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LUME-Lung 2 clinical trial

Nintedanib Plus Pemetrexed Compared to Placebo Plus Pemetrexed in Non-Squamous Non-Small Cell Lung Cancer After First-Line Therapy Failure

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.


Trial NCT00806819


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



Randomisation 1:1

Nintedanib 200 mg + Standard chemotherapy with pemetrexed 500 mg/m² Oral twice daily (Days 2–21 of every 3-week cycle) + Intravenous (IV; Day 1)
Placebo 200 mg + Standard chemotherapy with pemetrexed 500 mg/m² Oral twice daily (Days 2–21 of every 3-week cycle) + Intravenous (IV; Day 1)


Primary outcome measure:

  • Progression-free survival (PFS) assessed by independent central review


Key secondary outcome measure:

  • Overall survival (OS)


Other secondary outcome measures:

  • Disease control
  • Objective tumour response
  • Safety/tolerability



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. 

LUME-Lung 2: figure for PFS with nintedanib vs placebo

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.

LUME-Lung 2: retrospective conditional and predictive powers for PFS over time


The frequency of serious adverse events (AEs) and Grade 5 AEs were comparable between the two treatment groups. A similar incidence of Grade ≥3 hypertension, bleeding, thrombosis, mucositis and neuropathy was observed in both treatment groups. In patients treated with nintedanib plus pemetrexed there was a higher frequency of Grade ≥3 elevated alanine transaminase (23% vs 7%), elevated aspartate transaminase (12% vs 2%) and diarrhoea (3% vs 1%) compared with patients treated with placebo plus pemetrexed.


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.


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Hanna NH, et al. Lung Cancer 2016;102:65–73.


Lesaffre E, et al. Ann Oncol 2017;28(7):1419–26.

3 (Accessed: January 2019).

*Nintedanib is approved in the EU under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. For the full list of country-specific information please click here. Nintedanib is not approved in other oncology indications.