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Clinical Cancer Research : An Official... May 2021Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ()-positive (ROS1) non-small cell lung cancer (NSCLC) is crizotinib...
PURPOSE
Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ()-positive (ROS1) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1 NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1 disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.
EXPERIMENTAL DESIGN
Biopsies from patients with ROS1 NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing.
RESULTS
From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, mutations were identified in 38% and 46%, respectively. G2032R was the most commonly occurring mutation in approximately one third of cases. Additional mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1 causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1, ROS1, and ROS1 were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified amplification (4%), G12C (4%), amplification (4%), mutation (4%), and mutation (4%).
CONCLUSIONS
mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.
Topics: Adult; Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Aminopyridines; Antigens, Differentiation, B-Lymphocyte; Biopsy; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Female; Histocompatibility Antigens Class II; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Models, Molecular; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Structure-Activity Relationship; Young Adult
PubMed: 33685866
DOI: 10.1158/1078-0432.CCR-21-0032 -
The Oncologist Jan 2023The monarchE Cohort 1 patient population was enrolled based on high-risk clinicopathological features that can easily be identified as part of routine clinical breast... (Clinical Trial)
Clinical Trial
The monarchE Cohort 1 patient population was enrolled based on high-risk clinicopathological features that can easily be identified as part of routine clinical breast cancer evaluation. Efficacy data from Cohort 1 demonstrate substantial evidence of benefit for adjuvant abemaciclib+ET in patients with HR+, HER2- early breast cancer at high risk of recurrence (ClinicalTrials.gov: NCT03155997 [monarchE]).
Topics: Female; Humans; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Protein Kinase Inhibitors; Receptor, ErbB-2
PubMed: 36342342
DOI: 10.1093/oncolo/oyac234 -
Blood Nov 2021Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors...
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.
Topics: Adult; Aged; Aminopyridines; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Female; Hemoglobinuria, Paroxysmal; Humans; Indazoles; Male; Middle Aged; Proline; Pyrimidines; Treatment Outcome; Young Adult
PubMed: 34314483
DOI: 10.1182/blood.2021011388 -
Expert Review of Anticancer Therapy Mar 2021: CDK4/6 inhibitor approval for hormone-responsive breast tumors has significantly changed therapeutic algorithms, with three drugs currently approved.: Here, we analyze... (Comparative Study)
Comparative Study Meta-Analysis
: CDK4/6 inhibitor approval for hormone-responsive breast tumors has significantly changed therapeutic algorithms, with three drugs currently approved.: Here, we analyze the toxicity profiles of palbociclib, ribociclib, and abemaciclib through a systematic review and meta-analysis. Palbociclib and ribociclib showed high rates of hematological toxicity, primarily neutropenia, and were associated with a low rate of severe infections. Abemaciclib was associated with a high rate of gastrointestinal toxicities, primarily diarrhea, of grade 1-2 in most cases. Ribociclib was associated with a high rate of hepatic, and respiratory toxicity and with QTc prolongation. The toxicity rate of ribociclib was higher in metastatic patients than non-metastatic patients, with approximately 33% more grade 3-4 toxicities and 21% more grade 3-4 neutropenic events. A 5% higher risk of diarrhea was observed in postmenopausal patients. Pre-treated patients did not show a higher toxicity rate for palbociclib/ribociclib than previously untreated patients, while a 26% higher risk of any grade neutropenia and 6% higher risk of grade 3-4 diarrhea were observed with abemaciclib.: Considering the similar efficacies and indications of palbociclib, ribociclib, and abemaciclib, the evaluation of their toxicity profiles may facilitate treatment choice.
Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines
PubMed: 33233970
DOI: 10.1080/14737140.2021.1852934 -
Nature Reviews. Clinical Oncology Jan 2021
Topics: Aminopyridines; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles; Receptor Protein-Tyrosine Kinases
PubMed: 33262501
DOI: 10.1038/s41571-020-00458-w -
Leukemia & Lymphoma 2023Advances in the treatment of acute myeloid leukemia (AML) over the last 40 years have been limited. With an improved understanding of the pathophysiology of the... (Review)
Review
Advances in the treatment of acute myeloid leukemia (AML) over the last 40 years have been limited. With an improved understanding of the pathophysiology of the disease, the advent of new treatment options has enriched the armamentarium of the physician to combat the disease. Mutations of the isocitrate dehydrogenase (s) genes are common in AML and occur in 20-30% of cases. These mutations lead to DNA hypermethylation, aberrant gene expression, cell proliferation, and abnormal differentiation. Targeting mutant , either as monotherapy or in combination with hypomethylating agents (HMAs) or BCL-2 inhibitors, has opened new avenues of therapy for these patients.This review will outline the function of s and focus on the biological effects of mutations in AML, their prognosis and treatment options.
