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Background: The optimal triage strategy for patients suspected of acute ischemic stroke due to large vessel occlusion (LVO) remains debated. We explored trends in presentation mode and their outcomes for mechanical thrombectomy (MT) hospitalizations based on the National Inpatient Sample (NIS) database., Methods: We retrospectively explored the NIS database from 2016 to 2020 for stroke hospitalizations with MT. We compared outcomes at discharge for MT hospitalizations with direct vs. transferred presentation. Outcomes comprised favorable discharge disposition (home without assistance), in-hospital mortality, and radiographic intracranial hemorrhage (ICH)., Results: This study included 100,865 patients undergoing MT, of whom 32,685 patients (32.4 %) were transferred (median age 71[60-81] years, 16775(51.2 %) women). The utilization of MT in the U.S. nearly doubled during the study period, whereas the proportion of in-hospital transfers for MT remained unchanged (32.1-33.2 %). White race, higher presenting NIHSS, hospital size, status, and location were independent predictors of transferred status. Transferred status was significantly associated with a lower likelihood of achieving favorable outcome (OR:0.80,95 % CI: [0.72,0.89],P<0.001) and a higher likelihood of ICH (OR:1.18, 95 % CI:[1.07,1.31],P=0.001), whereas no association was observed between presentation mode and in-hospital mortality (OR:1.07,95 % CI:[0.93,1.23],P=0.33)., Conclusion: Patients with direct presentation for MT after a stroke had better discharge outcomes and a lower risk of hemorrhagic transformation compared to those who were transferred from another facility. Determining the optimal triage strategy for MT following LVO stroke is an insightful area for future clinical trials., Competing Interests: Declaration of competing interest The authors declare no conflicting or competing interest in the subject matter of this manuscript, (Copyright © 2024. Published by Elsevier Inc.)

Anticancer agents can impair ovarian function, resulting in premature menopause and associated long-term health effects. Ovarian toxicity is not usually adequately assessed in trials of anticancer agents, leaving an important information gap for patients facing therapy choices. This American Society of Clinical Oncology (ASCO) statement provides information about the incorporation of ovarian toxicity measures in trial design. ASCO recommends: (1) measurement of ovarian toxicity in relevant clinical trials of anticancer agents that enrol post-pubertal, pre-menopausal patients; (2) collection of ovarian function measures at baseline and at 12-24 months after anticancer agent cessation, as a minimum, and later in line with the trial schedule; and (3) assessment of both clinical measures and biomarkers of ovarian function. ASCO recognises that routine measurement of ovarian toxicity and function in cancer clinical trials will add additional complexity and burden to trial resources but asserts that this issue is of such importance to patients that it cannot continue to be overlooked., Competing Interests: Declaration of interests WC reports honoraria from AstraZeneca, Pfizer, Merck Serono, and Eisai. RAA reports grants or contracts (research funding) and consulting fees from Roche Diagnostics. ND reports employment by AstraZeneca; grants or contracts (research funding) from Amgen, Novartis, Genentech, Lilly, Pfizer, Daiichi Sankyo, and Immunomedics; and travel, accommodations, expenses, and stock options from AstraZeneca. DS reports grants or contracts (research funding) from Janssen; consulting fees (advisory role) from Janssen Oncology, AstraZeneca, Boston Scientific, Bayer, Blue Earth, Varian Medical Systems, Pfizer, and Myovant Sciences; and honoraria from Varian Medical Systems. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background and Purpose: Reversible cerebral vasoconstriction syndrome (RCVS) is a well-established cause of stroke, but its demographics and outcomes have not been well delineated., Methods: Analysis of the United States Nationwide Inpatient Sample database (2016-2017) to characterize the frequency of hospitalizations for RCVS, demographic features, inpatient mortality, and discharge outcomes., Results: During the 2-year study period, 2020 patients with RCVS were admitted to Nationwide Inpatient Sample hospitals, representing 0.02 cases per 100 000 national hospitalizations. The mean age at admission was 47.6 years, with 85% under 65 years of age, and 75.5% women. Concomitant neurological diagnoses during hospitalization included ischemic stroke (17.1%), intracerebral hemorrhage (11.0%), subarachnoid hemorrhage (32.7%), seizure disorders (6.7%), and reversible brain edema (13.6%). Overall, 70% of patients were discharged home, 29.7% discharged to a rehabilitation facility or nursing home and 0.3% died before discharge. Patient features independently associated with the poor outcome of discharge to another facility or death were advanced age (odds ratio [OR], 1.04 [95% CI, 1.03-1.04]), being a woman (OR, 2.45 [1.82-3.34]), intracerebral hemorrhage (OR, 2.91 [1.96-4.31]), ischemic stroke (OR, 5.72 [4.32-7.58]), seizure disorders (OR, 2.61 [1.70-4.00]), reversible brain edema (OR, 6.26 [4.41-8.89]), atrial fibrillation (OR, 2.97 [1.83-4.81]), and chronic kidney disease (OR, 3.43 [2.19-5.36])., Conclusions: Projected to the entire US population, >1000 patients with RCVS are hospitalized each year, with the majority being middle-aged women, and about 300 required at least some rehabilitation or nursing home care after discharge. RCVS-related inpatient mortality is rare.

