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Optimal low-depth quantum signal-processing phase estimation

Abstract Quantum effects like entanglement and coherent amplification can be used to drastically enhance the accuracy of quantum parameter estimation beyond classical limits. However, challenges such as decoherence and time-dependent errors hinder Heisenberg-limited amplification. We introduce Quantum Signal-Processing Phase Estimation algorithms that are robust against these challenges and achieve optimal performance as dictated by the Cramér-Rao bound. These algorithms use quantum signal transformation to decouple interdependent phase parameters into largely orthogonal ones, ensuring that time-dependent errors in one do not compromise the accuracy of learning the other. Combining provably optimal classical estimation with near-optimal quantum circuit design, our approach achieves a standard deviation accuracy of 10−4 radians for estimating unwanted swap angles in superconducting two-qubit experiments, using low-depth ( < 10) circuits. This represents up to two orders of magnitude improvement over existing methods. Theoretically and numerically, we demonstrate the optimality of our algorithm against time-dependent phase errors, observing that the variance of the time-sensitive parameter φ scales faster than the asymptotic Heisenberg scaling in the small-depth regime. Our results are rigorously validated against the quantum Fisher information, confirming our protocol’s ability to achieve unmatched precision for two-qubit gate learning.

Platelet-to-lymphocyte ratio as a useful biomarker of recurrence and mortality risks in patients with muscle-invasive bladder cancer who achieved ypT0 to neoadjuvant chemotherapy: A multicenter retrospective study.

873 Background: Platelet-to-lymphocyte ratio (PLR), a novel inflammatory marker, has been suggested to predict recurrence and mortality in several malignancies. Patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (ypT0) to neoadjuvant chemotherapy (NAC) have a favorable prognosis. However, the risk factors for recurrence and mortality remain unclear. Methods: This multi-institutional retrospective study assessed 950 patients with MIBC who underwent radical cystectomy (RC). Of the 950 patients, 128 patients who achieved a pathological complete response (ypT0) to 2–4 cycles of NAC were included. Univariable and multivariable Cox proportional hazards regression analyses were performed to identify the risk factors for recurrence and mortality. Results: The median age and follow-up period were 69 years and 80 months, respectively. Of the 128 patients, 15 (12%) and 30 (23%) experienced recurrence and died from any cause, respectively. The most frequent recurrence site was lymph nodes (n = 11, 73%), followed by urothelium (n = 4, 27%). The 10-year recurrence-free survival (RFS) and 10-year overall survival (OS) rates were 85.9% and 73.1%, respectively. In the univariable and multivariable analyses, clinical lymph node involvement, neobladder reconstruction, and PLR were independently and significantly associated with RFS (Table). In the univariable and multivariable analyses, age and PLR were independently and significantly associated with OS. Conclusions: Recurrence was not a rare event in patients with MIBC who achieved ypT0. PLR may be a useful biomarker to assess recurrence and mortality risks. Multivariable analysis for RFS. Factor P value Hazard ratio 95% CI Clinical lymph node involvement Positive 0.021 3.732 1.219–11.42 Urinary diversion Neobladder 0.281 0.281 0.094–0.842 PLR Continuous 0.029 1.003 1.000–1.006

Molecular subtypes, <i>NECTIN4/HER2</i> expression, and clinical outcomes in patients (pts) with advanced urothelial carcinoma (aUC) or muscle invasive bladder cancer (MIBC): Exploratory analyses from JAVELIN Bladder 100 and the Tempus database.

