ABSTRACT
BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).
Subject(s)
Acrylamides , Aniline Compounds , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Gene Amplification , Lung Neoplasms , Mutation , Proto-Oncogene Proteins c-met , Humans , Acrylamides/therapeutic use , Female , Male , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Proto-Oncogene Proteins c-met/genetics , Middle Aged , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Aged , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/administration & dosage , Disease Progression , Aged, 80 and over , Indoles , Piperidines , PyridazinesABSTRACT
Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is routinely prescribed as first-line therapy for advanced non-small cell lung cancer, regardless of the presence of the T790M resistance mutation. This study reports a rare case of Factor V inhibitor detection during osimertinib therapy in a patient with lung adenocarcinoma. These findings underscore the importance of vigilant monitoring for coagulation abnormalities during EGFR-TKI therapy.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Factor V Deficiency , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/genetics , Acrylamides/therapeutic use , Acrylamides/adverse effects , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Factor V Deficiency/genetics , Male , Aged , Neoplasm Staging , Mutation , Female , Middle Aged , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Indoles , PyrimidinesABSTRACT
BACKGROUND: Preclinical Alzheimer's disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer's disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities. OBJECTIVES: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial. DESIGN: Phase 3, 4.5-year, multicenter, placebo-controlled trial. SETTING: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography. MEASUREMENTS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging). RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001). CONCLUSION: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer's disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer's disease.
Subject(s)
Alzheimer Disease , Aniline Compounds , Positron-Emission Tomography , Humans , Aged , Female , Male , Aged, 80 and over , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Alzheimer Disease/drug therapy , Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Brain/metabolism , Ethylene Glycols , Double-Blind Method , Amyloid beta-Peptides/metabolismABSTRACT
BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).
Subject(s)
Acrylamides , Aniline Compounds , Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Acrylamides/therapeutic use , Acrylamides/adverse effects , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Chemoradiotherapy/adverse effects , Chemoradiotherapy/methods , Double-Blind Method , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Indoles , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Mutation , Neoplasm Staging , Progression-Free Survival , Pyrimidines , /therapeutic useABSTRACT
PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Humans , Acrylamides/therapeutic use , Acrylamides/pharmacokinetics , Acrylamides/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Aniline Compounds/pharmacokinetics , Aniline Compounds/therapeutic use , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Male , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , Middle Aged , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Aged , Adult , Aged, 80 and over , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Meningeal Carcinomatosis/secondary , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/genetics , Meningeal Neoplasms/secondary , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/genetics , Indoles , PyrimidinesABSTRACT
BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.
Subject(s)
Acrylamides , Aniline Compounds , ErbB Receptors , Lung Neoplasms , Pneumonia , Protein Kinase Inhibitors , Humans , Acrylamides/therapeutic use , Acrylamides/pharmacology , Male , Female , Aniline Compounds/therapeutic use , Aniline Compounds/pharmacology , Aniline Compounds/adverse effects , Aged , Pneumonia/chemically induced , Retrospective Studies , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Middle Aged , Aged, 80 and over , Japan , Indoles , PyrimidinesABSTRACT
Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.
Subject(s)
Dasatinib , Pleural Effusion , Protein Kinase Inhibitors , Humans , Dasatinib/adverse effects , Dasatinib/administration & dosage , Dasatinib/therapeutic use , Male , Female , Middle Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Aged , Pleural Effusion/chemically induced , Pleural Effusion/epidemiology , Adult , Incidence , Leukemia, Myeloid, Chronic-Phase/drug therapy , Aged, 80 and over , Quinolines/adverse effects , Quinolines/administration & dosage , Quinolines/therapeutic use , Nitriles/adverse effects , Nitriles/therapeutic use , Drug Substitution , Aniline Compounds/adverse effects , Aniline Compounds/therapeutic use , Aniline Compounds/administration & dosage , Imatinib Mesylate/adverse effects , Imatinib Mesylate/administration & dosage , Imatinib Mesylate/therapeutic use , Young Adult , Retrospective Studies , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/therapeutic useABSTRACT
This case report features a 62-year-old male with stage IB lung adenocarcinoma harboring an epidermal growth factor receptor exon 19 deletion, who underwent treatment with osimertinib following a left upper lobectomy and lymph node dissection. Despite a history of smoking and well-managed type 2 diabetes, the patient developed heart failure 18 months post-initiation of osimertinib therapy, marking one of the latest occurrences of heart failure following osimertinib treatment documented in limited literature. Cardiac MRI revealed significant left ventricular enlargement, lateral wall myocardial thinning, and localized myocardial fibrosis without perfusion defects, a finding not previously reported in literature. This case underscores the severe and unusual cardiac effects of osimertinib in patients with latent risk factors, highlighting the importance of vigilant cardiac monitoring and a multidisciplinary management approach.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , Cardiotoxicity , Lung Neoplasms , Humans , Acrylamides/adverse effects , Acrylamides/therapeutic use , Aniline Compounds/adverse effects , Aniline Compounds/therapeutic use , Male , Lung Neoplasms/drug therapy , Middle Aged , Carcinoma, Non-Small-Cell Lung/drug therapy , Cardiotoxicity/etiology , Antineoplastic Agents/adverse effects , Heart Failure/chemically induced , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Indoles , PyrimidinesABSTRACT
PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.
