bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation outcomes of a multidisciplinary approach for Lu177-PSMA-617 therapy.
Authors: Nedrud Marybeth , Wang John , Maldonado Grijalva Valeria , Kelleher Colm , Wong Terence Z. , McManus Hannah Dzimitrowicz , Labriola Matthew
Published: January 2024

80

Background: Lu177-PSMA-617 (LuPSMA) is a recently approved treatment for patients with metastatic castration resistant prostate cancer (mCRPC). Successful treatment in real-world practice requires coordination between nuclear medicine, radiation safety, and medical oncology. We report outcomes from implementation of a multidisciplinary approach for LuPSMA administration at our institution. Methods: Our practice prior to treatment included collaborative radiologist review of PSMA PET/CT and oncologist review of prior therapies, performance status, and baseline laboratory values to establish candidacy. For each administration, procedures included confirming IV patency, use of a shielded infusion pump, IV hydration, and standardized radiation safety recommendations. On treatment, practices included scheduled laboratory monitoring, standardized treatment holds and dose reductions, coordination of care with a dedicated advanced practitioner, and mid-treatment conventional imaging. Retrospective chart review was completed for 100 mCRPC patients who received ≥1 dose of LuPSMA from June 2022 to August 2023 under this protocol. Outcomes including number of treatments, dose reductions/holds, PSA, and clinical imaging responses were reviewed. Results: Ninety-eight patients were included in the analysis (2 patients were excluded due to prior LuPSMA on clinical trial). In patients completing LuPSMA at time of data collection, median number of treatments was 4.0 (IQR=4.0, n=95), with 41% receiving all 6 planned treatments (n=39/95). During treatment, 16% experienced a treatment hold (n=16/98) with 25% ultimately completing 6 treatments (n=4/16; median=3.0, IQR=3.25). Holds were due to worsening symptoms (44%, n=7/16) or cytotoxicity (44%, n=7/16). Dose reductions occurred in 8% (n=8/98), with 38% completing 6 treatments (n=3/8; median treatments= 4.5, IQR= 3.0). Early discontinuation primarily occurred due to clinician-assessed progression (57%, n=32/56) or cytotoxicity (25%, n=14/56). Of those with early discontinuation due to progression, 70% had a rising PSA at time of discontinuation (n=21/30) and all had worsening disease on available mid-treatment imaging (n=15/15). For the remainder with early discontinuation due to progression, 20% had stable PSA (n=6/30) and 10% had decreasing PSA at time of discontinuation (10%, n=3/60). In those with stable or rising PSA, 75% terminated treatment due to worsening disease on available mid-treatment imaging (n=6/8). Conclusions: Our protocol for LuPSMA administration allows for early identification of clinical progression and completion of therapy when appropriate. Treatment holds and dose reductions facilitate therapy completion in select patients. Mid-treatment imaging may identify worsening disease in the setting of stable or decreasing PSA, underlying the potential importance of this practice for clinical decision making.
Patient characteristics, treatment patterns, and outcomes among early adopters of lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617): A real-world United States (US) study.
Authors: Wei Xiao X. , George Daniel J. , Patel Jeetvan , Nguyen Jennifer , Kang Barinder , Sawhney Amrita , Gorritz Magdaliz , Chen Chi-Chang , Paltanwale Queenie , Sun Kainan , Shore Neal D.
Published: January 2024

81

Background: In March 2022, the US Food and Drug Administration approved 177Lu-PSMA-617 for the treatment of patients with prostate-specific membrane antigen (PSMA) positive metastatic castration resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. This real-world study aims to describe clinical characteristics, treatment use, clinical outcomes in patients treated with 177Lu-PSMA-617 in a growing US dataset. Methods: Adults (≥18 years) with ≥1 claim for 177Lu-PSMA-617 between 3/01/22 and 6/30/2023 in the IQVIA open-source pharmacy and medical claims databases were retrospectively identified and included in this analysis. Clinical characteristics and treatment use, including prior treatment exposures, were derived from this cohort. A subset of these patients with available PSA results were assessed for PSA response after initiation of 177Lu-PSMA-617. Baseline PSA was defined as the closest PSA value within 90 days prior to or on the first 177Lu-PSMA-617 claim (index date). Post-treatment PSA response was defined as the lowest PSA value ≥28 days after the index date. The proportion of patients with ≥ 50%, ≥80% and ≥90% PSA reductions were reported. Results: A total of 1,710 patients treated with 177Lu-PSMA-617, with mean (standard deviation) age was 72.2 (8.5) years, met eligibility and were included in the study. Common comorbidities included hypertension (34.7%), osteoarthritis (27.3%) and dyslipidemia (23.9%). Based on ICD-10 codes, 1,447 (84.6%) patients had bone metastases, and 575 (33.6%) had visceral metastases, of whom 128 (7.5%) had liver metastases. Only 59 (3.5%) patients had lymph node only metastasis. In the pre-index period, 83.4% patients had used prior ARPI and/or taxane chemotherapy, and 98% patients had used other systemic therapies. In a sub-analysis of 159 (9.3%) patients with pre- and post-index PSA values available (whose clinical characteristics are comparable to the overall cohort of 1,710 patients), median PSA at baseline before initiation of 177Lu-PSMA-617 was 61 ng/ml. Among these patients, 53.5%, 29.6% and 22.6% had PSA reductions of ≥50%, ≥80% and ≥90%, respectively, while on treatment. Rate of PSA response was similar regardless of history of ARPI or taxane use. Conclusions: To our knowledge, this is the first large-scale report of real-world US patients treated with 177Lu-PSMA-617. Clinical characteristics and PSA responses observed are consistent with results from the VISION clinical trial demonstrating benefit with 177Lu-PSMA-617 treatment. Subsequent analysis with longer follow up are needed to understand the long-term outcomes associated with 177Lu-PSMA-617 in real-world US patients.
Real-world clinical outcomes of patients treated with Lu-177-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC): A single-institution experience.
Authors: Maldonado Grijalva Valeria , Wang John , Nedrud Marybeth , Kelleher Colm , Wong Terence Z. , Labriola Matthew , McManus Hannah Dzimitrowicz
Published: January 2024

