Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial

Garon, Edward B.; Ciuleanu, Tudor-Eliade; Arrieta, Óscar; Prabhash, Kumar; Syrigos, Konstantinos; Göksel, Tuncay; Park, Keunchil; Gorbunova, Vera; Kowalyszyn, Rubén Dario; Pikiel, Joanna; Czyżewicz, Grzegorz; Орлов, С. В.; Lewanski, Conrad; Thomas, Michael; Bidoli, Paolo; Dakhil, Shaker R.; Gans, Steven; Kim, Joo Hang; Grigorescu, Alexandru; Karaseva, Nina; Reck, Martin; Cappuzzo, Federico; Alexandris, Ekaterine; Sashegyi, Andreas; Yurasov, Sergey; Pérol, Maurice

doi:10.1016/s0140-6736(14)60845-x

Cited by 1,032 publications

(803 citation statements)

References 32 publications

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“…Most recently, results of ramucirumab trials in NSCLC and breast cancer have been reported. As a second-line treatment, ramucirumab plus docetaxel in the phase III REVEL study (NCT01168973) was reported to significantly increase OS among patients with stage IV NSCLC versus docetaxel alone (10.5 vs. 9.1 months; HR: 0.86; 95% CI: 0.75-0.98; p 5 .023) [33]. Furthermore, ramucirumab was well tolerated, with most treatment-emergent AEs occurring at a similar frequency in the ramucirumab and placebo arms.…”

Section: Afliberceptmentioning

confidence: 99%

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

2015

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Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR‐2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet‐derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti‐VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors. Implications for Practice: Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF‐targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.

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Section: Afliberceptmentioning

confidence: 99%

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

2015

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“…However, increased toxicity was observed during bevacizumab treatment and class‐related adverse events including hypertension, proteinuria, febrile neutropenia and life‐threatening pulmonary hemorrhage, particularly in squamous NSCLC 8, 9, 10. The approval of ramucirumab and nintedanib has provided new options for NSCLC patients who progressed on initial treatment, with improved OS and tolerable toxicity when combined with standard second‐line chemotherapy 11, 12, 13. More recently, anlotinib, a novel multitarget tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), platelet‐derived growth factor receptor‐β (PDGFRβ), and fibroblast growth factor receptor‐1 (FGFR1), has provided significant progression‐free survival (PFS) and OS benefits as third‐line treatment 14…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of rh‐endostatin (Endostar) combined with pemetrexed/cisplatin followed by rh‐endostatin plus pemetrexed maintenance in non‐small cell lung cancer: A retrospective comparison with standard chemotherapy

Zhou

Zuo²,

et al. 2018

Thoracic Cancer

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BackgroundRecombinant human endostatin (rh‐endostatin) plus standard chemotherapy in advanced non‐small cell lung cancer (NSCLC) patients has shown improved efficacy; however, it is unclear whether it is effective and safe when added to pemetrexed/cisplatin and used as maintenance therapy.MethodsWe retrospectively evaluated the data of untreated NSCLC patients administered rh‐endostatin plus pemetrexed/cisplatin or pemetrexed/cisplatin. The primary endpoint was progression‐free survival (PFS).ResultsFifty‐six and 39 patients received rh‐endostatin plus pemetrexed/cisplatin and pemetrexed/cisplatin, and 34 and 29 underwent maintenance treatment, respectively. The median PFS was 10 months (95% confidence interval [CI] 5.85–14.15) in the rh‐endostatin and 8.2 months (4.04–12.36) in the chemotherapy group, but the difference was not statistically significant (P = 0.13). In patients administered maintenance treatment, rh‐endostatin plus pemetrexed was associated with prolonged PFS compared to single‐agent pemetrexed when PFS was calculated from first dosing (13.7 [9.41–17.99] vs. 8.2 [4.16–12.24]; P = 0.032); however, PFS did not differ between the groups (hazard ratio 0.618; 95% CI 0.368–1.038; P = 0.069) after adjusting for clinical factors. No difference was observed in the objective response rate between the groups (48.2% vs. 38.5%; P = 0.346), with the exception of men (62.1% vs. 33.3%; P = 0.032) or in the incidence of drug‐related or grade 3–4 adverse events.ConclusionIn previously untreated, advanced‐stage NSCLC patients, first‐line treatment with pemetrexed/cisplatin plus rh‐endostatin did not prolong PFS or overall survival when compared to pemetrexed/cisplatin, but a trend of improved PFS was observed in patients administered maintenance rh‐endostatin plus pemetrexed.

