Dacomitinib

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Tony Mok - One of the best experts on this subject based on the ideXlab platform.

  • Dacomitinib as first line treatment for egfr mutation positive non small cell lung cancer
    Expert Review of Precision Medicine and Drug Development, 2021
    Co-Authors: Thanyanan Reungwetwattana, Tony Mok, Nitesh Rohatgi, Kumar Prabhash
    Abstract:

    Introduction: Dacomitinib is a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Recent results from ARCHER 1050, the first randomized, open-label, Phase 3 tr...

  • safety and efficacy of first line Dacomitinib in asian patients with egfr mutation positive non small cell lung cancer results from a randomized open label phase 3 trial archer 1050
    Lung Cancer, 2021
    Co-Authors: Ying Cheng, Tony Mok, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Qing Zhou, Jianying Zhou, Xiaoqing Liu, Yiping Zhang, R Linke
    Abstract:

    Abstract Objectives To compare efficacy and safety of Dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial. Materials and methods In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral Dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review. Results Of 346 Asian patients, 170 were randomized to Dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with Dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391–0.662; 1-sided p Conclusion First-line Dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of Dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.

  • 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
    Drugs, 2021
    Co-Authors: Tony Mok, Seiji Niho, Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Alka Chawla, Rafael Rosell, Jesus Corral, M R Migliorino
    Abstract:

    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. This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. 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). 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. 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. NCT01774721 (registered 24 January 2013).

  • effects of dose modifications on the safety and efficacy of Dacomitinib for egfr mutation positive non small cell lung cancer
    Future Oncology, 2019
    Co-Authors: Jesus Corral, Tony Mok, Ki Hyeong Lee, Kazuhiko Nakagawa, Rafael Rosell, M R Migliorino, R Linke, Adam Pluzanski, Geeta Devgan, Weiwei Tan
    Abstract:

    Aim: We evaluated reasons for Dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral Dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma Dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all Dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with Dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721.

  • Dacomitinib in the management of advanced non small cell lung cancer
    Drugs, 2019
    Co-Authors: S Lau, Tony Mok, Ullas Batra, Herbert H Loong
    Abstract:

    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.

Pasi A Janne - One of the best experts on this subject based on the ideXlab platform.

  • combined pan her and alk ros1 met inhibition with Dacomitinib and crizotinib in advanced non small cell lung cancer results of a phase i study
    Journal of Thoracic Oncology, 2016
    Co-Authors: Pasi A Janne, Zelanna Goldberg, Giuseppe Giaccone, Alice T Shaw, Ross D Camidge, Martin S Shreeve, Yiyun Tang, Jeanfrancois Martini, Leonard P James, Benjamin Solomon
    Abstract:

    Abstract Introduction This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor Dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non–small cell lung cancer. Methods Patients with progression after at least one line of chemotherapy or targeted therapy received Dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose; secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers. Results Seventy patients were treated in the dose-escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as Dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths; none were considered treatment related. One patient (1%) had a partial response; 46% had stable disease. Most of the tumor samples analyzed had activating epidermal growth factor receptor gene ( EGFR ) mutations (18 of 20 [90%]); 50% (10 of 20) had a concurrent resistance mutation. Only one sample showed MMNG HOS Transforming gene ( MET ) amplification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity. Conclusion The combination of Dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non–small cell lung cancer and was associated with substantial toxicity.

  • Dacomitinib versus erlotinib in patients with egfr mutated advanced nonsmall cell lung cancer nsclc pooled subset analyses from two randomized trials
    Faculty of Health; Institute of Health and Biomedical Innovation, 2016
    Co-Authors: Suresh S Ramalingam, Tony Mok, Ian Taylor, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, H Zhang, Jane Q Liang, Eric Sbar, Luis Pazares
    Abstract:

    Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to Dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of Dacomitinib to erlotinib. Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with Dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with Dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with Dacomitinib. An ongoing phase III study will compare Dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

