Drug Administration-approved Indications Research Articles

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Abiraterone Clinical Trials

Purpose: Our study aimed to evaluate the risk and benefit profiles of clinical trials using abiraterone in cancer treatment.Materials and Methods: A comprehensive search was conducted on May 24, 2023, using databases such as PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov. We extracted data on adverse events, progression-free survival, overall survival, objective response rate (ORR), and prostate-specific antigen response rate (PSA-RR). The Common Terminology Criteria for Adverse Events were used to assess risks, while ORR and PSA-RR were used to assess benefits. Trials were categorized as positive, negative, or indeterminate based on their safety profiles and efficacy outcomes.Results: Nearly all clinical trials testing abiraterone in prostate cancer showed promising outcomes with 89% of studies meeting their endpoint. Our study supports abiraterone’s use in prostate cancer, its only U.S. Food and Drug Administration-approved indication to treat, with a median ORR of 20.0% and a median PSA-RR of 42.0%. However, when looking at the 3 novel indications tested, the risk-to-benefit profile was similar to that of its original approval. Even though most novel indications failed to meet their primary endpoint, the overall toxicity profile was similar to that found in prostate cancer.Conclusion: Abiraterone showed an overall risk-to-benefit portfolio that supports the use of its treatment in prostate cancer. Although the primary endpoints in ovarian and breast cancer trials were not met, the use was appropriate when assessing how the mechanism of action for abiraterone could be beneficial in patients with these types of cancers.

Omalizumab safety concerns.

IgE and mast cells play key roles in the pathophysiology of allergic diseases. In 2003, omalizumab was the first anti-IgE mAb licensed in the United States when initially US Food and Drug Administration-approved for the treatment of allergic asthma. Since that time, the number of US Food and Drug Administration-approved indications for treatment with omalizumab has grown to include chronic spontaneous urticaria, chronic rhinosinusitis with nasal polyps, and food allergy. Although omalizumab is generally considered relatively safe and well tolerated, a number of safety concerns have been raised since its initial approval. These concerns focus on specific adverse events of interest, including anaphylaxis, pregnancy, malignancy, cardiovascular events, and infections. For each of these issues, data from clinical trials and postmarketing surveillance have been evaluated extensively. In this review, we examine these safety data, provide context for safety and risk assessments, and summarize a safety profile for each of the adverse events of interest. In doing so, we aim to provide a resource for shared decision making when treatment with omalizumab is being considered.

Lipoprotein Apheresis: Utility, Outcomes, and Implementation in Clinical Practice: A Scientific Statement From the American Heart Association.

Despite the availability of multiple classes of lipoprotein-lowering medications, some high-risk patients have persistent hypercholesterolemia and may require nonpharmacologic therapy. Lipoprotein apheresis (LA) is a valuable but underused adjunctive therapeutic option for low-density lipoprotein cholesterol and lipoprotein(a) lowering, particularly in children and adults with familial hypercholesterolemia. In addition to lipid lowering, LA reduces serum levels of proinflammatory and prothrombotic factors, reduces blood viscosity, increases microvascular myocardial perfusion, and may provide beneficial effects on endothelial function. Multiple observational studies demonstrate strong evidence for improved cardiovascular outcomes with LA; however, use in the United States is limited to a fraction of its Food and Drug Administration-approved indications. In addition, there are limited data regarding LA benefit for refractory focal segmental glomerulosclerosis. In this scientific statement, we review the history of LA, mechanisms of action, cardiovascular and renal outcomes data, indications, and options for treatment.

Genomic landscape of malignant phyllodes tumors reveals multiple targetable opportunities.