Objective: To describe the racial and gender distribution in antiseizure medications (ASM) clinical trials using a systemic review of clinical trial registry database., Methods: We searched ClinicalTrials.gov database for ASM trials registered from September 1988 to January 2019. All randomized and non-randomized trials investigating ASM for epilepsy were included. Trials with intervention other than ASM or condition other than epilepsy were excluded. Data on age, race, ethnicity, and gender were extracted directly from database and from published data where available. Study location, trial identifier, year of completion, and funding sources were also collected. Meta-analysis of proportions was conducted using R software., Result: Two hundred and thirty studies conducted globally with 39,576 participants were included. Overall, there are 53 % male on all registered ASM studies globally. For trials conducted in the United States (61 studies/5126 participants), 52 % of the participants were male with the following weighted racial distribution (80 % White 13 % Black 3% Asian 7% Hispanic). Subgroup analysis revealed that non-pharma-sponsored studies (50 studies, 4296 participants) have a higher representation of minorities as compared to pharma-sponsored studies (180 studies, 35,280 participants), including Hispanic (9% vs 3% respectively) and Black (18 % vs 11 % respectively). Temporal trends in racial distribution were noted when the duration of 2007-2019 was split into two groups: 2007-2013 (0% Asian, 5% Hispanic, 20 % Black); 2014-2019 (4% Asian, 7% Hispanic, 8% Black)., Conclusion: In this systematic review, participation of racial and ethnic minorities of Asian and Hispanic background was under-represented. Disparities of all minorities including Black participants was more notable over time and in studies sponsored by industry. Generalizability of ASM clinical trials to certain subgroups should be further examined., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: More than half of patients with acute ischemic stroke have minor neurological deficits; however, the frequency and outcomes of reperfusion therapy in regular practice has not been well-delineated., Methods: Analysis of US National Inpatient Sample of hospitalizations with acute ischemic stroke and mild deficits (National Institutes of Health Stroke Scale [NIHSS] score 0-5) from October 1, 2016, to December 31, 2017. Patient- and hospital-level characteristics associated with use and outcome of reperfusion therapies were analyzed. Primary outcomes included excellent discharge disposition (discharge to home without assistance); poor discharge disposition (discharge to facility or death); in-hospital mortality; and radiological intracranial hemorrhage., Results: Among 179 710 acute ischemic stroke admissions with recorded NIHSS during the 15-month study period, 103 765 (57.7%) had mild strokes (47.3% women; median age, 69 [interquartile range, 59-79] years; median NIHSS score of 2 [interquartile range, 1-4]). Considering reperfusion therapies among strokes with documented NIHSS, mild deficit hospitalizations accounted for 40.0% of IVT and 10.7% of mechanical thrombectomy procedures. Characteristics associated with IVT and with mechanical thrombectomy utilization were younger age, absence of diabetes, higher NIHSS score, larger/teaching hospital status, and Western US region. Excellent discharge outcome occurred in 48.2% of all mild strokes, and in multivariable analysis, was associated with younger age, male sex, White race, lower NIHSS score, absence of diabetes, heart failure, and kidney disease, and IVT use. IVT was associated with increased likelihood of excellent outcome (odds ratio, 1.90 [95% CI, 1.71-2.13], P <0.001) despite an increased risk of intracranial hemorrhage (odds ratio, 1.41 [95% CI, 1.09-1.83], P <0.001)., Conclusions: In national US practice, more than one-half of acute ischemic stroke hospitalizations had mild deficits, accounting for 4 of every 10 IVT and 1 of every 10 mechanical thrombectomy treatments, and IVT use was associated with increased discharge to home despite increased intracranial hemorrhage.