  • Dacomitinib as first line treatment in patients with clinically or molecularly selected advanced non small cell lung cancer a multicentre open label phase 2 trial
    Lancet Oncology, 2014
    Co-Authors: Pasi A Janne, Makoto Nishio, Mark G Kris, J Oconnell, Saihong Ignatius Ou, Geoffrey R Oxnard, Renato Martins, Frank Dunphy, Cloud P Paweletz, Ian Taylor
    Abstract:

    Summary Background Patients with EGFR -mutant non-small-cell lung cancer generally have a progression-free survival of 9–13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of Dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. Methods In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [ EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave Dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of Dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients. Findings Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR -activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4–84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2–98·9) in the EGFR -mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. Interpretation Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer. Funding Pfizer.

  • Dacomitinib versus erlotinib in patients with advanced stage previously treated non small cell lung cancer archer 1009 a randomised double blind phase 3 trial
    Lancet Oncology, 2014
    Co-Authors: Suresh S Ramalingam, Tony Mok, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, Adam Pluzanski, Joachim Von Pawel, Mikhail Shtivelband, Lara Iglesias Docampo, Jaafar Bennouna
    Abstract:

    Summary Background Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for Dacomitinib compared with erlotinib. We aimed to compare Dacomitinib with erlotinib in a phase 3 study. Methods In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to Dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0–1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. Findings Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to Dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9–2·8) in both the Dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802–1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS , median progression-free survival was 2·6 months for Dacomitinib (95% CI 1·9–2·9) and erlotinib (95% CI 1·9–3·0; stratified HR 1·022, 95% CI 0·834–1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3–4 adverse events were diarrhoea (47 [11%] patients in the Dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [ Interpretation Irreversible EGFR inhibition with Dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. Funding Pfizer.

  • randomized double blinded study of Dacomitinib an irreversible pan human epidermal growth factor receptor her inhibitor versus erlotinib for second line third line therapy of locally advanced metastatic non small cell lung cancer archer 1009
    Journal of Clinical Oncology, 2014
    Co-Authors: Suresh S Ramalingam, Tony Mok, Jim P Doherty, Ian Taylor, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, H Zhang, Jane Q Liang, Cecile A Mather
    Abstract:

    8018 Background: Dacomitinib, an irreversible pan-HER kinase inhibitor, has demonstrated anti-cancer activity in phase 2 studies for patients with EGFR activating mutation and in those with EGFR an...

Ian Taylor - One of the best experts on this subject based on the ideXlab platform.

  • Dacomitinib versus erlotinib in patients with egfr mutated advanced nonsmall cell lung cancer nsclc pooled subset analyses from two randomized trials
    Faculty of Health; Institute of Health and Biomedical Innovation, 2016
    Co-Authors: Suresh S Ramalingam, Tony Mok, Ian Taylor, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, H Zhang, Jane Q Liang, Eric Sbar, Luis Pazares
    Abstract:

    Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to Dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of Dacomitinib to erlotinib. Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with Dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with Dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with Dacomitinib. An ongoing phase III study will compare Dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

  • targeting her2 aberrations as actionable drivers in lung cancers phase ii trial of the pan her tyrosine kinase inhibitor Dacomitinib in patients with her2 mutant or amplified tumors
    Annals of Oncology, 2015
    Co-Authors: Mark G Kris, Ian Taylor, H Zhang, Giuseppe Giaccone, J Oconnell, D R Camidge, Toyoaki Hida, Bob T Li, Maria E Arcila, Zelanna Goldberg
    Abstract:

    ABSTRACT Background HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied Dacomitinib in patients with HER2-mutant or amplified lung cancers. Patients and methods As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral Dacomitinib at 30–45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. Results We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of Dacomitinib (95% CI 7–21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of Dacomitinib with mirtazapine. Conclusions Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers. ClinicalTrials.gov NCT00818441.