828 Background: Consensus molecular subtypes of UC/BC include basal/squamous (Ba/Sq), stroma-rich (SR), luminal unstable (lumU), luminal papillary (lumP), luminal nonspecified (lumNS), and neuroendocrine (NE)-like. Nectin-4 and HER2 are targets for novel antibody-drug conjugates. We report exploratory analyses of molecular subtypes, including NECTIN4 and HER2 RNA expression, in pts with aUC or MIBC from the JAVELIN Bladder 100 phase 3 trial and Tempus real-world database. Methods: JAVELIN Bladder 100 (NCT02603432) enrolled pts with aUC without progression after first-line platinum-based chemotherapy. Pts with MIBC or aUC were identified in the Tempus database of deidentified pt data from US clinical practice. Whole-transcriptome profiles in tumor samples were generated using RNA sequencing. NECTIN4 and HER2 transcript levels were quantified using Personalis ACE technology (JAVELIN Bladder 100) or kallisto (Tempus). Results: In evaluable aUC tumors from the JAVELIN cohort (n=560), NECTIN4 and HER2 RNA expression was heterogenous across molecular subtypes and was highest in lumU/lumP/lumNS subtypes and lowest in the NE-like subtype (Table); 57% of tumors had high (≥ median) expression of both NECTIN4 and HER2 RNA. Variations in NECTIN4 / HER2 RNA expression across molecular subtypes were similar in MIBC/aUC tumors from the Tempus cohort (n=501); 39% of tumors had high NECTIN4/HER2 RNA expression. In both cohorts, a strong correlation between NECTIN4 and HER2 RNA expression was observed overall (R=0.6-0.655), although correlation was not observed within all subtypes. In pts treated with avelumab in JAVELIN Bladder 100 (n=283; excluding NE-like [n=1]), no significant difference in overall survival was noted by molecular subtype (median [95% CI], mo: Ba/Sq, 27.2 [18.2-not estimable (NE)]; LumNS, 34.4 [20.8-NE]; LumP, 20.8 [18.2-31.4]; LumU, 24.9 [18.6-43.1]; SR, 28.8 [19.3-NE]). Limitations include exploratory analyses and potential selection bias. Conclusions: In these analyses, including the first analysis of consensus molecular subtypes in a phase 3 trial in aUC, NECTIN4 and HER2 RNA expression was heterogeneous across molecular subtypes of aUC and MIBC tumors and was highest in luminal subtypes. No significant difference in overall survival was noted across subtypes in pts treated with avelumab first-line maintenance. Clinical trial information: NCT02603432 . Subtype JAVELIN (n=560) Tempus (n=501) n (%) Expression level* n (%) Expression level* NECTIN4 HER2 NECTIN4 HER2 Ba/Sq 95 (17.0) 0.812 0.779 177 (35.3) 0.828 0.769 LumNS 30 (5.4) 1.029 0.905 30 (6.0) 0.990 0.926 LumP 135 (24.1) 0.984 0.888 89 (17.8) 0.962 0.925 LumU 95 (17.0) – – 99 (19.8) – – NE-like 3 (0.5) 0.152 0.460 37 (7.4) 0.311 0.613 SR 202 (36.1) 0.833 0.862 69 (13.8) 0.884 0.879 *Fold difference in transcripts per million vs LumU.

Radical prostatectomy (RP) versus radiotherapy (RT) in high-risk prostate cancer (HR-PCa): Emulated randomized comparison with individual patient data (IPD) from two phase III randomized trials (RCTs).

309 Background: Standard of care (SOC) treatment options for HR-PCa include RT with long-term androgen deprivation (LT-ADT) or RP with selective use of post-operative RT +/- androgen deprivation therapy (ADT). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. Therefore, we conducted an emulated randomized comparison of RT vs RP in HR-PCa leveraging patients enrolled in RCTs. Methods: We searched Medline for RCTs in HR-PCa with a SOC arm of an RT- or RP-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. This identified 2 trials, NRG/RTOG 0521 (RT+LT-ADT +/- 6 cycles docetaxel [doce]), and CALGB 90203 (RP +/- neoadjuvant 6 cycles doce and ADT). Due to inherent difference in the biochemical recurrence criteria after RT vs RP, we chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis (DM) as the primary endpoint, considering deaths as competing events. Death after DM was measured to create a harmonized metric of deaths likely attributed to PCa. To assess potential residual selection bias, death without DM to capture non-cancer associated deaths was analyzed. Results: Overall, 1290 patients (RT n=557, RP n=733) were included, with similar median follow-up of 6.4 years. Prior to IPTW, RP patients were significantly younger with lower baseline PSA compared to RT patients. Adjuvant (18%) and salvage therapy (44%) was used in RP cohort. Cumulative incidence of DM was significantly lower in patients who underwent RT compared to RP (8-year DM: 16% vs 23%; p=0.01; subdistribution hazard ratio [sHR] 0.48 [95%CI 0.34-0.69], p&lt;0.001). 8-year rates of death after DM were 10% vs 8% (p=0.72) in the RP and RT patients, respectively. RT patients had significantly greater risk of death without DM (HR 2.09 [1.01-4.34], p=0.048) with early differences measured. On a cross-arm comparison, 8-year cumulative incidence of DM when comparing SOC RT+LT-ADT group versus the doce+ADT+RP group was 18% vs 21%, respectively (sHR 0.75 [0.45-1.24], p=0.26). Conclusions: HR-PCa patients enrolled on RCTs had significantly lower incidence of DM with an RT-based strategy compared to an RP-based approach. Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison (use of cooperative group RCT data, contemporaneous enrollment in the same country, patients fit enough for chemotherapy, and IPTW adjustments) there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm. Utilization of post-operative radiotherapy and ADT+Doce may mitigate differences between RP and SOC RT+LT-ADT.

Protein analysis of urachal carcinoma tissue based on different antibody-drug conjugate therapeutic targets.

