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Lancet (London, England) Feb 2021MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic... (Randomized Controlled Trial)
Randomized Controlled Trial
A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.
BACKGROUND
MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.
METHODS
We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.
FINDINGS
Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.
INTERPRETATION
Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.
FUNDING
National Institutes of Health and National Cancer Institute.
Topics: Aged; Anilides; Canada; Carcinoma, Renal Cell; Crizotinib; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazines; Pyridines; Sunitinib; Triazines; United States
PubMed: 33592176
DOI: 10.1016/S0140-6736(21)00152-5 -
Diabetes, Obesity & Metabolism Mar 2021Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with... (Review)
Review
Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD ) via the 'salvage pathway'. In addition to playing a key role as a mitochondrial co-factor, NAD metabolites may contribute to the increase in GSIS (via enhanced Ca mobilization). Imeglimin has also been shown to preserve β-cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon-like peptide-1 receptor agonists.
Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Triazines
PubMed: 33269554
DOI: 10.1111/dom.14277 -
Sleep Medicine Reviews Dec 2021Anti-seizure medications (ASMs) may improve or be detrimental to sleep. A literature review (as an update to the 2014 review by Jain and Glauser... (Review)
Review
Anti-seizure medications (ASMs) may improve or be detrimental to sleep. A literature review (as an update to the 2014 review by Jain and Glauser [https://doi.org/10.1111/epi.12478]) of 25 ASMs of interest (articles from 12 ASMs included) on the effect of ASMs/non-drug treatments on sleep in patients with epilepsy was conducted. The most common objective instrument was polysomnography, and the most common subjective measures were the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index. Eslicarbazepine acetate, lacosamide, and perampanel improved or had no effect on sleep. Perampanel was associated with low incidence of insomnia, and lacosamide with low incidence of daytime sleepiness adverse events. Clonazepam, felbamate, lamotrigine, oxcarbazepine, and phenobarbital worsened or had no effect on sleep. Lamotrigine may be associated with insomnia risk and phenobarbital with daytime sleepiness. Data for valproic acid were mixed. Overall, cannabidiol, carbamazepine, and levetiracetam had no effect on sleep. Epilepsy surgery may benefit sleep in patients with a good surgical outcome. Some ASMs, and, possibly, epilepsy surgery, may have positive effects on sleep, possibly linked to achieving seizure control. Nonetheless, other ASMs may worsen sleep in some settings. Clinicians should consider such observations when making treatment decisions, particularly for patients with comorbid sleep disorders.
Topics: Anticonvulsants; Disorders of Excessive Somnolence; Epilepsy; Humans; Lamotrigine; Sleep
PubMed: 34710770
DOI: 10.1016/j.smrv.2021.101559 -
Nature Medicine Dec 2021Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (...
Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 10/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.
Topics: Adult; Aged; Aged, 80 and over; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Mastocytosis, Systemic; Middle Aged; Pyrazoles; Pyrroles; Triazines
PubMed: 34873347
DOI: 10.1038/s41591-021-01538-9 -
Blood Apr 2021Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their...
Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
Topics: Adult; Aged; Aminopyridines; Antineoplastic Agents; Female; Glycine; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Pyridines; Treatment Outcome; Triazines; Young Adult
PubMed: 33024987
DOI: 10.1182/blood.2020007233 -
Diabetes, Obesity & Metabolism Apr 2022To evaluate the safety and efficacy of imeglimin for 52 weeks as monotherapy or combination therapy with existing antidiabetic agents in Japanese patients with type 2...
Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52-week, open-label, multicentre phase 3 trial.
AIM
To evaluate the safety and efficacy of imeglimin for 52 weeks as monotherapy or combination therapy with existing antidiabetic agents in Japanese patients with type 2 diabetes.
MATERIALS AND METHODS
TIMES 2 was a phase 3, pivotal, open-label trial including patients with type 2 diabetes inadequately controlled despite diet/exercise or despite treatment with a single agent from one of several available classes of antidiabetic drugs along with diet/exercise. All patients received imeglimin 1000 mg twice-daily orally for 52 weeks as monotherapy or combination therapy. The primary endpoint was safety (adverse events, laboratory results, ECG). The secondary endpoints were changes from baseline in HbA1c and fasting plasma glucose at week 52.
RESULTS
A total of 714 patients received the following treatments: imeglimin monotherapy (n = 134), combination with an α-glucosidase inhibitor (n = 64), biguanide (n = 64), dipeptidyl peptidase-4 inhibitor (DPP4-I; n = 63), glinide (n = 64), glucagon-like peptide-1 receptor agonist (GLP1-RA; n = 70), sodium-glucose co-transporter-2 inhibitor (n = 63), sulphonylurea (n = 127), or thiazolidinedione (n = 65). The percentage of patients experiencing at least one treatment emergent adverse event (TEAE) was 75.5%. Most of these events were mild or moderate in intensity. Serious TEAEs, none of them related to the study drug, occurred in 5.6% of all patients. No clinically significant changes in ECG, vital signs, physical examination, or laboratory tests were noted in any groups. At week 52, HbA1c decreased by 0.46% with imeglimin monotherapy, by 0.56%-0.92% with imeglimin as oral combination therapy, and by 0.12% with injectable GLP1-RA combination therapy. The greatest net HbA1c reduction (0.92%) occurred in patients receiving a DPP4-I in combination with imeglimin.
