Duration Of Benefit Research Articles

CTNI-63. RHENIUM (186RE) OBISBEMEDA (RHENIUM NANOLIPOSOME,186RNL) FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES (LM): SUMMARY OF THE PHASE 1 DOSE ESCALATION STUDY AND PHASE 2 ADMINISTERED DOSE SELECTION

Abstract BACKGROUND Leptomeningeal metastases (LM) is a devastating systemic cancer complication most often seen with breast, lung, and melanoma, with limited treatment options and poor survival. Rhenium (186Re) Obisbemeda (186RNL) provides the combination of effective therapeutic beta radiation, simultaneous gamma-decay for imaging, and ~90-hour physical half-life for optimal radiation delivery. A summary of the Phase 1 dose escalation study, expected to be completed, will be presented. METHODS ReSPECT-LM is a Phase 1 dose escalation study for patients with LM from any primary cancer. Adult patients are given a single dose of 186RNL via intraventricular catheter (Ommaya reservoir) in an outpatient setting to determine the maximum tolerated/feasible dose (MTD/MFD), safety, and tolerability. Seven administered dose cohorts in a 3 + 3 design, from 6.6 mCi to 109.96 mCi, were anticipated. RESULTS For the first 5 cohorts, doses were well-tolerated; most AEs were Grade 1 and 2 with 1 DLT (Cohort 5) at time of abstract submission. CSF tumor cell enumeration assays were performed with a maximum reduction over baseline seen at Day 28. Radiation absorbed doses were calculated for the ventricles, cranial subarachnoid space, and spinal fluid and showed a linear increase with administered dose, with liver and spleen remaining low. Neurological symptoms were reported to improve. We expect the Phase 1 conclusion and the RP2D to be determined for conference reporting; additionally, based on duration of benefit seen during the Phase 1, a multidose paradigm will be initiated to extend benefit. CONCLUSION A single dose of 186RNL for patients with LM has been well-tolerated, with high absorbed doses to the treatment area, acceptable organ doses, and promising clinical improvement and reductions in tumor cell count. Phase 2 is expected to begin enrollment by Q4 2024. Additionally, based on these data, a Phase 1 multidose study is planned to be initiated this year.

CTNI-77. PHASE 1 DOSE FINDING STUDY EVALUATING THE SAFETY, TOLERABILITY, AND EFFICACY OF IOPOFOSINE I 131 IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH INOPERABLE RELAPSED OR REFRACTORY HIGH-GRADE GLIOMAS: A TRIAL-IN-PROGRESS

Abstract Iopofosine I 131, a radioconjugate therapy targeting tumor lipid rafts, is being assessed in CLOVER-2 [NCT05610891]–an ongoing dose-finding study evaluating iopofosine in children, adolescents, and young adults with relapsed, refractory, recurrent high-grade gliomas (HGGs) and ependymoma. Major inclusion criteria include patients aged 10-25 years, previously confirmed HGGs or ependymoma, ≥1 measurable intracranial lesion (≥10 mm in longest diameter), and performance status ≥60. Patients are assigned 1:1 to 2 treatment arms which will be assessed in parallel. Arm 1 has 2 cycles, each composed of 2 doses of 20 mCi/m2 given 14 days apart (± 1 day). Cycle 2 is given 8 weeks (± 4 days) post-initial infusion. Arm 2 patients receive 3 cycles of 10 mCi/m2 per dose. Patients in either arm are eligible for 1 additional cycle at the physician’s discretion. If after the first 10 patients, Arm 1 is not tolerated, dosing is reduced to 15 mCi/m2 per infusion. If after the first 10 patients in Arm 2 are deemed to be ineffective and Arm 1 is deemed to be tolerated, dosing is increased to 15 mCi/m2 per infusion. Final visits occur 57 days following the last cycle initiation, with quarterly follow-ups in year 1 and annually in years 2 and 3. Primary endpoints include safety, tolerability, and progression-free survival (PFS). Secondary endpoints are dosimetry, recommended phase 2 dosing determination, overall survival, antitumor and therapeutic activity, and duration of response and clinical benefit. Safety analysis uses the Wilson score method and nonparametric Wilcoxon signed-rank test. Efficacy analyses use the Response Assessment in Pediatric Neuro-Oncology criteria and the Kaplan-Meier method to detect a median PFS of 5 months compared to a historical control of 2 months. For 90% power by a 1-sided, 1-sample log-rank test: ≥10 evaluable patients must be enrolled (≤90) across ≤15 sites.