852 Background: Urachal carcinoma (UrC) is an extremely rare cancer, and there is still a lack of standard drug treatment models for advanced UrC. Antibody-drug conjugate (ADC) therapy represents a promising cancer treatment method. However, the efficacy of ADC on UrC remains unclear due to the scarcity of knowledge about the immunohistochemical features of relevant targets. This study focused on the immunohistochemical features of UrC based on ADC therapeutic targets and its relationship with overall survival (OS), providing a basis for UrC treatment. Methods: A total of 45 postoperative pathological specimens confirmed to be UrC were collected. Using immunohistochemistry, protein expression levels of ADC targets HER2, Nectin-4, Claudin18.2, Trop2, Mesothelin, and the immunotherapy target PD-L1 were assessed, with the proportion of high expression (2+ or 3+) of target proteins evaluated. 38 cases with complete clinical information were screened to evaluate the relationship between the expression of target proteins and OS. Results: Among the ADC therapeutic targets, Trop2 had the highest high expression rate (55.6%) in UrC tissues, followed by Mesothelin (46.7%), Claudin18.2 (31.1%), Nectin-4 (22.2%), and HER2 (15.6%). The high expression rate of PD-L1 was 15.6%. The median age of UrC patients was 53.5 years. Sheldon stage I, III and IV patients accounted for 2.6%, 89.5% and 7.9%, respectively. Survival analysis revealed that the five-year survival rate was 85.7% in the low Trop2 expression group and 49.2% in the high expression group. High expression of Trop2 was associated with poor OS (P=0.031). Conclusions: The target proteins of ADC are expressed in UrC tissue. Trop2 exhibits a significant high expression rate, and UrC patients with high Trop2 expression have a worse prognosis. Trop2 could be a pivotal target for future ADC treatment of UrC.

Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer

Immune checkpoint inhibitors in patients with testicular cancer: A systematic review.

638 Background: Germ cell tumors (GCT) are chemosensitive neoplasms with high cure rates, even in the metastatic setting. However, a small group of these patients will present tumors refractory to chemotherapy, with a dismal prognosis and very few effective management options. Although immune checkpoint inhibitors (ICIs) are approved for use in chemotherapy-refractory GCT for those tumors with a high microsatellite instability (MSI-H/dMMR) or high tumor mutational burden (TMB-H), the evidence supporting this indication is scarce. Methods: Original research studies, conducted on patients with GCT refractory to chemotherapy treated with ICI up to December 2023 were included. Comprehensive search strategies of 5 databases and MeSH keywords were used to locate eligible literature. Study characteristics, participant demographics, and oncological outcomes were recorded. Results: A total of 13 studies (n = 106) were identified for inclusion; 5 of which corresponded to single-patient case reports, one was identified as a retrospective cohort, 6 were phase II RCTs and we included a recent abstract from the preliminary results of a phase II RCT. Most of the studies evaluated did not request biomarkers as inclusion criteria. The median overall response rate across all patients included was 3.4% (range, 0-57), versus 0% (range 0-6) in those reported in retrospective cohort and phase II studies. Progressive disease as best clinical response was reported in most patients, with 75% (range, 0-82.9) in the overall population and 82% (range, 75 -83) in patients from retrospective cohort and phase II trials. Some of the most durable clinical responses documented in this systematic review corresponded to TMB-H or MSI-H/dMMR tumors. Conclusions: Analysis from retrospective cohorts and clinical trials evaluating ICIs for the treatment of chemotherapy-refractory GCT documented a limited activity of these drugs as a single intervention in patients not selected by biomarkers, with a tendency to better results described in those with TMB-H or MSI-H/dMMR tumors. Future prospective study designs should attempt to select patients by biomarkers to shed light on the determination of clinical and molecular factors that can predict response to ICIs in this scenario.

Neuropathy, skin rash, and hyperglycemia as predictors of response to enfortumab vedotin in locally advanced and metastatic bladder and upper tract urothelial carcinoma.

771 Background: Enfortumab vedotin (EV) in combination with pembrolizumab is FDA approved for treatment of locally advanced and metastatic urothelial cancer. Neuropathy, skin rash, and hyperglycemia are common side effects of EV. We evaluated the impact of presence of neuropathy, skin rash, and hyperglycemia on progression free survival (PFS) in patients (pts) with bladder or upper tract urothelial carcinoma treated with EV. Methods: The Indiana University bladder cancer database was queried for pts with locally advanced and metastatic bladder and upper tract urothelial carcinoma who were treated with EV with or without pembrolizumab. Pts with variant histology were included. Toxicities were documented throughout the course of treatment. Association of neuropathy, skin rash and hyperglycemia and PFS were compared to patients without any of the side effects using the log-rank test. Results: Between 2018-2024, a total of 83 pts were treated with EV with at least 2 doses. The median age was 69 years (range, 39-89). 47 pts had EV + pembrolizumab, while 36 pts had EV as single agent. 43 pts received EV as 1st, 28 pts as 2nd, 10 pts as 3rd, and 2 pts as 4th line of treatment. Metastatic sites were lymph nodes in 42 pts, lungs in 34 pts, bones in 29 pts, liver in 16 pts, and brain in 7 pts. Median follow-up from the start of EV treatment was 14 months (range, 1-33). Neuropathy was reported in 30 (36%) pts, skin rash in 32 (39%) pts, and hyperglycemia in 6 (7%) pts. The median PFS in patients who did not experience neuropathy/skin rash/hyperglycemia was 4.5 months (95% CI, 2.4-11.0), 10.6 months (95% CI, 7.2-15.7) in pts who experienced neuropathy (P = 0,01), 8.6 months (95% CI, 7.3-20.2) in pts who experienced skin rash (P = 0.01), and 15.9 months (95% CI, 5.1-15.9) in pts who experienced hyperglycemia (P = 0.03). Conclusions: The presence of neuropathy, skin rash, or hyperglycemia in patients with metastatic bladder or upper tract urothelial carcinoma treated with EV was associated with improved PFS.

