The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib ...and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.
In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.
At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval CI, 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.
Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).
Purpose
To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients ...with BRAF V600 metastatic melanoma.
Experimental design
Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure trough (
C
min
) or average concentration on response rates and progression-free survival (PFS) was examined.
Results
Plasma concentrations (
n
= 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed
C
min
above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL).
Conclusions
No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.
Daratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 ...inhibitor, in RRMM.
This open-label, multiphase study enrolled adults with RRMM with ≥ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses.
Nine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee’s global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ≥ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ≥ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%.
No new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination.
Patients with relapsed or refractory multiple myeloma have an immunosuppressive state with upregulation of programmed death receptor-1 on immune effector cells. Treatment with daratumumab plus cetrelimab, which targets the programmed death receptor-1, was evaluated in 9 patients with relapsed or refractory multiple myeloma. No new safety concerns were identified for the combination. The potential clinical benefit of daratumumab plus cetrelimab remains uncertain.
In the ALCYONE trial, daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) reduced the risk of disease progression or death by 50% versus bortezomib, melphalan, and prednisone (VMP) in ...patients with transplant-ineligible newly diagnosed multiple myeloma. Here, we report a subanalysis of East Asian patients from ALCYONE. After a median follow-up of 17.1 and 15.9 months for Japanese (
n
= 50) and Korean (
n
= 41) patients, respectively, median progression-free survival for D-VMP versus VMP was not reached (NR) versus 20.7 months in Japanese patients and NR versus 14.0 months in Korean patients. The overall response rate for D-VMP versus VMP was 96% versus 92% in Japanese patients and 91% versus 61% in Korean patients. Using next-generation sequencing, minimal residual disease negativity at 10
−5
sensitivity for D-VMP versus VMP was 33% versus 8% among Japanese patients and 17% versus 0% among Korean patients. Rates of any grade and grade 3/4 pneumonia were consistent with the rates observed for the global safety population. Similar efficacy and safety findings were observed in the combined Japanese and Korean subgroup and ≥ 75 years of age subgroup. In conclusion, D-VMP was safe and efficacious in East Asian patients, consistent with the global ALCYONE population.
Introduction
VMP is a standard of care (SOC) for transplant ineligible NDMM. Daratumumab (D), a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and multifaceted immunomodulatory ...mechanism of action significantly improves PFS and depth of response in combination with SOC in relapsed MM. Treatment-naïve pts may benefit greatly with the addition of D to SOC regimens. Here we report the results from the ALCYONE study, where D is added to VMP in transplant ineligible NDMM.
Methods
Pts ≥65 years or otherwise ineligible for high-dose chemotherapy with autologous stem cell transplantation were randomized 1:1 to VMP ± D and stratified by International Staging System (ISS I, II, III), region (Europe vs other) and age (<75 vs ≥75 years). All pts received up to a maximum of nine 6-week cycles of VMP. V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, 32 (Cycle 1) and Days 1, 8, 22, and 29 (Cycles 2-9); M: 9 mg/m2 PO and P: 60 mg/m2 PO on Days 1-4 (Cycles 1-9). In the D-VMP arm, D was given at 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ (post VMP-treatment phase) until disease progression. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, minimal residual disease (MRD)-negativity rate (10-5 threshold, Adaptive clonoSEQ® Assay), overall survival (OS), and safety.
Results
Of 706 pts randomized (350 D-VMP; 356 VMP), median (range) age was 71 (40-93) years; 29.9% were ≥75 years; 46.3% were male. 74.9% of pts had ECOG scores ≥1, and 19.3%, 42.4%, and 38.4% were ISS stage I, II, and III, respectively. Of 616 pts evaluable for FISH/karyotyping cytogenetic analysis, 84.1% and 15.9% were standard and high risk (positive for del17p, t14;16, t4;14), respectively. At the timepoint of the prespecified analysis after 231 PFS events on 12 June 2017, pts had received a median (range) of 12 (1-24) vs 9 (1-9) treatment cycles for D-VMP vs VMP, respectively. 80% of pts in the D-VMP arm completed 9 treatment cycles of VMP vs 62% of pts in the VMP arm. Median (range) cumulative bortezomib doses were 46.9 (1.3-55.3) mg/m2 vs 42.2 (2.6-55.0) mg/m2 for D-VMP vs VMP, respectively.
