The history of anti-angiogenic treatment in non-small-cell lung cancer (NSCLC) is represented by many defeats and few victories. After the results of ECOG 4599 trial, reported by Sandler et al1, that showed a significant prolongation of survival with bevacizumab when associated with a first-line setting of carboplatin and paclitaxel especially for patients with adenocarcinoma histology, different trial evaluated the role of anti-angiogenic drugs in NSCLC. Indeed, sorafenib, vandetanib, sunitinib and montesanib failed to show an improvement in overall survival (OS), despite the improvements in response rate (RR) or progression-free survival (PFS) 2-7.
Recently, nintedanib, an oral triple angiokinase inhibitor, showed prolonged PFS (primary endpoint – 3.4 vs. 2.7 months, HR 0.79; p < 0.0019) but no OS (10.1 vs. 9.1 months, HR 0·94, 95% CI 0.83–1.05; p = 0.2720) when used in the second-line setting with docetaxel in NSCLC, in the overall population. Notably, the subgroup analysis of patients with adenocarcinoma histology demonstrated an improvement in OS (12.6 vs. 10.3 months, HR 0.83, CI 0.70-0.99, p = 0.0359)8.
Garon et al recently reported on Lancet, the results of the REVEL trial. This study was a multicentric, double-blind, randomised phase 3 trial that enrolled patients with squamous and non-squamous NSCLC how had progressed during or after a first-line platinum-based chemotherapy, to receive docetaxel plus ramucirumab or placebo in second-line setting.
Ramucirumab, is a fully human IgG1 monoclonal antibody that binds to the VEGFR-2 extracellular domain with high affinity, preventing binding of all VEGF ligands and receptor activation, that has showed to prolong survival in patients with gastric cancer, as monotherapy or associated with paclitaxel, in the second-line setting.
1253 patients were randomized to receive docetaxel 75 mg/m2 either and ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, death or unacceptable toxicity. Notably, about 15% of patients in both arms were previously treated with bevacizumab as part of their first-line regimen.
The trial met its primary endpoint demonstrating longer OS in the ramucirumab arm (10.5 vs. 9.1 months, HR 0.86, 95% CI 0.75-0.98; p = 0.023). There was also an improvement in PFS (4.5 vs. 3.0 months (HR 0.76, 95% CI 0.68-0.86; p < 0.0001) and overall response rate (ORR) (22.9% vs. 13.6%, p < 0.001).
No major difference was noted about adverse events, reported in 98% of patients treated with ramucirumab and 95% of patients treated in the control group. The numbers of deaths from AE was similar in both arms (5% vs. 6%). Patients treated in the ramucirumab arm had higher incidence of bleeding or haemorrhage of any grade (29% vs. 15%), although there was no difference in the incidence of grade ≥ 3 bleeding or haemorrhage, venous/arterial thromboembolic events or gastrointestinal perforation between the two arms.
Data on quality of life (QoL) showed that time to deterioration did not differ between treatment groups (stratified HR 1.00, 95% CI 0.84-1.19, p = 0.99); this analysis was based on 349 (56%) patients in the ramucirumab group compared with 365 (58%) patients in the control group.
In summary, this study met its primary endpoint of prolongation of OS with a reduction of the risk of death of 14% and a numerical difference in OS of 1.4 months favouring the ramucirumab arm. Unfortunately the search for biomarkers to predict benefit from anti-angiogenic agents is still ongoing and until then it is unlikely we’ll be able to select appropriately to maximize benefit. At this stage, Oncologists should weight pros and cons of a new treatment taking into account toxicity and impact on QoL, patient’s preferences and costs.
Is the improvement in OS from ramucirumab clinically meaningful?
Is this data good enough to change clinical practice?
- Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.
- Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:1835-42.
- Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Gemcitabine/Cisplatin Alone or With Sorafenib for the First-Line Treatment of Advanced, Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2012;30:3084-92.
- de Boer RH, Arrieta Ó, Yang CH, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011;29:1067-74.
- Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010;11:619-26.
- Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol 2012;30:2070-8.
- Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 2012;30:2829-36.
- Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.
Dr Califano has received honoraria from Lilly Oncology. Dr Passaro confirmed he has no conflict of interest.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.