Neutron imaging of the deuterium-tritium tamping gas volume in an inertial confinement fusion hohlraum.

To benchmark the accuracy of the models and improve the predictive capability of future experiments, the National Ignition Facility requires measurements of the physical conditions inside inertial confinement fusion hohlraums. The ion temperature and bulk motion velocity of the gas-filled regions of the hohlraum can be obtained by replacing the helium tamping gas in the hohlraum with deuterium-tritium (DT) gas and measuring the Doppler broadening and Doppler shift of the neutron spectrum produced by nuclear reactions in the hohlraum. To understand the spatial distribution of the neutron production inside the hohlraum, we have developed a new penumbral neutron imager with a 12 mm diameter field of view using a simple tungsten alloy spindle. We performed the first experiment using this imager on a DT gas-filled hohlraum and successfully obtained the spatial distribution of neutron production in the hohlraum plasma. We will report on the design of the spindle, characterization of the detectors, and methodology of the image reconstruction.

Learning from each other: Cross-cutting diagnostic development activities between magnetic and inertial confinement fusion (invited).

Inertial Confinement Fusion and Magnetic Confinement Fusion (ICF and MCF) follow different paths toward goals that are largely common. In this paper, the claim is made that progress can be accelerated by learning from each other across the two fields. Examples of successful cross-community knowledge transfer are presented that highlight the gains from working together, specifically in the areas of high-resolution x-ray imaging spectroscopy and neutron spectrometry. Opportunities for near- and mid-term collaboration are identified, including in chemical vapor deposition diamond detector technology, using gamma rays to monitor fusion gain, handling neutron-induced backgrounds, developing radiation hard technology, and collecting fundamental supporting data needed for diagnostic analysis. Fusion research is rapidly moving into the igniting and burning regimes, posing new opportunities and challenges for ICF and MCF diagnostics. This includes new physics to probe, such as alpha heating; increasingly harsher environmental conditions; and (in the slightly longer term) the need for new plant monitoring diagnostics. Substantial overlap is expected in all of these emerging areas, where joint development across the two subfields as well as between public and private researchers can be expected to speed up advancement for all.

Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice: biomarker associations and implications for optimal clinical next-generation sequencing testing.

BACKGROUND: Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups. DESIGN: Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt). RESULTS: A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing. CONCLUSIONS: PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.

Rapid calibration plan for NIF's Near Backscatter Imager (NBI).

A rapid calibration system is under development for the Near Backscatter Imager (NBI) in use at the National Ignition Facility (NIF). NBI is an optical diagnostic that quantifies the stimulated Brillouin and Raman backscatter produced by NIF's targets. Specifically, NBI measures the light that does not fall directly back into the laser aperture, which is measured by the Full Aperture Backscatter System (FABS). When working in tandem with FABS, NBI allows for the full characterization of backscattered light. This informs Hohlraum laser coupling, optical damage, and laser-plasma interaction models. NBI uses a large Spectralon plate covered by a protective glass layer and is mounted inside the target chamber where it is exposed to high energy backscatter, neutrons, and build-up debris left over from the exploded targets. This gradually alters the reflectivity of the plate, meaning that NBI needs to be calibrated regularly. Described here is NIF's design for a system capable of rapid in situ calibration of NBI that is to be installed in FY25.

Ex situ calibration of the scattered-light time-history diagnostic on the National Ignition Facility.

The scattered-light time-history diagnostic (SLTD) suite measures time-resolved scattered light in three wavelength bands: stimulated Brillouin scattering (350-352 nm), stimulated Raman scattering (430-760 nm), and plasma emission at half the laser frequency (695-735 nm), at 15 locations around the National Ignition Facility (NIF) target chamber. The SLTD, along with the full-aperture backscatter station (FABS), collects scattered light from direct- and indirect-drive inertial confinement fusion experiments. The SLTD calibration was revisited after a discrepancy between FABS and SLTD measurements was observed on NIF polar direct-drive [Skupsky et al., Phys. Plasmas 11, 2763 (2004)] experiments. An integrated calibration of the SLTD was performed for the first time, and individual components were also calibrated for the wavelengths of 351, 527, and 532 nm. The optical transmission of the instrument was measured to be (1.12 ± 0.04) × 10-7 and (1.96 ± 0.11) × 10-7 for the wavelengths of 351 and 532 nm, respectively. The revised calibration at 351 nm brings the SLTD measured scattered energy in agreement with the FABS measured scattered energy after additionally accounting for the degradation of an optical element in FABS. This decreased the inferred absorption by 7% for a representative experiment. However, discrepancies remain between FABS and SLTD measurements in the SRS band (532 nm).

