Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): A double-blind, randomised, phase 3 trial

Peter M. Ellis, Frances A. Shepherd, Michael Millward, Francesco Perrone, Lesley Seymour, Geoffrey Liu, Sophie Sun, ByoungChul Cho, Alessandro Morabito, Natasha B. Leighl, Martin R. Stockler, Christopher W. Lee, Rafal Wierzbicki, Victor Cohen, Normand Blais, Randeep S. Sangha, Adolfo G. Favaretto, Jin Hyoung Kang, Ming Sound Tsao, Carolyn F. WilsonZelanna Goldberg, Keyue Ding, Glenwood D. Goss, Penelope Ann Bradbury

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Background: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. Methods: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. Findings: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). Interpretation: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Funding: Canadian Cancer Society Research Institute and Pfizer.

Original languageEnglish
Pages (from-to)1379-1388
Number of pages10
JournalThe Lancet Oncology
Volume15
Issue number12
DOIs
Publication statusPublished - 2014 Nov 1

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Non-Small Cell Lung Carcinoma
Placebos
Survival
PF 00299804
Protein-Tyrosine Kinases
Neoplasms
Disease-Free Survival
Drug Therapy
Placebo Effect
Stomatitis
Mutation
Tobacco Use
Exanthema
Double-Blind Method
Cough

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Ellis, Peter M. ; Shepherd, Frances A. ; Millward, Michael ; Perrone, Francesco ; Seymour, Lesley ; Liu, Geoffrey ; Sun, Sophie ; Cho, ByoungChul ; Morabito, Alessandro ; Leighl, Natasha B. ; Stockler, Martin R. ; Lee, Christopher W. ; Wierzbicki, Rafal ; Cohen, Victor ; Blais, Normand ; Sangha, Randeep S. ; Favaretto, Adolfo G. ; Kang, Jin Hyoung ; Tsao, Ming Sound ; Wilson, Carolyn F. ; Goldberg, Zelanna ; Ding, Keyue ; Goss, Glenwood D. ; Bradbury, Penelope Ann. / Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26) : A double-blind, randomised, phase 3 trial. In: The Lancet Oncology. 2014 ; Vol. 15, No. 12. pp. 1379-1388.
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title = "Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): A double-blind, randomised, phase 3 trial",
abstract = "Background: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. Methods: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. Findings: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95{\%} CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95{\%} CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95{\%} CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7{\%}] of 480 patients vs three [1{\%}] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95{\%} CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39{\%}) of 477 patients who received dacomitinib and 86 (36{\%}) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12{\%}] patients on dacomitinib vs no controls), acneiform rash (48 [10{\%}] vs one [<1{\%}]), oral mucositis (16 [3{\%}] vs none), and fatigue (13 [3{\%}] vs four [2{\%}]). Interpretation: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Funding: Canadian Cancer Society Research Institute and Pfizer.",
author = "Ellis, {Peter M.} and Shepherd, {Frances A.} and Michael Millward and Francesco Perrone and Lesley Seymour and Geoffrey Liu and Sophie Sun and ByoungChul Cho and Alessandro Morabito and Leighl, {Natasha B.} and Stockler, {Martin R.} and Lee, {Christopher W.} and Rafal Wierzbicki and Victor Cohen and Normand Blais and Sangha, {Randeep S.} and Favaretto, {Adolfo G.} and Kang, {Jin Hyoung} and Tsao, {Ming Sound} and Wilson, {Carolyn F.} and Zelanna Goldberg and Keyue Ding and Goss, {Glenwood D.} and Bradbury, {Penelope Ann}",
year = "2014",
month = "11",
day = "1",
doi = "10.1016/S1470-2045(14)70472-3",
language = "English",
volume = "15",
pages = "1379--1388",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "12",

}

Ellis, PM, Shepherd, FA, Millward, M, Perrone, F, Seymour, L, Liu, G, Sun, S, Cho, B, Morabito, A, Leighl, NB, Stockler, MR, Lee, CW, Wierzbicki, R, Cohen, V, Blais, N, Sangha, RS, Favaretto, AG, Kang, JH, Tsao, MS, Wilson, CF, Goldberg, Z, Ding, K, Goss, GD & Bradbury, PA 2014, 'Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): A double-blind, randomised, phase 3 trial', The Lancet Oncology, vol. 15, no. 12, pp. 1379-1388. https://doi.org/10.1016/S1470-2045(14)70472-3

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26) : A double-blind, randomised, phase 3 trial. / Ellis, Peter M.; Shepherd, Frances A.; Millward, Michael; Perrone, Francesco; Seymour, Lesley; Liu, Geoffrey; Sun, Sophie; Cho, ByoungChul; Morabito, Alessandro; Leighl, Natasha B.; Stockler, Martin R.; Lee, Christopher W.; Wierzbicki, Rafal; Cohen, Victor; Blais, Normand; Sangha, Randeep S.; Favaretto, Adolfo G.; Kang, Jin Hyoung; Tsao, Ming Sound; Wilson, Carolyn F.; Goldberg, Zelanna; Ding, Keyue; Goss, Glenwood D.; Bradbury, Penelope Ann.

In: The Lancet Oncology, Vol. 15, No. 12, 01.11.2014, p. 1379-1388.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26)

T2 - A double-blind, randomised, phase 3 trial

AU - Ellis, Peter M.

AU - Shepherd, Frances A.

AU - Millward, Michael

AU - Perrone, Francesco

AU - Seymour, Lesley

AU - Liu, Geoffrey

AU - Sun, Sophie

AU - Cho, ByoungChul

AU - Morabito, Alessandro

AU - Leighl, Natasha B.

AU - Stockler, Martin R.

AU - Lee, Christopher W.

AU - Wierzbicki, Rafal

AU - Cohen, Victor

AU - Blais, Normand

AU - Sangha, Randeep S.

AU - Favaretto, Adolfo G.

AU - Kang, Jin Hyoung

AU - Tsao, Ming Sound

AU - Wilson, Carolyn F.

AU - Goldberg, Zelanna

AU - Ding, Keyue

AU - Goss, Glenwood D.

AU - Bradbury, Penelope Ann

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Background: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. Methods: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. Findings: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). Interpretation: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Funding: Canadian Cancer Society Research Institute and Pfizer.

AB - Background: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. Methods: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. Findings: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). Interpretation: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Funding: Canadian Cancer Society Research Institute and Pfizer.

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