Initial Approval Research Articles

Abstract PO2-18-03: Comparison of Provider Adoption of Antibody-Drug Conjugates Among Breast Cancer Patients (pts) and Impact on Duration of Therapy (DOT)

Abstract Background: An assessment was performed to understand the degree of post-approval provider adoption of two antibody-drug conjugates, fam-trastuzumab deruxtecan-nxki (FTD) and sacituzumab govitecan-hziy (SG), to treat breast cancer in the community oncology setting. In addition, an evaluation was performed to assess pt DOT based on the volume of pts on those therapies treated by each provider. In breast cancer, FTD was initially approved in the U.S. on December 20, 2019, and SG was initially approved in the U.S. on April 22, 2020. Methods: This assessment used the Integra Connect PrecisionQ real-world de-identified database of over 2 million cancer pts across 500 sites of care to assess SG and FTD treatment use by provider and DOT for those treated with SG and FTD. It included only breast cancer pts treated with SG or FTD who started after the initial approval dates of the respective therapies. In analyzing the DOT, pts were required to have had a follow-up of 12 months or greater, and only monotherapy treated pts were included to rule out any additional confounders. The FTD pts included were treated between December 2019 to May of 2023, whereas the SG pts included were treated between April 2020 to May 2023. Comparisons of proportions were conducted using a two sample two-tailed z-test and compared median DOT using a Wilcoxon Rank Sum Test. Descriptive analyses were used to summarize pt demographic statistics. Results: 827 pts treated with SG were identified across 376 providers, with an average age at SG treatment start of 60.2 (median of 61); 14% of pts identified as Black or African American and 59% identified as White or Caucasian. Among 827 pts treated with SG across 376 providers, 23% of pts were treated by providers who treated 6 or more pts with SG, which accounted for 6% of all providers. 23% of pts were found to be treated by a provider who used only SG once, which accounted for 56% of all providers. The median DOT among providers who treated 6 or more pts with SG was 168 days (N = 83) compared to 110 days (N = 303) among providers who treated 5 or less pts (p < 0.01). The median DOT for all SG pts was 119 days (N = 386). Of the 1438 pts treated with FTD, the average age at FTD treatment start was 62.1 (median of 63), with 8% of pts identified as Black or African American and 54% identified as White or Caucasian. Among 1438 pts treated with FTD across 485 providers, 38% of pts were treated by providers who treated 6 or more pts with FTD, which accounted for 12% of all providers. 14% of pts were found to be treated by a provider who only used FTD once, which accounted for 40% of all providers. The median DOT among providers who treated 6 or more pts with FTD was 281 days (N = 158) compared to 263 days (N = 234) among providers who treated 5 or less pts (p > 0.05). The median DOT for all FTD pts was 269 days (N = 392). The difference in the number of pts treated by a provider who used SG once (23% of 827 pts) vs. the number of pts treated by a provider who used FTD once (14% of 1438 pts) was found to be statistically significant (p < .01). The difference in pts treated by a provider who used SG in 6 or more pts (23% of 827 pts) vs. compared to providers who used FTD in 6 or more pts (38% of 1438 pts) was found to be statistically significant (p < .01). Conclusion: A large percentage of providers have only used the respective antibody-drug conjugates once (for SG it was 56% of all providers; for FTD 40%), which suggests an opportunity for greater awareness and guidance around effective therapy use and management of antibody-drug conjugates. Providers who used SG more often (6 or more pts) showed a longer DOT for their SG treated pts compared to those providers who used SG in 5 or less pts. This suggests that the slower adoption of SG and lack of experience across the community oncology provider base may be impacting overall pt DOT on SG. Citation Format: Rushir Choksi, Vikram Gorantla, Mike Gart, Simon Blanc, Erin Alwon, Dawn Brenneman, Prateesh Varughese, Justin Scott, Harvey Katzen. Comparison of Provider Adoption of Antibody-Drug Conjugates Among Breast Cancer Patients (pts) and Impact on Duration of Therapy (DOT) [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 PO2-18-03.

