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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. 2016;102:65-73.

Highlights

  • Nintedanib plus docetaxel improved PFS for pretreated NSCLC compared with docetaxel in LUME-Lung 1.
  • LUME-Lung 2 investigated nintedanib plus pemetrexed in pretreated non-squamous NSCLC.
  • The trial was stopped early although did meet the primary endpoint (PFS).
  • There were no safety concerns with the addition of nintedanib to pemetrexed.

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.

Abbreviations: NSCLC - non small cell lung cancer, VEGF(R) - vascular endothelial growth factor (receptor), PDGF(R) - platelet-derived growth factor (receptor), FGR(R) - fibroblast growth factor (receptor), PFS - progression-free survival, HR - hazard ratio, CI - confidence interval, OS - overall survival, RECIST - response evaluation criteria in solid tumors, ECOG PS - Eastern Cooperative Oncology Group performance status, CT - computed tomography, MRI - magnetic resonance imaging, AE - adverse event, CTCAE - common toxicity criteria for adverse events, QoL - quality of life, DMC - data monitoring committee, ITT - intention-to-treat, IQR - interquartile range, EGFR - epidermal growth factor receptor, ALK - anaplastic lymphoma kinase.

Keywords: Angiogenesis inhibitor, Phase III, Nintedanib, Non-small cell lung cancer, Second-line.

Footnotes

a Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA

b Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany

c Institute of Clinical Pharmacology, Georg-August-University Göttingen, Germany

d Department of Oncology, Auckland City Hospital, Auckland, New Zealand

e Instituto Nacional del Cáncer, Santiago, Chile

f Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

g Internal Medicine, National Kidney and Transplant Institute, Quezon City, Philippines

h Boehringer Ingelheim (Canada) Ltd, Burlington, ON, Canada

i Pneumology Clinic, Asklepios Fachkliniken, Gauting, Germany

j Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia

k Jewish General Hospital, Montréal, Québec, Canada

l Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

m Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea

Correspondence to: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA.

1 Drs Hanna and Kaiser contributed equally to this work.