Dose Optimization of Targeted Therapies for Oncologic Indications.

Therapeutic advances in oncology in the 21st century have contributed to significant declines in cancer mortality. Notably, targeted therapies comprised the largest proportion of oncology drugs approved by the United States (US) Food and Drug Administration (FDA) over the past 25 years and have become the standard of care for the treatment of many cancers. However, despite the metamorphosis of the therapeutic landscape, some aspects of cancer drug development have remained essentially unchanged.

FDA Approvals of Oncology Drugs for Tissue-Agnostic Indications.

Background: The development of molecularly targeted oncology drugs for tissue-agnostic indications represents a new paradigm, but marketing authorization may carry additional risks due to uncertainties about extrapolating drug safety and efficacy, and biomarker test accuracy, to unstudied tumor types.

Objective: To determine tumor types represented and method of mutation identification in trials supporting the US Food and Drug Administration (FDA) approvals of tissue-agnostic drugs, and to describe post-marketing requirements and commitments (PMRs/PMCs) issued for studies to evaluate additional tumor types and to validate companion diagnostic devices.

Methods: For each tissue-agnostic drug approval identified via the FDA's Hematology/Oncology Approvals and Safety Notifications website, prescribing information, approval packages, and letters were retrieved from the Drugs@FDA website.

The use of real-world evidence to support FDA post-approval study requirements for oncology drugs.

Background: The 21 Century Cures Act of 2016 included provisions for the Food and Drug Administration (FDA) to evaluate the potential for real-world evidence (RWE) to support or fulfill post-approval study requirements. This study reviewed post-marketing requirement (PMR) and post-marketing commitment (PMC) obligations for oncology drugs approved by the FDA post-Cures Act to identify those with RWE components.

Methods: Approval letters issued by the FDA between 2017-2020 for oncology drugs were systematically analyzed for PMRs or PMCs with requests for RWE.

The RACE for children act at one year: progress in pediatric development of molecularly targeted oncology drugs.

Background: The Research to Accelerate Cures and Equity (RACE) for Children Act of 2017 authorized the Food and Drug Administration (FDA) to require pediatric clinical trials for new oncology drugs with relevant molecular targets. This study reviewed oncology drug approvals within the first year after the new legislation came into effect, to evaluate the impact on development of molecularly targeted oncology drugs for pediatric cancers.

Research Design And Methods: For new oncology drugs approved by the FDA between 08/18/2020 and 08/18/2021, drug approval packages, letters, and prescribing information were reviewed for the submission and approval dates, indication, and molecular target of the drug, and post-marketing requirements that included pediatric clinical trials.

Impact of social determinants of health on cancer care: a survey of community oncologists.

Objective: Cancer survival rates have improved over the past few decades, yet socioeconomic disparities persist. Social determinants of health (SDOH) have consistently been shown to correlate with health outcomes. The objective of this study was to characterise oncologists' perceptions of the impact of SDOH on their patients, and their opinions on how these effects could be remediated.

Impact of Augmented Intelligence on Utilization of Palliative Care Services in a Real-World Oncology Setting.

Purpose: For patients with advanced cancer, timely referral to palliative care (PC) services can ensure that end-of-life care aligns with their preferences and goals. Overestimation of life expectancy may result in underutilization of PC services, counterproductive treatment measures, and reduced quality of life for patients. We assessed the impact of a commercially available augmented intelligence (AI) tool to predict 30-day mortality risk on PC service utilization in a real-world setting.

Augmented intelligence to predict 30-day mortality in patients with cancer.

An augmented intelligence tool to predict short-term mortality risk among patients with cancer could help identify those in need of actionable interventions or palliative care services. An algorithm to predict 30-day mortality risk was developed using socioeconomic and clinical data from patients in a large community hematology/oncology practice. Patients were scored weekly; algorithm performance was assessed using dates of death in patients' electronic health records.

Expanded Access and Right To Try Requests: The Community Oncologist's Experience.

Purpose: For patients with cancer who have exhausted approved treatment options and for whom appropriate clinical trials are not available, access to investigational drugs through the US Food and Drug Administration's Expanded Access (EA) program has been an alternative since the program's inception more than 30 years ago. In 2018, federal Right To Try legislation was passed in the United States, creating a second pathway-one that bypasses the US Food and Drug Administration-to obtain unapproved drugs outside of clinical trials. The use of the two programs by community medical oncologists and hematologist-oncologists has not been studied.

Comparison of Solid Tumor Treatment Response Observed in Clinical Practice With Response Reported in Clinical Trials.