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Lenvatinib Clinical Trials: A Systematic Review.

Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking. This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time. On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint). Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials. Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

PD-1/PD-L1 inhibitor-induced immune thrombocytopenia: A pharmacovigilance study and systematic review

IntroductionProgrammed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors. MethodsWe performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP. ResultsThere were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69–7.87), avelumab (ROR 10.32, 95 % CI 4.91–21.69), durvalumab (ROR 7.91, 95 % CI 4.91–12.75), nivolumab (ROR 9.76, 95 % CI 8.34–11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55–15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP. ConclusionThere is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Unintended consequences of the Inflation Reduction Act: clinical development toward subsequent indications.

To describe the clinical development landscape for high-spend Medicare Part D small molecule drugs and illustrate the potential impact of the Inflation Reduction Act of 2022 (IRA) on research and development investments toward subsequent indications. Descriptive analysis of research and development time lines of small molecule drugs in the top 50 of 2020 Medicare Part D spending using publicly available dates when pivotal clinical trials were first posted to ClinicalTrials.gov and FDA approval dates for initial and subsequent indications. We summarize the drugs, indications, and time lines using descriptive statistics. Thirty of the 50 drugs with highest gross spending by Medicare Part D in 2020 were small molecule drugs with subsequent indications. Subsequent indications based on preapproval research (n = 34) were often approved within 2 years of initial approval (n = 15) and, on average, 2.9years after a drug's first approval. Additional indications based on postapproval clinical trials or real-world evidence (n = 42) received FDA approval, on average, 7.5 years after a drug was first approved, with the majority (55.8%) receiving FDA approval more than 7 years after the initial approval. Our analysis of clinical development for new indications reveals aspects of innovation in small molecule drugs that are at risk under the IRA. Specifically, the time lines described in this research demonstrate how the IRA may reduce economic incentives to develop multiple indications, including single-indication launches and investments in postapproval research for additionalindications.

Intensive glycaemic targets in overweight and obese individuals with gestational diabetes mellitus: clinical trial protocol for the iGDM study

IntroductionThe prevalence of both obesity and gestational diabetes mellitus (GDM) has increased, and each is associated with adverse perinatal outcomes including fetal overgrowth, neonatal morbidity, hypertensive disorders of pregnancy and...

Perioperative Considerations for Modern Leadless Pacemakers.

Since their initial approval by the Food and Drug Administration in 2016, leadless pacemakers have become increasingly prevalent. This growth has been driven by an improved adverse effect profile when compared to traditional pacemakers, including lower rates of infection, as well as eliminated risk of pocket hematoma and lead complications. More recently, technology enabling leadless synchronized atrioventricular pacing in patients with atrioventricular block has vastly expanded the indications for these devices. Anesthesiologists will increasingly be relied upon to safely care for patients with leadless pacemakers undergoing non-electrophysiology procedures and surgery. This article provides an overview of the technology, evidence base, current indications, and unique perioperative considerations for leadless pacemakers.

CAR-T in cancer therapeutics and updates

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a groundbreaking approach in cancer treatment, utilizing the immune system's capabilities to combat malignancies. This innovative therapy involves extracting T-cells from a patient's blood, genetically modifying them to target specific cancer cells, and reinfusing them back into the patient's body. The genetically modified T-cells then seek out and eliminate cancer cells, offering a promising therapeutic strategy. Since its initial approval in 2017, CAR-T therapy has witnessed remarkable advancements and updates. Notably, CAR-T therapy, which was initially developed for hematological malignancies, has expanded its scope to target solid tumors. Currently, clinical trials are underway to explore the efficacy of CAR-T therapy in treating various solid tumors, such as lung cancer, breast cancer, and ovarian cancer. These trials hold great potential to revolutionize cancer treatment and provide new hope to patients with challenging-to-treat solid tumors. In this mini-review, we present an overview of CAR-T therapy's mechanisms, emphasizing its role in targeting cancer cells and the potential therapeutic benefits. Additionally, we discuss the recent progress and updates in CAR-T therapy, particularly its application in treating solid tumors, and highlight the ongoing clinical trials aimed at broadening its therapeutic horizon. The evolving landscape of CAR-T therapy signifies a promising direction in cancer therapeutics, with the potential to revolutionize the treatment of both hematological and solid tumor malignancies.

Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

Potassium (K+ ) is the main intracellular cation in the body. Elevated K+ levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K+ homeostasis and the effects of orally administered K+ binders, such as sodium zirconium cyclosilicate (SZC), on K+ redistribution and excretion in patients remain incompletely understood. We built a fit-for-purpose systems pharmacology model to describe K+ homeostasis in hyperkalemic subjects and capture serum K+ (sK+ ) dynamics in response to acute and chronic administration of SZC. The resulting model describes K+ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K+ , and K+ -SZC binding and excretion in the GI tract. The model, which was fit to time-course sK+ data for individual patients from two clinical trials, accounts for bolus delivery of K+ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose-response and inform clinical trial design in two new applications: emergency lowering of sK+ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end-stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit-for-purpose, model-informed drug development after initial approval of a drug.

HARMONIZATION AND IMPROVEMENT OF THE CALCULATION OF WAGES IN UZBEKISTAN TO INTERNATIONAL FINANCIAL REPORTING STANDARDS (IFRS)

The article considers issues of improvement of accounting of wages and benefits of employees, criteria of their accounting, on the basis of comparison with the standards of the main documents of international practice of organization of business accounting in the field of communications in accordance with international standards. The main stages of the process of initial approval of financial reporting on laborand wages in accordance with international standards have been proposed.

Characterization of biosimilars: Description of the analytical approach

Biological drugs stand out from chemically synthesized drugs by their complexity. The latter puts developers, manufacturers, and controllers of drugs facing really scientific and technological challenges to ensure a safe, effective, and high-quality product. Regulatory agencies evaluate biosimilars based on their level of similarity to the innovative drug, rather than their exact resemblance to it. The recommendations of the Food and Drugs Administration indicate that, when evaluating the product, “The totality of the evidence” will be considered. With the aim of providing access to cheaper treatment options for patients, the development of biosimilar now focuses on characterization analytical by comparing structural and functional similarities with the product reference biological as it has already undergone the efficacy tests required for its initial approval. Advances in analytical techniques allow for detailed characterization and the identification of differences that may affect the purity, safety, and efficacy of biological product potentially similar to the reference product. Comparative clinical trials will only take place when the regulatory authority considers them necessary as they are expensive and require more development time, which will against the aim of creating more available and affordable treatment options for patients. In this presentation, the notion of comparability of these agents and their analytical characterization will be presented.

Quantifying Challenges to Development of Generics and Biosimilars in Non-Hodgkin's Lymphoma Therapeutics: The Future of Low-Cost Alternatives from Monoclonal Antibodies to CAR-T

