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The Lancet. Oncology Nov 2017Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase... (Comparative Study)
Comparative Study Randomized Controlled Trial
Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
BACKGROUND
Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC).
METHODS
In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients.
FINDINGS
Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3-23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1-16·6) in the dacomitinib group and 9·2 months (9·1-11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47-0·74; p<0·0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia).
INTERPRETATION
Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population.
FUNDING
SFJ Pharmaceuticals Group and Pfizer.
Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Confidence Intervals; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gefitinib; Genes, erbB-1; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Prognosis; Quinazolines; Quinazolinones; Survival Analysis; Treatment Outcome
PubMed: 28958502
DOI: 10.1016/S1470-2045(17)30608-3 -
Drugs Dec 2018Dacomitinib (Vizimpro) is an orally administered, small-molecule irreversible inhibitor of HER1 (EGFR), HER2 and HER4 that was developed by Pfizer Inc. for the treatment... (Review)
Review
Dacomitinib (Vizimpro) is an orally administered, small-molecule irreversible inhibitor of HER1 (EGFR), HER2 and HER4 that was developed by Pfizer Inc. for the treatment of solid tumours. In September 2018, dacomitinib received its first global approval, in the USA, for use in the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Registration applications for the use of dacomitinib as first-line treatment for patients with EGFR-mutation-positive metastatic NSCLC have also been submitted in the EU and Japan. This article summarizes the milestones in the development of dacomitinib leading to this first approval for the first-line treatment of patients with EGFR-mutated metastatic NSCLC.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Approval; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors; Quinazolinones; United States; United States Food and Drug Administration
PubMed: 30506139
DOI: 10.1007/s40265-018-1028-x -
Future Oncology (London, England) Aug 2019Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) that irreversibly binds to and inhibits , and subtypes with an efficacy comparable to other... (Review)
Review
Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) that irreversibly binds to and inhibits , and subtypes with an efficacy comparable to other TKIs. In the ARCHER 1050 trial, progression-free survival was improved by dacomitinib compared with gefitinib, supporting dacomitinib as a first-line treatment option for advanced non-small-cell lung cancer with sensitive mutation. Regarding to the higher adverse events rate, dose reductions did not reduce the efficacy of dacomitinib and could effectively decreased the incidence and severity of adverse events. Considering the evolving landscape of -mutant non-small-cell lung cancer, future head to head comparison between dacomitinib and osimertinib could provide key information to determine the optimal TKI treatment schedule.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gefitinib; Lung Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Quinazolinones; Receptor, ErbB-2; Receptor, ErbB-4
PubMed: 31401844
DOI: 10.2217/fon-2018-0535 -
Drugs Jun 2019The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management... (Review)
Review
The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45 mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Quality of Life; Quinazolinones
PubMed: 31069718
DOI: 10.1007/s40265-019-01115-y -
Expert Opinion on Investigational Drugs Oct 2018Standard treatment of newly diagnosed glioblastoma (GB) is surgery with radiotherapy and temozolomide, but tumors will recur with a median overall survival of only... (Review)
Review
Standard treatment of newly diagnosed glioblastoma (GB) is surgery with radiotherapy and temozolomide, but tumors will recur with a median overall survival of only 15 months. It seems imperative to explore new possibilities of treatment based on targetable alterations known to be present in GB. Among others, Epidermal Growth Factor Receptor or EGFR (HER1) mutations or amplifications are the most prevalent alterations in GB. In fact, around 40% of GB cases show amplification of EGFR gene, and half of these patients carry the EGFRvIII mutation, a deletion that generates a continuous activation of the tyrosine kinase domain of the receptor. Areas covered: We review the current knowledge about Dacomitinib, an oral, irreversible, second-generation, pan-HER tyrosine kinase inhibitor, in the treatment of glioblastoma. Dacomitinib has noteworthy antiglioma activity in preclinical models and has been tested in one phase II trial in patients with recurrent GB with EGFR amplification. Expert opinion: Despite the poor global results of Dacomitinib in recurrent GB shown in a phase II trial, some patients had a significant benefit. Therefore, it is necessary to improve the knowledge about the mechanisms of failure or resistance to EGFR inhibitors in GB.
Topics: Animals; Drugs, Investigational; ErbB Receptors; Gene Amplification; Glioblastoma; Humans; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Quinazolinones; Survival Rate
PubMed: 30247945
DOI: 10.1080/13543784.2018.1528225 -
Drugs Feb 2021ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer... (Comparative Study)
Comparative Study Randomized Controlled Trial
Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations.
BACKGROUND
ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib.
OBJECTIVE
This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up.
PATIENTS AND METHODS
In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019).
RESULTS
After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib.
CONCLUSIONS
The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors; Quinazolinones; Survival Analysis
PubMed: 33331989
DOI: 10.1007/s40265-020-01441-6 -
Expert Review of Clinical Pharmacology Sep 2019: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally... (Review)
Review
: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting. : This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC. : The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Progression-Free Survival; Quinazolinones; Survival Rate
PubMed: 31356117
DOI: 10.1080/17512433.2019.1649136 -
Drugs of Today (Barcelona, Spain : 1998) Apr 2019Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4... (Review)
Review
Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4 tyrosine kinase. On September 27, 2018, the United States Food and Drug Administration (FDA) approved dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations. On January 8, 2019, the Ministry of Health, Labour and Welfare of Japan approved this second-generation EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR mutation-positive inoperable or recurrent NSCLC. The European Commission also approved dacomitinib on April 3, 2019, as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Approval of dacomitinib was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050; ClinicalTrials.gov Identifier NCT01774721) which demonstrated the safety and efficacy of dacomitinib compared to gefitinib in 452 patients with unresectable and metastatic NSCLC. Dacomitinib represents a powerful new treatment option compared with first-generation EGFR-TKIs. In this paper, we review the clinical and preclinical studies of dacomitinib and discuss the drug's clinical value.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolinones; Randomized Controlled Trials as Topic
PubMed: 31050691
DOI: 10.1358/dot.2019.55.4.2965337