Importance: In clinical trials supporting the regulatory approval of oncology drugs, solid tumor response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Calculation of RECIST-based responses requires sequential, timed imaging data, which presents challenges to the method's application in real-world evidence research.

Objective: To evaluate the feasibility and validity of a novel real-world RECIST method in assessing tumor burden associated with therapy for a large heterogeneous patient population undergoing treatment in routine clinical practice.

Use of Real-World Evidence to Support FDA Approval of Oncology Drugs.

Objectives: Real-world evidence (RWE) has gained increased attention in recent years as a complement to traditional clinical trials. The use of RWE to establish the efficacy of oncology drugs for Food and Drug Administration (FDA) approval has not been described. In this paper, we review 5 recent examples where RWE was submitted in support of the FDA approvals of original or supplementary indications for oncology drugs.

Neurological adverse events following CAR T-cell therapy: a real-world analysis.

To characterize real-world neurological adverse events (AEs) associated with chimeric antigen receptor T-cell therapies in patients with refractory/relapsed large B-cell lymphomas. Postmarketing case reports from the US FDA AEs reporting system involving axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for large B-cell lymphomas were analyzed. Of 804 AE cases identified (637 axi-cel, 167 tisa-cel), 428 (67%) of axi-cel cases and 43 (26%) of tisa-cel cases reported neurological AEs.

Real-world adverse events associated with CAR T-cell therapy among adults age ≥ 65 years.

Introduction: Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory large B-cell lymphoma (LBCL) with the Food and Drug Administration (FDA) approvals of axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel). Although the incidence of LBCL is highest among patients age ≥ 65, clinical trials supporting approval of these 2 products primarily enrolled younger patients. Safety data for axi-cel and tis-cel in older patients is limited.

Surrogate End Points and Patient-Reported Outcomes for Novel Oncology Drugs Approved Between 2011 and 2017.

This review of novel oncology drugs approved by the US Food and Drug Administration examines the use of surrogate end points for overall survival, evaluates the use of patient-reported outcomes in trials supporting approvals, and seeks to determine whether drugs initially approved without evidence of overall survival or patient-reported outcome benefits demonstrate improvements in either measure postapproval.

Fulfillment of Postmarketing Requirements to the FDA for Therapies Granted Oncology Indications Between 2011 and 2016.

This data analysis examines the fulfillment of postmarketing requirements associated with drugs granted accelerated approval for oncology indications in the past 6 years.

The safety and effectiveness of adenosine diphosphate receptor inhibitor pretreatment among acute myocardial infarction patients treated with percutaneous coronary intervention in community practice: Insights from the TRANSLATE-ACS study.

Objectives: To understand the optimal timing of adenosine diphosphate (ADP) receptor inhibitor pretreatment prior to percutaneous coronary intervention (PCI) among acute myocardial infarction (MI) patients.

Background: The role of ADP receptor inhibitor pretreatment in this population is unclear.

Methods: A total of 9,251 ADP receptor inhibitor-naïve MI patients undergoing PCI at 229 TRANSLATE-ACS sites were evaluated.

Multivessel Versus Culprit Vessel-Only Percutaneous Coronary Intervention Among Patients With Acute Myocardial Infarction: Insights From the TRANSLATE-ACS Observational Study.

Background: Among patients with acute myocardial infarction (MI) who have multivessel disease, it is unclear if multivessel percutaneous coronary intervention (PCI) improves clinical and quality-of-life outcomes compared with culprit-only intervention. We sought to compare clinical and quality-of-life outcomes between multivessel and culprit-only PCI.

Methods And Results: Among 6061 patients with acute MI who have multivessel disease in the TRANSLATE-ACS (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study, we used inverse probability-weighted propensity adjustment to study the associations between multivessel and culprit-only intervention during the index PCI and major adverse cardiovascular events, unplanned all-cause readmission, and angina frequency at 6 weeks and 1 year.

Association of measured platelet reactivity with changes in P2Y receptor inhibitor therapy and outcomes after myocardial infarction: Insights into routine clinical practice from the TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study.

Background: Little is known about the use of platelet function testing to guide choice of P2Y receptor inhibitor therapy in routine clinical practice.

Methods: We studied 671 myocardial infarction (MI) patients treated with percutaneous coronary intervention in the TRANSLATE-ACS Registry who had VerifyNow platelet function testing performed while on clopidogrel treatment during their index hospitalization (April 2010-October 2012).

Results: High platelet reactivity (>208 platelet reactivity units [PRU]) was present in 261 (38.