Background: There are numerous monotherapies and combination therapies available to treat Non-Hodgkin lymphoma's (NHL), however relatively few of these varied antineoplastics agents have commercially available, lower-cost generic forms in the United States. High cancer drug prices, in particular for socioeconomically vulnerable and underinsured patients, pose challenges to affordable cancer treatment in the United States. In 2017, FDA initiated the Drug Competition Action Plan (DCAP) that aimed to ensure timely market competition by enabling generic drug development, review, and approval, and streamlining regulatory complexities. This regulatory program was designed to limit so-called “gaming” recognized as a cause of delay to generic drug approvals, a phenomenon that has the further deleterious effect of extending brand monopolies beyond what Congress intended with Hatch-Waxman Amendments (1984) establishing modern generic drug regulatory processes. In 2018, FDA announced analogous Biosimilars Action Plan (BAP). However, to date the efficacy of these measures has not been comprehensively assessed in the NHL development landscape. Methods: A model was created by surveying the FDA Orange Book (drug approval database) and Purple Book (biologic product approval database) for initial approval of drugs/biologics with their initial generic/biosimilar approval. Approvals were classified by drug class and availability of generic/biosimilar for the innovator product with approval from 2002 to 2023 (Fig. 1) and t-test were used to determine significance. Results: Of small molecule drug NHL therapeutics approved in the last two decades, only 37% (19/52; Fig. 2) have available, lower-cost generics, with use in more than one indication and time on market both positively and significantly corresponding with availability of generics for the original innovator drug (P < 0.05). Notably, while generic drug approvals dropped during the 2020-2021 period (possibly due to impact of the COVID-19 pandemic), after 2017 implementation of DCAP more generics for common NHL antineoplastics were approved. Conversely, there are relatively few biologic drugs (total of 41 approvals; Fig. 2) with biosimilars, in part due to retained patents and exclusivity, and perhaps indicating a lack of efficacy in BAP among NHL antineoplastics therapies. For off-patent innovator monoclonal antibodies (mAbs), which make up the majority of these therapies, development of biosimilars is effectively blocked by secondary or “process-related” patents which effectively extend the period of non-competition for complex biologic therapies. It is expected that novel bispecific antibody (biAb) therapeutics and novel therapies, such as CD19 CAR-T will also have a delayed time to low-cost biosimilar availability following a similar trend. Conclusions: With drug price and ever-rising insurance and patient payments a critical area of public health, in particular in the United States, availability of lower cost generics and biosimilars is a critical issue for NHL patients. As we move into the maturation of gene therapies and CAR-T therapeutics, it merits consideration of that additional regulatory programs may be needed to incentivize the development of efficacious and lower cost biosimilars. However, it is critical that controlling competition be carefully balanced with investment in both biologic drug entity and process-related innovations among these relatively complex therapeutic entities.

Glucagon fill rates and cost among children and adolescents with type 1 diabetes in the United States, 2011–2021

AimsTo characterize glucagon fill rates and costs among youth with type 1 diabetes mellitus (T1DM). MethodsClaims-based analysis of commercially-insured youth with T1DM included in OptumLabs® Data Warehouse between 2011 and 2021. Glucagon fill rates and costs were calculated overall and by formulation (injectable, intranasal, autoinjector, and pre-filled syringe). Sociodemographic and clinical factors associated with glucagon fills were examined using Cox regression. ResultsWe identified 13,267 children with T1DM (76.4% non-Hispanic White). Over mean follow-up of 2.81 years (SD 2.62), 70.0% filled glucagon, with stable fill rates from 2011 to 2021. Intranasal glucagon had rapid uptake following initial approval, and it accounted for almost half (46.6%) of all glucagon fills by 2021. Family income was positively associated with glucagon fills in a stepwise fashion (HR 1.39 [95% CI 1.27–1.52] for annual household income ≥$200,000 vs. <$40,000), while Black race was negatively associated with fills (HR 0.83 [95% CI 0.76–0.91]) compared to White race). Annual mean out-of-pocket costs ranged from $21-$68 (IQR $29-$44). ConclusionRoughly 30% of commercially-insured youth with T1DM may lack access to unexpired glucagon, with significant disparities among Black and low-income patients. Health systems, clinicians, schools, and caregivers should work together to ensure children have reliable access to this critical medication.

Characteristics of clinical trials of new oncology drugs approved in China.