Employer Screening and Optimal Unemployment Insurance

Abstract Field experiments show that employers are less likely to consider long-term unemployed job-seekers for interviews. We study the implications for optimal unemployment insurance (UI). Based on a structural model of job search and recruitment, estimated with German data, we analyse the optimal two-tier unemployment system. We find that screening makes the optimal initial benefit level four percentage points higher and the potential benefit duration seven months longer. Using an extended Baily-Chetty formula, we study the mechanisms through which screening affects the consumption smoothing gain and moral hazard cost of providing UI and highlight the role of the externality from endogenous firm behaviour.

How unemployment benefit duration shapes startup motivation and growth

AbstractBusiness creation is economically important, and unemployment precedes the creation of a substantial share of new firms. Yet, most research has focused on analyzing the effects of unemployment insurance policies on re-employment outcomes, ignoring self-employment. In this paper, we analyze how the potential duration of unemployment benefits, a fundamental design choice of unemployment insurance systems, affects whether new firms are founded out of opportunity or necessity and their growth potential. To this end, we construct a comprehensive dataset on German firm founders that links administrative social insurance information with business survey data. Exploiting reform and age-related exogenous variation in the potential duration of unemployment benefits, we find that longer potential benefit duration implies longer actual unemployment and, as a consequence, more necessity entrepreneurship and worse startup outcomes in terms of sales and employment growth. We explain this overall effect of potential benefit duration through a mix of compositional and individual-level duration effects. Our findings underline that new firms started out of unemployment are a highly heterogeneous group and suggest that the (optimal) design of unemployment insurance systems has important externalities on whether innovation- and growth-oriented firms are started out of unemployment.

Duration of Benefit and Risk of Dual Antiplatelet Therapy up to 72 Hours After Mild Ischemic Stroke and Transient Ischemic Attack.

Clopidogrel-aspirin initiated within 72 hours of symptom onset is effective in patients with mild ischemic stroke or transient ischemic attack (TIA) in the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. Uncertainties remain about the duration of the treatment effect. This study aimed to assess duration of benefit and risk of clopidogrel-aspirin in these patients. The INSPIRES trial was a 2*2 factorial placebo-controlled randomized trial conducted in 222 hospitals in China. The 2 treatments did not interact and were evaluated separately. In this study, we performed secondary analyses based on antiplatelet treatment. All patients with mild stroke or TIA of presumed atherosclerotic cause within 72 hours of symptom onset enrolled in the trial were included. Patients were randomly assigned to receive clopidogrel-aspirin on days 1-21 followed by clopidogrel on days 22-90 or aspirin alone for 90 days. The primary efficacy outcome was major ischemic event which included the composite of ischemic stroke and nonhemorrhagic death. The primary safety outcome was moderate-to-severe bleeding. We estimated the risk difference between the 2 treatments for each stratified week. All 6,100 patients in the trial were included (3,050 in each group). The mean age was 65 years, and 3,915 patients (64.2%) were men. Compared with aspirin alone, the reduction of major ischemic events by clopidogrel-aspirin mainly occurred in the first week (absolute risk reduction [ARR] 1.42%, 95% CI 0.53%-2.32%) and remained in the second week (ARR 0.49%, 95% CI 0.09%-0.90%) and the third week (ARR 0.29%, 95% CI -0.05% to 0.62%). Numerical higher risk of moderate-to-severe bleedings in the clopidogrel-aspirin group was observed in the first 3 weeks (absolute risk increase 0.05% [95% CI -0.10% to 0.20%], 0.10% [95% CI -0.09% to 0.29%], and 0.18% [95% CI -0.03% to 0.40%] in the first, second, and third weeks, respectively). Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low, but ongoing hemorrhagic risk. ClinicalTrials.gov Identifier: NCT03635749. This study provides Class II evidence that among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low but ongoing hemorrhagic risk.

