FDA-approved Indications Research Articles

Fanconi anemia repair pathway as a predictor of anti-tumor activity of pembrolizumab: interim analysis of open-label, single-arm phase II trial

<h3>Objectives:</h3> Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected gynecologic cancers. We aimed to assess the Fanconi Anemia pathway (FA) homologous recombination repair and solid tumor response to pembrolizumab. <h3>Methods:</h3> We conducted a phase 2 trial of pembrolizumab in solid tumor patients progressing on standard of care and for whom pembrolizumab had no FDA approved indication. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of FA (FATSI) that we developed in treated patients' archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST). Secondary objectives were progression-free survival (PFS), and 20-weeks PFS. Pembrolizumab was given every 3 weeks and computed-tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥20% in the whole population vs the null hypothesis of an iORR ≤5%. The iORR was expected ≥40% in patients with functional FA deficiency (FATSI negative) and <10% in patients with intact HR repair. <h3>Results:</h3> A total of 52 patients were enrolled, of which 38 patients had a primary gynecologic malignancy. A total of 20 (53%) patients had endometrial, 13 (34%) had ovarian, 2 (5%) had cervical, 2 (5%) had vaginal, 1 (3%) had vulvar cancer respectively. No unexpected toxicities occurred. Response evaluation showed 3CR, 5PR, 9SD, 21PD with an iORR 21%. FATSI analyses in 36 patients showed 24 FATSI positive and 12 negative. A total of 2CR, 1PR, 5SD, 16PD occurred among the FATSI (+) (iORR 12%) and 1CR, 4PR, 2SD, 5PD among the FATSI (-) patients (iORR 42%). The median PFS for the FATSI negative group was 7.0 months, compared to 3.0 months for the FATSI (+) group, p=0.037). <h3>Conclusions:</h3> Pembrolizumab demonstrated antitumor activity in advanced recurrent gynecologic malignancies with no current FDA approved indications. The results support evaluation of FATSI as a discriminatory biomarker for population-selected future studies.

Trends in off-label use of antipsychotic medications among Texas Medicaid children and adolescents from 2013 to 2016.

BACKGROUND: Antipsychotics are frequently prescribed for off-label indications in the pediatric population. However, little is known regarding this issue in Texas Medicaid. OBJECTIVES: To (1) describe off-label antipsychotic use among Texas Medicaid children and adolescents and (2) examine factors associated with off-label use. METHODS: Texas Medicaid prescription and medical claims from January 2013 to August 2016 were analyzed retrospectively among subjects aged 2-17 years with an antipsychotic prescription. Three diagnostic status groups (on-label, off-label, no diagnosis) were categorized based on FDA-approved indications. Descriptive and chi-square tests were conducted to determine if diagnostic status differed by age group (2-4, 5-9, 10-14, and 15-17 years), sex, and antipsychotic type. A logistic regression analysis was used to identify factors associated with off-label use. RESULTS: In this study, 43,792, 44,335, 37,221, and 24,879 (January-August) children with at least 1 antipsychotic prescription were identified from 2013 to 2016, respectively. The proportions with off-label use declined from 66.9% (2013) to 59.8% (2016). Among off-label users, more than one-half (51.3%-55.8%) had a diagnosis of attention-deficit/hyperactivity disorder. Less than 8% (6.0%-7.7%) of subjects had no mental health disorder diagnosis. Chisquare analyses (2015 data) revealed that the proportion of off-label and no diagnosis users combined were significantly (P < 0.01) higher among users aged 5-9 years (82.5%) than adolescents 10-14 years (61.9%) and 15-17 years (56.5%); males (67.7%) than females (65.3%); and first-generation antipsychotics (FGAs; 79.3%) than second-generation antipsychotics (66.7%) users. Logistic regression analyses revealed younger age and FGA users had higher odds of off-label/no diagnosis use. CONCLUSIONS: The proportion of off-label/no diagnosis antipsychotic use declined from 2013 to 2016. Younger children and those receiving FGAs were more likely to be off-label antipsychotic users, with attention-deficit/hyperactivity disorder being the most prevalent off-label diagnosis. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. This study was presented as an abstract at the American Academy of Child and Adolescent Psychiatry's 67th Annual Meeting (Virtual), October 2020.

Reassessing the Net Benefit of Cancer Drugs With Evolution of Evidence Using the ASCO Value Framework.