83

Background: The radiopharmaceutical Lu177-PSMA-617 (LuPSMA) was FDA approved in March 2022 for patients with mCRPC previously treated with both an androgen receptor signaling inhibitor (ARSI) and a taxane, if eligible based on PSMA PET. However, data regarding real world LuPSMA treatment outcomes are limited. Methods: This is a retrospective analysis of the first 100 mCRPC patients who received at least 1 cycle of LuPSMA at a single institution from June 2022 to August 2023. Demographic and clinical characteristics as well as laboratory values were collected. Central review of qualifying PSMA PET/CT was performed to assess disease distribution. A PSA decrease of 30%, 50%, or 90% from baseline at any point during treatment was the primary measure of response (PSA30, PSA50, and PSA90 respectively). Results: Of the 100 patients identified, 2 were excluded from analysis due to prior receipt of LuPSMA on clinical trial. Three patients were still receiving LuPSMA at the time of data collection. Median age was 72 (range, 50 - 93) and median number of treatments received was 4.0. On baseline PET/CT, 43 patients (44%) had bone + nodal metastases only, 19 (19%) had bone metastases only, 8 (8%) had nodal metastases only, and 11 (11%) had liver metastases. As for prior therapies, 47% had received ≥2 ARSIs (n=47/98), 48% had received 2 prior taxanes (n= 47/98), 42% had received 1 prior taxane (n=41/98), 17% received radium-223 (n=17/98), and 10% were treated off-label with no prior chemotherapy (n=10/98). Median follow up from the start of LuPSMA treatment was 7.6 months (range= 0.6-14.1 months, n=98). During treatment, 21 (21%) patients achieved a PSA90 response, 51 (52%) patients achieved a PSA50 response and 60 (61%) patients achieved a PSA30 response. An increase or no change in baseline PSA was seen in 28% (n=26/94 evaluable patients). Among patients with an initial rise in PSA after the first treatment, 10% had a subsequent reduction from baseline PSA (n=3/29). Conclusions: In this cohort of heavily pretreated mCRPC patients, we observed a PSA50 response of 54% and 21% of patients experiencing a PSA reduction ≥90%. This data supports the clinical benefit of LuPSMA in real-world clinical practice. Characterization of response rates within subgroups by prior treatment and disease characteristics are ongoing.
Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T.
Authors: George Saby , Bourlon Maria Teresa , Chacon Matias Rodrigo , Cutuli Hernan , Lopez Chuken Yamil Alonso , Zurawski Bogdan , Mota Jose Mauricio , Magri Ignacio , Burotto Mauricio , Luz Murilo , De Menezes Juliana , Yanez Ruiz Eduardo Patricio , Maruzzo Marco , Bracarda Sergio , Prusty Subhransu , Rathod Dhanrajsinh , Vezina Heather , Yu Zhuoxin , Zhao Yue , Albiges Laurence
Published: January 2024

LBA360

Background: NIVO IV has improved outcomes in multiple tumor types. Evolving treatment paradigms have created a need for administration options that address treatment burden and improve efficiencies of healthcare systems. SC delivery of antibodies for various cancer indications has proved safe and effective. CheckMate 67T (NCT04810078) is a multicenter, randomized, open-label, phase 3 study that evaluated PK and objective response rate (ORR) noninferiority of NIVO SC vs IV in patients (pts) with locally advanced or metastatic ccRCC. Methods: Enrolled pts had measurable disease that progressed during or after 1–2 prior systemic regimens, no prior immuno-oncology treatment, and a Karnofsky performance score ≥ 70. Pts were randomized 1:1 to receive NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W or NIVO IV 3 mg/kg Q2W until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years’ treatment, or death. The co-primary PK endpoints for noninferiority testing were time-averaged serum concentration over the first 28 days (Cavgd28) and minimum serum concentration at steady state (Cminss) determined by a population PK analysis. ORR by blinded independent central review (BICR) was a key powered secondary endpoint for noninferiority testing. Other secondary objectives included additional PK exposure measures, safety, efficacy, and immunogenicity. Results: A total of 495 pts were randomized to NIVO SC (n = 248) or NIVO IV (n = 247). The median age was 64/66 years in the SC/IV arms. Most pts were male. Average injection time with NIVO SC was < 5 minutes. Noninferiority for the co-primary PK and key powered secondary ORR endpoints was met (see table). Incidence of NIVO SC local injection-site reactions was 8.1%; reactions were low grade and transient. Most deaths were due to disease progression; study drug toxicity led to 3/1 deaths with NIVO SC/IV. Conclusions: The co-primary PK and key powered secondary ORR endpoints were met, supporting the use of NIVO SC as a new option to improve healthcare efficiency. The safety profile for NIVO SC was consistent with NIVO IV. Clinical trial information: NCT04810078 .[Table: see text]
ARAMON: A phase 2, randomized, open-label study comparing darolutamide (DARO) vs enzalutamide (ENZA) monotherapy on serum testosterone levels in patients (pts) with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR).
Authors: Laccetti Andrew Leonard , Smith Matthew Raymond , Scher Howard I. , Verholen Frank , Adorjan Patrick , Dissanayake Manjari , Gao Xin
Published: January 2024