Oral Antibiotic Use in Adulthood and Risk of Early-Onset Colorectal Cancer: A Case-Control Study

Prior antibiotic use may be a factor in the rising incidence of colorectal cancer seen in those under 50 years of age (early-onset colorectal cancer [EOCRC]); however, the few studies to examine this link have reported conflicting results. Therefore, we evaluated the association between oral antibiotic use in adulthood and EOCRC in a large integrated healthcare system in the United States. A population-based nested case-control study was conducted among Kaiser Permanente Northern California patients 18-49 years of age diagnosed with EOCRC (adenocarcinoma of the colon or rectum) in 1998-2020 who had ≥2 years of continuous pharmacy benefit prior to diagnosis. Cases were matched 4:1 to healthy controls on birth year, sex, race and ethnicity, medical facility, and duration of pharmacy benefit. Antibiotic exposure >1 year before the diagnosis/index date was assessed using prescribing records. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A sensitivity analysis was performed among those with ≥10 years of continuous prescribing records. 1359 EOCRC cases were matched to 4711 healthy controls. Antibiotic use in adulthood was not significantly associated with EOCRC in unadjusted or adjusted analyses (adjusted OR: 1.04; 95% CI: 0.94-1.26). No associations were seen for cumulative number of oral antibiotic dispensations or for any prior period of antibiotic exposure. In a large United States healthcare setting, there was no conclusive evidence of an association between oral antibiotic use in adulthood and risk of EOCRC.

Does the use of stem-cell injection therapy benefit duration of healing in adults with large joint injuries?

Does the use of stem-cell injection therapy benefit duration of healing in adults with large joint injuries?

Clinician Perspectives of Gene Therapy as a Treatment Option for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive, life-limiting, neuromuscular disorder. Clinicians play an important role in informing families about therapy options, including approved gene therapies and clinical trials of unapproved therapies. This study aimed to understand the perspectives of clinicians about gene therapy for DMD, which has not previously been studied. We conducted interviews with specialist clinicians treating patients with DMD in the United States (n = 8) and United Kingdom (n = 8). Interviews were completed in 2022, before any approved gene therapies, to gain insight into barriers and facilitators to implementing gene therapy and educational needs of clinicians. Most respondents expressed cautious optimism about gene therapy. Responses varied regarding potential benefits with most expecting delayed progression and duration of benefit (1 year to lifelong). Concern about anticipated risks also varied; types of anticipated risks included immunological reactions, liver toxicity, and cardiac or renal dysfunction. Clinicians generally, but not uniformly, understood that gene therapy for DMD would not be curative. Most reported needing demonstrable clinical benefit to justify treatment-related risks. Our data demonstrate variability in knowledge and attitudes about gene therapy among clinicians who follow patients with DMD. As our knowledge base about DMD gene therapy grows, clinician education is vital to ensuring that accurate information is communicated to patients and families.

Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC

Immune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy. To estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge. This retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023. Data cutoff was August 31, 2023; data analysis was conducted from December 2023 to February 2024. Treatment continuation vs discontinuation at 1 and 2 years; rechallenge with ICI after at least a 60-day period off ICI therapy without intervening systemic treatment (immediate rechallenge), or with intervening systemic treatment (delayed rechallenge). Overall survival (OS) from ICI initiation was analyzed using the Kaplan-Meier method. Cox multivariable regression was used to examine associations of key variables (line of therapy, human papillomavirus [HPV] status, Eastern Cooperative Oncology Group [ECOG] performance status) with survival. The cohort included 4549 patients with R/M HNSCC who received ICI-containing therapy (median [IQR] age, 66 [59-72] years; 3551 [78.1%] male; 56 [1.2%] Asian, 260 [5.7%] Black or African American, 3020 [66.4%] White, 1213 [26.7%] other or unknown race; 3226 [70.9%] ECOG performance status 0 or 1). There were 3000 patients (65.9%) who received ICI in frontline and 1207 (26.5%) in second line; 3478 patients (76.5%) received ICI monotherapy. Median (IQR) OS was 10.9 (4.1-29.1) months and was longer in patients who received ICI in frontline therapy (12.2 [4.8-32.0] vs 8.7 [3.2-22.4] months), had HPV-positive cancer (16.6 [6.5-43.9] vs 8.8 [3.5-24.0] months), and had ECOG performance status 0 or 1 (13.5 [5.2-33.9] vs 5.5 [2.0-13.7] months). There were no survival differences on adjusted analysis between patients who stopped vs those who continued ICI at 1 or 2 years. Median (IQR) OS after ICI rechallenge was 15.7 (13.7-21.9) months in the immediate rechallenge group and 9.9 (3.7-18.1) months in the delayed rechallenge group. In this large cohort study of patients with R/M HNSCC receiving ICI-based therapy, survival estimates closely mirrored clinical trial results, both in frontline and later-line settings. Discontinuation of ICI in long-term responders at 1 or 2 years may be a reasonable strategy that does not appear to compromise survival. ICI rechallenge was associated with clinical benefit in a subset of patients.