Regulatory approval of oncology drugs is often based on interim data or surrogate endpoints. However, clinically relevant data, such as long-term overall survival and quality of life (QoL), are often reported in subsequent publications. This study evaluated the ASCO-Value Framework (ASCO-VF) net health benefit (NHB) at the time of approval and over time as further evidence arose. FDA-approved oncology drug indications from January 2006 to December 2016 were reviewed to identify clinical trials scorable using the ASCO-VF. Subsequent publications of clinical trials relevant for scoring were identified (until December 2019). Using ASCO-defined thresholds (≤40 for low and ≥45 for substantial benefit), we assessed changes in classification of benefit at 3 years postapproval. Fifty-five eligible indications were included. At FDA approval, 40.0% were substantial, 10.9% were intermediate, and 49.1% were low benefit. We then identified 90 subsequent publications relevant to scoring, including primary (28.9%) and secondary endpoint updates (47.8%), safety updates (31.1%), and QoL reporting (47.8%). There was a change from initial classification of benefit in 27.3% of trials (10.9% became substantial, 9.1% became low, and 7.3% became intermediate). These changes were mainly due to updated hazard ratios (36.4%), toxicities (56.4%), new tail-of-the-curve bonus (9.1%), palliation bonus (14.5%), or QoL bonus (18.2%). Overall, at 3 years postapproval, 40.0% were substantial, 9.1% were intermediate, and 50.9% were low benefit. Because there were changes in classification for more than one-quarter of indications, in either direction, reassessing the ASCO-VF NHB as more evidence becomes available may be beneficial to inform clinical shared decision-making. On average, there was no overall improvement in the ASCO-VF NHB with longer follow-up and evolution of evidence.

Outpatient Off-Label Gabapentin Use for Psychiatric Indications Among U.S. Adults, 2011-2016.

Gabapentin is widely prescribed off label in medical practice, including psychiatry. The U.S. Food and Drug Administration (FDA) warned of risks associated with gabapentin combined with central nervous system depressant (CNS-D) drugs, which are commonly prescribed in psychiatric treatment. This study examined off-label outpatient gabapentin use for psychiatric indications and concomitant CNS-D medication use. National Ambulatory Care Medical Survey data (2011-2016) were used to identify encounters involving gabapentin (gabapentin visits) for adults (ages ≥18) (N=5,732). FDA-approved uses and off-label psychiatric use indications were identified with ICD-9-CM and ICD-10-CM diagnosis codes. CNS-D drugs examined were opioids, benzodiazepines, sedatives-hypnotics, antidepressants, antipsychotics, first-generation antihistamines, and skeletal muscle relaxants. Concomitance was prescription of one or more CNS-D medications at the same visit. Visits were stratified by provider type and specialty. Between 2011 and 2016, 2.8% of visits listed gabapentin prescriptions (weighted estimate of 129.6 million visits). A small proportion (<1%) listed an FDA-approved indication. Among off-label gabapentin visits, 5.3% listed a depressive disorder, 3.5% an anxiety disorder, and 1.8% bipolar disorder. Over 6 years, 58.4% of off-label gabapentin visits listed one or more concomitant CNS-D medications, most frequently antidepressants (24.3%), opioids (22.9%), and benzodiazepines (17.3%). Most gabapentin visits were with primary care providers (34.9%) and other provider specialties (i.e., not primary care, neurology, or psychiatry) (48.1%). In this nationally representative sample, <1% of outpatient gabapentin use was for approved indications. High concomitant use of CNS-D drugs and off-label gabapentin for psychiatric diagnoses underlines the need for improved communication about safety.

A review of evidence supporting NCCN category 2B off-label recommendations for determination of Medicare reimbursement eligibility.

6576 Background: Antineoplastic indications supported by a category 1 or 2A NCCN recommendation are reimbursed by insurance and Medicare, as are FDA-approved indications. While initial reimbursement requests for “off-label” NCCN category 2B indications may be denied, Medicare will reimburse off-label antineoplastic use supported by evidence from a peer-reviewed publication from one of 26 designated journals. Here, we evaluated the published clinical evidence supporting NCCN category 2B indications. Methods: Category 2B drug indications for the 10 most common solid tumor types were identified in the NCCN compendium (n=104). The results were then filtered to include drugs with only category 2B indications in a particular tumor type (n=14). Similarly, FDA-approved indications were excluded, resulting in a list of drugs with only a 2B indication that are not FDA approved in the specified cancer type (n=8). Published clinical studies supporting these category 2B indications were assessed for study type and journal name in PubMed, and journal names were cross-referenced with the CMS-supported list. Results: Among the 8 non-FDA-approved drug indications with only category 2B recommendations, 7 (87%) had at least one publication of a clinical trial in one of the 26 designated journals. The only 2B indication without supporting literature was single-agent gemcitabine hydrochloride in bladder cancer. For further details, see Table. Conclusions: These results suggest that clinicians should consider pursuing the appeals process and provide supporting evidence in cases of claim denial. While coverage is not guaranteed, the evidence supporting 2B indications frequently meets the criteria identified in the Medicare statute. Further studies will evaluate if these findings extrapolate to less common tumor types.[Table: see text]

Temporal trends in oncology drug revenue among the world’s major pharmaceutical companies: A 2010-2019 cohort study.