Phase 2 study of perioperative lenvatinib (L) with pembrolizumab (P) in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.

555 Background: L is an oral multi-kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor α, RET, and KIT. P is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity for binding to the programmed cell death 1 receptor. The combination of P+L was approved for the treatment of advanced renal cell carcinoma (RCC). The enhanced response rates in metastatic RCC with this combination, along with emerging neoadjuvant data, support its potential use in the neoadjuvant setting. Methods: Patients with biopsy-confirmed clear cell RCC of clinical stage ≥ T3Nx, TanyN+, or those deemed unresectable by an experienced surgical team were eligible for this study. They received 4 cycles of P+L (starting dose: 20 mg daily) over 12 weeks, followed by surgery and 13 cycles of adjuvant P monotherapy. The primary endpoint was the objective response rate (ORR) at week 12, assessed per RECIST v1.1 by independent radiological review, including complete and partial responses. Secondary endpoints included safety, tolerability, disease-free survival (DFS), overall survival (OS), surgical outcomes, and quality of life. Results: At the time of analysis, 2 patients were still receiving neoadjuvant treatment. Of the 15 patients who completed the 12-week neoadjuvant regimen, 14 (93%) proceeded to surgery as planned without delay following a minimum 7-day washout period. One patient is awaiting surgery. One patient was not evaluable due to incomplete neoadjuvant treatment caused by concurrent immune-related adverse events (irAEs) rhabdomyolysis and hepatitis (grade 4), though surgery was performed after irAE management. Among evaluable patients, 3/15 (20%) exhibited a partial response, while 12/15 (80%) had stable disease. No patients experienced disease progression while on pembrolizumab+lenvatinib. The median reduction in primary renal tumor size was 21% (range: 3-37%).The most common adverse events (AEs) were fatigue (n=14), palmar-plantar erythrodysesthesia syndrome (n=9), hypertension (n=8), mucositis (n=8), and proteinuria (n=8). Intraoperative complications were not observed, and no postoperative complications related to the drug were noted. No other treatment related grade 4or 5 AEs related to lenvatinib or surgery occurred except for the unevaluable participant. At the time of analysis, two patients had disease recurrence, and one patient had died due to disease progression. Conclusions: The combination of P+L demonstrated clinical activity and a favorable safety profile in the perioperative setting for patients with locally advanced, non-metastatic clear cell RCC. Further data, including long-term outcomes, correlative studies, quality of life assessments, and frailty/sarcopenia indices, will be reported (NCT04393350). Clinical trial information: NCT04393350 .

Study of JAK inhibition in stem-like prostate cancer (JASPER): A phase 1/2 multicenter study of ruxolitinib and enzalutamide in castration resistant prostate cancer undergoing lineage plasticity.

TPS297 Background: Lineage plasticity (LP) is an increasingly recognized route of resistance in advanced metastatic prostate cancer, and present in approximately 35% of patients at time of death. LP is a continuum of disease states from adenocarcinoma driven by androgen receptor (AR) to AR-independent double negative prostate cancer (DNPC) and neuroendocrine prostate cancer (NEPC). LP has been associated with significantly decreased overall survival compared to other modes of resistance in castration resistant prostate cancer (CRPC). LP can be defined using a combination of molecular and clinical features, but treatment remains imprecise with doublet chemotherapy. Preclinical studies of LP evolution point toward JAK/STAT signaling as important to the process of early lineage plasticity. Furthermore, JAK inhibition combined with AR pathway inhibitor, enzalutamide (enza), was shown to sensitize enza resistant LP models to enza. Genomic studies of patient samples have similarly found JAK/STAT pathway upregulation in tumors which undergo lineage plasticity to DNPC. JAK inhibition in combination with enza may be a promising therapy for prostate cancer at risk or undergoing LP. Methods: JASPER is a phase1/2, multi-center study to evaluate the safety, tolerability, antitumor activity, and pharmacology of ruxolitinib (rux, a JAK inhibitor) combined with enza (160 mg per day) in patients with metastatic CRPC with poor response to prior abiraterone treatment. Poor response is defined as progression within 12 months of starting therapy within hormone-naïve prostate cancer or within 6 months of starting it within CRPC. In the dose escalation phase, a unique pharmacology approach is employed to understand enza’s CYP3A4 induction. A single dose of rux determines intrapatient pharmacokinetics. One week later, the combination starts and the plasma rux values correlated. The pharmacodynamic biomarker phospho-STAT3 in leukocytes will be measured by ELISA. A Bayesian Optimal Interval (BOIN) design determines the maximum tolerated dose (MTD) of rux with enza for the expansion cohort. The expansion cohort has a Simon’s 2 phase design with a 40% response rate goal (3 responses required out of first 13 patients at MTD, total of 39 maximum). The primary endpoint is the MTD of the combination based on rate of drug-related grade 3-5 adverse events experienced within the first 4 weeks of study treatment. Secondary endpoints are a) disease response rate within 6 months of combination therapy start defined by PSA50 decline and/or RECIST 1.1 criteria of partial response or complete response and b) progression free survival defined by Prostate Cancer Working Group 3 criteria. Enrollment is open. Clinical trial information: NCT06616155 .