Whole-Body Cryostimulation: An Effective Complementary Treatment in Fibromyalgia? A Follow Up Study.

Recent evidence suggests that whole-body cryostimulation (WBC) may be beneficial for patients with fibromyalgia (FM), but little is known about the duration of such effects. The purpose of this study was to verify the duration of clinical-functional benefits after one cycle of WBC. We conducted a follow-up study on the medium and long-term effects of WBC on well-being, use of pain-relieving/anti-inflammatory medications, pain level, fatigue, sleep quality, and psychological aspects such as mood and anxiety. Twelve months after discharge, we administered a 10 min follow-up telephone interview with FM patients with obesity who had undergone ten 2 min WBC sessions at -110 °C as part of a multidisciplinary rehabilitation program (n = 23) and with patients who had undergone rehabilitation alone (n = 23). Both groups reported positive changes after the rehabilitation program, and similar results regarding fatigue, mood, and anxiety scores; however, the implementation of ten sessions of WBC over two weeks produced additional benefits in pain, general well-being status, and sleep quality with beneficial effects lasting 3-4 months. Therefore, our findings suggest that adding WBC to a rehabilitation program could exert stronger positive effects to improve key aspects of FM such as general well-being, pain level, and sleep quality.

Impact of COVID-19 on work loss in the United States- A retrospective database analysis

Objectives This study investigates the utilization of work absence benefits among United States (US) employees diagnosed with COVID-19, examining frequency, duration, cost, and types of work loss benefits used. Methods This retrospective analysis of the Workpartners Research Reference Database (RRDb) included employees eligible for short- and long-term disability (STD and LTD employer-sponsored benefits, respectively), and other paid work absence benefits from 2018 to 2022. Workpartners RRDb includes over 3.5 million employees from over 500 self-insured employers across the US. Employees were identified by codes from adjudicated medical and disability claims for COVID-19 (2020–2022) and influenza, as well as prescription claims for COVID-19 treatments. Associated payments were quantified for each absence reason. Results Approximately 1 million employees were eligible for employer-sponsored paid leave benefits between January 2018 and December 2022. The mean age was 37 years (22% >50 years), and 49.4% were females. COVID-19 was the 2nd most common reason for an STD claim (6.9% of all STD claims) and 13th for an LTD claim (1.7% of all LTD claims) from 2020–2022. The mean duration for COVID-19 STD claims was 24 days (N = 3,731, mean claim=$3,477) versus 10 days for influenza (N = 283, mean claim=$1,721). The mean duration for an LTD claim for COVID-19 was 153 days (N = 11, mean claim=$19,254). Only 21.5% of employees with STD claims in the COVID-19 cohort had prior COVID-19-associated medical or pharmacy claims; over half (range 53%–61%) had documented high risk factors for severe COVID-19. Conclusion COVID-19 and influenza have the potential to cause work loss in otherwise healthy employees. In this analysis, COVID-19 was the second most frequent reason for an STD claim at the start of the pandemic and remained high (ranked 5th) in 2022. These results highlight the impact of COVID-19 on work loss beyond the acute phase. Comprehensively evaluating work loss implications may help employers prioritize strategies, such as vaccinations and timely treatments, to mitigate the impact of COVID-19 on employees and their companies.

People with short symptom duration of knee osteoarthritis benefit more from exercise therapy than people with longer symptom duration: An individual participant data meta-analysis from the OA trial bank