TPS243

Background: DARO, a structurally distinct and highly potent androgen receptor inhibitor, has low blood–brain barrier (BBB) penetration and limited potential for drug–drug interactions. In phase 3 trials, DARO showed significant efficacy and a favorable safety profile. In ARAMIS (NCT02200614), DARO and androgen-deprivation therapy (ADT) significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT in pts with nonmetastatic castration-resistant prostate cancer. In ARASENS (NCT02799602), DARO + ADT + docetaxel significantly improved OS in pts with metastatic hormone-sensitive prostate cancer vs placebo + ADT + docetaxel. In both studies, the incidence of adverse events (AEs) was similar between treatment groups. Currently, the ARASTEP study (NCT05794906) is evaluating DARO and ADT in pts with high-risk BCR following primary therapy who have prostate-specific membrane antigen PET/CT-positive lesions. Based on a neuroimaging study of healthy volunteers, cerebral blood flow was not altered with DARO but was significantly reduced in brain areas related to cognition with ENZA. It is postulated that the low BBB penetration of DARO may result in lower serum testosterone elevations than those seen with ENZA, which may reduce the frequency of AEs. The ARAMON study (NCT05526248) will compare the effect of DARO and ENZA monotherapy on post-treatment testosterone levels in pts with CSPC who developed a BCR after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of pts with histologically or cytologically confirmed adenocarcinoma of the prostate who experienced BCR after radical primary prostatectomy (RP) or radiation therapy (RT), with <5 asymptomatic oligometastatic disease sites. Key inclusion criteria are prostate-specific antigen (PSA) ≥2 ng/mL, PSA doubling time of ≤20 months, serum testosterone >150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During the lead-in phase, 25 pts will receive DARO 600 mg twice daily for 52 weeks. If serum testosterone criteria are met at 12 weeks, the study will proceed to the randomized phase where approximately 40 pts will be randomized 1:1 to DARO (600 mg twice daily) or ENZA (160 mg once daily) for 52 weeks. The primary endpoint is the change in serum testosterone level from baseline to Week 12. Secondary endpoints include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of endocrine, glycemic, and lipid metabolism markers; incidence of AEs; and quality of life. As of September 2023, 23 of 25 planned pts in the lead-in phase have been enrolled. Clinical trial information: NCT05526248 .
Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP).
Authors: Chehrazi-Raffle Alex , Morgans Alicia K. , Gschwend Jürgen E. , Shore Neal D. , Ross Ashley , Feng Felix Y , Hope Thomas A. , Trandafir Lucia , Kuss Iris , Le Berre Marie-Aude , Joensuu Heikki , Fizazi Karim
Published: January 2024

TPS254

Background: Patients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR, defined as a prostate-specific antigen (PSA) increase without evidence of metastases on conventional imaging. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), a more effective and precise imaging method, may detect small lesions in patients with BCR. Patients with BCR at high risk of metastatic progression and who have lesions identified by PSMA PET/CT need effective treatment to delay this progression. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor, which significantly improved metastasis-free survival (MFS) and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). The ARASTEP study (NCT05794906) is designed to evaluate whether DARO plus ADT improves radiological progression-free survival (rPFS) by PSMA PET/CT vs placebo (PBO) plus ADT in patients with BCR following primary therapy and PSMA PET/CT-positive lesions. Methods: Eligible patients must have prostate cancer treated by primary RT or RP followed by adjuvant RT (ART) or salvage RT (SRT), or RP alone if ART/SRT was not appropriate, with high-risk BCR (defined as PSA doubling time [PSADT] <12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone >150 ng/dL. Approximately 750 patients from 184 sites worldwide will be randomized to oral DARO 600 mg twice daily or PBO, both with ADT, for 24 months unless, during this period, there is disease progression, unacceptable toxicity, or any other withdrawal criteria are met. Patients will suspend treatment after 24 months if PSA values are undetectable (<0.2 ng/mL). Patients whose PSA values are still detectable (≥0.2 ng/mL) will continue with the study treatment until PSMA PET/CT progression. Image-guided radiotherapy or surgery is allowed within 12 weeks from randomization. Randomization is stratified by PSADT <6 vs ≥6–<12 months, intent to treat baseline PSMA PET/CT lesions with image-guided radiotherapy/surgery (Yes vs No) and distant ± locoregional vs locoregional-only metastases. The primary endpoint is rPFS by PSMA PET/CT, assessed by blinded independent central review (BICR). Secondary endpoints include MFS by BICR, time to CRPC, OS, quality of life, and safety. As of September 2023, 1 patient has been enrolled. Clinical trial information: NCT05794906 .
A phase I/II, open label, single arm study on safety, tolerability and anti-tumour effiacy of orellanine treatment in patients with metastatic clear-cell or papillary renal cell carcinoma.
Authors: Lundstam Sven , Haraldsson Boerje , Nystrom Jenny , Yachnin Jeffrey
Published: January 2024