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“…23 Based on this study, the FDA approved ramucirumab in combination with docetaxel for the second-line treatment of NSCLC following progression on platinum-based chemotherapy. Although the OS advantage is relatively modest, this regimen remains a consideration for patients in the second-line setting.…”

Section: Docetaxelmentioning

confidence: 99%

Second-Line Chemotherapy and Beyond for Non–Small Cell Lung Cancer

Durm

Hanna

2017

Hematology/Oncology Clinics of North America

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Keywordsnon-small cell lung cancer, chemotherapy, second-line treatment, docetaxel, pemetrexed, erlotinib Key Points• Docetaxel, pemetrexed, and erlotinib are approved for the second-line treatment of NSCLC.• The discovery of targetable mutations, the increasing use of maintenance strategies, and the introduction of immunotherapies has made the choice of second-line agents much more complicated.• Ramucirumab with docetaxel is the only combination regimen that has shown improved overall survival in the second-line setting.• Erlotinib is the only agent approved in the third-line setting for EGFR wild-type patients. First Line TreatmentIn patients without targetable genetic alterations, the standard first-line therapy for advanced (stage IIIB or IV) NSCLC is chemotherapy with a platinum doublet for 4-6 cycles with or without bevacizumab. 1 Historically, a number of drugs including paclitaxel, docetaxel, gemcitabine, and vinorelbine were considered acceptable platinum partners in the first-line metastatic setting with essentially no differences in progression free survival (PFS) or overall survival (OS). More recently, additional agents have been approved in combination with platinum in this setting including pemetrexed and nab-paclitaxel. [1][2][3] One particular advance in the last decade has been the recognition that histology should be considered in the choice of initial chemotherapy. This was discovered after an additional analysis of two studies showed pemetrexed to be more effective in non-squamous histologies and less active in squamous tumors. 3-5 Based on these findings, the choice of first-line agents in metastatic NSCLC is now strongly based on presenting histology, and this initial choice affects available second-line options. Maintenance TherapyHistorically, patients treated with first-line platinum doublet chemotherapy who had objective responses or stable disease were placed on surveillance following completion of 4-6 cycles. However, over the last decade, new data suggests that there is benefit to the addition of maintenance therapy following initial chemotherapy. There are two maintenance strategies including continuation of an agent used in the first-line setting or switching to a previously unused agent (switch maintenance). There is data supporting the use of bevacizumab, pemetrexed, and erlotinib in the maintenance setting either as single agents or in combination. [6][7][8][9][10][11] Prior maintenance therapy is of particular importance when discussing second-line chemotherapy options as the use of maintenance therapy, particularly when switch maintenance is employed, influences the availability of agents in the second-line setting and beyond. Chemotherapy as Second-Line TreatmentHistorically, nearly all patients received platinum doublet chemotherapy followed by single agent chemotherapy in the second-line setting. However, with the discovery of targetable mutations, the development of tyrosine kinase inhibitors (TKI), the increasing use of maintenance strategies, and the introduction of imm...

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Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial

Cited by 1,032 publications

References 32 publications

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

Efficacy and safety of rh‐endostatin (Endostar) combined with pemetrexed/cisplatin followed by rh‐endostatin plus pemetrexed maintenance in non‐small cell lung cancer: A retrospective comparison with standard chemotherapy

Second-Line Chemotherapy and Beyond for Non–Small Cell Lung Cancer

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