Topics: Humans; Aminopyridines; Antineoplastic Agents; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Mutation; Triazines
PubMed: 37462435
DOI: 10.1080/10428194.2023.2237153 -
Skin Therapy Letter Sep 2023Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health... (Review)
Review
Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health Canada for use in adolescents and adults, has proven efficacy and tolerability. It is non-steroidal, administered once-daily, and highly potent, with a unique delivery formulation. It can be used on most body areas, including the sensitive intertriginous regions and face. Herein, we review the safety and efficacy of roflumilast 0.3% cream, as demonstrated in clinical trials.
Topics: Adolescent; Adult; Humans; Psoriasis; Aminopyridines; Benzamides; Emollients; Phosphodiesterase 4 Inhibitors
PubMed: 37734074
DOI: No ID Found -
Expert Review of Clinical Immunology 2023New non-steroidal topical agents are needed for the treatment of psoriasis. Roflumilast cream 0.3% is a once daily phosphodiesterase-4 inhibitor that was recently... (Review)
Review
INTRODUCTION
New non-steroidal topical agents are needed for the treatment of psoriasis. Roflumilast cream 0.3% is a once daily phosphodiesterase-4 inhibitor that was recently approved by the FDA for the treatment of plaque psoriasis in adolescents and adults. It is indicated for use on all body surfaces including intertriginous areas.
AREAS COVERED
In this review, we summarize the current knowledge about roflumilast cream for the treatment of psoriasis, highlighting its efficacy and safety profile from published clinical trials. Roflumilast's mechanism of action and pharmacokinetic profile are also discussed.
EXPERT OPINION
Positive results were reported across trials with 48% of patients treated with roflumilast achieving an Investigator Global Assessment score of clear or almost clear at 8 weeks in phase III studies. Most adverse events were mild or moderate in severity and few application-site reactions were reported among participants. Unique advantages of the cream are its success in treating intertriginous areas and its ability to reduce symptoms of itch, results of which may significantly improve quality of life for patients. In the future, real-world data and active comparator trials with existing non-steroidal agents are needed to better understand roflumilast's place in the current treatment landscape.
Topics: Adult; Adolescent; Humans; Quality of Life; Psoriasis; Aminopyridines; Benzamides; Treatment Outcome; Severity of Illness Index
PubMed: 37243575
DOI: 10.1080/1744666X.2023.2219897 -
Journal of Drugs in Dermatology : JDD Apr 2021Impetigo is a contagious bacterial infection that affects the superficial skin layers. Increasing worldwide antimicrobial resistance (AMR) to existing topical agents... (Review)
Review
BACKGROUND
Impetigo is a contagious bacterial infection that affects the superficial skin layers. Increasing worldwide antimicrobial resistance (AMR) to existing topical agents commonly prescribed to treat impetigo is central to treatment failure. The Worldwide Health Organization developed a global action plan on AMR, but omitted information about AMR stewardship programs for topical antibiotics.
OBJECTIVES
The review aims to provide information to clinicians and stakeholders regarding AMR and antimicrobial stewardship on topical antimicrobial drugs for impetigo treatment.
METHODS
The literature searches reviewed the status of AMR to current topical antibiotics in impetigo, current therapeutic behavior, and concordance with antimicrobial stewardship principles. Two international panels convened to discuss the output of the searches, and the results of the panel discussions were used in the development of the manuscript.
RESULTS
The literature search included clinical trials, research studies, clinical guidelines, consensus papers, and reviews (if they provided original data), published between January 2008 and May 2019. The articles were selected based on clinical relevancy of impetigo management, clinical efficacy, and safety of the treatment and antimicrobial resistance. The searches resulted in one-hundred and ninety-eight articles. After applying the eligibility criteria, nineteen articles met inclusion criteria and were considered in the present review.
CONCLUSIONS
While published antimicrobial stewardship guidelines have focused on systemic antibiotics, few studies have attempted to evaluate topical antibiotic prescribing practices for impetigo treatment. Many of the topical impetigo treatments currently in use have developed resistance. The appropriate use of topical ozenoxacin can help eradicate impetigo while minimizing AMR.J Drugs Dermatol. 20(4):366-372. doi:10.36849/JDD.5795.
Topics: Administration, Cutaneous; Aminopyridines; Anti-Bacterial Agents; Antimicrobial Stewardship; Drug Prescriptions; Drug Resistance, Bacterial; Humans; Impetigo; Microbial Sensitivity Tests; Practice Guidelines as Topic; Quinolones; Staphylococcus aureus; Treatment Outcome
PubMed: 33852242
DOI: 10.36849/JDD.2021.5795 -
American Journal of Therapeutics
Topics: Humans; Female; Aminopyridines; Benzimidazoles; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 32496440
DOI: 10.1097/MJT.0000000000001179