Understanding the deficiency in inertial confinement fusion hohlraum x-ray flux predictions using experiments at the National Ignition Facility.

The predicted implosion performance of deuterium-tritium fuel capsules in indirect-drive inertial confinement fusion experiments relies on precise calculations of the x-ray drive in laser-heated cavities (hohlraums). This requires accurate, spectrally dependent simulations of laser to x-ray conversion efficiencies and x-ray absorption losses to the hohlraum wall. A set of National Ignition Facility experiments have identified a cause for the long-standing hohlraum "drive deficit" as the overprediction of gold emission at ∼2.5 keV in nonlocal thermodynamic equilibrium coronal plasma regions within the hohlraum. Reducing the emission and absorption opacity in this spectral region by ∼20% brings simulations into agreement with measured x-ray fluxes and spectra.

The impact of low-mode symmetry on inertial fusion energy output in the burning plasma state.

Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

National Diagnostic Working Group (NDWG) for inertial confinement fusion (ICF)/high-energy density (HED) science: The whole exceeds the sum of its parts.

The National Diagnostic Working Group (NDWG) has led the effort to fully exploit the major inertial confinement fusion/high-energy density facilities in the US with the best available diagnostics. These diagnostics provide key data used to falsify early theories for ignition and suggest new theories, recently leading to an experiment that exceeds the Lawson condition required for ignition. The factors contributing to the success of the NDWG, collaboration and scope evolution, and the methods of accomplishment of the NDWG are discussed in this Review. Examples of collaborations in neutron and gamma spectroscopy, x-ray and neutron imaging, x-ray spectroscopy, and deep-ultraviolet Thomson scattering are given. An abbreviated history of the multi-decade collaborations and the present semiformal management framework is given together with the latest National Diagnostic Plan.

Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study.

BACKGROUND: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. MATERIALS AND METHODS: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. RESULTS: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. CONCLUSIONS: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

NOTCH1 and PIK3CA mutation are related to HPV-associated vulvar squamous cell carcinoma.

NOTCH1 and PIK3CA are members of important cell signalling pathways that are deregulated in squamous cell carcinomas of various organs. Vulvar squamous cell carcinomas (vulvSCC) are classically divided into two pathways, HPV-associated or HPV-independent, but the effect of NOTCH1 and PIK3CA mutations in both groups is unclear. We analysed two different cohorts of vulvSCC using Hybrid Capture-based Comprehensive Genomic Profiling and identified NOTCH1 and PIK3CA mutations in 35% and 31% of 48 primary vulvSCC. In this first cohort, PIK3CA and NOTCH1 mutations were significantly correlated with HPV infection (p < 0.01). Furthermore, mutations in both genes were associated with an advanced tumor stage and poorly differentiated status (p < 0.05). PIK3CA and NOTCH1 mutations were also associated with shorter patient survival which did not reach significance. In the second cohort of 735 advanced vulvSCC from metastatic site biopsies or from sites of unresectable loco-regional disease, NOTCH1 and PIK3CA mutations were reported in 14% and 20.3%, respectively. 4 of 48 (8%) and 22 of 735 vulvSCC (3.0%) featured genomic alterations (short variants and/or copy number changes and/or rearrangements) in both NOTCH1 and PIK3CA. NOTCH1 mutations were mostly located in the extracellular EGF-like domains, were inactivating and indicated that NOTCH1 functions predominantly as a tumor suppressor gene in vulvSCC. In contrast, PIK3CA mutations favored hotspot codons 1624 and 1633 of the gene, indicating that PIK3CA acts as an oncogene in vulvar carcinogenesis. In conclusion, NOTCH1 and PIK3CA mutations are detectable in a substantial proportion of vulvSCC and are related to HPV infection and more aggressive tumor behaviour.

HPV-positive clinically advanced squamous cell carcinoma of the urinary bladder (aBSCC): A comprehensive genomic profiling (CGP) study.

