The ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.84), including in patients with del(17p)/TP53 mutation (HR, 0.51; 95% CI, 0.33-0.78) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR, 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common nonhematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs 6 cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

• MeSH
• adenin * analogy a deriváty   terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   mortalita   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• piperidiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• pyrazoly * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• pyrimidiny * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

• MeSH
• antitumorózní látky * škodlivé účinky   terapeutické užití   MeSH
• chinazoliny škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• nádory štítné žlázy * farmakoterapie   genetika   MeSH
• piperidiny škodlivé účinky   terapeutické užití   MeSH
• progrese nemoci MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• pyridiny * škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

CONTEXT: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. DESIGN: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. MAIN OUTCOME MEASURES: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading to death=11 patients (4.6%) versus 11 patients (4.8%). No sudden deaths occurred. CONCLUSIONS: In summary, zanubrutinib significantly improved PFS-IRC versus BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naïve CLL/SLL.

• MeSH
• B-buněčný lymfom * farmakoterapie   MeSH
• bendamustin hydrochlorid terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   patologie   MeSH
• cyklofosfamid terapeutické užití   MeSH
• inhibitory proteinkinas * škodlivé účinky   MeSH
• lidé MeSH
• piperidiny škodlivé účinky   MeSH
• proteinkinasa BTK MeSH
• protokoly antitumorózní kombinované chemoterapie * škodlivé účinky   MeSH
• pyrazoly škodlivé účinky   MeSH
• pyrimidiny škodlivé účinky   MeSH
• rituximab terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

CONTEXT: CLL/SLL treatment has been transformed with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib. Zanubrutinib, a next-generation BTKi, was designed to maximize BTK occupancy and minimize toxicity. ALPINE (NCT03734016) is a global, randomized, phase 3 study of zanubrutinib versus ibrutinib in patients with R/R CLL/SLL; presented here is a pre-planned interim analysis conducted ~12 months after 415 patients enrolled between November 5, 2018, and December 20, 2019. DESIGN: Patients were randomized 1:1 to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) arms; stratification factors were age (<65 years vs ≥65 years), geographic region, refractory status, and del(17)p/TP53 mutation. MAIN OUTCOME MEASURES: Primary endpoint was investigator-assessed overall response rate (ORR) per 2008 IWCLL guidelines or Lugano criteria; the noninferiority of zanubrutinib-to-ibrutinib response ratio was evaluated at the noninferiority margin of 0.8558. If noninferiority was demonstrated, superiority of zanubrutinib versus ibrutinib in ORR was tested. RESULTS: Baseline characteristics (zanubrutinib versus ibrutinib): age ≥65 years: 62.3% versus 61.5%, male sex 68.6% versus 75%; >3 prior therapies: 7.2% versus 10.1%; del(17)p: 11.6% versus 12.5%; TP53 mutation without del(17)p: 8.2% versus 5.8%. With a median follow-up of 15 months, ORR was 78.3% versus 62.5% for zanubrutinib versus ibrutinib, respectively (2-sided P=0.0006, prespecified a=0.0099). ORR was higher for zanubrutinib in patients with del(11)q (83.6% vs 69.1%) and del(17)p (83.3% vs 53.8%); zanubrutinib had higher overall 12-month progression-free survival (PFS; 94.9% vs 84.0%) and overall survival (97.0% vs 92.7%). Significantly fewer patients had atrial fibrillation/flutter (AF) with zanubrutinib versus ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, prespecified a=0.0099). Zanubrutinib had lower rates of major bleeding (2.9% vs 3.9%), adverse events leading to discontinuation (7.8% vs 13.0%), and death (3.9% vs 5.8%). Zanubrutinib had a higher neutropenia rate (28.4% vs 21.7%) while grade ≥3 infections (12.7% vs 17.9%) were lower. CONCLUSIONS: In summary, this interim analysis showed zanubrutinib had a superior ORR, improved PFS, and lower AF rate compared to ibrutinib.

• MeSH
• adenin analogy a deriváty   MeSH
• B-buněčný lymfom * farmakoterapie   genetika   MeSH
• chronická lymfatická leukemie * farmakoterapie   genetika   MeSH
• inhibitory proteinkinas * škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• piperidiny škodlivé účinky   MeSH
• pyrazoly škodlivé účinky   MeSH
• pyrimidiny škodlivé účinky   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

• Klíčová slova
• studie PRIME, Niraparib,
• MeSH
• dvojitá slepá metoda MeSH
• indazoly aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• nádory vaječníků * farmakoterapie   MeSH
• PARP inhibitory aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• piperidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• randomizované kontrolované studie MeSH

• Klíčová slova
• tofacitinib,
• MeSH
• antirevmatika aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• inhibitory Janus kinas * aplikace a dávkování   terapeutické užití   MeSH
• inhibitory TNF aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• piperidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• poruchy spánku a bdění etiologie   terapie   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• revmatoidní artritida farmakoterapie   komplikace   patologie   MeSH
• únava terapie   MeSH
• zánět komplikace   MeSH
• Check Tag
• lidé MeSH