Chromosome-level genomes of two Bracteacoccaceae highlight adaptations to biocrusts

Efficacy and safety of fruquintinib combined with serplulimab as 1 ^st line treatment in metastatic or unresectable non-clear cell renal cell carcinoma (nccRCC): Updated results from a single-arm, multicentre clinical trial.

542 Background: For advanced non-clear cell renal cell carcinoma (nccRCC), systemic therapy is the main option but the treatment standard remains unclear. In the past decade, promising results have emerged from clinical trials with vascular endothelial growth factor receptor (VEGFR) inhibitors, or anti-programmed death-1 (PD-1) antibodies. Fruquintinib (FRU) is a potent VEGFR inhibitor approved for metastatic colorectal cancer. This trial aims to evaluate the efficacy and safety of FRU combined with serplulimab (an anti-PD-1 antibody) in patients (pts) with advanced nccRCC. Methods: This is a multicentre single-arm prospective trial planning to enroll 39 pts with pathologically confirmed metastatic or unresectable nccRCC. Eligible patients were 18 to 80 years old with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and had not received prior systemic therapy. All pts received FRU (5mg, qd, po, 2w on/1w off) plus serplulimab (4.5mg/kg, d1, i.v.gtt, q3w). The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), safety, etc. Results: As of Sep.20 th , 2024, 16 nccRCC pts were enrolled. The median age was 63.5 years (range 24-78) and 75.0% were male. Seven (43.8%) pts had an ECOG PS of 2. Histologically, papillary subtype was the most prevalent (12, 75.0%), followed by chromophobe (2, 12.5%), 1 collecting duct carcinoma and 1 unclassified subtype, and sarcomatoid features were observed in 5 (31.3%) patients. The metastatic sites were primarily lymph nodes (56.3%), lungs (37.5%), peritoneum (25.0%) and abdominal cavity (25.0%). Among the 16 evaluable pts, 8 achieved partial response and 6 had stable disease, resulting in an ORR of 50.0% (95% CI: 25.5%-74.5%) and a DCR of 87.5% (95% CI: 61.7%-98.4%). Three pts experienced rapid progression, all with sarcomatoid features (2 papillary, 1 chromophobe). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were rash (37.5%), fever (31.3%), ALT increased (25.0%), AST increased (25.0%), hypertension (18.8%), hypothyroidism (18.8%), fatigue (18.8%) and most were grade 1/2 except 1 pt experiencing grade 3 AST increased. Conclusions: The preliminary data showed promising efficacy and tolerable toxicity of FRU combined with serplulimab in pts with metastatic or unresectable nccRCC. Clinical trial information: NCT05831891 .

Dose finding study of CBM588 in combination with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma: A phase I study.

TPS611 Background: The combination of nivolumab and ipilimumab is currently one of the standard-of-care treatments for patients with metastatic renal cell carcinoma (mRCC). However, in the vast majority of patients, disease progression eventually occurs. Thus, novel methods to increase the efficacy of nivolumab/ipilimumab are being explored. Recent evidence suggests that the gut microbiome can remarkably influence the efficacy of immune checkpoint inhibitors (ICI) in patients with mRCC, particularly through the modulation of microbial diversity and the presence of key bacterial species (Routy et al . Science 2018; Salgia et al . Eur Urol 2020). The current study explores the use of CBM588, Clostridium butyricum MIYARI588, which has demonstrated the potential to enhance clinical outcomes when combined with ICI therapy (Dizman et al . Nature Medicine 2022; Ebrahimi et al . Nature Medicine 2024). This ongoing phase I study aims to determine the maximum tolerated dose (MTD) of CBM588 in combination with nivolumab/ipilimumab in previously untreated mRCC patients, and to evaluate the biological effects of CBM588. Methods: This investigator-initiated, phase I, open-label, single-arm, dose-escalation study is being conducted in patients with untreated, histologically confirmed mRCC. Eligible patients must be ≥18 years old, have an ECOG performance status ≤2, and be diagnosed with clear cell and/or sarcomatoid histology. The study is open to all IMDC risk groups. Patients must have measurable disease by RECIST 1.1 and no prior systemic therapy for metastatic disease. The study follows a 3+3 dose-escalation design with three planned dose levels for CBM588 (4 × 10 8 CFU, 1.2 × 10 9 CFU, and 4 × 10 9 CFU), administered twice daily orally. Nivolumab (3 mg/kg every 3 weeks for four cycles, followed by 480 mg every 4 weeks) and ipilimumab (1 mg/kg every 3 weeks for four cycles) are administered intravenously. The primary objective is to assess the safety and tolerability with escalating doses of CBM588 in combination with nivolumab and ipilimumab. Secondary objectives include evaluating changes in the gut microbiome, modulation of immune pathways, alterations to the systemic metabolome, and clinical outcomes such as overall response rate (ORR) and progression-free survival (PFS). Responses are assessed by CT every 12 weeks. Dose level one has been completed without dose-limiting toxicities. Enrollment at dose level two began in October 2024. Clinical trial information: NCT06399419 .

Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial

PURPOSE Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti–vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. PATIENTS AND METHODS This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504 ). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m 2 ) plus gemcitabine (1,000 mg/m 2 ; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples. RESULTS Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo. CONCLUSION In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

Datopotamab deruxtecan (Dato-DXd) in locally advanced/metastatic urothelial cancer: Updated results from the phase 1 TROPIONPanTumor01 study.

663 Background: Dato-DXd is a TROP2-directed antibody-drug conjugate under investigation in various solid tumor types. We report updated results in patients (pts) with locally advanced/metastatic urothelial cancer (la/m UC) from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable la/m UC (stage III/IV) treated with ≥1 prior line of therapy, including an immune checkpoint inhibitor, received Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) per RECIST 1.1 by blinded independent central review (BICR). Results: At data cutoff (April 22, 2024), 40 pts had received Dato-DXd; 8 (20%) were receiving ongoing treatment. Median follow-up was 10.0 (range 5–28) months (mo). Pts were heavily pretreated: 24 (60%) had received ≥3 prior regimens in the locally advanced/metastatic setting, 36 (90%) received prior platinum chemotherapy, and 33 (83%) received prior enfortumab vedotin. Confirmed ORR by investigator was 27.5% (95% CI, 14.6–43.9), including 11 partial responses (PR). Confirmed ORR by BICR was 25.0% (95% CI, 12.7–41.2), including 1 complete response (CR) and 9 PR (Table). Median DOR was not reached (95% CI, 2.6–not evaluable [NE]); 76.2% (95% CI, 33.2–93.5) of responders had ongoing responses at 6 mo. Median PFS by BICR was 6.9 mo (95% confidence interval [CI], 2.9–NE). Treatment-emergent adverse events (TEAEs) occurring in &gt;20% of pts (any grade; grade ≥3) were stomatitis (53%; 5%), nausea (38%; 3%), decreased appetite (30%; 3%), and fatigue (28%; 0%). Grade ≥3 TEAEs occurred in 55% of pts. TEAEs associated with treatment discontinuation, dose reduction, and dose interruption occurred in 8%, 20%, and 35% of pts, respectively. No serious treatment-related AEs or treatment-related grade 4 or 5 AEs were reported. Two pts (5%) had adjudicated drug-related interstitial lung disease/pneumonitis (grade 2 and 3). Conclusions: In heavily pretreated pts with la/m UC, Dato-DXd demonstrated encouraging antitumor activity with a manageable safety profile. Dato-DXd is being evaluated in pts with urothelial cancer in the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . Efficacy by BICR. Response All patients N=40 Confirmed ORR, n (%) [95% CI] 10 (25.0) [12.7–41.2] CR 1 (2.5) PR 9 (22.5) SD 20 (50.0) Non-CR/non-PD 1 (2.5) PD 5 (12.5) NE 4 (10.0) DOR at 6 mo, % [95% CI] 76.2 [33.2–93.5] Median PFS, mo [95% CI] 6.9 [2.9–NE] BICR, blinded independent central review; CI, confidence interval; CR, complete response; DOR, duration of response; mo, months; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Asymmetric small-molecule acceptor enables suppressed electron-vibration coupling and minimized driving force for organic solar cells

Abstract Minimizing the energy loss, particularly the non-radiative energy loss (ΔE nr), without sacrificing the charge collection efficiency, is the key to further improve the photovoltaic performance of organic solar cells (OSCs). Herein, we proposed an asymmetric molecular design strategy, via developing alkyl/thienyl hybrid side chain based asymmetric small molecule acceptors (SMAs) BTP-C11-TBO and BTP-BO-TBO, to manipulate the intermolecular interactions to realize enhanced luminescence efficiency and reduced energy loss. Theoretical and experimental results indicate that compared to the three symmetric SMAs BTP-DC11, BTP-DTBO and BTP-DBO, the asymmetric SMAs BTP-C11-TBO and BTP-BO-TBO exhibit repressed electron-vibration coupling and reduced ΔE nr. Moreover, the asymmetric nature of BTP-BO-TBO allows the formation of multiple D:A interfacial conformations and interfacial energies, which have made the charge-transfer state energies closer to that of the strongly absorbing (and emitting) local-exciton state, thus gaining the low ΔE nr while maintaining efficient exciton dissociation. Consequently, the PM6:BTP-BO-TBO-based OSCs achieve a higher power conversion efficiency of 19.76%, with a high open circuit voltage of 0.913 V and an efficient fill factor of 81.17%, profiting from the more improved and balanced charge mobility and longer carrier lifetime. This work provides molecular design ideas to suppress nonradiative decay and paves the way to obtain high-performance OSCs.

