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The European Journal of General Practice Dec 2022Hepatitis C Virus (HCV) is a common cause of chronic liver disease and its ensuing complications. In the last years, there has been a revolution of the treatment for... (Review)
Review
BACKGROUND
Hepatitis C Virus (HCV) is a common cause of chronic liver disease and its ensuing complications. In the last years, there has been a revolution of the treatment for patients with HCV regarding efficacy, simplicity, safety and duration of treatment. The role of the family physician is vital in all steps of care: screening, diagnosis, linkage to treatment, treatment and follow-up.
OBJECTIVES
This review aims to summarise the family physician and the important updated recommendations for diagnosis and treatment of patients with chronic HCV.
METHODS
The updated recommendations were reviewed and summarised in a short and simple review.
RESULTS
Patients with any risk factor for HCV should first be screened for HCV antibodies. In the case of positive antibodies, reflex testing for RNA polymerase chain reaction (PCR) should be done without waiting for genotype. For patients with positive PCR, fibrosis assessment should be conducted using laboratory panels (Fibrosis-4 index (FIB-4) or aspartate aminotransferase to platelet ratio index (APRI)); if advanced fibrosis is suspected, additional non-invasive fibrosis assessment is needed, such as fibrotest or liver elastography. Naïve non-cirrhotic or compensated cirrhosis (Child-Pugh-Score A) could be treated with pangenotypic drugs, Glecaprevir/pibrentasvir (Maviret) for eight weeks, or Sofosbuvir/velpatasvir (Epclusa) for 12 weeks.
CONCLUSION
Patients without advanced fibrosis and comorbidities can be treated by the educated family physician. However, patients with comorbidities, cirrhosis or coinfection (HIV, Hepatitis B Virus (HBV)) should be referred to the liver clinic. In case of screening patients with risk factors or likelihood of dormant HCV, health organisations should provide the appropriate resources, logistics, finances and workforce.
Topics: Aminoisobutyric Acids; Antiviral Agents; Cyclopropanes; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis
PubMed: 35579223
DOI: 10.1080/13814788.2022.2056161 -
Nature Communications Feb 2021ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used....
ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.
Topics: Aminopyridines; Aniline Compounds; Animals; Apoptosis; Benzamides; Carbazoles; Cell Line; Cell Survival; Crizotinib; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Immunoblotting; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation; Neoplasm Recurrence, Local; Piperidines; Proto-Oncogene Proteins; Pyrazines; Pyrazoles; Receptor Protein-Tyrosine Kinases
PubMed: 33627640
DOI: 10.1038/s41467-021-21396-w -
Journal of Clinical Oncology : Official... Nov 2022Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced -positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN.
METHODS
Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted.
RESULTS
PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% 22% and 78% 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% 72%) and without (1% 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS.
CONCLUSION
First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced -positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Crizotinib; Anaplastic Lymphoma Kinase; Lung Neoplasms; Quality of Life; Lactams, Macrocyclic; Brain Neoplasms; Protein Kinase Inhibitors
PubMed: 35605188
DOI: 10.1200/JCO.21.02278 -
Nature Medicine May 2023Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a...
Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .
Topics: Adult; Humans; 3-Iodobenzylguanidine; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Lactams, Macrocyclic; Lung Neoplasms; Neoplasm Recurrence, Local; Neuroblastoma; Protein Kinase Inhibitors; Child; Infant; Child, Preschool; Adolescent
PubMed: 37012551
DOI: 10.1038/s41591-023-02297-5 -
The Oncologist Aug 2019Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known...
Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI. IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Severity of Illness Index; Treatment Outcome
PubMed: 30890623
DOI: 10.1634/theoncologist.2018-0380 -
International Journal of Molecular... Jan 2023Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis.
Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.
Topics: Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Central Nervous System Neoplasms; Lactams, Macrocyclic; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors
PubMed: 36768562
DOI: 10.3390/ijms24032242 -
Journal of Vascular Surgery Sep 2019
Topics: Rifampin; Vascular Surgical Procedures
PubMed: 31445640
DOI: 10.1016/j.jvs.2019.05.007 -
Critical Reviews in Oncology/hematology Jul 2023Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various... (Review)
Review
Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC.
Topics: Humans; Lung Neoplasms; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Lactams; Lactams, Macrocyclic; Protein Kinase Inhibitors
PubMed: 37187318
DOI: 10.1016/j.critrevonc.2023.104019 -
Cancer Discovery Mar 2023The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and...
The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion-positive patients. This article is highlighted in the In This Issue feature, p. 517.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Protein-Tyrosine Kinases; Aminopyridines; Lactams, Macrocyclic; Lactams; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrazoles; Lung Neoplasms; Brain; Mutation
PubMed: 36511802
DOI: 10.1158/2159-8290.CD-22-0968 -
Redox Biology May 2023Induction of ferroptosis is an emerging strategy to suppress melanoma progression. Strategies to enhance the sensitivity to ferroptosis induction would be a major...
Induction of ferroptosis is an emerging strategy to suppress melanoma progression. Strategies to enhance the sensitivity to ferroptosis induction would be a major advance in melanoma therapy. Here, we used a drug synergy screen that combined a ferroptosis inducer, RSL3, with 240 anti-tumor drugs from the FDA-approved drug library and identified lorlatinib to synergize with RSL3 in melanoma cells. We further demonstrated that lorlatinib sensitized melanoma to ferroptosis through inhibiting PI3K/AKT/mTOR signaling axis and its downstream SCD expression. Moreover, we found that lorlatinib's target IGF1R, but not ALK or ROS1, was the major mediator of lorlatinib-mediated sensitivity to ferroptosis through targeting PI3K/AKT/mTOR signaling axis. Finally, lorlatinib treatment sensitized melanoma to GPX4 inhibition in preclinical animal models, and melanoma patients with low GPX4 and IGF1R expression in their tumors survived for longer period. Altogether, lorlatinib sensitizes melanoma to ferroptosis by targeting IGF1R-mediated PI3K/AKT/mTOR signaling axis, suggesting that combination with lorlatinib could greatly expand the utility of GPX4 inhibition to melanoma patients with IGF1R-proficient expression.
Topics: Animals; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Ferroptosis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins; Lactams, Macrocyclic; Melanoma; TOR Serine-Threonine Kinases
PubMed: 36889082
DOI: 10.1016/j.redox.2023.102653