Potential biomarkers in breast cancer drug development: application of the biomarker qualification evidentiary framework.

Breast cancer treatments have evolved rapidly, and clinically meaningful biomarkers have been used to guide therapy. These biomarkers hold utility within the drug development process to increase the efficiency and effectiveness. To this purpose, the US FDA developed an evidentiary framework. Literature searches conducted of literature published between 2016 and 2022 identified biomarkers in breast cancer. These biomarkers were reviewed for drug development utility through the biomarker qualification evidentiary framework. In the breast cancer setting, several promising biomarkers (ctDNA, Ki-67 and PIK3CA) were identified. There is a need for increased transparency regarding the requirements for qualification of specific biomarkers and increased awareness of the processes involved in biomarker qualification.

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Real-world drug utilization and treatment patterns in patients with tenosynovial giant cell tumors in the USA.

Aim: Real-world treatment patterns in tenosynovial giant cell tumor (TGCT) patients remain unknown. Pexidartinib is the only US FDA-approved treatment for TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Objective: To characterize drug utilization and treatment patterns in TGCT patients. Methods: In a retrospective observational study using IQVIA's linked prescription and medical claims databases (2018-2021), TGCT patients were stratified by their earliest systemic therapy claim (pexidartinib [N = 82] or non-FDA-approved systemic therapy [N = 263]). Results: TGCT patients treated with pexidartinib versus non-FDA-approved systemic therapies were predominantly female (61 vs 50.6%) and their median age was 47 and 54 years, respectively. Pexidartinib-treated patients had the highest 12-month probability of remaining on treatment (54%); 34.1% of pexidartinib users had dose reduction after their first claim. Conclusion: This study provides new insights into the unmet need, utilization and treatment patterns of systemic therapies for the treatment of TGCT patients.

Treatment patterns in patients with tenosynovial giant cell tumors in the USAThis database study is the first investigation of how drugs are used to treat patients with tenosynovial giant cell tumor (TGCT) in the real world. We researched adult TGCT patients from IQVIA's prescription and medical claims databases who started treatment with pexidartinib (N = 82) or other non-US FDA-approved systemic therapies (N = 263). The patients included in this analysis were mostly women (61.0 and 50.6%) and their median age was 47 and 54 years for pexidartinib and other non-FDA-approved systemic therapies, respectively. The patients treated with pexidartinib were most likely to remain on treatment (54.0%) at the end of the first year. Most patients (79.3%) started pexidartinib treatment at a total daily dose of 800 mg/day, as per the product label. Only 34.1% of patients had reduced medication dose during follow-up. Of note, this study found that TGCT patients were treated with other systemic therapies which remain unproven to be safe and effective in medical studies of TGCT. Given the unmet need, and with pexidartinib being the only approved systemic treatment in USA, there is an opportunity for the larger population of adult TGCT patients to benefit from its use. Further research is needed to identify barriers for access to pexidartinib and treatment of TGCT patients.

Real-world treatment patterns, healthcare resource utilization and costs among patients with peripheral T-cell lymphoma.

Objective: To evaluate treatment patterns, healthcare resource utilization (HRU) and costs among peripheral T-cell lymphoma (PTCL) patients in the USA. Methods: A retrospective cohort study, using the IQVIA PharMetrics® Plus claims database from 1 April 2011 to 30 November 2021, identified PTCL patients receiving systemic treatments. Three mutually exclusive subcohorts were created based on line of therapy (LOT): 1LOT, 2LOT and ≥3LOT. Common treatment regimens, median time on treatment, all-cause and PTCL-related HRU and costs were estimated. Results: Among 189 PTCL patients identified, 61.9% had 1LOT, 21.7% had 2LOT and 16.4% had ≥3LOT. The most common treatment regimens in the 1LOT were CHOP/CHOP-like, CHOEP/CHOEP-like and brentuximab vedotin; monotherapies were most common in the 2LOT and ≥3LOT. All-cause and PTCL-related hospitalizations and prescriptions PPPM increased with increasing LOT. Nearly 70% of total treatment costs were PTCL related. Conclusion: Higher utilization of combination therapies in the 1LOT and monotherapies in subsequent LOTs were observed, alongside high PTCL-related costs.