Malignant phyllodes tumors (MPT) are rare fibroepithelial breast cancers with no known effective systemic therapy; metastatic progression portends a dismal prognosis. We sought to describe the genomic landscape of MPTs through genomic profiling and immunotherapeutic biomarker analysis. Cases of sequenced MPT were identified from a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited laboratory (Foundation Medicine). All cases underwent genomic profiling using adaptor ligation-based, next-generation sequencing assay of 324 genes. Tumor agnostic immunotherapy biomarkers, microsatellite instability, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression were evaluated. Fisher's Exact Tests and analysis of variance were used to test for differences between groups and for continuous variables as appropriate. Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic. Median age was 54 years (range 14-86). The median TMB was 2.5 mut/Mb and 3 were TMB-high (≥10 mut/Mb). 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥1). Most commonly altered genes included TERT-promoter (69.7%), CDKN2A (45.9%), TP53 (37.8%), NF1 (35.6%), CDKN2B (33.3%), MED12 (28.9%), MTAP (27.7%), KMT2D (22.2%), PIK3CA (20.0%), PTEN (18.5%), and RB1 (18.5%). Several tumors harboring genomic alterations with US Food and Drug Administration-approved indications in other tumor types were found including NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. In the largest genomic evaluation of MPT to date, multiple clinically actionable mutations were found. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment.

Neuromodulation guide for the non-neuromodulator clinician: What it is and how it can benefit patients?

Neuromodulation is being utilized across a variety of medical subspecialties to treat both painful and non-painful medical conditions. However, publications on neuromodulation topics infrequently occur in journals targeting generalists and medical specialties outside of pain medicine and neurosurgery. This study reviewed implantable neuromodulation devices, their respective Food and Drug Administration-approved indications for use, as well as off-label usage, and the associated potential risks and benefits for each device. PubMed and Medline databases were queried for systematic reviews with or without meta-analyses and randomized controlled trials of implantable neuromodulation devices. The literature review resulted in 106 studies eligible for inclusion, and 67 were included in the final review. In conclusion, as the clinical volume of neuromodulation continues to grow, supporting and educating medical professionals who care for patients that receive implanted neuromodulation devices is paramount. It is likely the use of neuromodulation will continue to expand across all medical subspecialties, and as such, every clinician should have a baseline understanding of this treatment.

Identifying therapeutic alternatives in Medicare drug price negotiation: The case of etanercept.

As the Centers for Medicare & Medicaid Services (CMS) navigates the process of negotiating drug prices, it plans to compare the cost, safety, and effectiveness of each drug with its therapeutic alternatives. How CMS selects therapeutic alternatives is a consequential decision, and there remains uncertainty about their methodology. To understand the challenges CMS will face in selecting therapeutic alternatives, we developed a methodology that leverages clinical guidelines by US medical professional associations to identify potential therapeutic alternatives for etanercept, one of the first 10 drugs selected for Medicare price negotiation. For each of etanercept's 5 US Food and Drug Administration-approved indications, we identified all drugs with the same mechanism of action as etanercept and considered drugs with different mechanisms if they were recommended in place of etanercept at the same treatment stage, or if there was no strong comparative safety or effectiveness evidence that the drug differed from etanercept. We identified 22 potential therapeutic alternatives to etanercept, including 4 drugs with the same mechanism, 10 biologics with different mechanisms, and 8 small-molecule drugs. We faced several challenges in selecting therapeutic alternatives using clinical guidelines, such as how to reconcile strong recommendations that were based on weak evidence and how to consider combination therapies. This exercise demonstrates the complex considerations that CMS will face as it negotiates drug prices based on therapies' cost, safety, and effectiveness relative to therapeutic alternatives.

Medicare drug price negotiation: The complexities of selecting therapeutic alternatives for estimating comparative effectiveness.

Under the 2022 Inflation Reduction Act, the Centers for Medicare and Medicaid Services (CMS) are able to negotiate prices for topselling drugs in the Medicare Part B and D programs. In determining initial price offers, CMS will compare the prices and clinical benefits of the drugs subject to negotiation to the prices and clinical benefits of therapeutic alternatives. Despite the central role that the selection of therapeutic alternatives will play in the price negotiations, the available guidance published by CMS provides few details about how the organization will undertake this process, which will be particularly complex for drugs approved for more than one indication. To better inform the selection process, we identified all US Food and Drug Administration-approved indications for the first 10 drugs subject to negotiation. Using 2020-2021 Medicare claims data, we identified Medicare Part D beneficiaries using each of the 10 drugs. We extracted medical claims with diagnosis codes for each of the approved indications to report the relative treated prevalence of use by indication for each drug. We reviewed published clinical guidelines to identify relevant therapeutic alternatives for each of the indications. We integrated the evidence on the relative treated prevalence of indications and clinical guidelines to propose therapeutic alternatives for each of the 10 drugs. We describe challenges that CMS may face in selecting therapeutic alternatives.

Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary

BackgroundCancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and...

Safety and Efficacy of the Off-Label Use of Pipeline Embolization Device Based on the 2018 Food and Drug Administration-Approved Indications for Intracranial Aneurysms: A Single-Center Retrospective Cohort Study.

The pipeline embolization device (PED; ev3/Covidien) has proven safe and effective for treating selected intracranial aneurysms. This device's versatility and popularity have driven increased interest in expanding the latest 2018 Food and Drug Administration-approved indications. To compare "off-label" and "on-label" PED treatment. Retrospective analysis of aneurysms treated with PED at a single center from 2013 to 2019. Comparisons were made based on the 2018 Food and Drug Administration-approved indications. A total of 492 treated aneurysms were included (65.2% on-label and 34.8% off-label). Aneurysm complete and near-complete occlusion rate was nonsignificantly lower in the off-label group (80.9% vs 85.7%; P = .19). Off-label treatment had higher rate of poor functional outcomes (modified Rankin Scale [mRS] >2: 10.3% vs 3.5%; P = .002). Although pretreatment mRS was already higher in the off-label group (5.3% vs 0.3%; P < .001) and there were no differences in mRS worsening during follow-up (5.5% vs 2.9%; P = .15). We also found a trend to a higher rate of intracranial hemorrhagic complications in the off-label group (4.7% vs 1.6%; P = .05), but there were no differences in hemorrhages requiring surgical intervention (1.8% vs 1.3%; P = .65). There were no differences in retreatment, thromboembolic complications, and mortality rates. Off-label PED treatment may be considered for select aneurysms, which are challenging to treat with other techniques. These cases have similar complete and near-complete occlusion rates compared with on-label cases. There are, however, higher risks of poor functional outcomes despite similar rates of thromboembolic and hemorrhagic complications. This is partly explained by the significantly higher pretreatment mRS score in the off-label group.

Integrated, Integral, and Exploratory Biomarkers in the Development of Poly(ADP-Ribose) Polymerase Inhibitors.

In this article, we highlight biomarkers for poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity and resistance and discuss their implications for the clinic. We review the predictive role of a range of DNA repair genes, genomic scars, mutational signatures, and functional assays available or in development. The biomarkers used for patient selection in the specific Food and Drug Administration-approved indications for breast, ovarian, prostate, and pancreatic cancer vary across tumor type and likely depend on disease-specific DNA repair deficiencies but also the specifics of the individual clinical trials that were conducted. Mutations in genes involved in homologous recombination and/or replication fork protection are synthetic lethal with PARPi. Cancers with homologous recombination deficiency exhibit high genomic instability, characterized by genome-wide loss of heterozygosity, among other genomic aberrations. Next-generation sequencing can identify multiple patterns of genomic changes including copy number variations, single-nucleotide variations, insertions/deletions, and structural variations rearrangements characteristic of homologous recombination deficiency. Clinical trial evidence supports the use of BRCA mutation testing for patient selection, and for ovarian cancer, there are 3 commercial assays available that additionally incorporate genomic instability for identifying subgroups of patients that derive different magnitudes of benefit from PARPi therapy. Finally, we summarize new strategies for extending the benefit of PARPi therapy toward broader populations of patients through the use of novel biomarkers. Ultimately, design of a composite biomarker test combining multiple mutational signatures or development of a dynamic assay for functional assessments of homologous recombination may help improve the test accuracy for future patient stratification.

Immunotherapy and radiation therapy sequencing: State of the data on timing, efficacy, and safety.