Since reforms were introduced to incentivize drug innovation in 2015, the Chinese pharmaceutical market has experienced unprecedented prosperity, with more new drugs than ever before, especially anticancer treatments. In 2021, Chinese regulatory agencies issued the new guideline for clinical research and development of antitumor drugs, triggering a series of responses on the drug market. Limited research has outlined the nature of the original new drugs in China to understand the dynamic response of the market. The objective of this article was to map the clinical development of approved new oncology drugs in China from 2015 to 2021 and differed from previous studies by focusing on original new drugs, using the United States as a benchmark, and elaborating the endogenous features of clinical trials. Clinical trials conducted in China have risen to a level similar to that of the United States in many aspects of trial design, but there is still distance between the implementation and operational details of clinical trials. In the meantime, China has made significant breakthroughs in drug approval. Greater than 60% of novel anticancer drugs in China received accelerated approved for their first listing. Approximately 90% of the pivotal clinical trials supporting initial drug approval used surrogate measures as end points, and one half were nonrandomized or did not have a control group. However, duplicate development without evidence of a clinical advantage compared with current therapies was widely observed. By presenting a multidimensional landscape of clinical trials and approvals in the real world, this review allows interested researchers, developers, and even regulators to understand what has been done and what should be done next in anticancer drug development in China.

The impact of prior authorization review on orthopaedic subspecialty care: a prospective multicenter analysis

BackgroundPrior authorization review (PAR), in the United States, is a process that was initially intended to focus on hospital admissions and costly high-acuity care. Over time, payors have broadened the scope of PAR to include imaging studies, prescriptions, and routine treatment. The potential detrimental effect of PAR on healthcare has recently been brought into the limelight, but its impact on orthopedic subspecialty care remains unclear. This study investigated the denial rate, the duration of care delay, and the administrative burden of PAR on orthopedic subspecialty care. MethodsA prospective, multicenter study was performed analyzing the PAR process. Orthopedic shoulder and/or sports subspecialty practices from six states monitored payor-mandated PAR during the course of providing routine patient care. The insurance carrier (traditional Medicare, managed Medicare, Medicaid, commercial, worker’s compensation or government payor (i.e. Tricare, VA), location of service, rate of approval/ denial, time to approval/ denial, and administrative time required to complete process were all recorded and evaluated. ResultsOf 1,065 total PAR requests, we found a 1.5% (16/1065) overall denial rate for advanced imaging or surgery when recommended by an orthopedic subspecialist. Commercial and Medicaid insurance resulted in a small but statistically significantly higher rate of denial compared to traditional Medicare, managed Medicare, worker’s compensation, or governmental insurance (p < 0.001). The average administrative time spent on a single PAR was 19.5 minutes, and patients waited an average of 2.2 days to receive initial approval. Managed Medicare, commercial insurance, worker’s compensation, and Medicaid required approximately 3 to 4 times more administrative time to process a PAR than to traditional Medicare or other governmental insurance (p<0.001). After controlling for the payor, we identified a significant difference in approval/denial based on geographic location (p<0.001). An appeal resulted in a relatively low rate of subsequent denial (20%). However, approximately a third of all appeals remained in limbo for 30 days or more after the initial request. ConclusionThis is the largest prospective analysis to date of the impact of PAR on orthopedic subspecialty care in the United States. Nearly all PAR requests are eventually approved when recommended by orthopedic subspecialists, despite requiring significant resource utilization and delaying care. Current PAR practices constitute an unnecessary process that increases administrative burden and negatively impacts access to orthopedic subspecialty care. As healthcare shifts to value-based care, PAR should be called into question, as it does not seem to add value but potentially negatively impacts cost and timeliness of care.

Call to action: Harmonization of pharmacovigilance regulations for post-marketing pregnancy and breastfeeding safety studies.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the postmarketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by the TransCelerate IGR PV Pregnancy and Breastfeeding Team. The International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards and Council for International Organizations of Medical Sciences guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonization of global regulations on research in pregnant and breastfeeding women and a lack of specific regulations on this topic in the majority of the territories included in the assessment. This article focuses on the ambiguities and lack of harmonization in global regulations on postmarketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonization would facilitate more timely completion of postmarketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for women who may conceive, as well as pregnant and breastfeeding women.