ObjectiveTo investigate whether duration of knee symptoms influenced the magnitude of the effect of exercise therapy compared to non-exercise control interventions on pain and physical function in people with knee osteoarthritis (OA). MethodWe undertook an individual participant data (IPD) meta-analysis utilizing IPD stored within the OA Trial Bank from randomised controlled trials (RCTs) comparing exercise to non-exercise control interventions among people with knee OA. IPD from RCTs were analysed to determine the treatment effect by considering both study-level and individual-level covariates in the multilevel regression model. To estimate the interaction effect (i.e., treatment x duration of symptoms (dichotomized)), on self-reported pain or physical function (standardized to 0-100 scale) a one-stage multilevel regression model was applied. ResultsWe included IPD from 1767 participants with knee OA from 10 RCTs. Significant interaction effects between study arm and symptom duration (≤1 year vs >1 year, and ≤2 years vs>2 years) were found for short- (~3 months) (Mean Difference (MD) -3.57, 95%CI -6.76 to -0.38 and -4.12, 95% CI-6.58 to -1.66, respectively) and long-term (~12 months) pain outcomes (MD -8.33, 95%CI -12.51 to -4.15 and -8.00, 95%CI -11.21 to -4.80, respectively), and long-term function outcomes (MD -5.46, 95%CI -9.22 to -1.70 and -4.56 95%CI -7.33 to-1.80, respectively). ConclusionsThis IPD meta-analysis demonstrated that people with a relatively short symptom duration benefit more from therapeutic exercise than those with a longer symptom duration. Therefore, there seems to be a window of opportunity to target therapeutic exercise in knee OA.

The Impact of Benefit Generosity on Workers’ Compensation Claims: Evidence and Implications

Leveraging unique administrative data and a sharp increase in benefit generosity in a difference-in-differences research design, we estimate the impact of workers’ compensation wage replacement benefits on individual behavior and program costs. We find that increased benefit generosity leads to longer income benefit durations and increased medical spending. Responses along these two margins are equally important drivers of increased program costs, collectively increasing program costs 1.4 times the mechanical increase in costs. Using these estimates and an estimate of the consumption drop among injured workers, our welfare calibrations suggest that a marginal increase in benefit generosity would not improve welfare. (JEL D91, I11, J28, J31)

Enhanced Recovery Protocol Versus Conventional Care in Patients Undergoing Esophagectomy for Cancer: Advantages in Clinical and Patient-Reported Outcomes.

This study was designed to compare the clinical and patient-reported outcomes (PROs) between the enhanced recovery after surgery (ERAS) protocol and conventional care in patients undergoing esophagectomy for cancer, which have not previously been compared. This single-center retrospective study included prospective PRO data from August 2019 to June 2021. Clinical outcomes included perioperative complications and postoperative length of stay (PLOS). Patient-reported outcomes were assessed by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) and esophagus-specific module (QLQ-OES18) preoperatively to 6 months postoperatively. Mixed-effects models were used to longitudinally compare quality of life (QOL) scores between the two modes. Patients undergoing conventional care and ERAS were analyzed (n = 348 and 109, respectively). The ERAS group had fewer overall complications, pneumonia, arrhythmia, and a shorter PLOS than the conventional group, and outperformed the conventional group in five functional QLQ-C30 domains and five symptom QLQ-OES18 domains, including less dysphagia (p < 0.0001), trouble talking (p = 0.0006), and better eating (p < 0.0001). These advantages persisted for 3 months postoperatively. For the cervical circular stapled anastomosis, the initial domains and duration of benefit were reduced in the ERAS group. The ERAS protocol has significant advantages over conventional care in terms of clinical outcomes, lowering postoperative symptom burden, and improving functional QOL in patients who have undergone esophagectomy. Selection of the optimal technique for cervical anastomosis is a key operative component of ERAS that maintains the symptom domains and duration of the advantages of PROs.

A phase 1, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of PF-07799544 (ARRY-134) as a single agent and in combination with PF-07799933 BRAF dimer inhibitor, in participants 16 years and older with advanced solid tumors.