Peripheral T-cell lymphomas (PTCL) are a rare and fast-growing form of blood cancer. About 8000­12,000 people in the USA are diagnosed with PTCL every year. As it is a rare disease and has many types, and there is a limited understanding of the patients who have PTCL and the treatments they receive in the real world. The purpose of this study was to evaluate how these patients are treated, what are they treated with and what are the costs of these treatments in the USA. The data collected on these patients was divided into three groups based upon the number of lines of treatment/therapy (LOT) they received: 1LOT, 2LOT and ≥3LOT. This study researched different treatments and their duration in each line of therapy. Among 189 PTCL patients included in the study, the average age of patients was 55 years and 62% were male. Among these patients, 62% had 1LOT, 22% had 2LOT and 16% had ≥3LOT. The most common treatments in the 1LOT were traditional chemotherapy regimens followed by targeted therapies: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) or CHOEP-like, and brentuximab vedotin. Treatment regimens with only one drug were most common in the 2LOT and ≥3LOT. The total cost of PTCL treatment in the USA is very high; 70% of this cost is related to their treatment with various drugs. More research is needed to better understand the treatment and cost of this rare cancer.

Elderly patients with acute myeloid leukemia who only receive supportive care in the Surveillance, Epidemiology and End Results-Medicare database: demographics, treatment patterns and outcomes.

Aim: Elderly acute myeloid leukemia (AML) patients are often not treated with antileukemic therapy due to their poor overall health condition, leaving supportive care as the sole treatment option. Objective: To evaluate patient characteristics, treatment patterns and outcomes of elderly patients with AML who are treated with supportive care only. Methods: A retrospective analysis of elderly AML patients included in the Surveillance, Epidemiology and End Results-Medicare database from 2008 to 2015. Results: Of elderly patients with AML (n = 7665), 3209 (41.9%) received supportive care only. Their mean age was 79 years, 50.5% were males; 48.2% died during the first 3 months and 67.3% died during the first 6 months. 82.2% died within the first year; only 13.2% survived >12 months. 77.9% patients died due to leukemia. Conclusion: In elderly AML patients treated with supportive care only, older age, concurrent hypertension, chronic obstructive pulmonary disease, chronic kidney disease and acute myocardial infarction were identified as prognostic factors associated with decreased likelihood of survival. Ideally, these patients should be treated with antileukemic therapy in addition to supportive care, as most of them die from disease progression.

This study analyzed data on elderly patients with acute myeloid leukemia (AML) who were only treated with supportive care. The source of this data was the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Of the 7665 patients diagnosed with AML during 2008­2015, 3209 (41.9%) received supportive care only. Their mean age at index date was 79 years; slightly more than half of these were males (50.5%). Almost half of these patients (48.2%) died within the first 3 months and approximately two-thirds (67.3%) died within the first 6 months. Only a small proportion (13%) of these patients were alive after 1 year. These patients who were alive after one were likely to be in remission (there was decrease in the signs and symptoms of AML). The results of this study showed that elderly AML patients who only received supportive care were more likely to die early if they also had chronic kidney disease, chronic obstructive pulmonary disease, history of acute myocardial infarction or hypertension. As elderly AML patients may be in poor general health and have other diseases (comorbidities), this could be the reason why they may not be treated with antileukemic therapy. Instead of treatment with supportive care only, these patients should ideally receive antileukemic therapy in addition to supportive care. More research should be done to find alternate treatments for these elderly AML patients.

Incidence and Risk Factors for Development of Cardiac Toxicity in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia.