Radiation therapy exerts a tumoricidal local effect as well as both local and systemic immunomodulation. Immune checkpoint blockade has become a widely used treatment modality across cancer types with a rapidly growing list of agents and US Food and Drug Administration-approved indications. Moreover, there may be synergy between radiation therapy and immune checkpoint blockade. Various strategies have been used, but the optimal sequencing of these therapies is unclear. In this review, the authors discuss the major mechanisms of available immune checkpoint inhibitors and explore the available preclinical and clinical evidence regarding treatment sequencing. They also review safety considerations and conclude with possible future directions.

A Retrospective Chart Review Evaluating Efficacy, Tolerability, and Cost of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i) in Older Adults.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are proven to have profound lowering of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease or familial hypercholesterolemia. The primary purpose of this study was to evaluate PCSK9i utilization in older adults, with a focus on efficacy outcomes within 6months of initiation. Secondary outcomes included tolerability, out-of-pocket expenses (OPE), and barriers to initiation of therapy. We conducted a retrospective chart review of patients ≥65 years prescribed PCSK9i therapy by a pharmacist-run lipid clinic within a cardiology practice. A total of 136 older adults were prescribed PCSK9i therapy for a Food and Drug Administration-approved indication between September 2015 and March 2019 with 98 patients included in the analyses. In terms of efficacy, 51 patients who took ≥ 3 doses of PCSK9i with baseline and follow-up lipid panels were assessed. On average, LDL-C reduced by 60% (169-67 mg/dL, p < 0.001). For tolerability, 15 patients reported treatment-emergent side effects, resulting in 10 therapy discontinuations. For the cost analysis, 72 patients reported anticipated OPE for 1 month of therapy. Ultimately 17 patients were approved for manufacturer patient assistance with $0 OPE and 31 patients utilized insurance coverage to obtain therapy reporting a median OPE of $9 United States Dollars ($0-$450). The main barrier to initiation was high OPE. PCSK9i are effective at lowering LDL-C in older adults. Tolerability was high among patients without a history of statin intolerance. PCSK9i remain high-cost medications to both insurance companies and patients in terms of cost-sharing responsibilities.

Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We Now?

Botulinum neurotoxin (BoNT) is a recognized therapeutic agent of modern medical care, routinely used to treat medical conditions affecting a variety of organ systems including the musculoskeletal, integumentary, and urological domains. Ongoing research is exploring BoNT's potential role as a therapeutic agent for a variety of male sexual pathologies. To review and analyze the literature regarding BoNT as a treatment option for male sexual dysfunction. A PubMed search was performed for English-language articles in peer-reviewed journals between 1970 and 2019 (with one article from 1897). Relevant articles referenced within these texts were also included. One article did not have an accompanied English full-text available. The following search terms were used: "Botox", "Botulinum toxin", "Botulinum toxin A", "Onabotulinum A", "Abobutlinum A", "BoNT", "BoNT-A", "Male sexual health", "Male sexual pathology", "Peyronie's disease", "Premature ejaculation", "Scrotal Pain", "Penile Retraction", "Scrotox", "Erectile Dysfunction", and "Botox in Urology". There is interest in the potential role of BoNT in the treatment of male sexual pathologies. We identified studies that used BoNT to treat chronic scrotal content pain, premature ejaculation, erectile dysfunction, Peyronie's disease, penile retraction, and more. However, despite preclinical/clinical data indicating some potential efficacy and safety in these settings, a lack of robust clinical trial data has resulted in no current Food and Drug Administration-approved indications for the use of BoNT in the treatment of male sexual pathology. As a result, much of the current use of BoNT by today's providers is "off-label," and ongoing clinical trials aim to further elucidate the potential role of this therapeutic agent. Current data suggest that BoNT could have a potential role as a treatment option for certain types of male sexual pathologies. However, more randomized controlled trial data regarding its long-term safety and efficacy are necessary before a widespread clinical adoption can take place. Reddy AG, Dick BP, Natale C, etal. Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We Now?. J Sex Med 2021;9:320-330.