TPS3180 Background: The MAPK pathway plays a role in several key signaling and phosphorylation events that contribute to tumorigenesis. Inhibition of MEK, along with RAF kinases, has proven to be a successful transformative strategy for melanoma and other MAPK pathway-altered tumors. However, the duration of clinical benefit is limited by a narrow therapeutic index, de novo and acquired resistance and poor brain penetration. PF-07799544 is a next-generation, fully brain penetrant MEK inhibitor. PF-07799933 is an oral selective ATP-competitive small-molecule RAF kinase inhibitor that suppresses BRAF signaling in BRAF V600-mutant and non-V600-BRAF mutant tumors. It displays significantly less paradoxical activation than approved BRAFi and is not “pan RAF” as it spares non-BRAF mutated-containing RAF dimers. We describe here the design of the Phase 1 study of PF-07799544 as Monotherapy or in Combination with a next generation BRAF dimer inhibitor PF-07799933 in participants with BRAF mutated (BRAFm) advanced solid tumors. Methods: The purpose of this first-in-human study is to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and potential clinical benefits of PF-07799544 administered as a single agent in participants with advanced solid tumors (Phase 1a) and in combination with PF-07799933 in participants with BRAF Class 1, 2 and 3 mutated solid tumors with or without brain involvement (Phase 1b). Phase 1a will enroll participants with advanced solid tumors who have progressed on standard of care. The primary objective is to determine monotherapy MTD/RDE of PF-07799544. Once PK measurements indicate the potential for significant WT MEK mutation target coverage, participants with untreated and symptomatic brain metastases (bm) will be allowed to enroll. Phase 1b is comprised of multiple sub-studies, all of which evaluate PF-07799544 in combination with PF-07799933 in participants with BRAFm solid tumors who have progressed on standard of care therapies, including Class 1 BRAFi where indicated. Sub-study B: BRAFm melanoma (V600 and non-V600) will determine the MTDc/RDEc of the combination (Part 1 primary objective), followed by dose expansion cohorts (Part 2) (~80 participants): Cohort 1: BRAF V600 melanoma (asymptomatic and untreated bm permitted), Cohort 2: BRAF V600 melanoma (symptomatic bm), Cohort 3 BRAFm Class 2/3 melanoma (asymptomatic and untreated bm permitted); Sub-study C: BRAFm Class 2 or 3 advanced solid tumor Cohort 1 (asymptomatic and untreated bm permitted and Cohort 2 (symptomatic bm) (~20 each cohort). The main objectives of the dose expansion cohorts in all substudies, will be to evaluate anti-tumor activity, safety, PK and PD. Clinical trial information: NCT05538130 .

CheMo4METPANC: A randomized phase 2 study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) compared to chemotherapy alone in metastatic treatment-naïve pancreatic adenocarcinoma.

TPS4208 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) carries a 5-year relative survival of 3%. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). Signaling through the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells in mouse PDAC models. Longitudinal survival studies testing combinations of CXCR4i, aPD-1, and gemcitabine in the KPC mouse model of PDAC demonstrated a survival benefit with the combination of all three agents. Results from a multicenter, investigator-initiated, single arm pilot study evaluating the preliminary safety and efficacy ofMotixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDAC were recently presented. Seven patients (64%) achieved a partial response, including 6 confirmed partial responses, and 10 patients (91%) had disease control, compared to historic partial response and disease control rates of 23% and 48%, respectively, with gemcitabine and nab-paclitaxel (GN). Preliminary median progression-free survival (PFS) was 9.6 months compared to historic median PFS of 5.5 months with GN. Analysis of paired pre- and on-treatment biopsy samples from demonstrated an increase in CD8+ T-cell density in tumors from all 11 patients treated with MCGN (p=0.007). Based on these promising results, the protocol was amended from a single arm expansion totaling 40 patients to a randomized phase 2 study. Methods: This is an open-label, multicenter, investigator-initiated phase 2 clinical trial. Patients are randomized 2:1 to receive MCGN or GNalone (N=108). The primary endpoint is progression free survival. The study has 80% power to detect an improvement in PFS from 6 to 9.2 months (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include response rate, disease control rate, duration of clinical benefit and overall survival. Patients will undergo optional paired biopsies which will be analyzed in conjunction with samples collected from the phase I pilot study. Exploratory studies include interrogation of the TME using quantitative multiplex immunofluorescence and single-cell RNA sequencing. The randomized phase 2 trial is open to enrollment and one patient has been randomized as of 1/29/2024. Clinical trial information: NCT04543071 .

