-cell depletion, acute or chronic GvHD requiring steroid treatment, or those who were treated due to CMV infection before day 100. Based on day 100 risk stratification, cumulative incidence of late CMV disease occurred in 7.6% (95% CI 6.4%-8.9%) and 2.8% (95% Ci 1.4%-4.8%) in high and low risk groups, respectively. In a subgroup analysis (HCT 2001-2011), adherence to late CMV surveillance recommendations was reduced: by week 20 post-HCT, approximately 6 weeks post-discharge, only 65% of patients had CMV PCR tests performed. By 1-year post-HCT, only 40% of patients were still being tested. In multivariable analyses, steroid treatment after day 100 at a dose of ≥1mg/kg, post-transplant cyclophosphamide, GvHD prior day 100, and CMV viremia before day 100 were associated with increased risk of late CMV disease. (Figure 2). The only factors contributing to recurrence of CMV disease were HLA mismatched donor status (aHR 2.92, 95% CI 1.03-8.28) and treatment with high dose steroids ≥1mg/kg after day 100 (as time dependent variable) (aHR 7.60, 95% CI 3.32-17.4). In a landmark analysis of 1-year survivors, the risk of late CMV disease was increased in chronic GvHD patients (aHR 2.11, 95% CI 0.99-4.51, p=0.054) and those with a CMV disease episode prior to 1 year (aHR 2.80, 95% CI 1.23-6.40). Among 144 patients with late CMV disease, 32 (22%) died within 6 weeks of diagnosis of the last episode. Patients who developed late CMV pneumonia were at the highest risk of death by year 2 after HCT (aHR 4.08, 95% CI 2.62-6.35), while GI disease was associated with a somewhat lower risk (aHR 1.62, 95% CI 1.05-2.5). Conclusion: In a large cohort for which late surveillance and PET was recommended, late CMV disease occurred frequently, and was associated with the use of high dose steroids, post-transplant cyclophosphamide, and CMV reactivation before day 100. Late CMV pneumonia and GI disease were associated with overall mortality. Improved strategies to prevent late CMV disease are needed in high-risk patients, including continued antiviral prophylaxis or surveillance strategies that are more suitable for the late setting, such as home-based CMV testing.

Association of Bypass Surgery and Mortality in Moyamoya Disease.

Background Patients with moyamoya disease (MMD) have a high risk of stroke or death. We investigated whether extracranial to intracranial bypass surgery can reduce mortality by preventing strokes in patients with MMD. Methods and Results This nationwide retrospective cohort study encompassed patients with MMD registered under the Rare Intractable Diseases program via the Relieved Co-Payment Policy between 2006 and 2019, using the Korean National Health Insurance Service database. Following a 4-year washout period, landmark analyses were employed to assess mortality and stroke occurrence between the bypass surgery group and the nonsurgical control group at specific time points postindex date (1 month and 3, 6, 12, and 36 months). The study included 18 480 patients with MMD (mean age, 40.7 years; male to female ratio, 1:1.86) with a median follow-up of 5.6 years (interquartile range, 2.5-9.3;mean, 6.1 years [SD, 4.0 years]). During 111 775 person-years of follow-up, 265 patients in the bypass surgery group and 1144 patients in the nonsurgical control group died (incidence mortality rate of 618.1 events versus 1660.3 events, respectively, per 105 person-years). The overall adjusted hazard ratio (HR) revealed significantly lower all-cause mortality in the bypass surgery group from the 36-month landmark time point, for any stroke mortality from 3- and 6-month landmark time points, and for hemorrhagic stroke mortality from the 6-month landmark time point. Furthermore, the overall adjusted HRs for hemorrhagic stroke occurrence were beneficially maintained from all 5 landmark time points in the bypass surgery group. Conclusions Bypass surgery in patients with MMD was associated with a lower risk of all-cause and hemorrhagic stroke mortality and hemorrhagic stroke occurrence compared with nonsurgical control.