Importance: Comparative assessment of acute ischemic stroke care quality provided by hospitals in the United States has been hampered by the unavailability of the National Institutes of Health Stroke Scale (NIHSS) in administrative data sets, preventing adequate adjustment for variations in patient case-mix risk. In response to stakeholder concerns, the US Centers for Medicare & Medicaid Services in 2016 implemented optional reporting of NIHSS scores., Objective: To analyze the distributional, convergent, and predictive validity of nationally submitted NIHSS values in the National Inpatient Sample., Design, Setting, and Participants: This population-based retrospective cross-sectional study took place from October 1 to December 31, 2016. The nationally representative sample included US adults who had ischemic stroke hospitalizations during the first calendar quarter in which optional NIHSS reporting was implemented. Analysis began September 2019., Main Outcomes and Measures: Distribution of NIHSS scores, functional independence at discharge, inpatient mortality, and administrative reporting of NIHSS., Results: Among 154 165 ischemic stroke hospitalizations during the first 3 months of the reporting policy, NIHSS scores were reported in 21 685 patients (14%) (10 925 women [50.4%]; median [interquartile range] age, 72 [61-82] years). Median (interquartile range) NIHSS score was 4 (2-11), and frequency of severity categories included absent (NIHSS score, 0) in 2080 patients (9.6%), minor (NIHSS score, 1-4) in 8760 patients (40.4%), and severe (NIHSS score, 21-42) in 1930 patients (8.9%). National Institutes of Health Stroke Scale score of 10 or more, an indicator of possible large vessel occlusions, was present in 6290 patients (29%). Presenting NIHSS score was higher in very elderly patients (age ≥80 y) and women and also in patients receiving endovascular thrombectomy vs intravenous thrombolysis alone vs no reperfusion therapy (median [interquartile range], 17 [12-22] vs 6 [4-12] vs 4 [2-9], respectively) (P < .001). National Institutes of Health Stroke Scale scores were similarly higher for discharge outcomes of mortality vs discharge to skilled nursing facility vs discharge home (median [interquartile range], 19 [12-25] vs 7 [3-15] vs 2 [1-5], respectively) (P < .001). Likelihood of NIHSS scores being reported independently increased with interfacility transfer, receipt of acute reperfusion therapies, larger hospital size, academic centers, and region other than the West., Conclusions and Relevance: In the initial national optional reporting period in the United States, NIHSS scores were reported in nearly 1 in 7 ischemic stroke hospitalizations. The distribution of NIHSS scores was similar to that from narrow population-based studies and registries, and NIHSS scores were powerfully associated with discharge outcome, supporting the validity and potential to aid care quality assessment.

A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of development, product type, sponsors' regulatory experience, and occurrence of a pre-IND meeting. INDs that were placed on hold were mostly for first-in-human trials or submitted by sponsors with limited regulatory experience. INDs that went on hold or were safe-to-proceed had pre-IND meetings with comparable rates but sponsors with substantial experience appeared to benefit more from pre-IND meetings compared to those with limited experience. The time interval between the pre-IND meeting and the IND submission was longer for INDs that went on hold. To obtain useful FDA feedback on product development, it is essential to provide focused questions and supporting information in pre-IND meeting packages., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose- Recent landmark trials provided overwhelming evidence for effectiveness of endovascular stroke therapy (EST). Yet, the impact of these trials on clinical practice and effectiveness of EST among lower volume centers remains poorly characterized. Here, we determine population-level patterns in EST performance in US hospitals and compare EST outcomes from higher versus lower volume centers. Methods- Using validated diagnosis codes from data on all discharges from hospitals and Emergency Rooms in Florida (2006-2016) and the National Inpatient Sample (2012-2016) we identified patients with acute ischemic stroke treated with EST. The primary end point was good discharge outcome defined as discharge to home or acute rehabilitation facility. Multivariate regressions adjusted for medical comorbidities, intravenous tPA (tissue-type plasminogen activator) usage and annual hospital stroke volume were used to evaluate the likelihood of good outcome over time and by annual hospital EST volume. Results- A total of 3890 patients (median age, 73 [61-82] years, 51% female) with EST were identified in the Florida cohort and 42 505 (median age, 69 [58-79], 50% female) in the National Inpatient Sample. In both Florida and the National Inpatient Sample, the number of hospitals performing EST increased continuously. Increasing numbers of EST procedures were performed at lower annual EST volume hospitals over the studied time period. In adjusted multivariate regression, there was a continuous increase in the likelihood of good outcomes among patients treated in hospitals with increasing annual EST procedures per year (odds ratio, 1.1; 95% CI, 1.1-1.2 in Florida and odds ratio, 1.3; 95% CI, 1.2-1.4 in National Inpatient Sample). Conclusions- Analysis of population-level datasets of patients treated with EST from 2006 to 2016 demonstrated an increase in the number of centers performing EST, resulting in a greater number of procedures performed at lower volume centers. There was a positive association between EST volume and favorable discharge outcomes in EST-performing hospitals.