TPS486

Background: Poisoning by the mushroom ”deadly webcap”( Cortinarius sp.) causes irreversible kidney damage but there are no known effects on other organs. The fungal toxin, orellanine, selectively targets proximal tubular cells in rats and in humans by disturbing the cell metabolism causing decreased protein synthesis and apoptosis. Clear cell and papillary renal cell carcinoma (RCC) originate from proximal tubule cells. Orellanine induced concentration-dependent decline in viability in RCC cell lines and in primary cultures from human clear cell and papillary RCC. Orellanine induced apoptosis and tumour shrinkage in RCC(SKRC-17) transplanted to rats on peritoneal dialysis and the tumours become necrotic with almost no viable tissue. Based on these data a drug has been developed based on chemically synthesized orellanine ( www.oncorena.com ). Methods: The primary objectives of this study are to evaluate the safety and tolerability and to determine the maximum tolerable dose (MTD) of orellanine in patients with metastatic clear cell or papillary RCC and end stage renal disease who are on chronic haemodialysis and who have failed standard of care treatment. The secondary objectives are to study the pharmacokinetic (PK)profile of orellanine and to assess the efficacy of orellanine in treating these patients with respect to objective response (OR). Exploratory objectives are to access progression free and overall survival (PFS and OS) and to conduct analysis of circulating tumour specific DNA in the blood. Serum will be collected for unspecific future research which may include sequencing or genomic analyses. Orellanine will be given intravenously once monthly. A total of 6 to 20 patients will be enrolled in a dose escalation phase to determine MTD or a dose causing complete response (CR). An independent Data Review Committee (DRC) will access cumulative data and provide recommendations and decisions for every change in dose level. Once MTD has been determined up to 20 patients will be treated in a dose expansion phase to better characterize safety, tolerability and primary efficacy. CT/MRI will occur every 4 weeks (Q4W) during dose escalation phase and Q8W during the dose expansion phase. Enrollment has started and since the occurrence of end stage renal disease in patients with metastatic RCC is uncommon, patients in this first in man study are recruited both from western Europe and north America. The study is performed in the Centre for Clinical Cancer Studies (CKC) at Karolinska University Hospital, Stockholm, Sweden Reference: Lisa Buvall et. al. Orellanine specifically targets renal cell carcinoma.Oncotarget. 2017; 8:91085-91098. https://doi.org/10.18632/oncotarget.19555 . Clinical trial information: NCT05287945 .
ABLE-41: Nadofaragene firadenovec-vncg early use and outcomes in a real-world setting in the United States.
Authors: Daneshmand Siamak , Shore Neal D. , Scholz Kristen , Guo Amy , Juul Kristian , Guedes Sandra , Delattre Diane Dalila , Lotan Yair
Published: January 2024

TPS705

Background: Approximately one-third of patients with non–muscle-invasive bladder cancer (NMIBC) initially responding to Bacillus Calmette-Guérin (BCG) experience recurrence and/or progression in the first year after treatment.1 Local, effective, bladder-preserving options are needed for patients with BCG-unresponsive NMIBC. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical gene therapy for treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) ± papillary tumors. In a single-arm, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of patients (55/103) with CIS ± high-grade Ta/T1 BCG-unresponsive NMIBC achieved complete response (CR) 3 months after the first instillation of nadofaragene firadenovec.2 The safety profile of nadofaragene firadenovec was manageable, with 103 (66%) patients reporting mild (grade 1/2) study drug-related adverse events (AEs). Six (3.8%) patients had grade 3/4/5 study drug-related AEs. ABLE-41 (NCT06026332) is an observational study evaluating the effectiveness, overall experiences, patterns of use, and safety in patients treated with nadofaragene firadenovec in a US real-world setting. Methods: This noninterventional study includes approximately 50 urology sites in the U.S. with anticipated enrollment of 800 patients. Adults ≥18 years with prescribed and scheduled treatment with nadofaragene firadenovec per physician discretion or those who received their first instillation of nadofaragene firadenovec per physician discretion after September 5, 2023, but before site activation are eligible to enroll. The primary objective is to assess the effectiveness of nadofaragene firadenovec measured as the CR rate as determined by investigator. Secondary outcomes include: nadofaragene firadenovec patterns of use; duration of CR, recurrence-free survival, cystectomy-free survival, progression-free survival, overall survival, and bladder cancer–specific mortality; patient, caregiver and physician experiences; adjunctive use of molecular markers; and safety. Patient and caregiver experiences will be assessed using the respective EuroQol 5 Dimension 5 Level questionnaire and Work Productivity and Activity Impairment questionnaire, adapted for caregiving. Patients and caregivers will be surveyed before all nadofaragene firadenovec administrations. Physicians will be surveyed 1, 12, and 24 months after first patient first instillation. All AE data will be collected starting from index date. The estimated follow-up period is 24 months, until study discontinuation, or withdrawal. Final results from this large, prospective, multi-institutional, real-world registry providing early use and outcomes of nadofaragene firadenovec are expected December 2026. References: 1. Sylvester RJ et al. Eur Urol. 2010;57:766-73; 2. Boorjian SA et al. Lancet Oncol. 2021;22:107-17. Clinical trial information: NCT06026332 .
Intravesical recombinant BCG followed by perioperative chemo-immunotherapy for patients with muscle-invasive bladder cancer (MIBC): A multicenter, single arm phase 2 trial (SAKK 06/19).
Authors: Cathomas Richard , Spahn Martin , Hayoz Stefanie , Chiquet Sabrina , Schneider Martina , Rentsch Cyrill A. , Rothschild Sacha , Petrausch Ulf
Published: January 2024