BACKGROUND: Advanced bladder squamous cell carcinoma (aBSCC) is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of aBSCC based on the association with human papilloma virus (HPV) to determine if differences in GA would be observed between the positive and negative groups. METHODS: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 aBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Programmed cell death ligand -1 (PD-L1) expression was determined by IHC (Dako 22C3) with negative expression when PD-L1 was 0, lower expression of positivity set at 1 to 49%, and higher expression set at ≥50% expression. RESULTS: Overall, 11 (6.4%) of the aBSCC were found to harbor HPV sequences (10 HPV16 and 1 HPV 11). HPV+ status was identified slightly more often in women (NS) and in younger patients (P = 0.04); 2 female patients with aBSCC had a prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV+ aBSCC had fewer GA/tumor (P < 0.0001), more inactivating mutations in RB1 (P = 0.032), and fewer inactivating GA in CDKN2A (P < 0.0001), CDKN2B (P = 0.05), TERT promoter (P = 0.0004) and TP53 (P < 0.0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV+ and HPV- aBSCC groups. MTAP loss (homozygous deletion) which has emerged as a biomarker for PRMT5 inhibitor-based clinical trials was not identified in any of the 11 HPV+ aBSCC cases, which was significantly lower than the 28% positive frequency of MTAP loss in the HPV- aBSCC group (P < 0.0001). MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. Putative biomarkers associated with immunotherapy (IO) response, including MSI and TMB status, were also similar in the 2 groups. PD-L1 expression data was available for a subset of both HPV+ and HPV- cases and showed high frequencies of positive staining which was not different in the 2 groups. CONCLUSIONS: HPV+ aBSCC tends to occur more often in younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV+ aBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation.

Genomic characterization of thymic epithelial tumors in a real-world dataset.

BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms arising in the mediastinum, including thymic carcinomas and thymomas. Due to their rarity, little is known about the genomic profiles of TETs. Herein, we investigated the genomic characteristics of TETs evaluated in a large comprehensive genomic profiling database in a real-world setting. METHODS: We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the United States and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. Samples profiled were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also evaluated. RESULTS: A total of 794 patients were collected in our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), and CDKN2A (5.8%) in thymoma. TMB-high (≥10 mutations/Mb) and MSI were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Within C-CAT data, CDKN2A (38.5%), TP53 (36.5%) and CDKN2B (30.8%) were also frequently altered in thymic carcinoma, while alterations of TSC1, SETD2 and LTK (20.0% each) were found in thymoma. CONCLUSIONS: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB and MSI status of TETs were investigated. Potential targets for treatment previously unbeknownst in TETs are identified in this study, entailing newfound opportunities to advance therapeutic development.

Experimental evidence of early-time saturation of the ion-Weibel instability in counterstreaming plasmas of CH, Al, and Cu.

The collisionless ion-Weibel instability is a leading candidate mechanism for the formation of collisionless shocks in many astrophysical systems, where the typical distance between particle collisions is much larger than the system size. Multiple laboratory experiments aimed at studying this process utilize laser-driven (I≳10^{15} W/cm^{2}), counterstreaming plasma flows (V≲2000 km/s) to create conditions unstable to Weibel-filamentation and growth. This technique intrinsically produces temporally varying plasma conditions at the midplane of the interaction where Weibel-driven B fields are generated and studied. Experiments discussed herein demonstrate robust formation of Weibel-driven B fields under multiple plasma conditions using CH, Al, and Cu plasmas. Linear theory based on benchmarked radiation-hydrodynamic FLASH calculations is compared with Fourier analyses of proton images taken ∼5-6 linear growth times into the evolution. The new analyses presented here indicate that the low-density, high-velocity plasma-conditions present during the first linear-growth time (∼300-500 ps) sets the spectral characteristics of Weibel filaments during the entire evolution. It is shown that the dominant wavelength (∼300µm) at saturation persists well into the nonlinear phase, consistent with theory under these experimental conditions. However, estimates of B-field strength, while difficult to determine accurately due to the path-integrated nature of proton imaging, are shown to be in the ∼10-30 T range, an order of magnitude above the expected saturation limit in homogenous plamas but consistent with enhanced B fields in the midplane due to temporally varying plasma conditions in experiments.

Burning plasma achieved in inertial fusion.

Obtaining a burning plasma is a critical step towards self-sustaining fusion energy1. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule2,3 through two different implosion concepts4-7. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics3,8. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.

Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial.

