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Dabrafenib plus trametinib in patients with previously treated BRAFV600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial

Summary Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAFV600E -mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitor... Full description

Journal Title: The lancet oncology 2016, Vol.17 (7), p.984-993
Main Author: Planchard, David, MD
Other Authors: Besse, Benjamin, MD , Groen, Harry J M, Prof , Souquet, Pierre-Jean, MD , Quoix, Elisabeth, Prof , Baik, Christina S, MD , Barlesi, Fabrice, Prof , Kim, Tae Min, MD , Mazieres, Julien, Prof , Novello, Silvia, MD , Rigas, James R, MD , Upalawanna, Allison, PharmD , D'Amelio, Anthony M, PhD , Zhang, Pingkuan, MD , Mookerjee, Bijoyesh, MD , Johnson, Bruce E, Prof
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: London: Elsevier Ltd
ID: ISSN: 1470-2045
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title: Dabrafenib plus trametinib in patients with previously treated BRAFV600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
format: Article
creator:
  • Planchard, David, MD
  • Besse, Benjamin, MD
  • Groen, Harry J M, Prof
  • Souquet, Pierre-Jean, MD
  • Quoix, Elisabeth, Prof
  • Baik, Christina S, MD
  • Barlesi, Fabrice, Prof
  • Kim, Tae Min, MD
  • Mazieres, Julien, Prof
  • Novello, Silvia, MD
  • Rigas, James R, MD
  • Upalawanna, Allison, PharmD
  • D'Amelio, Anthony M, PhD
  • Zhang, Pingkuan, MD
  • Mookerjee, Bijoyesh, MD
  • Johnson, Bruce E, Prof
subjects:
  • Cancer therapies
  • Chemotherapy
  • Family medical history
  • Hematology, Oncology and Palliative Medicine
  • Immunotherapy
  • Lung cancer
  • Melanoma
  • Metastasis
  • Mutation
  • Studies
ispartof: The lancet oncology, 2016, Vol.17 (7), p.984-993
description: Summary Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAFV600E -mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAFV600E -mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAFV600 -mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAFV600E -mutant NSCLC. Methods In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAFV600E -mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov , number NCT01336634. Findings Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3–75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in t
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1470-2045
fulltext: fulltext
issn:
  • 1470-2045
  • 1474-5488
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titleDabrafenib plus trametinib in patients with previously treated BRAFV600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
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creatorPlanchard, David, MD ; Besse, Benjamin, MD ; Groen, Harry J M, Prof ; Souquet, Pierre-Jean, MD ; Quoix, Elisabeth, Prof ; Baik, Christina S, MD ; Barlesi, Fabrice, Prof ; Kim, Tae Min, MD ; Mazieres, Julien, Prof ; Novello, Silvia, MD ; Rigas, James R, MD ; Upalawanna, Allison, PharmD ; D'Amelio, Anthony M, PhD ; Zhang, Pingkuan, MD ; Mookerjee, Bijoyesh, MD ; Johnson, Bruce E, Prof
creatorcontribPlanchard, David, MD ; Besse, Benjamin, MD ; Groen, Harry J M, Prof ; Souquet, Pierre-Jean, MD ; Quoix, Elisabeth, Prof ; Baik, Christina S, MD ; Barlesi, Fabrice, Prof ; Kim, Tae Min, MD ; Mazieres, Julien, Prof ; Novello, Silvia, MD ; Rigas, James R, MD ; Upalawanna, Allison, PharmD ; D'Amelio, Anthony M, PhD ; Zhang, Pingkuan, MD ; Mookerjee, Bijoyesh, MD ; Johnson, Bruce E, Prof
descriptionSummary Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAFV600E -mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAFV600E -mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAFV600 -mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAFV600E -mutant NSCLC. Methods In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAFV600E -mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov , number NCT01336634. Findings Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3–75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3–4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator). Interpretation Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAFV600E -mutant NSCLC. Funding GlaxoSmithKline.
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subjectCancer therapies ; Chemotherapy ; Family medical history ; Hematology, Oncology and Palliative Medicine ; Immunotherapy ; Lung cancer ; Melanoma ; Metastasis ; Mutation ; Studies
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13Zhang, Pingkuan, MD
14Mookerjee, Bijoyesh, MD
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0Dabrafenib plus trametinib in patients with previously treated BRAFV600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
1The lancet oncology
descriptionSummary Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAFV600E -mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAFV600E -mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAFV600 -mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAFV600E -mutant NSCLC. Methods In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAFV600E -mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov , number NCT01336634. Findings Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3–75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3–4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator). Interpretation Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAFV600E -mutant NSCLC. Funding GlaxoSmithKline.
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titleDabrafenib plus trametinib in patients with previously treated BRAFV600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
authorPlanchard, David, MD ; Besse, Benjamin, MD ; Groen, Harry J M, Prof ; Souquet, Pierre-Jean, MD ; Quoix, Elisabeth, Prof ; Baik, Christina S, MD ; Barlesi, Fabrice, Prof ; Kim, Tae Min, MD ; Mazieres, Julien, Prof ; Novello, Silvia, MD ; Rigas, James R, MD ; Upalawanna, Allison, PharmD ; D'Amelio, Anthony M, PhD ; Zhang, Pingkuan, MD ; Mookerjee, Bijoyesh, MD ; Johnson, Bruce E, Prof
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atitleDabrafenib plus trametinib in patients with previously treated BRAFV600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
jtitleThe lancet oncology
date2016
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volume17
issue7
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pages984-993
issn1470-2045
eissn1474-5488
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abstractSummary Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAFV600E -mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAFV600E -mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAFV600 -mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAFV600E -mutant NSCLC. Methods In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAFV600E -mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov , number NCT01336634. Findings Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3–75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3–4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator). Interpretation Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAFV600E -mutant NSCLC. Funding GlaxoSmithKline.
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doi10.1016/S1470-2045(16)30146-2