Initial Clinical Experience with NIPT for Rare Autosomal Aneuploidies and Large Copy Number Variations

Objective: Amniocentesis, chorionic villi sampling and first trimester combined testing are able to screen for common trisomies 13, 18, and 21 and other atypical chromosomal anomalies (ACA). The most frequent atypical aberrations reported are rare autosomal aneuploidies (RAA) and copy number variations (CNV), which are deletions or duplications of various sizes. We evaluated the clinical outcome of non-invasive prenatal testing (NIPT) results positive for RAA and large CNVs to determine the clinical significance of these abnormal results. Methods: Genome-wide NIPT was performed on 3664 eligible patient samples at a single genetics center. For patients with positive NIPT reports, the prescribing physician was asked retrospectively to provide clinical follow-up information using a standardized questionnaire. Results: RAAs and CNVs (>7 Mb) were detected in 0.5%, and 0.2% of tested cases, respectively. Follow up on pregnancies with an NIPT-positive result for RAA revealed signs of placental insufficiency or intra-uterine death in 50% of the cases and normal outcome at the time of birth in the other 50% of cases. We showed that CNV testing by NIPT allows for the detection of unbalanced translocations and relevant maternal health conditions. Conclusion: NIPT for aneuploidies of all autosomes and large CNVs of at least 7 Mb has a low “non-reportable”-rate (<0.2%) and allows the detection of additional conditions of clinical significance.

Early Treatment with fluvoxamine among patients with COVID-19: a cost-consequence model

ABSTRACT Background Three randomized trials have been conducted indicating a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. We assessed the cost-consequences associated with the use of this early treatment in outpatient populations. Methods Using results from the three completed trials of fluvoxamine vs. placebo for the treatment of COVID-19, we performed a meta-analysis. We conducted a cost-consequence analysis using a decision-model to assess the health system benefits of the avoidance of progression to severe COVID-19. Outcomes of relevance to resource planning decisions in the US and elsewhere, including costs and days of hospitalization avoided, were reported. We constructed a decision-analytic model in the form of a decision tree to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19, from the perspective of a third-party payer: (1) treatment with a 10-day course of fluvoxamine (100mg twice daily); (2) current standard-of-care; (3) molnupiravir 5-day course. We used a time horizon of 28 days. Results Administration of fluvoxamine to symptomatic outpatients with COVID-19 at high-risk of developing progression to severe COVID-19 complications is substantially cost-saving in the US, in the amount of $232 per eligible patient, and saves an average of 0.15 hospital days per patient treated is likely to be similarly beneficial in other settings. Fluvoxamine is cost saving in locations where total hospital costs are >$738. Molnupiravir had an additional cost to the healthcare system of $404 per patient treated. Conclusions Fluvoxamine is cost-saving for COVID-19 outpatient therapy.

Health and Budget Impact of Liquid-Biopsy-Based Comprehensive Genomic Profile (CGP) Testing in Tissue-Limited Advanced Non-Small Cell Lung Cancer (aNSCLC) Patients

BACKGROUND AND OBJECTIVES: Molecular genetic testing using tissue biopsies can be challenging for patients due to unfavorable tumor sites, the invasive nature of a tissue biopsy, and the added time of booking a repeat biopsy (re-biopsy). Centers in Canada have found insufficient tissue rates to be approximately 10%, and even among successful biopsies, insufficient DNA in tissue samples is approximately 16%, triggering the lengthy process of re-biopsies. Using aNSCLC as an example, this study sought to characterize the health and budget impact of alternative liquid-biopsy(LBx)-based comprehensive genomic profile (CGP) testing in tissue-limited patients (TL-LBx-CGP) from a Canadian publicly funded healthcare perspective. MATERIAL AND METHODS: An economic model was developed to estimate the incremental cost and life-years gained as a population associated with adopting TL-LBx-CGP. The eligible patient population was modeled using a top-down epidemiological approach based on the published literature and expert clinician input. Treatment allocation was modeled based on biomarker prevalence in the published literature, and the availability of funded therapies. Costs included molecular testing, as well as drug, administrative, and supportive costs, and relevant health data included median overall survival and median progression-free survival data. RESULTS: Incorporation of TL-LBx-CGP demonstrated an overall impact of $14.7 million with 168 life-years gained to the Canadian publicly funded healthcare system in the 3-year time horizon.