BACKGROUND: Durvalumab and cabozantinib have shown single-agent activity in patients with metastatic urothelial carcinoma (UC). ARCADIA is a phase 2 study evaluating their combination in patients with platinum-treated, advanced UC (NCT03824691). Herein, we report the results of the planned interim safety analysis and the preliminary activity. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1, UC and non-UC histology, and failure of a maximum of two regimens received cabozantinib 40 mg daily, orally, in combination with durvalumab 1500 mg, intravenously, every 28 days. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 every two cycles and by fluorodeoxyglucose positron emission tomography (FDG-PET) scans. RESULTS: As of August 20, 2020, 16 patients were enrolled with a median follow-up of 6.7 months (range, 2-11). Four patients (25%) had ECOG PS 1 and had received two prior regimens. No grades 3 or 4 treatment-related adverse events (TRAEs) occurred within the first two cycles. The most common grades 1 and 2 TRAEs were fatigue (7, 43.8%), diarrhea (5, 31.3%), and dysphonia (5, 31.3%). Objective responses were seen in six patients (37.5%; 95% confidence interval, 15.2-64.6), including two complete responses (12.5%). One additional patient with bone-only disease obtained a decrease in FDG uptake and in circulating tumor DNA consistent with response. Angiogenesis-related gene alterations were found in 57% responders versus 0% nonresponders. CONCLUSION: The durvalumab and cabozantinib combination was safe and endowed with preliminary clinical activity in patients with advanced UC. Mature results will clarify the role of cabozantinib and that of tumor biomarkers in this tumor type.

The Scattered Light Time-history Diagnostic suite at the National Ignition Facility.

The Scattered Light Time-history Diagnostic (SLTD) is being implemented at the National Ignition Facility (NIF) to greatly expand the angular coverage of absolute scattered-light measurements for direct- and indirect-drive inertial confinement fusion (ICF) experiments. The SLTD array will ultimately consist of 15 units mounted at a variety of polar and azimuthal angles on the NIF target chamber, complementing the existing NIF backscatter suite. Each SLTD unit collects and diffuses scattered light onto a set of three optical fibers, which transport the light to filtered photodiodes to measure scattered light in different wavelength bands: stimulated Brillouin scattering (350 nm-352 nm), stimulated Raman scattering (430 nm-760 nm), and ω/2 (695 nm-745 nm). SLTD measures scattered light with a time resolution of ∼1 ns and a signal-to-noise ratio of up to 500. Currently, six units are operational and recording data. Measurements of the angular dependence of scattered light will strongly constrain models of laser energy coupling in ICF experiments and allow for a more robust inference of the total laser energy coupled to implosions.

Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆.

BACKGROUND: Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). PATIENTS AND METHODS: We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. RESULTS: After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. CONCLUSIONS: The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

Pembrolizumab and nab-paclitaxel as salvage therapy for platinum-treated, locally advanced or metastatic urothelial carcinoma: interim results of the open-label, single-arm, phase II PEANUT study.

BACKGROUND: Pembrolizumab is a new standard of care for patients with platinum-treated, metastatic urothelial carcinoma (UC). Nab-paclitaxel is active in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC. PATIENTS AND METHODS: PEANUT was an open-label, single-arm, phase II trial that included patients who had failed one or two chemotherapy regimens, including platinum chemotherapy. Biomarker analyses focused on programmed cell-death ligand-1 combined positive score (CPS) and comprehensive genomic profiling on tumor samples and circulating tumor DNA. Patients received 200 mg pembrolizumab on day 1 (D1), and 125 mg/m2 nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) according to RECIST (v1.1). The assumption was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). RESULTS: Between January 2019 and January 2020, the PEANUT study enrolled 70 patients: 24% had failed two prior systemic therapies; 31% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1; and 28.6% had liver metastases. After a median follow-up of 9.8 months, 40 patients have relapsed (57.1%). The median PFS was 5.9 months [95% confidence interval (CI) 3.1-11.5]. The confirmed objective response rate (ORR) was 38.6% (95% CI 27-51) with 17 partial responses and 10 complete responses (14.3%). The median duration of response was not reached. Five patients (7.1%) had ongoing responses lasting >12 months. The most common any-grade treatment-related adverse events included alopecia (71.4%), neutropenia (32.9%), and peripheral neuropathy (34.3%). Neither tumor mutational burden nor CPS was significantly associated with PFS at univariable analyses. The single-arm design of the trial was the major limitation. CONCLUSIONS: Pembrolizumab combined with nab-paclitaxel, as second- and third-line chemoimmunotherapy for metastatic UC, showed a favorable safety profile, durable PFS, and a clinically meaningful ORR in these preliminary analyses. This combination warrants additional randomized studies in earlier disease stages. CLINICALTRIALS. GOV NUMBER: ClinicalTrials.govNCT03464734; https://clinicaltrials.gov/ct2/show/NCT03464734.