At a median follow-up of 16.5 months, the hazard ratio for PFS (D-VMP vs VMP) was 0.50 (95% confidence interval, 0.38-0.65, P <0.0001), representing a 50% reduction in the risk of progression or death in pts treated with D-VMP (Figure). Median PFS was not reached vs 18.1 months for D-VMP vs VMP. The PFS treatment benefit of D-VMP vs VMP was consistent across all pre-specified subgroups, including age ≥75 years, ISS stage III, and high-risk cytogenetics. ORR (90.9% vs 73.9%), ≥VGPR (71.1% vs 49.7%), ≥CR (42.6% vs 24.4%) and MRD-negativity rate (22.3% vs 6.2%) were significantly higher for D-VMP vs VMP (all P < 0.0001; Table). OS data were immature after 93 deaths (45 vs 48 deaths for D-VMP vs VMP).
The most common (≥20%) all-grade treatment emergent adverse events (TEAE; D-VMP/VMP) were neutropenia (49.7%/52.5%), thrombocytopenia (48.8%/53.7%), anemia (28.0%/37.6%), peripheral sensory neuropathy (28.3%/34.2%), upper respiratory tract infection (26.3%/13.8%), diarrhea (23.7%/24.6%), pyrexia (23.1%/20.9%), and nausea (20.8%/21.5%). Most common (≥10%) grade 3/4 TEAEs (D-VMP/VMP) were neutropenia (39.9%/38.7%), thrombocytopenia (34.4%/37.6%), anemia (15.9%/19.8%), and pneumonia (11.3%/4.0%). Only 1 pt in each arm discontinued treatment due to pneumonia. The rates of grade 3/4 infections were 23.1% vs 14.7% and treatment discontinuations due to infections were 0.9% vs 1.4% for D-VMP vs VMP. D-associated infusion-related reactions (27.7%) mostly were grade 1/2 (grade 3/4, 4.3%/0.6%) and most (92.7%) occurred during the first infusion. Tumor lysis syndrome occurred in <1% of pts in each arm. Second primary malignancy occurred in 2.3% vs 2.5% pts in D-VMP vs VMP.
Conclusion
The combination of D with VMP in transplant ineligible NDMM pts doubled the PFS (HR 0.50), which was driven by more pts achieving deep responses, including significantly higher ≥CR rate and tripling of the MRD-negativity rate. No new safety signals were observed when combining D with VMP. Three phase 3 studies have now demonstrated a consistent doubling of PFS and more than threefold increase in MRD-negativity rate when combining D with SOC regimens. These results support the use of a D-based combination, D-VMP, in transplant ineligible NDMM.
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Mateos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology. Cavo:Celgene:: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Suzuki:Bristol Myers Squibb: Honoraria; Novarltis: Honoraria; Celgene: Honoraria; Ono Pharmaceuticals: Honoraria; Fujimoto: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Jakubowiak:Amgen Inc., BMS, Celgene, Janssen, Karypharm, Millennium-Takeda, Sanofi, SkylineDX: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Chicago: Employment. Knop:Bristol-Myers Squibb Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Janssen Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees. Doyen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lucio:Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy. Cook:Amgen: Honoraria, Other: Travel support; Takeda: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding. Garg:Janssen: Other: travel support, Research Funding, Speakers Bureau; Takeda: Other: travel support; Novartis: Other: travel support, Research Funding. Chiu:Janssen: Employment. Wang:Janssen: Employment. Carson:Janssen: Employment. Crist:Janssen: Employment. Deraedt:Janssen: Employment. Nguyen:Janssen: Employment. Qi:Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. San-Miguel:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cilag: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Inappropriate antimicrobial drug use is associated with adverse events in hospitalized patients and contributes to the emergence and spread of resistant pathogens. Targeting effective interventions ...to improve antimicrobial use in the acute care setting requires understanding hospital prescribing practices.