Value appropriation in hepatitis C

Background In 2015, the Swedish government in an unprecedented move decided to allocate 150 million € to provide funding for new drugs for hepatitis C. This was triggered by the introduction of the first second generation of direct-acting antivirals (DAAs) promising higher cure rates and reduced side effects. The drugs were cost-effective but had a prohibitive budget impact. Subsequently, additional products have entered the market leading to reduction in prices and expansions of the eligible patient base. Methods We estimated the social surplus generated by the new DAAs in Stockholm, Sweden, for the years 2014–2019. The actual use and cost of the drugs was based on registry data. Effects on future health care costs, indirect costs and QALY gains were estimated using a Markov model based primarily on Swedish data and using previous generations of interferon-based therapies as the counterfactual. Results A considerable social surplus was generated, 15% of which was appropriated by the producers whose share fell rapidly over time as prices fell. Most of the consumer surplus was generated by QALY gains, although 10% was from reduced indirect costs. QALY gains increased less rapidly than the number of treated patients as the eligibility criteria was loosened. Conclusions The transfer of funds from the government to the regions helped generate substantial surplus for both consumers and producers with indirect costs playing an important role. The funding model may serve as a model for the financing of innovative treatments in the future.

Potential Biomarkers for Predicting the Overall Survival of Kidney Renal Papillary Cell Carcinoma: A Analysis of N6-Methylandenosine-Related lncRNAs

Background: It is well established that disease-free survival and overall survival after breast conservation surgery (BCS) followed by radiotherapy are equivalent to that after mastectomy. However, in Asian countries, the rate of BCS continues to remain low. The cause may be multifactorial including the patient’s choice, availability and accessibility of infrastructure and surgeon’s choice. We aimed to elucidate the Indian surgeons’ perspective while choosing between BCS and mastectomy, in women oncologically eligible for BCS. Methods: We conducted a survey-based cross-sectional study over 3 weeks between January-February 2021. Indian surgeons with general surgical or specialised onco-surgical training, who consented to participate were included in the study. Multinomial logistic regression was performed to assess the effect of study variables on offering mastectomy or BCS to an eligible patient.Results: A total of 347 responses were included. The mean age of the participants was 43(11) years. 63% of the surgeons were in the 25-44 years age group with the majority (80%) being males. 66.4% of surgeons ‘almost always’ offered BCS to oncologically eligible patients. Surgeons who had undergone specialised training in oncosurgery or breast conservation surgery were 35 times more likely to offer BCS (p<0.01). Surgeons working in hospitals with in-house radiation oncology facilities were 9 times more likely to offer BCS (p<0.05). Surgeons’ years of practice, age, sex and hospital setting did not influence the surgery offered.Conclusion: Our study found that two-thirds of Indian surgeons preferred BCS over mastectomy. Lack of radiotherapy facilities and specialised surgical training were deterrents to offering BCS to eligible women.

Breast Conservative Surgery for Breast Cancer: Indian Surgeon’s Preferences and Factors Influencing Them

Background: It is well established that disease-free survival and overall survival after breast conservation surgery (BCS) followed by radiotherapy are equivalent to that after mastectomy. However, in Asian countries, the rate of BCS continues to remain low. The cause may be multifactorial including the patient’s choice, availability and accessibility of infrastructure and surgeon’s choice. We aimed to elucidate the Indian surgeons’ perspective while choosing between BCS and mastectomy, in women oncologically eligible for BCS. Methods: We conducted a survey-based cross-sectional study over 3 weeks between January-February 2021. Indian surgeons with general surgical or specialised onco-surgical training, who consented to participate were included in the study. Multinomial logistic regression was performed to assess the effect of study variables on offering mastectomy or BCS to an eligible patient.Results: A total of 347 responses were included. The mean age of the participants was 43(11) years. 63% of the surgeons were in the 25-44 years age group with the majority (80%) being males. 66.4% of surgeons ‘almost always’ offered BCS to oncologically eligible patients. Surgeons who had undergone specialised training in oncosurgery or breast conservation surgery were 35 times more likely to offer BCS (p<0.01). Surgeons working in hospitals with in-house radiation oncology facilities were 9 times more likely to offer BCS (p<0.05). Surgeons’ years of practice, age, sex and hospital setting did not influence the surgery offered.Conclusion: Our study found that two-thirds of Indian surgeons preferred BCS over mastectomy. Lack of radiotherapy facilities and specialised surgical training were deterrents to offering BCS to eligible women.

The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is a rare and aggressive malignancy arising from mesothelial cells that line the serous membranes of the body. Cytotoxic chemotherapy has been a mainstay of therapy, resulting in a modest improvement in overall survival, but toxicity limits the eligible patient population. Few targeted agents beyond bevacizumab have demonstrated superior efficacy compared to placebos. With an improved understanding of the relationship between the immune system and cancer progression, immunotherapies are playing a greater role in the treatment of many cancers. Several early- and late-phase trials in malignant pleural mesothelioma, including assessments of the first-line efficacy of combination ipilimumab/nivolumab treatment, have now demonstrated promising results for both immune checkpoint inhibition and cell-based therapies. These immune therapies are likely to play a central role in the treatment of this disease going forward.