  • Dacomitinib as first line treatment in patients with clinically or molecularly selected advanced non small cell lung cancer a multicentre open label phase 2 trial
    Lancet Oncology, 2014
    Co-Authors: Pasi A Janne, Makoto Nishio, Mark G Kris, J Oconnell, Saihong Ignatius Ou, Geoffrey R Oxnard, Renato Martins, Frank Dunphy, Cloud P Paweletz, Ian Taylor
    Abstract:

    Summary Background Patients with EGFR -mutant non-small-cell lung cancer generally have a progression-free survival of 9–13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of Dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. Methods In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [ EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave Dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of Dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients. Findings Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR -activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4–84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2–98·9) in the EGFR -mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. Interpretation Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer. Funding Pfizer.

  • safety and efficacy of Dacomitinib in korean patients with kras wild type advanced non small cell lung cancer refractory to chemotherapy and erlotinib or gefitinib a phase i ii trial
    Journal of Thoracic Oncology, 2014
    Co-Authors: Keunchil Park, Byoung Chul Cho, Dongwan Kim, Diana Gernhardt, Ian Taylor, H Zhang, Myungju Ahn, A Campbell, Sang Yoon Lee, Nagdeep Giri
    Abstract:

    Introduction Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib). Methods The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of Dacomitinib. In the phase II portion, patients received Dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS 4m ). Results Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS 4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p -value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of Dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms "cough" and "pain" showed improvement within 3 weeks of initiating treatment. Conclusions Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor.

  • randomized double blinded study of Dacomitinib an irreversible pan human epidermal growth factor receptor her inhibitor versus erlotinib for second line third line therapy of locally advanced metastatic non small cell lung cancer archer 1009
    Journal of Clinical Oncology, 2014
    Co-Authors: Suresh S Ramalingam, Tony Mok, Jim P Doherty, Ian Taylor, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, H Zhang, Jane Q Liang, Cecile A Mather
    Abstract:

    8018 Background: Dacomitinib, an irreversible pan-HER kinase inhibitor, has demonstrated anti-cancer activity in phase 2 studies for patients with EGFR activating mutation and in those with EGFR an...

Nagdeep Giri - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of the potential effect of Dacomitinib an egfr tyrosine kinase inhibitor on ecg parameters in patients with advanced non small cell lung cancer
    Investigational New Drugs, 2020
    Co-Authors: Weiwei Tan, Nagdeep Giri, Keith D Wilner, Susan Quinn, Kourosh Parivar
    Abstract:

    Purpose The study evaluated the potential effect of Dacomitinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, on the electrocardiogram (ECG) parameters in adult patients with advanced non-small cell lung cancer enrolled in a multicenter, open-label, phase 2 study. Methods Patients received Dacomitinib for six doses of 45 mg every 12 h in a 7-day lead-in cycle (cycle 0), then 60 mg every 12 h for six doses in a 14-day cycle (cycle 1). Clock time-matched triplicate ECGs were performed at 0, 2, 4, 6, 8 and 10 h on day 1 (baseline) and day 4 of cycle 0, and prior to dose on days 1 and 4 of cycle 1. The QT interval was corrected for heart rate using Fridericia’s correction (QTcF) and a study specific correction factor (QTcS). Results Thirty-two patients in the study comprised the QTc-evaluable population. Dacomitinib had no effect on the heart rate. The upper limits of the 95% confidence interval (CI) for the mean change from baseline in QTcF and QTcS were < 10 ms at all time points. A lack of relationship between plasma concentrations of Dacomitinib or total active moiety on QTcF and QTcS was evidenced. All upper 90% CIs of the PR intervals were < 200 ms, although a small mean increase from baseline (2.7–6.6 ms) was observed. Conclusions There was a lack of a clinically relevant effect of Dacomitinib on ECG parameters at Dacomitinib concentrations comparable to those obtained at its highest therapeutic dosing regimen of 45 mg once daily. ClinicalTrials.gov identifier: NCT01858389.