Abstract PO3-06-10: Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study

Abstract Background Sacituzumab govitecan (SG) is approved for treatment of metastatic triple negative breast cancer (mTNBC) in the second line and beyond. Little is known about the real-world outcomes of SG. We aim to evaluate the real-world effectiveness and toxicity outcomes of SG in heterogenous heavily pretreated mTNBC patients (pts) to investigate the consistency of the outcomes in comparison to the clinical trial population. Methods A multi-center retrospective study of pts with mTNBC treated with SG in the US from January 2021 until May 2023 was conducted. Demographics and clinicopathological variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs), HER2 immunohistochemistry (IHC) score at time of metastasis, clinical response, clinical benefit rate (CBR) defined as (complete response, partial response (PR) or stable disease (SD) &amp;gt; 6 months) and last follow-up were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. Univariate and multivariate cox regression models examined RDI and survival outcomes. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results A total of 111 pts were analyzed. The median age was 58 years (range 29-84). The majority of pts were heavily pretreated: 59.1% received &amp;gt;3 prior lines of treatment (Tx) in the metastatic setting, 54.1% received prior immune checkpoint inhibitor (ICI), 8.1% received prior olaparib. 55% of pts had significant disease burden defined by &amp;gt;=3 organs involved by metastatic disease, with 22.5% having brain metastasis at the time of initiation of SG. Of note, 51% had primary refractory disease defined as relapse within 12 months of completion of adjuvant chemotherapy. 98.1% experienced any grade AEs, with the most common being anemia 63.1%. Grade 3 AEs occurred in 51.4% pts with neutropenia being the highest 32.4% followed by anemia 14.4%, diarrhea 7.2% and fatigue 7.2%. Tx interruptions and dose reductions due to AEs occurred in 52.3% of patients and Tx discontinuation rate due to AEs was 11.8%. Elderly pts (defined as &amp;gt;65 years) did not have higher rates of dose reductions due to AEs compared to young pts (&amp;lt; = 65 years) (37.8% vs 59.7 %), p=0.043). The median RDI is 92% (interquartile range (IQR) 33%-100%). The median RDI in elderly pts was 94% (IQR 50%-100%). Among pts in which response was assessed, objective response rate (ORR) was 26.6% (25 pts had PR), and 38.3% had SD. Interestingly, the rate of alopecia was higher in pts who had PR as the best response (28%), compared to 5.6% in pts who had SD, and 3% in progressive disease (PD) p=0.004. The median prior line of therapy in pts who had PR and SD as best response was 2 (IQR 1, 5) (IQR1, 12), respectively, compared to a median of 3 (IQR 1, 7) in pts with PD, p&amp;lt; 0.001. The CBR was 49% (46/94). The median duration of clinical benefit was 7 months IQR (2, 16) with median overall survival of 13 months IQR (2.5, 39) compared to 5.7 months IQR (0.03, 27) in pts without clinical benefit (p&amp;lt; 0.001). 56.9% (62/109) of pts had HER2 low disease and the clinical benefit rate in this subgroup was 14.3% (23/62). Conclusion: In a heavily pretreated cohort, SG retains clinical activity and tolerability in mTNBC. This is reassuring given pts on clinical trials tend to be healthier compared to real-world clinical practice. Citation Format: Sabah Alaklabi, Arya Mariam Roy, Paola Zagami, Nicole Held, Saba Shaikh, Lubna Chaudhary, Yara Abdou, Shipra Gandhi. Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-10.

Abstract 1924: RTK signaling and WT RAS activity as vulnerabilities in tumors with acquired resistance to GDP-state selective KRASG12C inhibitors in preclinical models