6505 Background: In the past decade there has been a 70% increase in the number of clinical trials for cancer drugs. During this time, there has also been a substantial increase in the price of cancer drugs. It is unclear how these trends have changed the revenue landscape of major pharmaceutical companies. In this study we characterize temporal trends in cancer drug revenue relative to non-cancer drugs. Methods: This retrospective cohort study used publicly available global sales data from the 10 pharmaceutical companies with the highest annual revenue in 2019; Abbvie (AB), AstraZeneca (AZ), Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), Johnson &amp; Johnson (JJ), Merck (M), Novartis (N), Pfizer (P), Roche (R) and Sanofi (S). We quantified the contribution of cancer drugs to net revenue for each company from 2010 – 2019 using consolidated annual financial reports (i.e. 10-K or 20-F forms). Cancer drugs were defined as those with an FDA-approved indication for anti-cancer effect or supportive care. All sales data were converted to USD and adjusted for global inflation. Trends in the percentage of company revenues accounted for by cancer drugs were assessed with the Kendall-Mann test. P-values were adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Results: During 2010-2019, cumulative annual revenue generated from cancer drugs in our cohort of companies (n = 10) increased by 96%, from $52.8 billion to $103.5 billion. The cumulative revenue from non-oncology drugs decreased by 19%, from $342.5 billion to $276.9 billion. The proportion of total revenue generated from cancer drugs grew over time; from 13% in 2010 to 27% in 2019 (p &lt; 0.001). During 2015-2019, annual revenue for the study cohort grew by 12%: from $339.7 billion to $380.4 billion. During this period non-oncology revenues remained stagnant (mean $278.9 billion, range 276.9 – 281.9), while oncology revenues grew by 66%; from $61.4 billion to $103.5 billion. Six companies (AB, AZ, BMS, JJ, N, and P) saw substantial increases in the proportion of revenue attributable to cancer drugs. R had both the highest net revenue ($23.9 billion), and highest proportion of revenue (57%) from cancer drugs in 2010 among the cohort, similar to 2019 ($27.7 billion, 57%; p = 0.37). While not reaching significance over the total study period, M saw increases in oncology revenue from $1.5 billion in 2015 to $12.3 billion in 2019 (4% to 30% of total revenue); driven almost exclusively by sales of Pembrolizumab. Conclusions: Amongst the world’s largest pharmaceutical companies, sales revenue from cancer drugs have increased by 96% over the past decade, while revenues from non-cancer drugs have decreased by 19%. Revenues from cancer drugs accounted for 27% of company revenues in 2019. Further work is needed to understand if this massive increase in sales revenues has translated into proportional improvements in patient and population outcomes.

Impact of multidisciplinary severe immunotherapy complication service on outcomes for cancer patients receiving immune checkpoint inhibition.

2654 Background: The exponential increase in FDA-approved indications for immune checkpoint inhibitors (ICI) in cancer care has resulted in therapeutic success but also in the occurrence of immune-related adverse effects (irAEs) that can represent a significant clinical challenge. On October 3 2017, the Massachusetts General Hospital (MGH) implemented the Severe Immunotherapy Complications (SIC) Service, a multi-disciplinary care team for patients hospitalized with irAEs. The objectives of this study were to evaluate the impact of SIC Service on 1) healthcare utilization and 2) patients outcomes. Methods: Using pharmacy and hospital admission databases, a list of patients was identified that both received ICI for a malignancy and were hospitalized with severe irAEs in the period prior to initiation of the SIC service and after SIC initiation. The pre-SIC period was defined as an admission between 4/2/2016 through 10/3/2017, and the post-SIC period as an admission from 10/3/2017 through 10/24/2018. The rate of readmission after the index hospitalization was the primary outcome. Secondary outcomes included lengths of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre- and post-SIC periods. Results: Among 1169 patients treated in the pre-SIC service intervention period; 127 were hospitalized for irAE. Among 1159 patients treated in the post-SIC intervention 122 were hospitalized for irAE. SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs. pre-SIC 25.9%; odds ratio [OR], 0.46; 95% CI, 0.22-0.95; p=0.036). The length of stay, rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates were not significantly different before and after SIC Service implementation. Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy. Such care teams may play an essential part in optimizing irAE care.