TPS707

Background: The integration of immune checkpoint inhibitors (ICI) in the perioperative setting of localized muscle-invasive bladder cancer (MIBC) is extensively investigated and several results from phase 2 trials have been published. While promising, the pathological complete remission rate (pCR, ypT0 ypN0) achieved with ICI-containing regimens appears similar to cisplatin-based chemotherapy alone. Further improvement is needed. Intravesical BCG has successfully been used for decades for non-muscle invasive bladder cancer (NMIBC) in patients (pts) with carcinoma in situ (CIS) and as adjuvant treatment for high-risk papillary tumors. Intravesical BCG induces a local inflammation leading to induction of the innate immune system, probably followed by a tumor-specific adaptive immune response. Recently, a novel recombinant BCG vaccine (VPM1002BC) has been developed and a clinical study in BCG-refractory NMIBC (SAKK 06/14, Eur Urol Oncol. 2022 Apr;5(2):195-202.) has demonstrated good safety with low local toxicity and promising efficacy. We hypothesize that induction therapy with intravesical VPM1002BC improves the efficacy of systemic perioperative chemo-immunotherapy in pts with operable MIBC. Methods: SAKK 06/19 is an open-label single arm phase II trial for pts with operable pT2 or cT2-T4a cN0-1 MIBC without contraindication for cisplatin. Prior intravesical BCG is excluded as are pts unable to keep BCG instillation for less than 1 hour. Intravesical VPM1002BC is administered weekly for 3 instillations. Atezolizumab (atezo) 1200mg is given on day 1 and then every 3 weeks (q3w) for four times. Chemotherapy with cisplatin (70mg/m2 day 1) and gemcitabine (1000mg/m2 day 1 & 8) q3w is started on day 22 and given for four cycles followed by radical cystectomy and lymphadenctomy. Atezo is continued after surgery for 13 cycles in case of residual muscle invasive disease (≥ypT2) or positive lymph nodes (ypN+) only. pCR at cystectomy is the primary endpoint. A total of 46 pts is needed (including 15% dropout rate) using Simon’s minimax two-stage design with type I error 5%, power 80%, a null hypothesis of ≤35% pCR and an alternative hypothesis of ≥55% pCR. Secondary endpoints include pathological response rate (<ypT2N0), event-free survival, recurrence-free survival, overall survival, feasibility and toxicity. An interim safety analysis will be performed after the first 12 pts have completed neoadjuvant treatment specifically assessing toxicity possibly associated with intravesical BCG application. An interim efficacy analysis will be performed after the first 21 pts have undergone surgery. Accrual to the study is currently ongoing (NCT04630730). Clinical trial information: NCT04630730 .
Phase I/II study of ipilimumab plus nivolumab (IPI-NIVO) combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma.
Authors: Jain Rohit K. , Yang Yuanquan (Aaron) , Chadha Juskaran , Zhang Jingsong , Raymond Sarah , Oschmann Erika , Poehlman Trey , Fan Wenyi , Kim Youngchul , Dhillon Jasreman , Chahoud Jad , Chatwal Monica Sheila , Sonpavde Guru P.
Published: January 2024