Abstract 12237: All-Cause and Cause-Specific 30-day Readmission After Left Ventricular Assist Device Implantation: Comparing the HeartMate 3 vs Pre-HeartMate 3 Eras

Introduction: In recent years, the HeartMate 3 (HM3) has become the most commonly implanted left ventricular assist device (LVAD) for patients with end-stage HF in the United States. We assessed 30-day readmission rates and leading causes of readmission for patients newly receiving an LVAD in the pre-HM3 era compared to the HM3 era. Methods: Using the Nationwide Readmission Database (NRD), all adult admissions (age ≥18) with LVAD implantation from October 2015 - December 2020 were identified. Admissions were excluded if the patient had: died while inpatient, missing data for age, sex, or mortality, transferred to another acute care facility or December admission. Multivariable Cox regression analysis with all-cause and cause-specific readmission within 30 days as the ‘failure event’ and time from index hospitalization discharge to failure event as the ‘time to failure event’ was analyzed. Based on the timing of initial FDA approval of HM3, the study period was divided into two eras: 2015-2017 was defined as the pre-HM3 era and 2019-2020 as the HM3 era. The year 2018 was deemed the transition period and excluded from the analysis. Results: Among 13,867 hospitalizations for LVAD implantations, 57.6% of index hospitalizations were during the pre-HM3 era (mean age= 56 years, men= 77.2%), and 42.4% were during the HM3 era (mean age= 56 years, men= 76.6%). Hazards of 30-day all-cause readmissions were similar in the two eras (Figure 1 Panel A) . LVAD implantation in the HM3 era was associated with lower risks of 30-day readmission with a gastrointestinal (GI) bleed or pump thrombosis and a higher risk of 30-day readmission with an acute kidney injury (AKI) compared to the pre-HM3 era ( Figure 1 Panel B). Conclusion: There was no significant difference in risk of 30-day all-cause readmission after LVAD implantation in the HM 3 and Pre-HM 3 eras. However, implant in the HM3 era was associated with lower risk of readmission with GI bleed and pump thrombosis and higher risk of readmission with AKI.

A Quantitative Multiparametric MRI Analysis Platform for Estimation of Robust Imaging Biomarkers in Clinical Oncology.

There is a need to develop user-friendly imaging tools estimating robust quantitative biomarkers (QIBs) from multiparametric (mp)MRI for clinical applications in oncology. Quantitative metrics derived from (mp)MRI can monitor and predict early responses to treatment, often prior to anatomical changes. We have developed a vendor-agnostic, flexible, and user-friendly MATLAB-based toolkit, MRI-Quantitative Analysis and Multiparametric Evaluation Routines ("MRI-QAMPER", current release v3.0), for the estimation of quantitative metrics from dynamic contrast-enhanced (DCE) and multi-b value diffusion-weighted (DW) MR and MR relaxometry. MRI-QAMPER's functionality includes generating numerical parametric maps from these methods reflecting tumor permeability, cellularity, and tissue morphology. MRI-QAMPER routines were validated using digital reference objects (DROs) for DCE and DW MRI, serving as initial approval stages in the National Cancer Institute Quantitative Imaging Network (NCI/QIN) software benchmark. MRI-QAMPER has participated in DCE and DW MRI Collaborative Challenge Projects (CCPs), which are key technical stages in the NCI/QIN benchmark. In a DCE CCP, QAMPER presented the best repeatability coefficient (RC = 0.56) across test-retest brain metastasis data, out of ten participating DCE software packages. In a DW CCP, QAMPER ranked among the top five (out of fourteen) tools with the highest area under the curve (AUC) for prostate cancer detection. This platform can seamlessly process mpMRI data from brain, head and neck, thyroid, prostate, pancreas, and bladder cancer. MRI-QAMPER prospectively analyzes dose de-escalation trial data for oropharyngeal cancer, which has earned it advanced NCI/QIN approval for expanded usage and applications in wider clinical trials.

