Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial

Herbst, Roy S.; Arkenau, Hendrik‐Tobias; Santana-Dávila, Rafael; Calvo, Emiliano; Paz‐Ares, Luis; Cassier, Philippe; Bendell, Johanna C.; Penel, Nicolas; Krebs, Matthew; Martín-Liberal, Juan; Isambert, Nicolás; Soriano, Andres O.; Wermke, Martin; Cultrera, Jennifer L.; Gao, Ling; Widau, Ryan C.; Mi, Gu; Jin, Jin; Ferry, David; Fuchs, Charles S.; Petrylak, Daniel P.; Chau, Ian

doi:10.1016/s1470-2045(19)30458-9

Cited by 205 publications

(149 citation statements)

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“…(45) Moreover, a recent study of ramucirumab with pembrolizumab showed a manageable safety profile with favorable antitumor activity in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. (46) In conclusion, we show here that dual PD-1/ VEGFR-2 antibody blockade is effective in HCC models. The efficacy was seen both when using "vascular normalizing" and antivascular doses of AA and was mediated by the vascular normalizing effects of anti-PD-1 therapy itself mediated by CD4 + cells.…”

Section: Discussionmentioning

confidence: 51%

“…However, a follow‐up biomarker‐driven randomized phase 3 clinical trial showed significant survival benefit in HCC patients with high baseline serum AFP level or preserved liver function (REACH‐2 trial, NCT02435433) . Moreover, a recent study of ramucirumab with pembrolizumab showed a manageable safety profile with favorable antitumor activity in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma, non‐small‐cell lung cancer, and urothelial carcinoma …”

Section: Discussionmentioning

confidence: 99%

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Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2019

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Background and Aims Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD‐1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and Results We recapitulated these clinical outcomes using orthotopic—grafted or induced—murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR‐2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti‐PD‐1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti‐PD‐1/VEGFR‐2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8–positive (CD8+) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor‐associated macrophages and reducing T regulatory cell (Treg) and chemokine (C‐C motif) receptor 2–positive monocyte infiltration in HCC tissue. In these models, VEGFR‐2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD‐ligand 1 expression in HCC cells was induced in a paracrine manner upon anti‐VEGFR‐2 blockade in endothelial cells in part through interferon‐gamma expression. Moreover, we found that VEGFR‐2 blockade increased PD‐1 expression in tumor‐infiltrating CD4+ cells. We also found that under anti‐PD‐1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti‐VEGFR‐2 antibody. Conclusions We show that dual anti‐PD‐1/VEGFR‐2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti‐PD‐1 therapy–resistant and anti‐PD‐1 therapy–responsive HCC models.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2019

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“…Finally, interesting data from KEYNOTE-098 phase I study was reported. Actually, the study showed that Ram in combination with an immunotherapeutic agent such as the anti-PD1 Pembrolizumab, applied as second or later line therapy, had a controllable safety profile with antitumor activity in patients previously treated for advanced GC/ GEJC, non-small-cell lung cancer and urothelial carcinoma 25 . www.nature.com/scientificreports www.nature.com/scientificreports/ The combined regimen represents a promising option to increase the efficacy of PTX and to prevent its resistance also in patients receiving taxane-based first-line palliative chemotherapy 14 .…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines

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Lolli

et al. 2020

Sci Rep

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Ramucirumab is approved both as monotherapy and in combination with paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. in tumor cells, the VeGfA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. the present in vitro study investigated the effects of single and combined treatments with Ramucirumab and paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the paclitaxel resistance.VEGFR2 plays a crucial role in gastric cancer pathogenesis and progression and Ramucirumab (Ram), a monoclonal antibody against VEGFR2, is the first antiangiogenic agent with demonstrated activity against advanced gastric cancer. Based on the results obtained by two different phase III studies, Ram is approved both as monotherapy and in combination with Paclitaxel (PTX) for this malignancy in patients with disease in progression after a preceding therapy based on platinum and fluoropyrimidin 1-5 .The proangiogenic actions of VEGFs in endothelial cells are mediated primarily through the binding and activation of VEGFR2 6 and retrospective studies considered VEGF and its receptors as possible biomarkers in gastric carcinoma 7-9 . Moreover, the recent discovery of the production of different VEGF ligands and of the expression of VEGFR1, VEGFR2 and VEGFR3 in epithelial cancer cells, suggests a direct role for these ligands and their receptors in the autocrine control of some biological processes. In epithelial tumor cells, the binding of VEGFA, the main ligand of VEGFR2, activates downstream survival and migration signaling pathways represented by PI3K/ Akt/mTOR and MAPK cascades in a cell autonomous and angiogenesis independent manner 10-13 .The combined treatment with Ram seems to be a promising option to prevent the resistance to PTX also in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy 14 . PTX is known to interfere with microtubule architecture by binding to β-tubulin, thereby blocking cell cycle progression at th...

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“…Therefore, several ongoing clinical trials are evaluating simultaneous targeting of angiogenesis and tumor immunity. A phase Ia/b multicohort trial studied ramucirumab with the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab with good safety and preliminary efficacy results [45]. A phase Ib/II trial of lenvatinib plus pembrolizumab in patients with multiple solid tumor types, including HNSCC, demonstrated promising preliminary clinical activity in 22 patients with recurrent/ metastatic HNSCC (response rate of 46% and median PFS of 4.7 months) with expected toxicities [46].…”

Section: Anti-angiogenics With Immune Checkpoint Inhibitorsmentioning

confidence: 99%

An update on angiogenesis targeting in head and neck squamous cell carcinoma

2020

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Angiogenesis is an integral aspect of the growth and proliferation of solid tumors, including head and neck squamous cell carcinoma (HNSCC), and has potential implications in prognosis and treatment of both localized and recurrent/metastatic HNSCC. Therefore, there has been a significant interest in utilizing anti-angiogenic agents either alone or in combination with currently approved and emerging therapies. A phase III randomized trial (E1305) of chemotherapy with or without bevacizumab in the first-line treatment of recurrent/metastatic HNSCC showed an increased response rate and longer progression-free survival but fell short in demonstrating a statistically significant improved survival with bevacizumab. Moreover, toxicity, especially bleeding, was increased. Nevertheless, the study of other anti-angiogenic agents and novel combinations with other therapies, including immunotherapy, remains of interest. Several clinical trials are currently underway.

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Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial

Cited by 205 publications

References 30 publications

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines

An update on angiogenesis targeting in head and neck squamous cell carcinoma

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