Evaluating neoadjuvant intravesical mitomycin C in NMIBC: A phase III randomized clinical trial.

803 Background: The primary treatment for non-muscle invasive bladder cancer (NMIBC) is transurethral resection (TUR), often followed by adjuvant intravesical therapies. Given the variable response to intravesical therapy, enhancing its efficacy is critical to reducing recurrence and progression to MIBC. Recent studies have shown that MMC induces immunogenic cell death, suggesting its potential in enhancing the effectiveness of other intravesical therapies, such as BCG, activating acquired immunity. This study aimed to evaluate the safety and efficacy of neoadjuvant MMC in patients with NMIBC. Methods: This is a prospective, phase III randomized clinical trial in patients with primary or recurrent BC who had not received intravesical therapy between May 2022 and June 2024 (EudraCT 2021-003751-42; ICH-013). Patients were randomized 1:1 to either the neoadjuvant MMC arm (neoA) or the standard treatment arm (StA). In the two weeks preceding the scheduled TURBT (day 0), patients in the neoA arm received intravesical MMC (40 mg/40 ml) on days -14 and -7, along with cystoscopy and cold-cup biopsy on day -14. Clinical decisions regarding adjuvant therapy and follow-up (FU) schedules in both groups were based on the tumor histology according the European Association of Urology (EAU) guidelines. The primary endpoint was to evaluate the safety, and efficacy of neoadjuvant MMC in reducing the recurrence rate of BC. Patients with MIBC or pT0 were excluded from survival analyses. Results: A total of 63 patients were included: 31 (49%) in the StA group and 32 (51%) in the neoA group. The groups were homogeneous in clinical and pathological characteristics.In the neoA group, 8 adverse events (AEs) were reported in 5 patients (14%), all mild (Grade 1 and 2). Following TUR, 26 AEs grade 1 and 2 were observed in 16 (50%) patients in the StA group, and 24 AEs in 14 (45%) patients in the neoA group, with no significant differences between the groups (p=0.6).In the neoA group, 16 patients had TaLG, 9 had TaHG, 3 had T1HG, 1 had CIS, and 2 had benign findings. No complete tumor ablation occurred, with only 2 cases showing reduced tumor size. In the StA group, 17 had TaLG, 6 had TaHG, 5 had T1HG, and 3 had T2 tumors. After a median FU of 14.5 months, 5 patients in the StA group and 4 in the neoA group recurred. Only one patient, in the neoA group, progressed to MIBC. The 12-month recurrence-free survival (RFS) was 91% (95% CI: 68-98) in the StA group and 84% (95% CI: 62-94) in the neoA group, with no statistically significant difference between the two groups (log-rank test p=0.8). Conclusions: Neoadjuvant MMC showed a favorable safety and tolerability profile. Although no significant RFS difference was found between the neoA and standard arms, a larger cohort and longer FU are needed for definitive conclusions on MMC's oncological efficacy. The upcoming analysis of the adjuvant BCG subgroup will further clarify MMC's role in enhancing BCG efficacy.

Darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume: Subgroup analysis of the phase 3 ARANOTE trial.

