A randomised, double‐blind, multicentre, Phase III trial of nintedanib plus pemetrexed vs placebo plus pemetrexed in patients with advanced or recurrent non-small cell lung cancer (NSCLC) after failure of first-line therapy.
LUME-Lung 2 – Nintedanib Plus Pemetrexed Compared to Placebo Plus Pemetrexed in Non-Squamous Non-Small Cell Lung Cancer After First-Line Therapy Failure
Histologically or cytologically confirmed Stage IIIB/IV or recurrent NSCLC (non-squamous histologies)
Relapse or failure of one first-line chemotherapy
Eastern Cooperative Oncology Group performance status of 0–1
Nintedanib 200 mg
Oral twice daily (Days 2–21 of
every 3-week cycle)
with pemetrexed 500 mg/m2
Intravenous (IV; Day 1)
Placebo 200 mg
Oral twice daily (Days 2–21 of every 3-week cycle)
Standard chemotherapy with pemetrexed 500 mg/m2
IV (Day 1)
Primary outcome measures:
Progression-free survival (PFS) assessed by independent central review
Key secondary outcome measure:
Overall survival (OS)
Other secondary outcome measures:
Objective tumour response
The LUME-Lung 2 trial was stopped early due to futility at a prespecified interim analysis based on the investigator-assessed PFS only. Subsequent analysis of the available intention-to-treat population, using independently reviewed data, showed a PFS benefit for patients treated with nintedanib plus pemetrexed compared with placebo plus pemetrexed, but no difference in OS between the two treatment arms. Objective response rate by central independent review was similar between the two treatment arms; however, the disease control rate favoured the nintedanib arm over the placebo arm.
A preplanned futility analysis of investigator-assessed PFS was performed by an independent data monitoring committee (DMC), using a predefined threshold for conditional power. The analysis indicated that the study was unlikely to reach its primary endpoint, and the DMC recommended halting further recruitment; no safety concerns were raised. However, retrospective analysis indicated that the conditional power only dropped below the threshold at the time of the futility analysis for investigator-assessed PFS, and that the conditional power for PFS by independent central review did not fall below the threshold at any point. Had the futility analysis been performed at another time point, or had centrally reviewed data been used, the outcome might have been different.
Even though the study was stopped early due to a preplanned futility analysis, the primary endpoint was met indicating that nintedanib plus pemetrexed significantly improved PFS (p=0.04) in patients with advanced non-squamous NSCLC who had progressed on first-line chemotherapy. No safety concerns were raised; the AE profile of nintedanib plus pemetrexed was manageable and similar to that seen in the LUME-Lung 1 trial.
Hanna NH, Kaiser R, Sullivan RN, et al. 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.
Lesaffre E, Edelman MJ, Hanna NH, et al. Statistical controversies in clinical research: Do futility analyses in oncology always get it right? An example from a randomised controlled trial. Ann Oncol 2017;DOI: https://doi.org/10.1093/annonc/mdx042.
Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT00806819 (Accessed: February 2017).