The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1-2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4-5 events. The 9-year CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 was 15%, and grade 5 was 2.1%; of grade 1-2, arrhythmia was 1.9%, grade 3-4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3-4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.

Characteristics and outcomes of elderly patients with acute myeloid leukemia who receive no treatment in the Surveillance, Epidemiology and End Results-Medicare database.

Background: Without treatment, acute myeloid leukemia (AML) is rapidly fatal. Nevertheless, a large proportion of elderly AML patients do not receive any treatment. Aim: To characterize the demographics, comorbidities, survival and prognostic factors of elderly AML patients who do not receive any AML treatment or supportive care (SC). Methods: A retrospective cohort analysis of the Surveillance, Epidemiology and End Results-Medicare database (2008-2015). Results: Of 7665 AML patients, 2373 (31%) did not receive any AML treatment or SC. The mean age was 80.4 years, 52.8% were males and 79.7% and 95.3% died within the first 60 and 180 days, respectively; 2.1% survived >12 months and only 5.5% of patients had remission or relapse codes populated. Conclusion: Older age, male gender, concurrent depression, ischemic heart disease, chronic kidney disease and benign prostatic hyperplasia were associated with a decreased likelihood of survival. Multiple factors contribute to the complex clinical status of these patients preventing intensive chemotherapy; they should still ideally be treated, at least with the best SC.

An analysis of the data collected in the Surveillance, Epidemiology and End Results-Medicare database from 2008 to 2015 was performed. This database includes data collected by a national cancer registry on people diagnosed with cancer in the United States and those who enroll in Medicare. This study focused on acute myeloid leukemia (AML) patients who did not receive any AML treatment or supportive care (SC). Of 7665 patients with AML, 2373 (31%) did not receive any AML treatment or SC. At the time the data was indexed for each patient in the database, their mean age was 80.4 years and around 53% were males. Within the first 60 days, around 80% of these patients died; over 95% died within the first 180 days. Only 2% of patients survived more than a year without treatment; these patients were likely in remission. Without treatment, AML patients who were older, were male or who also had depression, ischemic heart disease, chronic kidney disease or benign prostatic hyperplasia had a higher chance of dying early. There could be many reasons why these patients are not treated. The main reasons are their poor health condition and the presence of two or more health conditions in a patient at the same time (comorbidities). However, they should still ideally be treated, at least with the best SC. Additional treatment options are urgently needed for elderly AML patients who have comorbidities and are in poor general health.

Turalio risk evaluation and mitigation strategy for treatment of tenosynovial giant cell tumor: framework and experience.

For drugs with enhanced serious safety risks, Risk Evaluation and Mitigation Strategy (REMS) may be required. Pexidartinib is approved for treatment of adult symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its approval was conditional on its prescription via a mandatory REMS due to serious and potentially fatal liver injury seen in clinical trials. Turalio® REMS aims to mitigate this risk by ensuring provider education on pexidartinib use and required REMS components, prescriber adherence to baseline and periodic monitoring, and enrolling patients in a registry to further assess safe use and acute, chronic and irreversible hepatotoxicity. Through Turalio REMS, benefits of treating patients with pexidartinib may be preserved.

For drugs with serious side effects, specific safety measures may be put in place to manage these serious side effects in the form of Risk Evaluation and Mitigation Strategy (REMS) programs. Pexidartinib (Turalio^®) is approved for treatment of adults who have symptoms of severe tenosynovial giant cell tumor or have limitations in function that do not improve with surgery. Turalio^® has an REMS program because liver injuries that can be serious or fatal were seen in Pexidartinib clinical trials. This program aims to decrease the seriousness of the liver injuries by assuring doctors and pharmacists are educated on how to use the drug, patients are advised of this potential risk and that baseline and periodic monitoring of patients are conducted.

Industry Assessment of the Contribution of Patient Support Programs, Market Research Programs, and Social Media to Patient Safety.