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

• MeSH
• adenin aplikace a dávkování   analogy a deriváty   MeSH
• analýza přežití MeSH
• bendamustin hydrochlorid aplikace a dávkování   škodlivé účinky   MeSH
• indukce remise MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• lymfom z plášťových buněk * farmakoterapie   mortalita   MeSH
• piperidiny aplikace a dávkování   škodlivé účinky   MeSH
• progrese nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie * škodlivé účinky   terapeutické užití   MeSH
• pyrazoly aplikace a dávkování   škodlivé účinky   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   MeSH
• rituximab aplikace a dávkování   škodlivé účinky   MeSH
• senioři MeSH
• udržovací chemoterapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

INTRODUCTION: The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. PATIENTS AND METHODS: Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. RESULTS: Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. CONCLUSION: Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

• MeSH
• edém chemicky indukované   farmakoterapie   MeSH
• exony genetika   MeSH
• hypoalbuminemie farmakoterapie   MeSH
• inhibitory proteinkinas * škodlivé účinky   MeSH
• klinické zkoušky, fáze II jako téma MeSH
• kreatinin terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• nádory plic * farmakoterapie   genetika   MeSH
• nauzea chemicky indukované   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   genetika   MeSH
• piperidiny škodlivé účinky   MeSH
• pleurální výpotek MeSH
• průjem MeSH
• pyridaziny škodlivé účinky   MeSH
• pyrimidiny škodlivé účinky   MeSH
• senioři MeSH
• zvracení chemicky indukované   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The black market for new psychoactive substances has been constantly evolving and the substances that appear on this market cause a considerable number of issues, in extreme cases leading to human deaths. While monitoring the drug black market, we detected a sample of a dissociative anesthetic methoxphenidine, the salt of which contained an unusual anion in the form of bromo- and chloro-zincate complex. Concerning the unknown and potentially hazardous properties of this sample, we performed an in vitro cytotoxicity screening in cell lines of various origins (e.g., kidney, liver, bladder) which was compared with the toxicity results of the methoxphenidine standard prepared for this purpose. The street methoxphenidine sample exhibited markedly higher toxicity than the standard, which was probably caused by the anion impurity. Since it is not usual to analyze anions in salts of novel psychoactive substances, but such samples may be commonly available at the drug black market, we have developed a method for their identification with X-ray powder diffraction (XRPD), which also enabled us to distinguish between different polymorphs/solvates of methoxphenidine that were crystallized in the laboratory. XRPD offers additional data about samples, which may not be discovered by routine techniques, and in some cases, they may help to find out essential information.

• MeSH
• anestetika disociativní škodlivé účinky   MeSH
• difrakce rentgenového záření metody   MeSH
• kultivované buňky MeSH
• lidé MeSH
• piperidiny škodlivé účinky   MeSH
• psychotropní léky škodlivé účinky   MeSH
• zakázané drogy škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Inhibitory Janusových kináz (JAK) jsou v léčbě imunopatologických stavů cíleny na dysregulovanou buněčnou signalizaci. Tyto tzv. malé molekuly mají velký potenciál širokého imunomodulačního účinku, a představují tak významnou skupinu inovativních léčiv k léčbě poruch imunity. Prvním schváleným inhibitorem JAK pro léčbu ulcerózní kolitidy je tofacitinib, který inhibuje především JAK1 a JAK3. Klinické studie OCTAVE Induction, OCTAVE Sustain a OCTAVE Open prokázaly signifikantně vyšší pravděpodobnost dosažení remise ulcerózní kolitidy u nemocných léčených tofacitinibem ve srovnání s placebem. Lék je indikován jako účinná možnost léčby u dospělých pacientů se středně těžkou až těžkou formou nemoci v případě, že nelze použít konvenční a/nebo biologickou terapii, anebo v případě neodpovídavosti nebo ztráty odpovědi na tuto léčbu. Aktuální práce přináší stručný souhrn informací o použití tofacitinibu v klinické praxi léčby ulcerózní kolitidy.

Janus kinase (JAK) inhibitors are used to target dysregulated signalling pathways in immunopathological diseases. These small-molecule drugs have the potential for a broad efficacy, and thus often offer important innovative advantages for the treatment of immunopathologies. First JAK inhibitor approved for the treatment of ulcerative colitis is tofacitinib, which inhibits mainly JAK1 and JAK3 kinases. OCTAVE Induction, OCTAVE Sustain and OCTAVE Open clinical trials demonstrated superiority of tofacitinib when compared with placebo in disease remission achievement. Tofacitinib is recommended as an effective treatment option for adult patients with moderate to severe ulcerative colitis when conventional therapy or a biological treatment cannot be used, or the disease has responded inadequately, or lost response to treatment. Current review brings a brief commentary on use of tofacitinib in clinical practice of ulcerative colitis treatment.

• Klíčová slova
• tofacitinib,
• MeSH
• inhibitory Janus kinas * farmakologie   terapeutické užití   MeSH
• Janus kinasy fyziologie   MeSH
• lidé MeSH
• piperidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• proteinkinasy fyziologie   MeSH
• psoriatická artritida farmakoterapie   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• ulcerózní kolitida * farmakoterapie   MeSH
• Check Tag
• lidé MeSH