  • phase 1 study to investigate the pharmacokinetic properties of Dacomitinib in healthy adult chinese subjects genotyped for cyp2d6
    Xenobiotica, 2018
    Co-Authors: Xia Chen, Ji Jiang, Nagdeep Giri
    Abstract:

    Abstract1. This study aimed to characterise the pharmacokinetics of Dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects.2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single Dacomitinib 45-mg oral dose. Pharmacokinetic samples for Dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study.3. The geometric mean (per cent coefficient of variability) area under the concentration–time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1662 ngċh/mL (26%) and 21.51 ng/mL (27%), respectively, for Dacomitinib and 469 ngċh/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to Cmax were 8 and 4 h postdose for Dacomitinib and PF-05199265, respectively; mean terminal half-life of Dacomitinib was 62.7 h. Geometric mean...

  • phase 2 study of intermittent pulse Dacomitinib in patients with advanced non small cell lung cancers
    Lung Cancer, 2017
    Co-Authors: Myungju Ahn, Byoung Chul Cho, Nagdeep Giri, H Zhang, Eric Sbar, David E Gerber, Ronald B Natale, Mark A Socinski, Susan Quinn, Giuseppe Giaccone
    Abstract:

    Abstract Background Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Pre-clinical data suggest that intermittent pulsatile dosing of Dacomitinib may result in inhibition of EGFR T790M. Methods We evaluated safety, pharmacokinetics and efficacy of intermittent pulsatile Dacomitinib in both molecularly unselected patients and patients with lung cancers harboring EGFR T790M (Clinical Trial Registration Number NCT01858389). Results Thirty-eight patients were treated on study with pulse Dacomitinib; sixteen with EGFR T790M in Cohort A and 22 who were not molecularly selected in Cohort B. One patient out of 16 patients in Cohort A had a partial response to study therapy (ORR 6.3%, 95% CI 0.2-30.2%). The median progression-free survival (PFS) in Cohort A was 2.3 months and median PFS in Cohort B was 1.6 months. The adverse event profile was similar to standard daily dose Dacomitinib with the most frequent treatment-related toxicities occurring in >20% of patients being diarrhea, rash, stomatitis, nausea, dry skin, paronychia, fatigue, and decreased appetite. Conclusion Intermittent pulsatile Dacomitinib is safe and relatively well tolerated but is not effective in patients that harbor EGFR T790M or in unselected patients with non-small cell lung cancer.

  • impact of a planned dose interruption of Dacomitinib in the treatment of advanced non small cell lung cancer archer 1042
    Lung Cancer, 2017
    Co-Authors: Dongwan Kim, Nagdeep Giri, Dorothy M K Keefe, Edward B Garon, Aminah Jatoi, Mario E Lacouture, Stephen T Sonis, Diana Gernhardt, Tao Wang, Jim P Doherty
    Abstract:

    Objectives Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day Dacomitinib dose interruption on plasma exposure of Dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study.

  • a phase i clinical trial and independent patient derived xenograft study of combined targeted treatment with Dacomitinib and figitumumab in advanced solid tumors
    Clinical Cancer Research, 2017
    Co-Authors: Emiliano Calvo, Diana Gernhardt, Tao Wang, J Oconnell, Jeancharles Soria, Wen Wee, Rastilav Bahleda, Anthony W Tolcher, Robert Millham, Nagdeep Giri
    Abstract:

    Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of Dacomitinib-figitumumab combination therapy in patients with advanced solid tumors.Experimental Design: A standard 3 + 3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and Dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma.Results: Of the 74 patients enrolled, the most common malignancies were non-small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across five dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of Dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug-drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas Dacomitinib did not. Figitumumab-sensitive tumors showed downregulation of genes in the insulin-like growth factor receptor 1 pathway.Conclusions: Dacomitinib-figitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor adenoid cystic carcinoma. Clin Cancer Res; 23(5); 1177-85. ©2016 AACRSee related commentary by Sundar et al., p. 1123.

H Zhang - One of the best experts on this subject based on the ideXlab platform.