CONCLUSIONS
Imeglimin provides well-tolerated, long-term safety and efficacy in both monotherapy and oral combination therapy in Japanese patients with type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Japan; Treatment Outcome; Triazines
PubMed: 34866306
DOI: 10.1111/dom.14613 -
Minerva Medica Oct 2020The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria,... (Review)
Review
The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.
Topics: Aminopyridines; Antineoplastic Agents; Cell Differentiation; Clinical Trials as Topic; Glutarates; Glycine; Humans; Isocitrate Dehydrogenase; Isocitrates; Ketoglutaric Acids; Leukemia, Myeloid, Acute; Multicenter Studies as Topic; Mutation, Missense; NADP; Pyridines; Syndrome; Triazines
PubMed: 32955829
DOI: 10.23736/S0026-4806.20.07024-X -
JAMA Network Open Aug 2021Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2;... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2; however, questions remain about which treatment is associated with the best outcomes and fewest adverse events.
OBJECTIVE
To compare the efficacy and safety of neuraminidase inhibitors and the endonuclease inhibitor for the treatment of seasonal influenza among healthy adults and children.
DATA SOURCES
Medline, Embase, and the Cochrane Register of Clinical Trials were searched from inception to January 2020 (the last search was updated in October 2020).
STUDY SELECTION
Included studies were randomized clinical trials conducted among patients of all ages with influenza treated with neuraminidase inhibitors (ie, oseltamivir, peramivir, zanamivir, or laninamivir) or an endonuclease inhibitor (ie, baloxavir) compared with other active agents or placebo.
DATA EXTRACTION AND SYNTHESIS
Two investigators identified studies and independently abstracted data. Frequentist network meta-analyses were performed; relative ranking of agents was conducted using P-score probabilities. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Data were analyzed in October 2020.
MAIN OUTCOMES AND MEASURES
The time to alleviation of influenza symptoms (TTAS), complications of influenza, and adverse events (total adverse events, nausea, and vomiting).
RESULTS
A total of 26 trials were identified that investigated antiviral drugs at high or low doses; these trials included 11 897 participants, among whom 6294 (52.9%) were men and the mean (SD) age was 32.5 (16.9) years. Of all treatments comparing with placebo in efficacy outcomes, high-quality evidence indicated that zanamivir was associated with the shortest TTAS (hazard ratio, 0.67; 95% CI, 0.58-0.77), while baloxavir was associated with the lowest risk of influenza-related complications (risk ratio [RR], 0.51; 95% CI, 0.32-0.80) based on moderate-quality evidence. In safety outcomes, baloxavir was associated with the lowest risk of total adverse events (RR, 0.84; 95% CI, 0.74-0.96) compared with placebo based on moderate-quality evidence. There was no strong evidence of associations with risk of nausea or vomiting among all comparisons, except for 75 mg oseltamivir, which was associated with greater occurrence of nausea (RR, 1.82; 95% CI, 1.38-2.41) and vomiting (RR, 1.88; 95% CI, 1.47-2.41).
CONCLUSIONS AND RELEVANCE
In this systematic review and network meta-analysis, all 4 antiviral agents assessed were associated with shortening TTAS; zanamivir was associated with the shortest TTAS, and baloxavir was associated with reduced rate of influenza-related complications.
Topics: Adolescent; Adult; Antiviral Agents; Child; Dibenzothiepins; Endonucleases; Enzyme Inhibitors; Female; Humans; Influenza A virus; Influenza, Human; Male; Middle Aged; Morpholines; Network Meta-Analysis; Neuraminidase; Pyridones; Randomized Controlled Trials as Topic; Seasons; Triazines; Young Adult; Zanamivir
PubMed: 34387680
DOI: 10.1001/jamanetworkopen.2021.19151 -
European Journal of Cancer (Oxford,... Mar 2021PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this...
BACKGROUND
PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population.
METHODS
NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point.
RESULTS
Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached.
CONCLUSION
Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Male; Middle Aged; Mutation; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Time Factors; Triazines
PubMed: 33465704
DOI: 10.1016/j.ejca.2020.12.008 -
MMW Fortschritte Der Medizin Nov 2020
Review
Topics: Dibenzothiepins; Humans; Influenza, Human; Morpholines; Oxazines; Pyridones; Tablets; Thiepins; Triazines
PubMed: 33140344
DOI: 10.1007/s15006-020-4497-2