Subject(s)
Aniline Compounds , Mutation , Neoplasms , Proto-Oncogene Proteins p21(ras) , Pyridones , Pyrimidinones , Sulfonamides , bcl-X Protein , Humans , Female , Pyridones/administration & dosage , Pyridones/adverse effects , Pyridones/therapeutic use , Male , Middle Aged , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Aniline Compounds/therapeutic use , Pyrimidinones/administration & dosage , Pyrimidinones/adverse effects , Aged , Proto-Oncogene Proteins p21(ras)/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/genetics , Adult , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , GTP Phosphohydrolases/genetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.
Subject(s)
Acrylamides , Carcinoma, Non-Small-Cell Lung , Indoles , Lung Neoplasms , Pyrimidines , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/chemically induced , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Retrospective Studies , Protein Kinase Inhibitors/adverse effects , ErbB Receptors/genetics , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Receptors, Growth Factor/therapeutic use , Mutation/geneticsABSTRACT
INTRODUCTION: Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients. MATERIALS AND METHODS: This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction. RESULTS: 34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57-1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43-1.50] to 2.19 [95 % CI, 2.12-2.25]. DISCUSSION/CONCLUSION: In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions.
Subject(s)
Lung Neoplasms , Protein Kinase Inhibitors , Proton Pump Inhibitors , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Proton Pump Inhibitors/therapeutic use , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/adverse effects , Male , Female , Aged , Middle Aged , Cohort Studies , Afatinib/therapeutic use , Afatinib/pharmacology , Aniline Compounds/therapeutic use , Aniline Compounds/pharmacology , Aniline Compounds/adverse effects , Acrylamides/therapeutic use , Acrylamides/pharmacology , Aged, 80 and over , Drug Interactions , France/epidemiology , Adult , Gefitinib/therapeutic use , Gefitinib/pharmacology , Retrospective StudiesABSTRACT
Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Male , Acrylamides/therapeutic use , Acrylamides/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , ErbB Receptors/genetics , Aniline Compounds/administration & dosage , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Aged , Middle Aged , Retrospective Studies , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Aged, 80 and over , Adult , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Progression-Free Survival , Indoles , PyrimidinesSubject(s)
Dermatitis, Allergic Contact , Dermatitis, Occupational , Patch Tests , Humans , Dermatitis, Allergic Contact/etiology , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Occupational/etiology , Dermatitis, Occupational/diagnosis , Aniline Compounds/adverse effects , Female , Cell Phone , Adult , MaleSubject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Quinolines , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Aniline Compounds/adverse effects , Nitriles/adverse effects , Quinolines/adverse effects , Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/therapeutic useABSTRACT
RATIONALE: Osimertinib is the third-generation, pyrimidine-based, irreversible epidermal growth factor receptor-tyrosine kinase inhibitor that received approval from the FDA in November 2015 and has become the standard approach in patients with advanced, epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC), especially with brain metastases. Osimertinib is beneficial in terms of progression-free and overall survival in patients with EGFR-mutated NSCLC. However, the rarity of bilateral pneumothorax among adverse events necessitates further research on its potential fatality rate. PATIENT CONCERNS: A 72-year-old man diagnosed with stage IV (T2NxM1) NSCLC with the 21L858R mutation of the EGFR gene received osimertinib treatment. Unfortunately, 10 weeks after osimertinib treatment, the patient developed severe interstitial lung disease and pneumothorax. Thus, osimertinib treatment was discontinued, and prednisolone (160 mg/day) and supportive treatment were administered. DIAGNOSES: Osimertinib-induced severe interstitial lung disease and pneumothorax. INTERVENTIONS: Osimertinib treatment was discontinued, and prednisolone (160 mg/day) and supportive treatment were administered. OUTCOMES: The bilateral pneumothorax was difficult to correct and the patient eventually died. LESSONS: Osimertinib-induced pneumothorax occurred approximately 10 weeks after receiving the drug and had severe cough and chest tightness as initial symptoms. In addition, the incidence of drug-induced pneumothorax increases in patients treated with osimertinib when combined with underlying respiratory diseases.