Efficacy and Safety of BCMA-Specific CAR T Cell-Based Therapy in Relapsed/Refractory Multiple Myeloma Patients with Extramedullary Disease

Background Extramedullary disease (EMD) is an aggressive subentity of multiple myeloma (MM), characterized by the ability of a subclone to grow independent of the bone marrow microenvironment, resulting in a high-risk state associated with increased proliferation, evasion of immune surveillance and treatment resistance. Relapsed/refractory multiple myeloma (R/R MM) patients with EMD have unfavorable prognoses and no effective treatment options. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown promising efficacy in R/R MM; however, data on patients with EMD remain limited. We aimed to assess the efficacy and safety of CAR T-cell therapy in R/R MM patients with EMD. Methods We conducted a retrospective multi-institutional study of 55 R/R MM patients confirmed with EMD at referral. The definition of EMD included (1) soft tissue masses in extraosseous locations resulting from hematogenous spread (EM-E) and (2) bone-related plasmacytomas that extend via disruption of cortical bones into contiguous soft tissues (EM-B). The overall response, long-term outcomes, and safety were assessed. We also characterized differential response between medullary and extramedullary disease, analyzed unique attributes of compartmental toxicity, and explored patterns of relapse in the setting of EMD. Gene expression profiling was performed using nCounter Human CAR-T Characterization Panel (NanoString, #XT-CSO-HCART1-12) on 40 biopsy specimens from patients enrolled in this study, including EMD and bone marrow biopsy specimens at pretreatment or/and at relapse. Results were analyzed based on outcome (no durable response [progression within 6 months, NDR] vs durable response [progression beyond 6 months, DR]). Multiplex immunofluorescence (mIF) was performed for detection of populations and phenotyping of infiltrated CD8 + T cells (Panel A: CD8/PD-1/LAG-3/TIM-3) and macrophages (Panel B: CD68/CD86/CD163) with EMD biopsies. Results The infusion resulted in an overall response rate of 90.9% (95% confidence interval [CI], 80.4-96.1) in medullary disease and 70.9% (95% CI, 57.9-81.2) in EMD ( P = 0.008). Discrepant outcomes between medullary and extramedullary response were observed, with suboptimal and delayed overall response and shortened duration of response achieved in EMD. With a median follow-up of 27.3 months, the median progression-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). Landmark analysis was conducted to compare OS in patients who progressed versus remained progression-free at the 6-month landmark time point. We demonstrated that progression before 6 months post-infusion is strongly associated with an increased risk of death (HR = 11.15 [95% CI, 3.49 to 35.60]; P &amp;lt; 0.001). Local cytokine release syndrome (CRS) was depicted in 21.8% patients and was moderately associated with the occurrence of systemic CRS (r = 0.322; P = 0.017). 78.2% patients experienced post-infusion progression in EMD, and BCMA + progression constituted the main pattern of EMD progression. At the time of EMD progression, peripheral CAR + cells were detectable, and 50% patients had ongoing documented B cell aplasia. We next interrogated NanoString gene expression data of tumor microenvironment (TME) genes for possible association with clinical response and toxicity. Pretreatment TME enriched for immune checkpoint, and type I interferon signaling were associated negatively with clinical outcomes. We found that the infiltration of type 2 macrophages (CD68 +CD163 +) in pretreatment TME is associated with the density of activated or exhausted CD8 + T cell ( PD-1 +LAG-3 +/-), and is associated with no durable response in EMD. We interrogated TME dynamic changes of patients developing EMD progression between cohorts of DR and NDR. An increase in immune counter-regulatory marker and lower diversity of T-cell receptor (TCR) repertoire, was observed at relapse in cohort of NDR. Discussion Our study shows that anti-BCMA CAR-T therapy has provided apparent therapeutic advantage over the existing drugs in response rate and long-term survival. Compared with medullary disease, BCMA-specific CAR T cell-based therapy showed limited and discrepant efficacy in EMD, perhaps due to the the properties of EMD-specific microenvironment.