TPS713

Background: Treatment options are suboptimal and limited for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Sacituzumab govitecan (SG) is a Trop-2 directed antibody-drug conjugate (ADC) coupled with SN-38 through a hydrolysable linker. In the phase II TROPHY-U-01 study, SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in mUC patients who progressed after platinum-based chemotherapy and immune checkpoint inhibitors (ICI), receiving accelerated approval by the US FDA. In CheckMate 032 study, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1+I3) every 3 weeks (Q3W) x 4 cycles followed by nivolumab monotherapy 3mg/kg Q2W showed promising activity post-platinum that led to the ongoing phase III trial in the first-line setting (NCT03036098). Given potential synergism between immunogenic cell death induced by ADC and ICI, we hypothesized that the combination of SG and IPI-NIVO would benefit patients with manageable toxicities. We designed this study to assess the safety and clinical activity of IPI-NIVO with SG as first-line therapy for cisplatin-ineligible mUC patients. Methods: This is an ongoing phase I/II, single arm, multicenter study for cisplatin-ineligible mUC. The Phase I portion enrolled 9 patients using a 3+3 design with safety and RP2D as primary endpoints. In this part, patients received fixed doses of IPI-NIVO (N1+I3) IV Q3Wx 4 cycles combined with SG (DL1 8 mg/kg or DL2 10mg/kg) IV on days 1, 8 Q3W x 4 cycles. This was followed by maintenance nivolumab 360 mg IV Q3W with SG on days 1, 8 Q3W. The RP2D of SG was determined as 8 mg/kg and combination was deemed safe and tolerable. ORR is the primary endpoint in the ongoing phase II portion of the study using Simon 2 stage design (n=34) with a futility interim analysis after 13 patients. The null hypothesis of ORR ≤ 38% will be tested with a desirable ORR of >60% under a statistical power of 80% and a one-sided type I error rate of 5%. Thirteen of the 34 patients have been enrolled and the study has passed the predefined interim analysis for futility. We aim to continue accrual. Exploratory biomarker analyses will be conducted using tumor and blood samples collected during screening and at progression. Clinical trial (NCT04863885). Clinical trial information: NCT04863885 .
Pembrolizumab with favezelimab or vibostolimab for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Phase 2 KEYNOTE-057 cohort C.
Authors: Kulkarni Girish S. , Gupta Shilpa , Necchi Andrea , Shore Neal D. , Dave Hema Kishore , Kapadia Ekta , Zhao Qing , Kamat Ashish M.
Published: January 2024

TPS719

Background: In cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), the PD-1 inhibitor pembrolizumab demonstrated antitumor activity (3-month complete response rate, 41%) in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS) ± papillary tumors who are ineligible for or declined radical cystectomy (RC). However, treatment combinations that improve outcomes and durability of response with pembrolizumab monotherapy are needed. Coinhibitory receptors LAG-3 and TIGIT contribute to immune tolerance in the tumor microenvironment, and co-blockade of PD-1 with LAG-3 or TIGIT has demonstrated antitumor activity in clinical studies. In cohort C of KEYNOTE-057, efficacy and safety of coformulations of pembrolizumab and the LAG-3 inhibitor favezelimab or the TIGIT inhibitor vibostolimab are being evaluated in patients with BCG-unresponsive HR NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (CIS ± high-grade Ta or T1 at baseline) that is BCG-unresponsive (persistent or recurrent CIS ± Ta/T1 ≤12 month of completing adequate BCG therapy) who are ineligible for or declined RC and have an ECOG PS of 0-2. Enrollment is planned for 60 patients. Patients will be randomly assigned 1:1 to receive the coformulation of pembrolizumab 200 mg and vibostolimab 200 mg or the coformulation of pembrolizumab 200 mg and favezelimab 800 mg intravenously every 3 weeks for ≤35 cycles or until central pathology–confirmed ≥T1 at any time point, persistent or recurrent CIS or high-grade Ta at 24-week efficacy review or thereafter, unacceptable toxicity, patient or physician decision to withdraw, or administrative reasons to discontinue. Tumor assessment will be performed every 12 weeks for 2 years and every 24 weeks thereafter for up to 5 years. Primary end point is 12-month complete response rate of HR NMIBC by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary end points include duration of response of HR NMIBC; overall complete response rate and complete response rates at 3 and 6 months; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and overall survival. Efficacy will be evaluated in patients who receive ≥1 dose of treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CTU imaging. Safety and tolerability will be evaluated in patients who receive ≥1 dose of treatment. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT02625961 .
A 15-Year Analysis of Supply and Demand for Hematology and Oncology Training in the United States
Authors: Silvestre Jason , Aakhus Erin , Weldeslase Terhas A. , DeLisser Horace M.
Published: January 2024

PURPOSE

There is a paucity of research on the supply of the hematology and oncology workforce despite projected shortages in the United States Over the past 15 years of the hematology and oncology match (HOM), we hypothesized that there would be more growth in the number of training positions relative to applicants, higher match rates for US allopathic graduates relative to non-US allopathic graduates, and fewer applicants matching at their top fellowship choices.

METHODS

This was a national, retrospective cohort study of all applicants in the HOM (2009-2023). Match rates and applicant-to-training position ratios were calculated and compared over time with Pearson tests.

RESULTS

Growth in the number of annual training positions (426-708; 66% increase) exceeded growth in the number of interested applicants (706-945; 34% increase;
P
< .001). Annual applicant-to-training position ratios decreased from 1.7 to 1.3 (
r
= –0.813;
P
< .001). Match rates increased over the study period for both US allopathic graduates (79%-88%;
r
= 0.761;
P
= .001) and non-US allopathic graduates (45%-63%;
r
= 0.801;
P
< .001). During each year, match rates for US allopathic graduates exceeded those for non-US allopathic graduates (
P
< .001). From 2018 to 2023, US allopathic graduates (83%) had higher match rates than US osteopathic graduates (60%) and international medical graduates (50%;
P
< .001). The percentage of applicants that matched at one of their top three fellowship choices increased from 53% to 60% (
r
= 0.480;
P
= .070). Fewer available annual training positions went unfilled over the study period (3%-0.3%;
r
= – 0.870;
P
< .001).