  • phase 2 study of intermittent pulse Dacomitinib in patients with advanced non small cell lung cancers
    Lung Cancer, 2017
    Co-Authors: Myungju Ahn, Byoung Chul Cho, Nagdeep Giri, H Zhang, Eric Sbar, David E Gerber, Ronald B Natale, Mark A Socinski, Susan Quinn, Giuseppe Giaccone
    Abstract:

    Abstract Background Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Pre-clinical data suggest that intermittent pulsatile dosing of Dacomitinib may result in inhibition of EGFR T790M. Methods We evaluated safety, pharmacokinetics and efficacy of intermittent pulsatile Dacomitinib in both molecularly unselected patients and patients with lung cancers harboring EGFR T790M (Clinical Trial Registration Number NCT01858389). Results Thirty-eight patients were treated on study with pulse Dacomitinib; sixteen with EGFR T790M in Cohort A and 22 who were not molecularly selected in Cohort B. One patient out of 16 patients in Cohort A had a partial response to study therapy (ORR 6.3%, 95% CI 0.2-30.2%). The median progression-free survival (PFS) in Cohort A was 2.3 months and median PFS in Cohort B was 1.6 months. The adverse event profile was similar to standard daily dose Dacomitinib with the most frequent treatment-related toxicities occurring in >20% of patients being diarrhea, rash, stomatitis, nausea, dry skin, paronychia, fatigue, and decreased appetite. Conclusion Intermittent pulsatile Dacomitinib is safe and relatively well tolerated but is not effective in patients that harbor EGFR T790M or in unselected patients with non-small cell lung cancer.

  • Dacomitinib versus erlotinib in patients with egfr mutated advanced nonsmall cell lung cancer nsclc pooled subset analyses from two randomized trials
    Faculty of Health; Institute of Health and Biomedical Innovation, 2016
    Co-Authors: Suresh S Ramalingam, Tony Mok, Ian Taylor, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, H Zhang, Jane Q Liang, Eric Sbar, Luis Pazares
    Abstract:

    Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to Dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of Dacomitinib to erlotinib. Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with Dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with Dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with Dacomitinib. An ongoing phase III study will compare Dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

  • targeting her2 aberrations as actionable drivers in lung cancers phase ii trial of the pan her tyrosine kinase inhibitor Dacomitinib in patients with her2 mutant or amplified tumors
    Annals of Oncology, 2015
    Co-Authors: Mark G Kris, Ian Taylor, H Zhang, Giuseppe Giaccone, J Oconnell, D R Camidge, Toyoaki Hida, Bob T Li, Maria E Arcila, Zelanna Goldberg
    Abstract:

    ABSTRACT Background HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied Dacomitinib in patients with HER2-mutant or amplified lung cancers. Patients and methods As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral Dacomitinib at 30–45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. Results We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of Dacomitinib (95% CI 7–21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of Dacomitinib with mirtazapine. Conclusions Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers. ClinicalTrials.gov NCT00818441.

  • safety and efficacy of Dacomitinib in korean patients with kras wild type advanced non small cell lung cancer refractory to chemotherapy and erlotinib or gefitinib a phase i ii trial
    Journal of Thoracic Oncology, 2014
    Co-Authors: Keunchil Park, Byoung Chul Cho, Dongwan Kim, Diana Gernhardt, Ian Taylor, H Zhang, Myungju Ahn, A Campbell, Sang Yoon Lee, Nagdeep Giri
    Abstract:

    Introduction Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib). Methods The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of Dacomitinib. In the phase II portion, patients received Dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS 4m ). Results Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS 4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p -value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of Dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms "cough" and "pain" showed improvement within 3 weeks of initiating treatment. Conclusions Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor.

  • randomized double blinded study of Dacomitinib an irreversible pan human epidermal growth factor receptor her inhibitor versus erlotinib for second line third line therapy of locally advanced metastatic non small cell lung cancer archer 1009
    Journal of Clinical Oncology, 2014
    Co-Authors: Suresh S Ramalingam, Tony Mok, Jim P Doherty, Ian Taylor, Kenneth J Obyrne, Michael Boyer, Pasi A Janne, H Zhang, Jane Q Liang, Cecile A Mather
    Abstract:

    8018 Background: Dacomitinib, an irreversible pan-HER kinase inhibitor, has demonstrated anti-cancer activity in phase 2 studies for patients with EGFR activating mutation and in those with EGFR an...