Longitudinal Assessment of Minimal Residual Disease (MRD) in the ATLAS Randomized Phase 3 Trial of Post-Transplant Treatment with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide (R) Alone in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Introduction The interim results of the ATLAS trial (Dytfeld, Lancet Oncology 2023) suggest a progression-free survival (PFS) benefit for NDMM patients after autologous hematopoietic stem cell transplantation (ASCT) treated with MRD-directed and risk-adapted maintenance using KRd compared to single-agent R. In order to gain a better understanding of the differences in response dynamics and depth achieved by the two regimens, we conducted a detailed analysis of MRD results assessed at multiple timepoints. Methods ATLAS is an ongoing phase 3 trial that randomized 180 patients with NDMM after ASCT to receive maintenance therapy with KRd or R. In the KRd arm, patients with standard-risk cytogenetics who achieved MRD-negativity after cycle 6 de-escalated therapy to receive R alone, starting from cycle 9. MRD assessments were performed using multicolor flow cytometry (MFC) with a limit of detection (LoD) of 10 -5 and next-generation sequencing (NGS) with LoD 10 -6 at screening, cycle 6 (C6), C12, C18, C24, and C36. Patients with MRD&amp;gt;10 -5 were considered MRD positive. When both MFC and NGS results were available, at least one positive result qualified a patient as MRD-positive. In line with the MRD reporting harmonization guidelines (Costa, Leukemia 2021), patients who have not reached a landmark timepoint for analysis were excluded from the denominator. MRD rates between the treatment arms were compared using the chi-square test. PFS and MRD-free survival (death, progression or MRD resurgence counted as an event) were analyzed using the Kaplan-Meier method to calculate survival rates, and the log-rank test was performed to compare the groups. Results We previously reported MRD rates at the end of 6 cycles (Dytfeld, Lancet Oncology2023). In this analysis, MRD results were evaluable for the following number of subjects at the respective timepoints: 180 at screening, 180 at C6, 180 at C12, 179 at C18, 175 at C24, and 160 at C36. All the reported data, including MRD results, response rates, and time to event, were obtained at the cut-off date 31-DEC-2021, as in the Lancet Oncology manuscript. In the landmark analysis, MRD-negativity after C6 was associated with improved PFS for the entire study patient population [HR=0.49 (95% CI: 0.27-0.90), p=0.01]. Although the proportion of MRD-negative patients at screening was higher in the R arm (46/87, 53%) compared to the KRd arm (36/93, 39%, p=0.06), MRD-negative rates were higher in the KRd arm in the subsequent landmark evaluations. The MRD-negativity rates for KRd and R were: 61/93 (66%) vs 41/87 (47%, p=0.01) at C6; 49/93 (53%) vs 41/87 (47%, p=0.46) at C12; 48/93 (52%) vs 35/86 (41%, p=0.14) at C18; 43/90 (48%) vs 26/85 (31%, p=0.02) at C24; 34/82 (41%) vs 16/78 (21%, p= 0.004) at C36. These findings were consistent with a higher number of patients in the KRd arm who converted from MRD-positivity at screening to MRD-negativity at any timepoint (Figure 1). Of the 50 patients with detectable MRD at screening in the KRd arm, 33 (66%) achieved MRD-negativity as their best response. Among them, 24 achieved MRD-negativity at the end of C6, with 2 patients converting as late as C24. The numbers were significantly lower for the R arm, with 14 out of 32 (44%) MRD-positive patients at screening achieving MRD-negativity (p=0.047). Sustained MRD-negativity for at least 12 months was reached in 51 out of 93 patients (55%) in the KRd arm and in 36 out of 87 (41%) in the R arm (p=0.06). Those who achieved sustained MRD-negativity have had significantly longer PFS (HR=0.35 (0.20-0.59), p&amp;lt;0.0001). Among patients with sustained MRD-negativity, patients in the KRd arm had superior PFS [HR=0.30 (0.12-0.79), p=0.01], and MRD-free survival [HR=0.42 (0.20-0.89), p=0.02, Figure 2]. In the KRd arm, sustained MRD-negativity was confirmed in 32 out of 41 (78%) patients who had de-escalated therapy from KRd to R. In this group there were 8 events (25%) of progressive disease or MRD resurgence, which compared favorably to 17/36 (47%, p=0.057) events observed in the R arm. Conclusions The improved PFS in patients with NDMM receiving post-ASCT KRd maintenance may be attributed to higher rates of MRD conversion and longer duration of MRD-negativity. Importantly, this benefit, compared to R alone, appears to be sustained even in the subset of patients who received only 8 cycles of MRD-directed, risk-adapted KRd and subsequently de-escalated to R alone.

