In a phase III trial (LUME-Lung 1) reported in The Lancet Oncology, Reck et al assessed the addition of nintedanib to docetaxel in second-line treatment of non–small cell lung cancer (NSCLC).1 The combination significantly improved progression-free survival in all patients and improved overall survival in patients with adenocarcinoma.
Nintedanib is an angiokinase inhibitor targeting pathways mediated by VEGFR 1-3, FGFR 1-3, and PDGFR α and β; it also reportedly inhibits receptor kinases of RET, FLT3, and the Src family.
This placebo-controlled, double-blind trial included 1,314 patients from 211 centers in 27 countries with stage IIIB/IV recurrent NSCLC that had progressed after first-line chemotherapy. Patients were randomly assigned between December 2008 and February 2011 to receive docetaxel at 75 mg/m2 on day 1 plus either nintedanib at 200 mg orally twice daily (n = 655) or matching placebo (n = 659) on days 2 to 21 every 3 weeks.
The primary endpoint was progression-free survival on independent central review analyzed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival analyzed by intention to treat after 1,121 events had occurred in a prespecified order: first in patients with adenocarcinoma who had disease progression within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients.
The combination and docetaxel groups were generally balanced for age (median, 60 years in both, 31% and 33% ≥ 65 years), sex (73% male in both), race (81% and 80% white), Eastern Cooperative Oncology Group performance status (1 in 71% in both), smoking history (25% and 24% never smokers), clinical stage (eg, stage IV in 61% and 62%), metastases at screening (90% and 92%), histology (squamous cell in 42% in both, adenocarcinoma in 49% and 51%), baseline sum of longest tumor diameters (median, 81 and 76 mm), time since first diagnosis (median, 8.8 and 8.6 months), previous surgery (22% in both), previous radiotherapy (29% in both), previous first-line therapy (platinum-based in 97% and 98%), first-line bevacizumab (4.1% and 3.5%), and best response to first-line therapy (eg, complete or partial response in 35% and 30%, progressive disease in 20% and 21%).
Progression-Free and Overall Survival
After median follow-up of 7.1 months, median progression-free survival was significantly longer in the docetaxel/nintedanib group on independent review (3.4 vs 2.7 months, hazard ratio [HR] = 0.79, P = .0019). The effect of nintedanib was consistent in prespecified subgroup analyses for sex, age, ethnic origin, smoking status, performance status, brain metastases, previous bevacizumab, time since start of first-line treatment, and best response to first-line treatment.
Treatments after progression were balanced between both groups, with 48% of patients with squamous cell carcinoma and 56% of those with adenocarcinoma receiving subsequent treatment. After median follow-up of 31.7 months, median overall survival was significantly longer in combination patients (n = 206) vs docetaxel patients (n = 199) with adenocarcinoma who progressed within 9 months after start of first-line treatment (10.9 vs 7.9 months, HR = 0.75, P = .0073) and in all combination patients (n = 322) vs docetaxel patients (n=336) with adenocarcinoma (12.6 vs 10.3 months, HR = 0.83, P = .0359), but not in the total study population (10.1 vs 9.1 months, HR = 0.94, P = .2720).
Grade 3 or higher adverse events that were more common in the nintedanib/docetaxel group were diarrhea (6.6% vs 2.6%), increased ALT (7.8% vs 0.9%), and increased AST (3.4% vs 0.5%). Increases in liver enzymes were reversible. Adverse events led to dose reductions for nintedanib or placebo in 19% of the nintedanib/docetaxel group and 6% of the docetaxel group, mostly due to gastrointestinal adverse events and increased liver enzymes in the combination group, and for docetaxel in 16% and 12%, mostly due to hematologic adverse events.
Adverse events led to discontinuation of study treatment in 23% of combination patients and 22% of docetaxel patients. Adverse events led to death considered possibly unrelated to disease progression in 5.4% of the combination group and in 3.8% of the docetaxel group, including sepsis in five patients vs one patient, pneumonia in two vs seven, respiratory failure in four vs zero, and pulmonary embolism in zero vs three.
The investigators concluded, “Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma.” ■
Disclosure: The study was funded by Boehringer Ingelheim. For full disclosures of the study authors, visit www.thelancet.com.
1. Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib vs docetaxel plus placebo in patients with previously treated non-small cell lung cancer (LUME-Lung 1): A phase III, double-blind, randomized controlled trial. Lancet Oncol 15:143-155, 2014.