Abstract Background: KRASG12C-GDP Inhibitors such as sotorasib and adagrasib have demonstrated clinical benefit in lung cancer patients harboring an oncogenic KRASG12C mutation. However, the durability of monotherapy benefit is limited by the development of resistance. Hence, identification of novel treatment approaches to overcome resistance and extend duration of benefit becomes necessary to address this unmet clinical need. Experimental Design: We generated two NSCLC models of KRASG12C−GDP inhibitor acquired resistance, named sotorasib-R LU65 (cell-line derived, in vitro) and adagrasib-R LUN156 (PDX-derived, in vivo) following extended treatment with sotorasib and adagrasib, respectively. We then performed transcriptomic and mass spectrometry-based phosphoproteomics analyses on baseline and KRASG12C-GDP inhibitor-resistant samples to determine resistance and escape mechanisms. Results: In the sotorasib-R LU65 cells, we discovered upregulation of various RTKs including HER2, HER3, and AXL using a mass spectrometry-based proteomics approach and Immunoblot analysis. Simultaneously, from a transcriptome analysis, we observed activation of RAS and PI3K/AKT signaling in these cells. In the adagrasib-R LUN156 model, increased phosphorylation of MET was observed via phospho-RTK array and by immunoblotting. Transcriptomic analysis revealed an enrichment for RAS pathway dependency in the adagrasib-R tumor models. RAS GTP-binding assessed by RAF-RBD pulldown and multiple reactions monitoring mass-spectrometry suggest increased GTP-bound RAS isoforms in sotorasib-R LU65 cells and active RAS signaling in adagrasib-R LUN156. Given the convergence of our findings on re-activation/maintenance of wild-type RAS signaling as a means of resistance to KRASG12C-GDP-state inhibitors, we hypothesized that RMC-7977, a tri-complex RASMULTI-GTP inhibitor, which inhibits signaling via mutant and wild-type RAS, had the potential to counteract these mechanisms. We tested RMC-7977 monotherapy, which drove complete tumor regressions in the adagrasib-R LUN156 model. Additionally, RMC-7977 attenuated tumor growth in sotorasib-R cell derived LU65 xenograft model wherein we observed co-activation of PI3K/AKT signaling. Thus, we tested a combination with the pan-PI3K inhibitor pictilisib and observed combinatorial activity consistent with our findings. Conclusions: These data suggest that in KRASG12C-GDP inhibitor-resistant models RTK activation maintains MAPK dependency and in the case of one model, PI3K signaling. Consistent with these mechanisms, RMC-7977 as a single agent or in combination with pictilisib drove significant tumor regressions in these models. These preclinical results indicate RASMULTI-GTP inhibition alone or combination with PI3K inhibition has the potential to address KRASG12C-GDP inhibitor resistance. Citation Format: Hitendra S. Solanki, Harshit Shah, Denis Imbody, Bina Desai, Paul A. Stewart, Bin Fang, Yaakov Stern, Lancia N. Darville, John M. Koomen, Andriy Marusyk, Ethan Ahler, Ida Aronchik, Mallika Singh, Eric B. Haura. RTK signaling and WT RAS activity as vulnerabilities in tumors with acquired resistance to GDP-state selective KRASG12C inhibitors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1924.

Job search with commuting and unemployment insurance: A look at workers’ strategies in time

Unemployed workers search for jobs that ideally offer both high wages and short commutes. But would they accept jobs with lower wages or longer commutes or both as the unemployment spell lengthens? Using a unique panel of Austrian workers, we find that job seekers do indeed accept jobs with significantly lower wages. However, the majority group of job seekers who used to commute to jobs located outside their municipality of residence tend to increasingly accept jobs in their home municipality, and do not necessarily broaden geographically their search. Based on quasi-experimental variations in the duration of unemployment benefits, we find that this evolution of commuting patterns is not linked to the loss of benefits. We explain these findings through the lens of a job search model where flexible parameters such as search costs are allowed to vary across space and time. We estimate that search costs are substantial and increase differently over time for local and non-local jobs, accounting for the patterns found in the data. A counterfactual policy exercise suggests that unemployment insurance does not hinder geographical mobility. Competing mechanisms are discussed and their role is left to future research.

Evaluating the Effectiveness of Lacrimal Gland Botulinum Toxin Using the TEARS Score.

Botulinum toxin (BoNTA) lacrimal gland injections are one treatment option for managing epiphora. Outcomes for epiphora in existing studies are subjective and lack grading. This study utilized validated grading instruments to evaluate the efficacy of BoNTA lacrimal gland injections. Prospective study evaluating the TEARS score and quality of life in patients receiving incobotulinum toxin (Xeomin) lacrimal gland injections for epiphora. Epiphora was graded using the TEARS score. Quality of life was evaluated using the watery eye quality of life score. Etiology, benefit duration, complications and additional injections were recorded. Of the 28 patients, (median age 67.5 years), 19 (68%) had facial palsy gustatory epiphora (GE). Median effect duration was 13 weeks. Improvements in tearing frequency (T), clinical effects (E), and activity limitation (A) were seen in 57%, 57%, and 71% of patients, respectively. Median watery eye quality of life score improved from 42.4/100 ± 10.1 to 10.6 ± 15.5 (p < 0.001). Alongside crocodile tears, reflex tearing R-scores improved in 68% of patients with GE vs. 11% with non-GE causes (p = 0.004618). In total 89% of patients with GE and 56% with non-GE requested repeat injections. Self-reported percentage improvement ranged from 0% to 100% (median 60%, interquartile range 10%-76.25%). This is the first study reporting the outcomes of BoNTA lacrimal gland injections using validated TEARS and watery eye quality of life scores. Clinical and quality of life improvements are seen in most patients. Patients with GE achieve an additional improvement in dry eye-related reflex tearing alongside crocodile tears which both improve with BoNTA. TEARS data supports using BoNTA in these patients and is a useful validated grading instrument for epiphora.