Considerations for Optimal Administration of Chimeric Antigen Receptor (CAR) T-Cell Therapy Programs: A Multi-Stakeholder Qualitative Analysis

CAR-T therapies represent a novel advance in oncology, albeit at list prices that exceed $373,000 (and that does not capture their total cost to the healthcare system). Since initial product approval in 2017, stakeholders and observers have attempted to investigate clinical and financial impacts of CAR-T therapies, and potential approaches to optimizing access and use by eligible patients. Most existing research is from a single stakeholder perspective - patients, providers, or payers - limiting the ability to draw broader conclusions on trends and offer prospective recommendations. To address this knowledge gap, we sought to identify and describe critical success factors for optimal delivery of CAR-T therapies. We undertook a qualitative study based on interviews with multiple US-based stakeholders including clinicians, financial and operations staff, and payer-insurers. Interviewees--which included oncologists (n=6), facility financial and operational personnel (n=4), and coverage and reimbursement decision-makers from US health plans (n=3)--completed structured, live, hour-long, interviews covering clinical, administrative, and general topics on patient access to CAR-T therapies. All clinicians had experience with ≥1 FDA-approved CAR-T therapies in both registered clinical trials and clinical practice; financial and operational personnel were affiliated with the same facilities as the clinicians, and also had real-world experience with these therapies; payer representatives were directors from a large national commercial plan, regional integrated delivery network, and a Medicare administrative contractor, respectively. Consensus facility feedback (i.e., clinicians, operational personnel) was that CAR-T is effective, and that their administrative processes had been optimized through care team coordination and experience-based efficiencies; in contrast, 2 of 3 payer interviewees expressed that, while CAR-T therapies have shown efficacy, their real-world benefits and applicability are less well-defined. Facility interviewees noted that: (1) reimbursement from commercial insurers is higher than from Medicare, with the latter associated with per-patient net-neutral or negative margins; (2) when possible, differential reimbursement between inpatient and outpatient settings may drive patient management towards outpatient care; and (3) negative-margin cases are currently deemed acceptable due to nonclinical factors (i.e., competitive pressure within a geographic region, anticipated branding/marketing value) and relatively small treated populations. From payer interviewees, CAR-T cost and perceived cost-to-value have made health plans more receptive to considering outcomes-based contracting, capitated provider payments, or other mitigation methods. Left unoptimized, these factors may adversely impact patient access to, and long-term provider attractiveness of, CAR-T therapies. All interviewees agreed that as the CAR-T marketplace grows, a strong preference exists for manufacturers to develop and communicate for their therapies durable outcomes data, clear and comprehensive reimbursement information, and competitive pricing. With the potential for many approved products in a single indication, and/or a single approval for indications with relatively large eligible patient populations, interviewees also conveyed interest in compelling health economic data. Facility interviewees also acknowledged that if it remains an overall net-negative margin service, new providers will be less able to start CAR-T programs and smaller programs may encounter sustainability issues, collectively jeopardizing patient access to these life-changing therapies. Overall, findings from this study suggest that during the continued maturation of the landscape, stakeholders will need to be proactive to ensure that CAR T-cell therapies can be maintained amidst financial and operational pressures. Several CAR-T therapy options for multiple myeloma are on the immediate horizon, likely increasing demand among eligible patients. Accordingly, the need to link real-world evidence of the clinical value and institutional investment burden of these therapies to reimbursement is imperative, both to insulate payers and enable clinicians to provide innovative therapies. Figure 1 Figure 1. Disclosures Faber: Amgen: Honoraria; Adaptive: Honoraria; Cardinal Health: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; GlaxoSmith Kline: Honoraria; Janssen: Honoraria; Juno: Honoraria; Karyopharm: Honoraria; Kite: Honoraria; Takeda: Honoraria; Sanofi Genzyme: Honoraria. Hunter: BMS: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Deol: Kite, a Gilead Company: Consultancy. Crivera: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Riccobono: Legend Biotech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Garrett: Legend Biotech USA: Current Employment. Jackson: Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Fowler: Amgen: Ended employment in the past 24 months; Janssen: Current Employment. Berger: Janssen Scientific Affairs: Consultancy, Research Funding. Lorden: Janssen Scientific Affairs: Consultancy, Research Funding. Stewart: Janssen Scientific Affairs: Consultancy, Research Funding.