Effect of geriatric assessment (GA) and genetic profiling on overall survival (OS) of older adults with acute myeloid leukemia (AML).

7021 Background: GA can predict the risk of toxicities of chemotherapy in older adults. Genetic risk categories correlate with OS in AML. We previously reported a reduction in early mortality in a pre-planned interim analysis of a phase II trial with the use of GA and genetic profiling to personalize therapy selection (NCT03226418) (Blood 2019; 134(s1):120). Here, we present the results of a propensity score matched analysis demonstrating an improvement in OS over a historical control. Methods: Patients ≥60 years with a new diagnosis of AML underwent GA. Patients were considered fit for intensive chemotherapy if they had robust physical function [normal activities of daily living (ADL) and instrumental ADL, and short physical performance battery score of ≥10 out of 12], normal cognitive function (Montreal Cognitive Assessment score of ≥26 out of 30), and hematopoietic cell transplantation comorbidity index (HCT CI) of 0-2 (except for treatment related AML, where a score of 0-2 in addition to the prior history of malignancy was acceptable). Genetic profiling for therapy selection relied on karyotyping and followed the 2017 ELN criteria. Fit patients with good or intermediate-risk AML received intensive chemotherapy. Patients with high-risk AML received low-intensity chemotherapy, or CPX 351 if they were fit and met the FDA-approved indications. Pragmatic aspects of the trial included broad eligibility criteria (e.g. patients on treatment for other malignancy were enrolled) and co-management of patients with community oncologists. Mortality was compared with a historical control treated during the years 2004-2016 (after approval of HMA) and matched on gender, age, Karnofsky Performance Status (KPS), HCT CI and ELN risk category. Results: Treatment group (n = 27) vs. historical controls (n = 32) were matched in terms of age (median age, 70 vs. 68.5 years), ELN risk category (adverse risk 59% vs. 53%), HCT CI (median score of 2), KPS (median 80 vs. 85), and gender (male 44% vs. 50%). In the treatment group, 3 patients received intensive chemotherapy: CPX 351 (n = 2) or 7+3+ gemtuzumab (n = 1). Other patients received HMA alone (n = 16), decitabine and midostaurin (n = 3), or azacitidine and venetoclax after the approval of venetoclax (n = 5). Treatment in the historical control included intensive chemotherapy (n = 20) such as 7+3, or mostly HMA based low intensity chemotherapy (n = 12). OS was significantly higher in the treatment group over historical control with 1-year OS of 66% (95% CI 60-87%) vs. 16% (95% CI 7-35%). Conclusions: Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both GA for patient profiling and genetic profiling of leukemia cells. Our results appear promising with superior OS (an absolute difference of 50% in 1-year OS) compared to a matched historical control. Clinical trial information: NCT03226418.

Consensus disease definitions for the spectrum of neurologic immune related adverse events.

2647 Background: Expanding FDA-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in both therapeutic success and immune related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes evidence-based treatments and research progress. The objectives of this study were to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. Methods: A working group of 4 neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the Neuro irAE Disease Definition Panel, consisting of neurologists, oncologists, neuro-oncologists and irAE subspecialists. A modified Delphi consensus process was used, with 2 rounds of anonymous ratings by panelists and 2 virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. The working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions. Results: Twenty-seven panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for 7 core disorders: irMeningitis, irEncephalitis/Encephalomyelitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, 6 sub-classifications are described: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation and present or absent concurrent irAE. Conclusions: These disease definitions standardize irAE-N classification. They are being incorporated into a multi-institutional registry that our group has initiated to study irAEs. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

Assessment of hemp oil–based cannabidiol use in a community-based pharmacy setting