CONCLUSION

Match rates have increased in the HOM but remain competitive especially for non-US allopathic graduates. Future investigation is needed to understand disparities in match outcomes by additional applicant and fellowship program characteristics. Ongoing surveillance of HOM outcomes remains critical given the projected shortages in the US hematology and oncology workforce.
Enhancing relay synchronization in multiplex networks by repulsive relay layer
Authors: Wei Zhouchao , Sriram Gokulakrishnan , Rajagopal Karthikeyan , Jafari Sajad
Published: January 2024

Relay synchronization, which is the interlayer synchronization of two indirectly connected layers, is an important phenomenon in multiplex networks. In this study, relay synchronization is investigated through a triplex network of Hindmarsh-Rose neurons while considering attractive and repulsive intralayer couplings. Relay synchronization is improved when the remote layers have attractive coupling, and the relay layer has repulsive coupling. The essential conditions for the local stability of relay synchronization is found within the framework of master stability function approach. The analytical results are supported by numerical data on synchronization error. Furthermore, enhanced relay synchronization is also shown for larger networks and different internal couplings. Finally, the generality of the results is confirmed by investigating a triplex network of Rössler systems.
Dynamic modeling of neuromodulation techniques: Towards elaboration and individual specificity
Authors: Yu Ying , Han Fang , Wang Qingyun
Published: January 2024

Neurological disorders place a significant burden on patients, their families, and society, posing immense scientific challenges in terms of treatment and mechanistic research. Neuromodulation involves the application of invasive or non-invasive technologies to externally manipulate the nervous system of the brain, aiming to provide excitatory or inhibitory modulation that can improve abnormal neural activity. In the previous studies, neurodynamic analysis methods have not only provided novel tools for the study of neuromodulation techniques, but also provided new modulation strategies for the diagnosis and treatment of neurological diseases. In this paper, we present a brief overview of the current state of dynamic modeling and analysis for various neuromodulation techniques, including electrical, optical, magnetical, and ultrasonic approaches, and discuss the future prospects of modeling and analysis developments in neuromodulation.
Cholam Talks: The Origins of Migueleño in a Multilingual Region
Authors: Scharlotta Ian
Published: January 2024

Archaeological settlement CA-MNT-2328 (Cholame Valley, California) is likely the named Migueleño Salinan Rancheria of Cholam. Several areas of uncertainty about the origin of the Migueleño dialect and how it related to regional trade language(s) became apparent while trying to clarify this attribution. Multiple Salinan dialects were recognized in use at Missions San Antonio, San Miguel, and San Luis Obispo during the eighteenth and nineteenth centuries, with variable interpretations of their associated ethnogeography. Missing or contradictory information in historical and ethnographic records cloud attribution of linguistic or cultural affiliation to archaeological settlements in areas known as travel and trade corridors.
Non-invasive methods for heart rate measurement in fish based on photoplethysmography
Authors: Deng Yacheng , Hu Tianyu , Chen Jia , Zeng Junjia , Yang Jinqian , Ke Qiaozhen , Miao Lingwei , Chen Yujia , Li Rui , Zhang Rongxin , Xu Peng
Published: January 2024

Heart rate is a crucial physiological indicator for fish, but current measurement methods are often invasive or require delicate manipulation. In this study, we introduced two non-invasive and easy-to-operate methods based on photoplethysmography, namely reflectance-type photoplethysmography (PPG) and remote photoplethysmography (rPPG), which we applied to the large yellow croaker (Larimichthys crocea). PPG showed perfect synchronization with electrocardiogram (ECG), with a Pearson's correlation coefficient of 0.99999. For rPPG, the results showed good agreement with ECG. Under active provision of green light, the Pearson's correlation coefficient was 0.966, surpassing the value of 0.947 under natural light. Additionally, the root mean square error was 0.810, which was lower than the value of 1.30 under natural light, indicating not only that the rPPG method had relatively high accuracy but also that green light may have the potential to further improve its accuracy.
Gender Differences in Medical Evaluations: Evidence from Randomly Assigned Doctors
Authors: Cabral Marika , Dillender Marcus
Published: January 2024

Little is known about what drives gender disparities in health care and related social insurance benefits. Using data and variation from the Texas workers’ compensation program, we study the impact of gender match between doctors and patients on medical evaluations and associated disability benefits. Compared to differences among their male patient counterparts, female patients randomly assigned a female doctor rather than a male doctor are 5.2 percent more likely to be evaluated as disabled and receive 8.6 percent more subsequent cash benefits on average. There is no analogous gender-match effect for male patients. Our estimates indicate that increasing the share of female patients evaluated by female doctors may substantially shrink gender gaps in medical evaluations and associated outcomes. (JEL H75, I11, I12, J14, J16, J28)
The Immigrant Next Door
Authors: Bursztyn Leonardo , Chaney Thomas , Hassan Tarek A. , Rao Aakaash
Published: January 2024