756. Clostridioides difficile Burden of Disease: A Prospective Population-Based Surveillance Study of Hospitalized Adults in Louisville, Kentucky

Background Clostridioides difficile (C. difficile) is an important cause of morbidity and mortality. C. difficile infection (CDI) may be frequently under-diagnosed because laboratory confirmation requires collection of a stool specimen from a patient with diarrhea and appropriate laboratory testing. Methods A prospective population-based CDI surveillance study was launched in 8 adult hospitals in Louisville, Kentucky on September 16, 2019. Surveillance officers in each hospital identified all cases of new-onset diarrhea (≥3 loose stools in the past but not preceding 24 hours) in Louisville residents ≥50 years of age. After informed consent, stool samples were collected and tested at the University of Louisville reference laboratory for 1) glutamate dehydrogenase (GDH) and 2) Clostridioides difficile toxins A and B using C. DIFF QUIK CHEK COMPLETE®, Techlab. We defined CDI as GDH positive and toxin positive. The study was paused on April 3, 2020, due to COVID-19 restrictions. Results There were 85,719 eligible patient-days during the study period. A total of 1541 patients had new-onset diarrhea corresponding to 1.8 cases of new-onset diarrhea per 100 eligible patient-days. We enrolled 84% (1291/1541) of patients with new-onset diarrhea and tested stool samples for C. difficile from 82% (1055/1291) for a testing density of 123 per 10,000 patient-days. Of the 1055 tested stool specimens, 73 (7%) were GDH positive and toxin positive (Figure 1) yielding a hospital-based CDI incidence of 8.5 CDI cases per 10,000 patient-days. Figure 1. Patient Ascertainment Flow Chart Conclusion New-onset diarrhea was common among hospitalized adults ≥50 years of age. CDI was frequently identified through stool specimens collected from eligible inpatients with new-onset diarrhea. Further analysis of these data and additional laboratory testing will contribute to a better understanding of the frequency of CDI underdiagnosis and the burden of CDI in the United States. Disclosures Ruth Carrico, PhD, DNP, APR, CIC, Pfizer (Consultant, Research Grant or Support, Speaker's Bureau)Sanofi Pasteur (Consultant, Grant/Research Support, Speaker's Bureau) Fredrick J. Angulo, DVM, PhD, Pfizer, Inc. (Employee) Joann Zamparo, MPH, Pfizer, Inc. (Employee) Elisa Gonzalez, MS, Pfizer, Inc. (Employee) Kimbal D. Ford, PharmD, Pfizer, Inc. (Employee) Julio Ramirez, M.D., FACP, Pfizer, Inc. (Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)

107. Impact of Penicillin Allergy Assessment During Pre-Anesthesia Testing (PAT) on Beta-Lactam Surgical Prophylaxis in Bariatric Surgery Patients

Background Due to utilization of alternative antibiotics, documented penicillin (PCN) allergies are associated with an increased risk of surgical site infections, cost, and infections caused by resistant organisms. In October 2019, a community hospital implemented a beta-lactam (BL) allergy assessment service in a pre-anesthesia testing (PAT) clinic without access to allergy specialists or PCN skin testing (PST). In phase 1, the surgeon was contacted to change surgical prophylaxis for BL eligible patients based on the assessment. In phase 2, an automatic protocol was implemented to allow advanced practice providers (APPs) to switch from alternative antibiotics in BL eligible patients. The objective of this study was to assess the impact of the PCN assessment service and protocol on BL surgical prophylaxis. Methods This retrospective cohort study included bariatric surgery patients who visited PAT clinic with a documented BL allergy between Jun 2019-Sept 2019 (control), Nov 2019-Feb 2020 (phase 1), and Nov 2020-Feb 2021 (phase 2). Patients with procedures not requiring surgical prophylaxis were excluded. Patients were determined to be eligible for BL surgical prophylaxis if: intolerance or mild-moderate reaction to PCN, previously tolerated cephalosporin, intolerance to cephalosporin, or surgeon deemed it appropriate. The primary outcome was overall utilization of BL surgical prophylaxis. Results This study included 38 patients in the control group, 14 in the phase 1 group, and 17 in the phase 2 group. Overall utilization of BL surgical prophylaxis significantly increased with 16% in the control group, 43% in the phase 1 group, and 65% in the phase 2 group (p=0.001). In the BL eligible patient subgroup, BL surgical prophylaxis significantly increased with 35% (n=6/17) in the control group, 50% (n=6/12) in the phase 1 group, and 92% (n=11/12) in the phase 2 group (p= 0.001). There were no reported surgical site infections or adverse drug reactions. Conclusion Overall utilization of BL surgical prophylaxis significantly increased after implementation of a PCN allergy assessment service with an automatic protocol for patients determined as BL eligible. This service and protocol demonstrates successful optimization of surgical prophylaxis when allergy specialists or PST is not available. Disclosures All Authors: No reported disclosures