Valve-Sparing Aortic Root Replacement With Reimplantation vs Remodeling: A Meta-analysis

BackgroundLong-term outcomes of valve-sparing aortic root replacement (VSARR) with reimplantation vs remodeling in patients undergoing aortic root surgery remains a controversial subject. MethodsThis study was a pooled meta-analysis of Kaplan-Meier–derived data from comparative studies published by December 31, 2022. ResultsFifteen studies met our eligibility criteria, comprising 3044 patients (1991 in the reimplantation group and 2018 in the remodeling group). Patients who underwent VSARR with remodeling had a higher risk of all-cause death (hazard ratio [HR], 1.54; 95% CI, 1.16-2.03; P = .002, log-rank test P < .001). Landmark analysis (with 4 years as the landmark time point) demonstrated that survival was lower in patients who underwent VSARR with remodeling (HR, 2.15; 95% CI, 1.43-3.24; P < .001) in the first 4 years. Beyond the 4-year time point, no difference in survival was observed (HR, 1.04; 95% CI, 0.72-1.50; P = .822). The risk for need of aortic valve and/or root reintervention was higher in patients undergoing VSARR with remodeling (HR, 1.49; 95% CI, 1.07-2.07; P = .019, log-rank test P < .001). We did not find statistically significant coefficients for the covariates of age, female sex, connective tissue disorders, bicuspid aortic valve, aortic dissection, coronary bypass surgery, total arch replacement, or annular stabilization, which means that these covariates did not modulate the effects observed in our pooled analyses. ConclusionsVSARR with reimplantation is associated with better overall survival and lower risk of need for reintervention over time compared with VSARR with remodeling. Regarding overall survival, we observed a time-varying effect that favored the reimplantation technique up to 4 years of follow-up, but not beyond this time point.

Prognostic value of POD18 combined with improved IELSG in primary central nervous system lymphoma.

The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations. A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan-Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor. The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828). In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model.

International Bladder Cancer Group Intermediate-risk Non-muscle Invasive Bladder Cancer (IBCG IR-NMIBC) Scoring System Predicts Outcomes of Patients on Active Surveillance.

To determine if the International Bladder Cancer Group (IBCG) intermediate risk (IR)-NMIBC scoring system can predict the requirement of delayed transurethral resection of bladder tumor (TURBT) in low grade (LG) non-muscle invasive bladder cancer (NMIBC) managed by active surveillance (AS). A prospective study of recurrent LG Ta/T1 NMIBC patients managed with AS with the following characteristics were used: LG papillary NMIBC, ≤5 apparent LG NMIBC, tumor diameter ≤1 cm, absence of gross hematuria and negative urinary cytology. Subsequent TURBT was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the IBCG IR-NMIBC scoring system to predict receipt of subsequent TURBT was determined. Multivariable Cox proportional-hazards analysis was used to determine factors associated with subsequent TURBT. A total of 163 patients with LG Ta/T1 NMIBC were included for analysis. After a median follow-up of 33 months (21-46), TURBT was performed on 109 patients. At landmark timepoint of 24 months, patients with 0 RF factors were over two-fold more likely to continue AS compared to patients with ≥3 RF (59% versus 24%). Multivariable Cox regression suggest that the IBCG IR-NMIBC scoring system was associated with subsequent TURBT (1-2 RF [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 RF [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T-stage and sex. The IBCG IR-NMIBC scoring system can predict the risk of a subsequent TURBT in patients with LG NMIBC on AS.