Who goes first? Patterns of cancer drug approvals across four major regulatory authorities: EMA, FDA, Health Canada, and PMDA.

149 Background: New anticancer therapies have led to substantial improvements in prognosis across many cancers. Commercial access to a drug is not possible until the drug has received regional regulatory authority market authorization. In prior work (1), we found that European Medicines Agency (EMA) drug approvals frequently lagged US Food and Drug Administration (FDA) approvals from 2010-2019. Here, we expand the analytic time period to 2004-2023 and include two additional regulatory agencies – Health Canada (HC) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Methods: Drugs with an anticancer indication and first global approval from 2004-2023 were preliminarily identified. Only drugs with an approval by all 4 regulators were included. For each drug, the first and last regulator’s initial approval dates were determined, and the interval between first and last approval was calculated. For drugs approved by all 4 regulators within 1 year (y), it was further determined whether they were considered first-in-class. Results: 209 drugs met the preliminary criteria, and 98 (47%) had approvals by all 4 regulators. The FDA was most commonly the first to approve (84 drugs), followed by PMDA (9 drugs), then EMA (5 drugs); HC was never first to approve. 43 of the FDA-first approvals (51%) were by the accelerated approval (AA) pathway; none of the EMA-first approvals were on the conditional marketing pathway. PMDA was most commonly the last to approve (62 drugs), followed by HC (21 drugs), the EMA (14 drugs), then the FDA (1 drug). The median (IQR) time between first and last regulator’s first approval was 2.4 y (1.3-3.5 y). Some drugs had &gt;5 y between first and last regulator’s approval (Table 1). Conversely, only 16 drugs were approved by all regulators within 1 y, and only 1 drug (isatuximab) was approved by all within 6 months. Of the 16 drugs approved within 1 y by all regulators, 6 (37.5%) were first-in-class: asciminib, elotuzumab, idecabtagene vicleucel, inotuzumab ozogamicin, sotorasib, and trastuzumab emtansine. Conclusions: This study shows that patients with cancer in the US usually have access to new cancer drugs earlier than those in Europe, Japan, and Canada, at least in part due to AA pathways. Less than 8% of newly approved cancer therapies are approved by all 4 regulatory agencies within 1 y of first approval, with a lengthy median first-to-last delay that could exceed the life expectancy of many patients with advanced cancer. Greater global regulatory collaboration in the approval of new anticancer drugs is essential to ensure patients have aligned and coordinated access. (1) Lythgoe et al. JAMA Network Open 2022.[Table: see text]

Real-World Outcomes with Chimeric Antigen Receptor T Cell Therapies in Large B Cell Lymphoma: A Systematic Review and Meta-Analysis

Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.

Secondary Pure Red Cell Aplasia During Daratumumab/ Hyaluronidase Therapy for Multiple Myeloma

Predominantly autoimmune in origin, severe normochromic, normocytic anemia with reticulocytopenia in the setting of the normal production of leukocytes and megakaryocytic lineages is known as pure red cell aplasia (PRCA), which is unlike aplastic anemia in which all lineages are affected due to a stem cell defect. PRCA can be primary (such as autoimmune) or acquired, which can be an acute self-limited illness or a chronic disease that may be induced by medications, including immunotherapy such as monoclonal antibodies (mAbs). Daratumumab is a mAb directed against CD38 used for the treatment of multiple myeloma and systemic amyloid light-chain amyloidosis. The intravenous formulation of daratumumab received initial FDA approval, and later approval was received for the subcutaneous formulation daratumumab and hyaluronidase-fihj. The subcutaneous version increases patient convenience and has become the preferred route of administration since its approval. We herein present the case of a patient with multiple myeloma who developed acquired DNMT3A-positive PRCA while transitioning to daratumumab/hyaluronidase after initial treatment with daratumumab.