BackgroundThe Agricultural Improvement Act of 2018 legalized the commercial use of hemp-based products, including cannabidiol (CBD). However, the U.S. Food and Drug Administration (FDA) does not currently regulate the commercial sale of hemp oil–based CBD, and there is no FDA-approved indication for its nonprescription formulations despite the growing demand for, and use of, hemp oil–based CBD. ObjectivesCharacterize the use of hemp oil–based CBD, including brands, formulations, and reasons for use, in a community pharmacy setting and identify the perceived barriers related to the use of hemp oil–based CBD. MethodsA pretested 17-question survey was distributed at the point of care at 2 community pharmacy locations and at hemp oil–based CBD education presentations over a 3-month period. The survey consisted of multiple-choice, open-ended, and select-all-that-apply questions, which were analyzed using univariate and bivariate analyses. ResultsA total of 101 participants completed the survey: 38 were CBD-naive, and 63 were CBD-exposed. Most of the participants were women (79%) and Caucasian (81.6%), with an average age of 59 years (SD 17.26). In the CBD-naive group, the most commonly stated barrier to using hemp oil–based CBD was not enough information about the product. Among the participants who had used or were using at least 1 CBD product, the most commonly used dosage form was sublingual, followed by topical: 46 (46/63 [73%]) and 34 (34/63 [54%]) participants, respectively. Thirty-eight participants used hemp oil–based CBD for pain, 24 participants for sleep, and 17 participants for anxiety. Of these, 62% of the participants informed a health care provider that they were using a hemp oil–based CBD product. ConclusionThe participants were using different brands and formulations of hemp oil–based CBD for multiple reasons. The greatest barrier to trying CBD was limited education, which may suggest a need for community education about hemp oil–based CBD products.

Abstract P355: Real-Word Performance of Two Automated Software Platforms for Identification of Salvageable Tissue in Stroke Patients: A Single Center Experience

Background and purpose: Modern stroke treatment has been revolutionized by image-guided selection of patients for endovascular thrombectomy. Current automated platforms allow for real-time identification of large vessel occlusion and salvageable brain tissue. We sought to evaluate the performance of these platforms with regard to identification of infarcted and salvageable tissue. Methods: We studied all patients that presented to Henry Ford Health System hospitals over a period of 6 weeks, received CT perfusion imaging of the brain upon initial presentation. The images were processed with two automated software platforms. We prospectively measured volumes of tissue with cerebral blood flow (CBF) &lt; 30% of contralateral hemisphere, Tmax &gt;6 secs, and hypoperfusion indices (defined as the ratio of volumes Tmax&gt;10 secs and Tmax&gt;6 secs). We compared the outputs of the two platforms and analyzed the performance of each platform. Results: 66 scans were included in our study. Both platforms were able to image all stroke patients within their FDA-approved indications. With regard to all scans, both platforms were noted to demonstrate comparable CBF&lt;30% volumes (6.32 ml. vs 4.97 ml, p=0.276), and hypoperfusion indices (0.278 vs 0.338, p=0.344). However, there was statistically significant discrepancy in the volumes of tissue with Tmax&gt;6 secs (23.96 vs 14.18 ml, p=0.023). Analysis of a subset of 12 scans, with evidence of LVO or severe symptomatic stenosis on corresponding CTA, showed again comparable CBF&lt;30% volumes (12.84 ml vs 13.67 ml, p=0.725), and hypoperfusion indices (0.344 vs 0.314, p=0.699). However, the Tmax&gt;6 secs volume discrepancy was greater and still statistically significant (75.54 ml vs 39.58 ml, p=0.048) Conclusions: Automated software platforms are an invaluable aid in the identification of salvageable tissue, and selection of patients for endovascular thrombectomy in the 6-24 hour window. However, the substantial difference in the identified volumes of hypoperfused tissue-at-risk may result in largely different clinical decisions and patient outcomes. Further validation efforts (and harmonization of algorithms) are required. Stroke teams should be aware of the limitations of automated analysis and need for expert review.

Abstract P377: Real-Word Performance of Two Automated Software Platforms for Large-Vessel Occlusion Identification in Acute Ischemic Stroke Patients: A Single Center Experience

Background and purpose: Modern stroke treatment has been revolutionized by image-guided selection of patients for endovascular thrombectomy. Current automated platforms allow for real-time identification of large vessel occlusion and salvageable brain tissue. We had previously demonstrated that a “CTA for all” policy for stroke patients immediately upon arrival assists in the earlier identification of treatment candidates. We now sought to evaluate the performance of these platforms under this policy. Methods: All patients that presented to Henry Ford Health System hospitals over a period of 6 weeks received CTA of the head and neck upon initial presentation. The images were processed with two automated software platforms. We prospectively collected processing times, large-vessel-occlusion alerts, performance warnings, and LVO density ratios. We compared these with the interpretations of board-certified radiologists, and analyzed the performance of each platform. Results: 276 patients presented with stroke symptoms and received CT angiography upon presentation. Both platforms were able to image all stroke patients within their FDA-approved indications. Both platforms were noted to have comparable sensitivity, specificity, PPV and NPV, and excellent accuracy. The overall prevalence of LVO was extremely low (8/276). As a result, for both, NPV was much better than PPV because of the percentage of false positive results. Further ROC analysis, demonstrated an area under the ROC curve of 0.982, and overall model quality of 0.97. Optimal LVO density cutoff was &lt;0.093 in order to maximize overall accuracy, or &lt; 0.271, in order to maintain a sensitivity of 100% as an absolute priority (both significantly lower than the current threshold of &lt;0.45). Conclusions: Automated software platforms are an invaluable aid in the selection of patients for endovascular thrombectomy. Different LVO detection algorithmic thresholds may be necessary (and should be part of individual stroke center validation pathways) to avoid fatigue alert, and optimize test accuracy, when LVO prevalence is low. Stroke teams should be aware of the limitations of automated analysis and need for expert review.