Development and Utility of the Observational Research in Oncology Toolbox: Cancer Medications Enquiry Database-Healthcare Common Procedure Coding System (HCPCS).

Health-care claims are of increasing utility as a rich, real-world data resource for conducting treatment-related cancer research. However, multiple dynamic coding nomenclatures exist, leading to study variability. To promote increased standardization and reproducibility, the National Cancer Institute (NCI) developed the Cancer Medications Enquiry Database (CanMED)-Healthcare Common Procedure Coding System (HCPCS) within the Observational Research in Oncology Toolbox. The CanMED-HCPCS includes codes for oncology medications that a) have a US Food and Drug Administration-approved indication for cancer treatment or treatment-related symptom management; b) are present in National Comprehensive Cancer Network guidelines; or c) carry an orphan drug designation for treatment or management of cancer. Included medications and their HCPCS codes were primarily identified based on Center for Medicare and Medicaid Services annual HCPCS Indices (2012-2018). To demonstrate the utility of the CanMED-HCPCS, use of systemic treatment for stage II-IV colorectal cancer patients included in the Surveillance, Epidemiology, and End Results-Medicare data (2007-2013) was assessed. The CanMED-HCPCS (v2018) includes 332 HCPCS codes for cancer-related medications: chemotherapy (156), immunotherapy (74), hormonal therapy (54), and ancillary therapy (48). Observed treatment trends within the NCI Surveillance, Epidemiology, and End Results-Medicare data were as expected; utilization of each treatment type increased with stage, and immunotherapy was largely confined to use among stage IV patients. The CanMED-HCPCS provides a comprehensive resource that can be used by the research community to facilitate systematic identification of medications within claims or electronic health data using the HCPCS nomenclature and greater reproducibility of cancer surveillance and health services research.

Advantages of Outpatient Treatment with Long-Acting Lipoglycopeptides for Serious Gram-Positive Infections: A Review.

Treatment of serious gram-positive infections presents multiple challenges. Treatment often results in prolonged hospitalization for administration of intravenous antimicrobials and presents an inefficient use of hospital resources. Prolonged hospitalization is typically also unfavorable to patient preferences and potentially subjects patients to additional health care-associated complications. Current strategies of transition to outpatient settings-outpatient parenteral antimicrobial therapy and use of oral antibiotics-often do not adequately serve vulnerable populations for whom there is often no alternative to inpatient therapy. Specifically, people who use drugs, those who cannot reliably adhere to unsupervised treatment (poor mental or physical health), people with complicating life circumstances (e.g., homelessness, incarceration, rural location), and those with inadequate health insurance remain hospitalized for weeks longer than persons without such conditions. We suspected that long-acting lipoglycopeptides (laLGP), such as dalbavancin and oritavancin, may be useful in patient transitions to outpatient settings. Thus, we conducted a search of the peer-reviewed literature using the PubMed, Google Scholar, and MEDLINE databases. Based on accumulating literature, it appears that laLGPs offer a reliable alternative therapeutic strategy that addresses many of the personal and systemic barriers to the traditional transitioning approaches. Current evidence also suggests that these agents may be cost-effective from patient, payer, and hospital perspectives. Barriers to broader use of laLGPs include, among others, a relative lack of prospective data regarding efficacy in serious infections, a narrow United States Food and Drug Administration-approved indication restricted to only acute bacterial skin and skin structure infections, and lack of reimbursement infrastructure for inpatient settings.

Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Endovascular Revascularization Incorporating Infrapopliteal Coronary Drug-Eluting Stents Improves Clinical Outcomes in Patients with Critical Limb Ischemia and Tissue Loss

Critical limb ischemia (CLI) involving infrapopliteal arterial atherosclerosis and tissue loss remains a formidable clinical scenario with significant morbidity and mortality. Despite level IA evidence, tibial revascularization with coronary drug-eluting stents (DES) remains a seldom-used technique in the United States due, in part, to lack of a Food and Drug Administration-approved indication and dedicated stent technology for infrapopliteal application. Furthermore, follow-up data beyond 1year remain scarce, and further evidence for improvement in clinical outcomes using this technique is needed. Herein, we present our multi-institutional experience with endovascular revascularization of patients with CLI and tissue loss using coronary DES for infrapopliteal lesions of appropriate dimensions and the Wound, Ischemia, and foot Infection (WIfI) score as supportive evidence for improvement in clinical outcomes. In this retrospective study, 40 sequential tibial revascularization procedures performed in 32 patients with CLI were reviewed. Outcomes including changes in WIfI scores, patency rates, freedom from major amputation, target lesion recurrence, and all-cause mortality were analyzed. Average follow-up duration was 19.3months (interquartile range: 7-27.1months). Freedom from major amputation was 88.6%. One-year primary patency was 90.3%. Mean ankle-brachial indices increased after revascularization (0.57±0.26 to 0.97±0.26; P=0.03). All components of the WIfI score significantly improved after revascularization (W: 1.9 to 1.1, P=0.03; I: 2.0 to 0.6, P=0.001; and fI: 1.5 to 0.8, P=0.01). WIfI risk of major amputation score before revascularization was 3.58±0.75 (high risk), which was reduced to 2.04±1.31 (low risk; P<0.001). One-year survival rate was 90.6%. Coronary DES continue to demonstrate promising primary patency and limb salvage rates in appropriately selected patients undergoing multilevel endovascular revascularization for CLI and tissue loss. In addition to its value as a predictor for major amputation and revascularization benefit, the WIfI score can also serve as a multicomponent tool for objective assessment of outcomes after revascularization.

Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer—A Phase 1 Study

Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. ClinicalTrials.gov identifier: NCT02595866.

Barriers to receipt of novel oral oncolytics: A single-institution quality improvement investigation.

Novel oral oncolytic agents have become the standard of care and first-line therapies for many malignancies. However, issues impacting access to these drugs are not well explored. As part of a quality improvement project in a large tertiary academic institution, we aim to identify potential barriers that delay treatment for patients who are prescribed novel oral oncolytics. This was a retrospective review of adults who were newly prescribed a novel oral oncolytic for Food and Drug Administration-approved indications at a single tertiary care center. Patients were identified via electronic prescription data (e-Scribe). Demographics, insurance information, and prescription dates were extracted from the electronic medical record and pharmacy claims data. Statistical analyses were performed to determine whether time-to-receipt was associated with insurance category, pharmacy transfers, cost assistance, and drug prescribed. Of the 270 successfully filled prescriptions, the mean time-to-receipt was 7.3 ± 10.3 days (range: 0-109 days). Patients with Medicare experienced longer time-to-receipt (9.1 ± 13.1 days) compared to patients with commercial insurance (4.4 ± 3.3). Uninsured patients experienced the longest time-to-receipt (15.7 ± 7.8 days) overall. Pharmacy transfers and cost assistance programs were also significantly associated with longer time-to-receipt. Ten prescriptions remained unfilled 90 days after the study period and were considered abandoned. Insurance has a significant effect on the time-to-receipt of newly prescribed novel oral oncolytics. Pharmacy transfers and applying for cost assistance are also associated with longer wait times for patients. Our retrospective analysis identifies areas of improvement for future interventions to reduce wait times for patients receiving novel oral oncolytics.

Bivalirudin for Pediatric Procedural Anticoagulation: A Narrative Review.

Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ), a direct thrombin inhibitor, has found increasing utilization as a heparin alternative in the pediatric population, most commonly for the treatment of thrombosis secondary to heparin-induced thrombocytopenia. Due to the relative rarity of heparin-induced thrombocytopenia as well as the lack of Food and Drug Administration-approved indications in this age group, much of what is known regarding the pharmacokinetics and pharmacodynamics of bivalirudin in this population has been extrapolated from adult data. This narrative review will present recommendations regarding the use of bivalirudin for procedural anticoagulation in the pediatric population based on the published literature.