We study how decades-long exposure to individuals of a given foreign descent shapes natives’ attitudes and behavior toward that group. Using individualized donations data, we show that long-term exposure to a given foreign ancestry leads to more generous behavior specifically toward that group’s ancestral country. Focusing on exposure to Arab Muslims to examine mechanisms, we show that long-term exposure (i) decreases explicit and implicit prejudice against Arab Muslims, (ii) reduces support for policies and political candidates hostile toward Arab Muslims, (iii) increases charitable donations to Arab countries, (iv) leads to more personal contact with Arab Muslims, and (v) increases knowledge of Arab Muslims and Islam. (JEL D64, D83, D91, J15)
Old Age Risks, Consumption, and Insurance
Authors: Blundell Richard , Borella Margherita , Commault Jeanne , De Nardi Mariacristina
Published: January 2024

In the United States, after age 65, households face income and health risks, and a large fraction of these risks are transitory. While consumption significantly responds to transitory income shocks, out-of-pocket medical expenses do not. In contrast, both consumption and out-of-pocket medical expenses respond to transitory health shocks. Thus, most US elderly keep their out-of-pocket medical expenses close to a satiation point that varies with health. Consumption responds to health shocks mostly because adverse health shocks reduce the marginal utility of consumption. The effect of health on marginal utility changes the optimal transfers due to health shocks. (JEL D12, E21, G22, G51, I10, J14, J26)
Pricing Power in Advertising Markets: Theory and Evidence
Authors: Gentzkow Matthew , Shapiro Jesse M. , Yang Frank , Yurukoglu Ali
Published: January 2024

Existing theories of media competition imply that advertisers will pay a lower price in equilibrium to reach consumers who multi-home across competing outlets. We generalize and extend this theoretical result and test it using data from television and social media advertising. We find that the model is a good match, qualitatively and quantitatively, to variation in advertising prices across demographic groups, outlets, platforms, and over time. We use the model to quantify the effects of competition within and across platforms. (JEL G34, K21, L13, L82, M37)
Prolonged Learning and Hasty Stopping: The Wald Problem with Ambiguity
Authors: Auster Sarah , Che Yeon-Koo , Mierendorff Konrad
Published: January 2024

This paper studies sequential information acquisition by an ambiguity-averse decision-maker (DM), who decides how long to collect information before taking an irreversible action. The agent optimizes against the worst-case belief and updates prior by prior. We show that the consideration of ambiguity gives rise to rich dynamics: compared to the Bayesian DM, the DM here tends to experiment excessively when facing modest uncertainty and, to counteract it, may stop experimenting prematurely when facing high uncertainty. In the latter case, the DM’s stopping rule is nonmonotonic in beliefs and features randomized stopping. (JEL C61, D81, D83, D91)
Distinguishing Common Ratio Preferences from Common Ratio Effects Using Paired Valuation Tasks
Authors: McGranaghan Christina , Nielsen Kirby , O’Donoghue Ted , Somerville Jason , Sprenger Charles D.
Published: January 2024

Without strong assumptions about how noise manifests in choices, we can infer little from existing empirical observations of the common ratio effect (CRE) about whether there exists an underlying common ratio preference (CRP). We propose to solve this inferential challenge using paired valuations, which yield valid inference under common assumptions. Using this approach in an online experiment with 900 participants, we find no evidence of a systematic CRP. To reconcile our findings with existing evidence, we present the same participants with paired choice tasks and demonstrate how noise can generate a CRE even for individuals without an associated CRP. (JEL C91, D81, D91)
Nonparametric option pricing under Beta-t-GARCH process with dynamic conditional score
Authors: Pereira Manoel F. de S. , Veiga Alvaro
Published: January 2024

One of the advantages of nonparametric option pricing methods is that they only require a set of future price scenarios, eliminating the need for an explicit risk-neutral model for the price of the underlying asset. In this paper, we explore the score-driven Beta-t-GARCH volatility model, introduced by Harvey (2013), to generate the price scenarios necessary for a nonparametric option pricing method based on the empirical Esscher transform, as proposed by Pereira and Veiga (2017). An experiment was conducted using real data from the Brazilian Stock Market, comparing observed option prices across different strike prices and maturities with the prices produced by two variants of the proposed method and those produced by parametric models, specifically Black and Scholes (1973) and Heston and Nandi (2000). The results indicate that the combined approach of the Beta-t-GARCH model and the empirical Esscher transform show significantly better outcomes most of the time.
The importance of expectations in determining sovereign spreads
Authors: Poiatti Natalia
Published: January 2024

This paper investigates how changes in expectations regarding the ability of the European Monetary Union to address the debt crisis have asymmetrically impacted the cost of sovereign borrowing in central and peripheral European countries. It shows that most of the variations in sovereign spreads can be explained by fundamentals in a model that allows for structural breaks. We test for both the presence and the time of structural breaks, deriving their asymptotic distribution and confidence intervals. The two estimated breakpoints are: the second quarter of 2010, a period when financial markets lacked confidence in a resolution for the crisis; and the third quarter of 2010, when financial markets regained confidence following Mario Draghi's ‘whatever it takes’ announcement. Market fears, measured by the degree of international risk aversion, became more important to price sovereign debt only for peripheral economies during the crisis.