To determine the prevalence of and describe the rationale for antimicrobial use in participating hospitals.
One-day prevalence surveys were conducted in acute care hospitals in 10 states between May and September 2011. Patients were randomly selected from each hospital's morning census on the survey date. Data collectors reviewed medical records retrospectively to gather data on antimicrobial drugs administered to patients on the survey date and the day prior to the survey date, including reasons for administration, infection sites treated, and whether treated infections began in community or health care settings.
Antimicrobial use prevalence, defined as the number of patients receiving antimicrobial drugs at the time of the survey divided by the total number of surveyed patients.
Of 11,282 patients in 183 hospitals, 5635 (49.9%; 95% CI, 49.0%-50.9%) were administered at least 1 antimicrobial drug; 77.5% (95% CI, 76.6%-78.3%) of antimicrobial drugs were used to treat infections, most commonly involving the lower respiratory tract, urinary tract, or skin and soft tissues, whereas 12.2% (95% CI, 11.5%-12.8%) were given for surgical and 5.9% (95% CI, 5.5%-6.4%) for medical prophylaxis. Of 7641 drugs to treat infections, the most common were parenteral vancomycin (1103, 14.4%; 95% CI, 13.7%-15.2%), ceftriaxone (825, 10.8%; 95% CI, 10.1%-11.5%), piperacillin-tazobactam (788, 10.3%; 95% CI, 9.6%-11.0%), and levofloxacin (694, 9.1%; 95% CI, 8.5%-9.7%). Most drugs administered to treat infections were given for community-onset infections (69.0%; 95% CI, 68.0%-70.1%) and to patients outside critical care units (81.6%; 95% CI, 80.4%-82.7%). The 4 most common treatment antimicrobial drugs overall were also the most common drugs used for both community-onset and health care facility-onset infections and for infections in patients in critical care and noncritical care locations.
In this cross-sectional evaluation of antimicrobial use in US hospitals, use of broad-spectrum antimicrobial drugs such as piperacillin-tazobactam and drugs such as vancomycin for resistant pathogens was common, including for treatment of community-onset infections and among patients outside critical care units. Further work is needed to understand the settings and indications for which reducing antimicrobial use can be most effectively and safely accomplished.
Acute care physical therapy is a rapidly evolving practice area, but little is known about the skills, knowledge, and behaviors necessary for a clinician to be most effective in this area.
The ...objective of this study was to perform the first nationwide survey of acute care physical therapists to validate the knowledge, skill, and behavior sets that reflect practice parameters specific for acute care physical therapy.
A survey format was used.
The Acute Care Physical Therapy Practice Analysis Survey was created on the basis of current literature and consensus of a 9-member Subject Matter Expert (SME) Group. The survey sections addressed knowledge areas, professional behaviors, and patient/client management approaches reflecting practice parameters specific for acute care physical therapy. Additionally, respondent demographic information was collected. Pilot testing necessitated minor changes in the survey. After revision, the survey questionnaire was sent to a sample of experienced acute care physical therapists throughout the United States.
A convenience sample of 522 physical therapists who identified themselves as having extensive experience in acute care practice was used. Of these, 254 completed the survey, for a response rate of 48.7%. Through the use of predetermined decision rules, 34 items were eliminated on the basis of a descriptive analysis of survey results as well as a failure of the items to meet the threshold of specificity for acute care practice, as determined through SME Group consensus.
The potential for self-selection bias, a sample weighted heavily with American Physical Therapy Association members and Acute Care Section members, and a small proportion of clinicians (<3%) with less than 1 year of acute care experience may limit generalizability of these results.
The results of this practice analysis describe distinct knowledge, skills, and behaviors specific for acute care physical therapy. The outcomes of the survey might assist in the development of professional (entry-level) acute care competencies, a petition for the recognition of specialization in acute care physical therapy, or both. In addition, the findings of this practice analysis could serve as the foundation for the development of residencies or fellowships in acute care practice.
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