Abstract PS14-13: National comprehensive cancer network (NCCN) recommendations for drugs without US food and drug administration (FDA) approval in metastatic breast cancer: A cross-sectional study

Abstract Background: NCCN guidelines include recommendations not approved by the FDA. We aimed to compare the NCCN recommendations for metastatic breast cancer (MBC) with the FDA approved indications and to identify characteristics that are associated with NCCN recommendations for off-label treatment. Methods: All NCCN recommendations for MBC and their supporting data were identified. Drug labels were reviewed to determine whether recommendations are FDA approved indications. Odds ratio (OR) and 95% confidence interval (CI) were calculated to compare between FDA approved and off-label recommendations for pre-specified categories including drug type, tumor subtype, level of recommendation and line of therapy. Results: Of 124 recommendations identified, 68 (55%) were off-label. Chemotherapy and human epidermal growth factor receptor 2 (HER2) targeted drugs were associated with less frequent approved indications (OR=0.28, 95% CI 0.12-0.62, p=0.001 and OR=0.29, 95% CI 0.12-0.70, p=0.005, respectively). Recommendations for endocrine therapy (OR=3.44, 95% CI 1.32-9.09, p=0.009) and non-HER2 targeted treatment (OR=10.0, 95% CI 3.03-33.33, p&amp;lt;0.001) were associated with FDA approved indications. Compared to combination therapies, monotherapies were more likely to be FDA approved (OR=3.45, 95% CI 1.64-7.23, p=0.001). Category 1 (OR=7.63, 95% CI 2.19-26.55, p=0.001) and preferred NCCN recommendations (OR=5.49, 95% CI 2.36-12.77, p&amp;lt;0.001) were more likely to be FDA-approved indications. Compared to off-label recommendations, NCCN recommendations of approved drugs were based on significantly higher sample size (mean 477 vs. 342 patients, p=0.017) and were non- significantly associated with availability of randomized data (OR=1.92, 95% CI 0.87-4.24, p=0.10).Conclusion: More than half of all NCCN recommendations for MBC are off-label, mostly involving chemotherapy containing regimes for HER2 negative disease and combinations which include HER2 targeting drugs. The clarity of the NCCN guidelines can be improved by underlining the strength of the evidence supporting various recommendations for MBC and the hierarchy between various treatment options. Citation Format: Tal Etan, Eitan Amir, Adriana Tibau, Rinat Yerushalmi, Assaf Moore, Daniel Shepshelovich, Hadar Goldvaser. National comprehensive cancer network (NCCN) recommendations for drugs without US food and drug administration (FDA) approval in metastatic breast cancer: A cross-sectional study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-13.

Neurological Complications of Targeted Therapies and Immunotherapies for Cancer

Targeted therapies and immunotherapies for cancer are associated with a wide spectrum of neurological complications. This review summarizes the neurological toxicity associated with some of the most recently FDA-approved agents or indications. Neurological complications of oral small molecule inhibitors are generally rare or mild, though some recently approved receptor tyrosine kinase inhibitors display significant central nervous system toxicities. Immune checkpoint inhibitors are associated with many neurological adverse events, some fatal, and consensus guidelines have been established in regard to managing these complications. Finally, chimeric antigen receptor T cell therapy revolutionized the treatment of relapsed refractory leukemia and lymphoma but is associated with an immune effector cell-associated neurotoxicity syndrome. This review focuses on the characterization of neurotoxicities from targeted therapies and immunotherapies and recently reviewed recommendations for management. The neurological complications of new cancer therapies are a complex and rapidly evolving field though ongoing studies are shedding light on the mechanisms and best supportive care for these toxicities.