151 Background: Darolutamide (DARO) plus ADT significantly reduced the risk of radiological progression or death by 46% (HR 0.54; 95% CI: 0.41–0.71; P &lt;0.0001) versus placebo (PBO) plus ADT in patients with mHSPC in the ARANOTE trial. The incidence of treatment-emergent adverse events (TEAEs) was low and similar between arms, with fewer patients discontinuing study drug due to TEAEs in the DARO vs PBO arm (6.1% vs 9.0%). Here, we report the efficacy and safety by disease volume in both arms of ARANOTE. Methods: Patients with mHSPC were randomized 2:1 to receive DARO 600 mg twice daily + ADT or PBO + ADT. High-volume (HV) disease was defined by the presence of visceral metastases and/or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis (CHAARTED criteria). The primary endpoint was radiological progression-free survival (rPFS). Secondary endpoints included time to metastatic castration-resistant prostate cancer (mCRPC), time to prostate-specific antigen (PSA) progression, and safety. Results: Of the 669 patients included in the full analysis set, 472 (71%; DARO n=315; PBO n=157) had HV disease and 197 (29%; DARO n=131; PBO n=66) had low-volume (LV) disease. Baseline demographics and patient characteristics were generally balanced between the treatment arms in HV and LV subgroups. Patients with LV disease had better prognostic factors (eg, a higher proportion of patients with ECOG PS 0, Gleason &lt;8, having received prior local therapy, and lower baseline median PSA levels). DARO + ADT improved rPFS vs PBO + ADT in both HV and LV subgroups. In the LV subgroup, DARO + ADT reduced the risk of radiological progression or death by 70% (HR 0.30; 95% CI: 0.15–0.60) with median rPFS not reached in either group. In the HV subgroup, DARO + ADT reduced the risk of radiological progression or death by 40% (HR 0.60; 95% CI: 0.44–0.80) with median rPFS of 30.2 months with DARO vs 19.2 months with PBO. For the secondary endpoints, DARO delayed time to CRPC (HV: HR 0.46; 95% CI: 0.36–0.60; LV: HR 0.21; 95% CI: 0.12–0.37) and time to PSA progression (HV: HR 0.34; 95% CI: 0.25–0.46; LV: HR 0.19; 95% CI: 0.10–0.37) and a higher proportion achieved PSA &lt;0.2 ng/mL with DARO vs PBO (HV: 54.6% vs 15.5%; LV: 82.6% vs 25.4%) in HV and LV subgroups. Incidences of TEAEs were low and similar between treatment groups across the HV and LV subgroups and consistent with the overall population. Lower rates of fatigue and treatment discontinuations due to TEAEs with DARO vs PBO were observed in the LV subgroup: 2.3% vs. 13.8% and 3.1% v 10.8%, respectively. Conclusions: Efficacy outcomes with DARO + ADT in patients with mHSPC were improved vs PBO + ADT regardless of disease volume. DARO + ADT was well-tolerated in both volume subgroups, consistent with the overall population. Patients with LV mHSPC had marked treatment efficacy with minimal treatment burden. Clinical trial information: NCT04736199 .

Closing the Gap: Evaluating Medicare's Low-Income Subsidy Support for Optimal Cancer Care

Clinicopathological characteristics and prognosis of metastatic non-clear cell renal cell carcinoma.

504 Background: Non-clear cell renal cell carcinoma (nccRCC) is a clinicopathological heterogeneous disease that comprises a complex mixture of different pathology subtypes, accounting for approximately 20% of all RCC cases. Due to its heterogeneity and rarity, standard treatment strategy for metastatic nccRCC remain poorly defined. Methods: We conducted retrospective analysis of 105 metastatic nccRCC patients at our center from June 2010 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The data of 872 metastatic ccRCC patients were also collected for comparison.The end points included progression-free survival (PFS) and overall survival (OS). Results: Among 105 metastatic nccRCC patients, the most prevalent histology was papillary RCC (pRCC, 39.0%). The second most common histological type was translocation RCC (tRCC, 29.5%), followed by unclassified RCC (24.8%). The median age of metastatic nccRCC patients was 50 years old. 68.6% patients had advanced primary tumor stage of T3/4, and 48.6% patients had regional lymph node metastasis. The most common distant metastasis site was lung metastasis (52.4%), followed by bone metastasis (33.3%), and 21.0% patients had liver metastasis. The proportion of the favorable, intermediate, and poor IMDC risk group were 19.0%, 54.3%, and 26.7%, respectively. Among metastatic nccRCC patients, 26 received first-line IO-TKI therapy, 79 received first-line TKI monotherapy therapy. During the median follow-up of 22.2 months, there was no statistical significance between the prognosis of IO-TKI and TKI monotherapy group (PFS: 10.9 months vs. 8.6 months, P = 0.23; OS: 23.3 months vs. 24.0 months, P = 0.39). The PFS of tRCC was significantly longer than pRCC and unclassified RCC (P＜0.001). According to the Cox regression model, unclassified RCC pathology (HR=2.027，P=0.023) and poor IMDC risk group (HR=2.285，P=0.011) were identified as the independent risk factors for PFS. Poor IMDC risk group was also identified as the independent risk factors for OS (HR=2.638，P=0.007). Compared to metastatic ccRCC, the metastatic nccRCC patients were younger, with more advanced T and N stage, having a higher proportion for liver metastasis. The outcome of metastatic nccRCC was also poorer than metastatic ccRCC patients (P＜0.001), with a median OS of 24.0 months and 38.0 months, respectively. Conclusions: Compared to metastatic ccRCC, the prognosis of the patients with metastatic nccRCC was poorer, and the metastatic nccRCC patients were younger, with more advanced T and N stage, having a higher proportion for liver metastasis. Unclassified RCC pathology and poor IMDC risk group were the independent risk factors for poor prognosis. For metastatic nccRCC, the efficacy of IO-TKI was not superior than TKI monotherapy.Therefore, it is of great significance to investigate novel therapeutic targets for metastatic nccRCC.