BACKGROUND: Over the past decade, the volume of adverse events (AEs) reported to marketing authorization holders and regulators has been rapidly increasing each year, which has led to significant challenges in patient safety assessment. Three data sources that have largely contributed to the expansion in adverse event reports are patient support programs (PSPs), market research programs (MRPs), and social media. In this study, we sought to further understand the contribution of these safety data sources to the characterization of a product's safety profile. METHODS: Three separate approaches were taken that, when combined, can be used to evaluate each data source. The first identified any core company data sheet changes or drug safety label changes. The second evaluated the similarity of information through proportions of AEs between each solicited data source and spontaneous sources. Lastly, the completeness of information reported was evaluated through vigiGrade and compared across each data source. RESULTS: One drug safety label change was identified from a patient support program, which involved regular contact with health care providers. No label changes were identified from market research programs or social media. Patient support programs, market research programs, and social media report similar proportions for HLGT as spontaneous sources. Market research programs and social media display very low vigiGrade scores. When broken down by subtype, traditional PSPs display high vigiGrade scores, while patient assistance programs display lower vigiGrade scores that were program dependent. CONCLUSIONS: This study did not demonstrate that certain data sources such as market research programs, social media, and patient assistance programs meaningfully contributed to the further understanding of the characterization of a product's safety profile.

Risk Factors for and Incidence of Seizures in Metastatic Castration-Resistant Prostate Cancer: A Real-World Retrospective Cohort Study.

BACKGROUND AND OBJECTIVE: This real-world study assessed the prevalence, risk factors for, and incidence of seizures in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Patients with mCRPC were selected from MarketScan Commercial and Medicare Supplemental Databases between 1 January 2009 and 31 July 2012. Prevalence of seizure risk factors were described separately and in combination with other risk factors. Seizure incidence was calculated overall and for each risk factor group. RESULTS: The most common risk factors were history of seizure threshold-lowering medication use (35%), history of loss of consciousness (6%), history of transient ischemic attack or cerebrovascular accident (2%), treated brain metastasis (0.9%), history of seizure (0.6%), and dementia (0.5%). Overall, seizure incidence was 1.8 per 100 person-years (PYs) (95% confidence interval [CI] 1.5-2.1), being higher among patients with at least one risk factor (2.8 per 100 PYs; 95% CI 2.2-3.4) than those without risk factors (1.2 per 100 PYs; 95% CI 1.0-1.6). Seizure incidence was highest among a few patients (0.6%) with a history of seizure (82.0 per 100 PYs; 95% CI 45.9-135.2) and within this small subpopulation, higher among those with a history of anticonvulsant use (120.9 per 100 PYs; 95% CI 60.3-216.3) than without anticonvulsant use (43.5 per 100 PYs; 95% CI 11.9-111.3). CONCLUSION: History of seizure is an important risk factor for seizure occurrence in patients with mCRPC, particularly in those with a history of anticonvulsant use. These findings improve understanding of the risk of seizure occurrence in patients with mCRPC, who are potential users of androgen receptor antagonists, including enzalutamide.

Clinical characteristics of language regression in children.

The spectrum of language regression in childhood is incompletely understood. To describe the features of this disorder more fully, we reviewed the records of 196 consecutive children (143 males and 53 females) with language regression or perceived plateau evaluated between 1988 and 1994 by a child neurologist. Mean age at regression was 21.2 months and the mean interval to referral was 34.8 months. A trigger for the regression was identified in 74 of the children (38%) and was associated with a more rapid regression. Mean age at follow-up was 64 months (SD 55). Seventy per cent of the children became nonverbal, and 75% were cognitively impaired. Language regression was associated with a more global autistic regression in 93% of children. There was a history of seizures in 15% of the children. Some recovery occurred in 61% but only one child recovered fully. Improvement was more likely in the 49% who were entirely developmentally normal before the regression. We conclude that language regression in childhood is a serious disorder with significant long-term morbidity.