Switching of adenosine diphosphate receptor inhibitor after hospital discharge among myocardial infarction patients: Insights from the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study.

Unlabelled: The reasons for postdischarge adenosine diphosphate receptor inhibitor (ADPri) switching among patients with myocardial infarction (MI) are unclear. We sought to describe the incidence and patterns of postdischarge ADPri switching among patients with acute MI treated with percutaneous coronary intervention.

Methods: We used TRANSLATE-ACS (2010-2012) data to assess postdischarge ADPri switching among 8,672 MI patients discharged after percutaneous coronary intervention who remained on ADPri therapy 1 year post-MI.

Impact of Proton Pump Inhibitor Use on the Comparative Effectiveness and Safety of Prasugrel Versus Clopidogrel: Insights From the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.

Background: Proton pump inhibitors (PPIs) reduce gastrointestinal bleeding events but may alter clopidogrel metabolism. We sought to understand the comparative effectiveness and safety of prasugrel versus clopidogrel in the context of proton pump inhibitor (PPI) use.

Methods And Results: Using data on 11 955 acute myocardial infarction (MI) patients treated with percutaneous coronary intervention at 233 hospitals and enrolled in the TRANSLATE-ACS study, we compared whether discharge PPI use altered the association of 1-year adjusted risks of major adverse cardiovascular events (MACE; death, MI, stroke, or unplanned revascularization) and Global Use of Strategies To Open Occluded Arteries (GUSTO) moderate/severe bleeding between prasugrel- and clopidogrel-treated patients.

Early Cessation of Adenosine Diphosphate Receptor Inhibitors Among Acute Myocardial Infarction Patients Treated With Percutaneous Coronary Intervention: Insights From the TRANSLATE-ACS Study (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome).

Background: Guidelines recommend the use of adenosine diphosphate receptor inhibitor (ADPri) therapy for 1 year postacute myocardial infarction; yet, early cessation of therapy occurs frequently in clinical practice.

Methods And Results: We examined 11 858 acute myocardial infarction patients treated with percutaneous coronary intervention discharged alive on ADPri therapy from 233 United States TRANSLATE-ACS study (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) participating hospitals to determine the prevalence of early ADPri cessation (within 1 year), patient-reported reasons for cessation, and associated risk of major adverse cardiovascular events at 1 year. Overall, 2514 (21.

Factors Associated With Initial Prasugrel Versus Clopidogrel Selection for Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Insights From the Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.

Background: Few studies have examined how antiplatelet therapies are selected during the routine care of acute myocardial infarction patients, particularly relative to the patient's estimated mortality and bleeding risks.

Methods And Results: We examined patients presenting with acute myocardial infarction treated with percutaneous coronary intervention at 233 US hospitals in the TRANSLATE-ACS observational study from April 2010 to October 2012. We developed a multivariable logistic regression model to identify factors associated with prasugrel selection.

Comparing Inverse Probability of Treatment Weighting and Instrumental Variable Methods for the Evaluation of Adenosine Diphosphate Receptor Inhibitors After Percutaneous Coronary Intervention.

Importance: There is increasing interest in performing comparative effectiveness analyses in large observational databases, yet these analyses must adjust for treatment selection issues.

Objectives: To conduct comparative safety and efficacy analyses of prasugrel vs clopidogrel bisulfate after percutaneous coronary intervention and to evaluate inverse probability of treatment weighting (a propensity score method) and instrumental variable methods.

Design, Setting, And Participants: This study used data from the Treatment With Adenosine Diphosphate Receptor Inhibitors-Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study.

How Reliable are Patient-Reported Rehospitalizations? Implications for the Design of Future Practical Clinical Studies.

Background: Longitudinal clinical investigations often rely on patient reports to screen for postdischarge adverse outcomes events, yet few studies have examined the accuracy of such patient reports.

Methods And Results: Patients with acute myocardial infarction (MI) in the TRANSLATE-ACS study were asked during structured interviews at 6 weeks, 6 months, and 12 months postdischarge to report any rehospitalizations. The accuracy of patient-reported rehospitalizations within 1 year of postdischarge was determined using claims-based medical bill validation as the reference standard.

Outcomes of Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention Receiving an Oral Anticoagulant and Dual Antiplatelet Therapy: A Comparison of Clopidogrel Versus Prasugrel From the TRANSLATE-ACS Study.

Objectives: The purpose of this study was to determine whether bleeding risk varies depending on which P2Y12 receptor inhibitor agent is used.

Background: Prior studies have shown significant bleeding risk among patients treated with triple therapy (i.e.