Immune checkpoint inhibitors: Significant advancements in non-small cell lung cancer treatment.

This article explores the efficacy, toxicity, place in therapy, and considerations for use of recently approved immune checkpoint inhibitors (ICIs) in the treatment of non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer mortality in the United States and is responsible for more cancer-related deaths than breast, prostate, and colorectal cancer combined. The landscape for lung cancer treatment is evolving with the approval of new and exciting novel therapies. Within the last decade numerous ICIs have been approved for use in the management of the most common subtype of lung cancer, NSCLC. The ICI agents currently approved by the Food and Drug Administration (FDA) for use in NSCLC include ipilimumab, pembrolizumab, nivolumab, durvalumab, and atezolizumab. These agents are approved for specific indications; therefore, they are not interchangeable. This review focuses on the landmark trials that led to each FDA-approved indication, as well as common toxicities seen with use of these agents. It also discusses the use of ICIs in special populations and unique considerations prior to initiation of treatment with these novel therapies in a patient with NSCLC. ICIs can provide a breakthrough treatment option for the management of NSCLC and are rapidly being adopted into clinical practice. It is important to be familiar with appropriate selection of an ICI therapy option for each patient based on approved indication, unique considerations, and anticipated toxicities.

Cefiderocol: a novel siderophore cephalosporin for multidrug-resistant Gram-negative bacterial infections.

Cefiderocol is a novel siderophore cephalosporin that forms a complex with extracellular free ferric iron, which leads to transportation across the outer cell membrane to exert its bactericidal activity through cell wall synthesis inhibition. This pharmacological property has rendered cefiderocol active against several clinically relevant MDR Gram-negative bacteria as evidenced by several in vitro and in vivo studies. Cefiderocol was first approved by the US FDA on 14 November 2019 for the treatment of complicated urinary tract infections. On 28 September 2020, cefiderocol was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. The FDA-approved indications are based on clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In APEKS-cUTI, cefiderocol demonstrated non-inferiority to imipenem/cilastatin for the treatment of complicated urinary tract infection caused by MDR Gram-negative bacteria. In APEKS-NP, cefiderocol demonstrated non-inferiority to meropenem for treatment of nosocomial pneumonia. However, in CREDIBLE-CR, higher all-cause mortality was observed with cefiderocol compared with best available therapy for the treatment of severe infections caused by Gram-negative bacteria, primarily in the subset of patients with Acinetobacter spp. infections. Several case reports/series have demonstrated clinical success with cefiderocol for a variety of severe infections. The purpose of this article is to review available data on the mechanism of action, in vitro and in vivo data, pharmacokinetics, pharmacodynamics, susceptibility testing, efficacy and safety of cefiderocol to address its role in therapy.

Does Biosimilar Bevacizumab Offer Affordable Treatment Options for Cancer Patients in the USA? A Budget Impact Analysis from US Commercial and Medicare Payer Perspectives.

BackgroundBevacizumab remains the most widely used and most thoroughly characterized angiogenesis inhibitor for a range of advanced cancers. Bevacizumab-bvzr (Zirabev®), a biosimilar of bevacizumab, was recently approved by the US Food and Drug Administration (FDA), which provides a less costly option. This study aimed to evaluate the financial impact of introducing bevacizumab-bvzr from US commercial and Medicare payer perspectives.MethodsA Microsoft Excel-based budget impact model was developed over a 5-year time horizon. Target population was patients to be treated with bevacizumab for FDA-approved indications. Drug costs (2020 US$) were based on average sales price and wholesale acquisition cost, accounting for payer-specific reimbursement models and provider settings. Drug dosing and duration were based on prescribing information and pivotal trial publications.ResultsIn a hypothetical 10-million-member health plan, 503 and 723 patients were estimated to be treated with bevacizumab in year 1 and year 5, respectively. Assuming an annual market shift of 1.7%, 3.6%, 6.7%, 9.4%, and 11.9% to bevacizumab-bvzr, an annual cost saving of $313,363 ($0.003 per member per month [PMPM]) was estimated for a commercial payer and $92,880 ($0.001 PMPM) for Medicare in year 1. Cumulative 5-year cost savings were $7,030,924 ($0.012 PMPM) for a commercial payer and $4,059,257 ($0.007 PMPM) for Medicare. More than half of the cost savings was attributed to patients with metastatic colorectal cancer.ConclusionsThe introduction of biosimilar bevacizumab-bvzr was estimated to provide substantial cost savings for US payers, which would allow additional patients access to bevacizumab treatment.

Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Acute Lymphoblastic Leukemia (B-ALL).

With the exploitation of adoptive immunotherapies, the outcomes of patients with relapsed and refractory B cell hematologic malignancies have seen drastic improvements. To this end, a paradigm shift away from toxic and ineffective chemotherapies has been visible with the FDA approval of genetically modified autologous T cell products designed to express chimeric antigen receptors able to specifically recognize the CD19 cell surface marker. To date, CAR-T cells have two FDA-approved indications including relapsed or refractory acute lymphoblastic leukemia in children and young adults as well as large B cell lymphoma that is relapsed and/or refractory to two prior therapies. This chapter will discuss the utility of this therapy in B-ALL, common toxicities and their management, relationship to other therapies such as stem cell transplantation, and future directions.

1577. Real-World, Multicenter Experience with Eravacycline for Various Infections

BackgroundEravacycline (ERV) is Food and Drug Administration approved in patients for the treatment of adults complicated intra-abdominal infections in 2018. Real-world data regarding the indications for ERV use are is limited. We evaluated the clinical/safety outcomes of patients treated with ERV in FDA and non-FDA approved indications.MethodsMulticenter, retrospective, observational study from September 2018 to June 2020. Adult patients treated with ERV for ³ 72 hours were included. The primary outcome was 30-day survival. Secondary outcomes included a lack of 30-day infection-recurrence, resolution of signs/symptoms of infection and safety. All outcomes were measured from ERV start date.ResultsOverall, 108 patients were included from 12 geographically-distinct medical centers across the United States. The median(IQR) age was 60(52-67) years and 60% were male. Median(IQR) APACHE II and Charlson Comorbidity scores were 15(11-21) and 3 (2-6), respectively. The most common sources of infection were intra-abdominal (32%), and respiratory (24%). Common pathogens included Acinetobacter baumannii (19%), Klebsiella pneumoniae and Enterococcus faecium (16%). Infectious diseases consultation was obtained in 98%, and surgical interventions in 51% of cases. Patients often received active therapy prior to ERV(40%). Median(IQR) ERV therapy duration was 7.7(4.4-14.0) days. Among cases with documented cultures, ERV was initiated within a median(IQR) of 4.8(2.5-9.9) days. Combination therapy ³ 48 hours was given in 45%. The primary endpoint was achieved in 79%(85/108). Of patients who died(n=23), 57% were on monotherapy, 39% were critically ill, 39% had intra-abdominal as a source, and 30% had positive blood cultures. For secondary outcomes, 94%(102/108) lacked 30-day infection-recurrence and 74%(80/108) resolved signs/symptoms of infection. ERV was selected primarily for consolidation of the regimen(40%). Eight patients experienced a probable ERV-related adverse event, mainly gastrointestinal(87.5%) and none experienced clostridium difficile.Conclusion30-day survival was achieved in the majority of patients treated with ERV. Studies with longer follow-up are required to confirm these findings.DisclosuresMadeline King, PharmD, Tetraphase (Speaker’s Bureau) Bruce M. Jones, PharmD, BCPS, ALK-Abello (Research Grant or Support)Allergan/Abbvie (Speaker’s Bureau) Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)

Comparing prescribing patterns for topical corticosteroids based on their FDA indication by age.

Atopic dermatitis (AD) affects up to 20% of the pediatric population, with a growing prevalence over the past 30years. Topical corticosteroids (TCS) are commonly used as a first-line topical therapy for AD and are prescribed in 59% of all AD visits. However, some topical corticosteroids are prescribed outside of their age range indications. This paper aims to explore the frequency with which topical corticosteroids are prescribed for AD outside of their FDA-approved age range. Data on prescribing patterns for AD were obtained from the National Ambulatory Medical Care Survey (NAMCS). We assessed the frequency of off-label use of topical corticosteroids with respect to age indications in four specific age-groups, as delineated in the data (0-1, 2-7, 8-18, and 19+years). All prescribed topical corticosteroids found in the NAMCS database have an indication for AD or other inflammatory dermatoses or pruritic dermatoses. However, some medications were prescribed outside of their FDA-approved age indications. These off-label prescription rates ranged from 52% for desoximetasone to 0% for halobetasol and alclometasone, or rates lower than could be detected by our study. Much like other medications for AD treatment, TCS are sometimes used off-label. The off-label use of topical corticosteroids to treat pediatric AD highlights a gap between clinical practice and regulating guidelines. Additional pediatric studies would offer a greater body of evidence to maintain or expand label indications for the use of TCS in younger patients.