Subject(s)
Acrylamides , Carcinoma, Non-Small-Cell Lung , Indoles , Lung Diseases, Interstitial , Lung Neoplasms , Pneumothorax , Pyrimidines , Male , Humans , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Pneumothorax/chemically induced , Protein Kinase Inhibitors/adverse effects , Aniline Compounds/adverse effects , ErbB Receptors/genetics , Prednisolone/therapeutic use , Mutation , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/drug therapyABSTRACT
PURPOSE: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. METHODS: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). RESULTS: Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. CONCLUSION: The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.
Subject(s)
Aniline Compounds , Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Mutation , Pyrazines , Sulfonamides , fms-Like Tyrosine Kinase 3 , Humans , Middle Aged , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Male , Aged , Female , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Aniline Compounds/therapeutic use , Aniline Compounds/adverse effects , Aniline Compounds/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Adult , Pyrazines/administration & dosage , Pyrazines/adverse effects , Pyrazines/therapeutic use , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/therapeutic use , Aged, 80 and over , Drug Resistance, Neoplasm/geneticsSubject(s)
Antineoplastic Agents , ErbB Receptors , Indoles , Pyrimidines , Aged , Female , Humans , Acrylamides/adverse effects , Aniline Compounds/adverse effects , Antineoplastic Agents/adverse effects , Drug Eruptions/etiology , ErbB Receptors/antagonists & inhibitors , Indoles/adverse effects , Pyrimidines/adverse effects , /adverse effectsABSTRACT
Bosutinib, widely used as a primary treatment for chronic myeloid leukemia (CML), is known to frequently cause cutaneous drug eruptions. Fixed Drug Eruption (FDE) is common, typically presenting as recurrent lesions that heal with residual hyperpigmentation. Diagnosing FDE, especially Non-Pigmenting Fixed Drug Eruption (NPFDE), is often challenging. A correlation exists between the dosage of certain medications, such as levetiracetam, and the emergence of drug eruptions. This report details a unique case of dose-dependent NPFDE caused by bosutinib. In managing cutaneous drug eruptions, particularly when the causative drug is crucial for treatment, a strategy of tapering the dosage should be considered.
Subject(s)
Drug Eruptions , Quinolines , Humans , Drug Eruptions/diagnosis , Drug Eruptions/etiology , Drug Eruptions/pathology , Aniline Compounds/adverse effects , Nitriles/adverse effectsABSTRACT
Introducció: la metahemoglobinèmia adquirida és unacausa de cianosi poc freqüent en l'edat pediàtrica, causadaper l'exposició de l'hemoglobina a agents oxidants, com elsnitrits presents en algunes verdures, els anestèsics locals ialtres fàrmacs. La metahemoglobina produeix una disminució de la cessió d'oxigen als teixits i, com a conseqüència, símptomes derivats de la hipòxia tissular. Cas clínic: es presenta el cas clínic d'una pacient de 3 anysque va presentar dos episodis de metahemoglobinèmia secundària a l'absorció tòpica de les anilines amb quès'havien tenyit unes sabates. Comentaris: l'anilina és un compost orgànic que s'utilitzaper fabricar, entre altres, pintures sintètiques i colorantsindustrials. L'anilina pot ser tòxica si s'ingereix, si s'inhalao si s'absorbeix per via cutània, i pot provocar una metahemoglobinèmia
Introducción. La metahemoglobinemia adquirida es una causa de cianosis poco frecuente en la edad pediátrica, causada por la exposición de la hemoglobina a agentes oxidantes, como los nitritos resentes en algunas verduras, anestésicos tópicos y otros fármacos. La metahemoglobinemia produce una disminución de la cesión de oxigeno a los tejidos y, como consecuencia, síntomas derivados de la hipoxia tisular. Caso clínico. Se expone el caso clínico de una paciente de 3 años que presentó dos episodios de metahemoglobinemia secundaria a la absorción tópica de anilinas con las que se habían teñido sus zapatos. Comentarios. La anilina es un compuesto orgánico que se utiliza para fabricar pinturas sintéticas y colorantes industriales. La anilina puede ser tóxica si se ingiere, inhala o si se absorbe por vía cutánea, pudiendo provocar una metahemoglobinemia (AU)
Introduction. Acquired methemoglobinemia, a rare cause of cyanosis in children, is due to the exposure of hemoglobin to oxidizing agents such as nitrites, which are found in some vegetables, local anesthetics, and other drugs. Methemoglobin is an oxidized form of hemoglobin with decreased affinity for oxygen, which leads to decreased delivery of oxygen to tissues and resulting hypoxia. Clinical case. We report the case of a 3-year old child with two episodes of methemoglobinemia secondary to topical absorption of anilines. Comments. Anilines are organic compounds that are used for making synthetic paints and industrial dyes. If consumed, inhaled, or absorbed through the skin, they are toxic and may cause methemoglobinemia (AU)