On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%-74.5%]. The median DOR was 17.5 months (95% CI, 15.8-not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%-72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥ 30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea., (©2015 American Association for Cancer Research.)

Antibody-drug conjugates (ADCs) are complex molecules composed of monoclonal antibodies conjugated to potent cytotoxic agents through chemical linkers. Because of this complexity, sponsors have used different approaches for the design of nonclinical studies to support the safety evaluation of ADCs and first-in-human (FIH) dose selection. We analyzed this data with the goal of describing the relationship between nonclinical study results and Phase 1 study outcomes. We summarized the following data from investigational new drug applications (INDs) for ADCs: plasma stability, animal study designs and toxicities, and algorithms used for FIH dose selection. Our review found that selecting a FIH dose that is 1/6th the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys or 1/10th the STD10 in rodents scaled according to body surface area (BSA) generally resulted in the acceptable balance of safety and efficient dose-escalation in a Phase 1 trial. Other approaches may also be acceptable, e.g. 1/10th the HNSTD in monkeys using BSA or 1/10th the NOAEL in monkeys or rodents using body weight for scaling. While the animal data for the vc-MMAE platform yielded variable range of HNSTDs in cynomolgus monkeys, MTDs were in a narrow range in patients, suggesting that for ADCs sharing the same small molecule drug, linker and drug:antibody ratio, prior clinical data can inform the design of a Phase 1 clinical trial., (Published by Elsevier Inc.)

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval., (©2014 American Association for Cancer Research.)

The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65-83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23-42%). For patients with sALCL, ORR was 86% (95% CI, 77-95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44-70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen., (©2012 AACR.)

On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2). The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (study 1) or 48 weeks (study 2). The key secondary endpoint in study 1 was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a ≥ 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001). Ruxolitinib treatment was associated with an increased incidence of grades III and IV anemia, thrombocytopenia, and neutropenia. This is the first drug approved for myelofibrosis., (©2012 AACR.)

Purpose: On December 15, 2008, the US Food and Drug Administration approved plerixafor (Mozobil; Genzyme Corp.), a new small-molecule inhibitor of the CXCR4 chemokine receptor, for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This summary reviews the database supporting this approval., Experimental Design: The safety and efficacy of plerixafor were demonstrated by 2 multicenter, randomized, placebo-controlled studies in patients with NHL and MM who were eligible for autologous HSC transplantation. The primary efficacy end points were the collection of > or = 5 x 10(6) CD34+ cells/kg from the peripheral blood in 4 or fewer apheresis sessions in patients with NHL or > or = 6 x 10(6) CD34+ cells/kg from the peripheral blood in 2 or fewer apheresis sessions in patients with MM., Results: The 2 randomized studies combined enrolled 600 patients (298 with NHL and 302 with MM). Fifty-nine percent of patients with NHL who were mobilized with G-CSF and plerixafor had peripheral blood HSC collections of > or = 5 x 10(6) CD34+ cells/kg in 4 or fewer apheresis sessions, compared with 20% of patients with NHL who were mobilized with G-CSF and placebo (p < 0.001). Seventy-two percent of patients with MM who were mobilized with Mozobil and G-CSF had peripheral blood HSC collections of > or = 6 x 10(6) CD34+ cells/kg in 2 or fewer apheresis sessions, compared with 34% of patients with MM who were mobilized with placebo and G-CSF (p < 0.001). Common adverse reactions included diarrhea, nausea, vomiting, flatulence, injection site reactions, fatigue, arthralgia, headache, dizziness, and insomnia., Conclusions: This report describes the Food and Drug Administration review supporting the approval of plerixafor., (Copyright 2010 S. Karger AG, Basel.)

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, "Nonclinical Aspects of Biopharmaceutical Development," industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.

Purpose: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval., Experimental Design: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response., Results: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention., Conclusions: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.