Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial

Nasser Hanna, Rolf Kaiser, Richard N. Sullivan, Osvaldo Rudy Aren, Myung Ju Ahn, Beatrice Tiangco, Isabelle Voccia, Joachim von Pawel, Vladimir Kovcin, Jason Agulnik, Birgit Gaschler-Markefski, José Barrueco, Patricia Sikken, Charles Schloss, Joo Hang Kim

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Objectives LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). Materials and methods Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500 mg/m2 on Day 1 plus nintedanib 200 mg orally twice daily or matching placebo on Days 2–21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. Results Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n = 353 nintedanib/pemetrexed; n = 360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.70–0.99, p = 0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR = 1.01, 95% CI 0.85–1.21, p = 0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. Conclusion Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

Original languageEnglish (US)
Pages (from-to)65-73
Number of pages9
JournalLung Cancer
Volume102
DOIs
StatePublished - Dec 1 2016

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Pemetrexed
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Placebos
Disease-Free Survival
Safety
Clinical Trials Data Monitoring Committees
Confidence Intervals
Medical Futility
nintedanib
Drug Therapy
Survival
Aspartate Aminotransferases
Alanine Transaminase
Diarrhea
Histology
Adenocarcinoma

Keywords

  • Angiogenesis inhibitor
  • Nintedanib
  • Non-small cell lung cancer
  • Phase III
  • Second-line

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2) : A randomized, double-blind, phase III trial. / Hanna, Nasser; Kaiser, Rolf; Sullivan, Richard N.; Aren, Osvaldo Rudy; Ahn, Myung Ju; Tiangco, Beatrice; Voccia, Isabelle; Pawel, Joachim von; Kovcin, Vladimir; Agulnik, Jason; Gaschler-Markefski, Birgit; Barrueco, José; Sikken, Patricia; Schloss, Charles; Kim, Joo Hang.

In: Lung Cancer, Vol. 102, 01.12.2016, p. 65-73.

Research output: Contribution to journalArticle

Hanna, N, Kaiser, R, Sullivan, RN, Aren, OR, Ahn, MJ, Tiangco, B, Voccia, I, Pawel, JV, Kovcin, V, Agulnik, J, Gaschler-Markefski, B, Barrueco, J, Sikken, P, Schloss, C & Kim, JH 2016, 'Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial', Lung Cancer, vol. 102, pp. 65-73. https://doi.org/10.1016/j.lungcan.2016.10.011
Hanna, Nasser ; Kaiser, Rolf ; Sullivan, Richard N. ; Aren, Osvaldo Rudy ; Ahn, Myung Ju ; Tiangco, Beatrice ; Voccia, Isabelle ; Pawel, Joachim von ; Kovcin, Vladimir ; Agulnik, Jason ; Gaschler-Markefski, Birgit ; Barrueco, José ; Sikken, Patricia ; Schloss, Charles ; Kim, Joo Hang. / Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2) : A randomized, double-blind, phase III trial. In: Lung Cancer. 2016 ; Vol. 102. pp. 65-73.
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title = "Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial",
abstract = "Objectives LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). Materials and methods Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500 mg/m2 on Day 1 plus nintedanib 200 mg orally twice daily or matching placebo on Days 2–21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. Results Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n = 353 nintedanib/pemetrexed; n = 360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR] = 0.83, 95{\%} confidence interval [CI] 0.70–0.99, p = 0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR = 1.01, 95{\%} CI 0.85–1.21, p = 0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3{\%} vs 7.3{\%}), elevated aspartate aminotransferase (12.1{\%} vs 1.7{\%}) and diarrhea (3.5{\%} vs 1.1{\%}) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. Conclusion Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.",
keywords = "Angiogenesis inhibitor, Nintedanib, Non-small cell lung cancer, Phase III, Second-line",
author = "Nasser Hanna and Rolf Kaiser and Sullivan, {Richard N.} and Aren, {Osvaldo Rudy} and Ahn, {Myung Ju} and Beatrice Tiangco and Isabelle Voccia and Pawel, {Joachim von} and Vladimir Kovcin and Jason Agulnik and Birgit Gaschler-Markefski and Jos{\'e} Barrueco and Patricia Sikken and Charles Schloss and Kim, {Joo Hang}",
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T1 - Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2)

T2 - A randomized, double-blind, phase III trial

AU - Hanna, Nasser

AU - Kaiser, Rolf

AU - Sullivan, Richard N.

AU - Aren, Osvaldo Rudy

AU - Ahn, Myung Ju

AU - Tiangco, Beatrice

AU - Voccia, Isabelle

AU - Pawel, Joachim von

AU - Kovcin, Vladimir

AU - Agulnik, Jason

AU - Gaschler-Markefski, Birgit

AU - Barrueco, José

AU - Sikken, Patricia

AU - Schloss, Charles

AU - Kim, Joo Hang

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Objectives LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). Materials and methods Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500 mg/m2 on Day 1 plus nintedanib 200 mg orally twice daily or matching placebo on Days 2–21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. Results Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n = 353 nintedanib/pemetrexed; n = 360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.70–0.99, p = 0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR = 1.01, 95% CI 0.85–1.21, p = 0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. Conclusion Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

AB - Objectives LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). Materials and methods Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500 mg/m2 on Day 1 plus nintedanib 200 mg orally twice daily or matching placebo on Days 2–21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. Results Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n = 353 nintedanib/pemetrexed; n = 360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.70–0.99, p = 0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR = 1.01, 95% CI 0.85–1.21, p = 0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. Conclusion Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

KW - Angiogenesis inhibitor

KW - Nintedanib

KW - Non-small cell lung cancer

KW - Phase III

KW - Second-line

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