Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial

Scagliotti, Giorgio Vittorio; Gaafar, Rabab; Nowak, Anna K.; Nakano, Takashi; Meerbeeck, Jan P. van; Popat, Sanjay; Vogelzang, Nicholas J.; Grosso, Federica; Aboelhassan, Rasha; Jakopović, Marko; Ceresoli, Giovanni Luca; Taylor, Paul D.; Orlandi, F; Fennell, Dean A.; Novello, Silvia; Scherpereel, Arnaud; Kuribayashi, Kozo; Cedrés, S.; Sørensen, Jens Benn; Pavlakis, Nick; Reck, Martin; Velema, Derek; Wangenheim, Ute von; Kim, Miyoung; Barrueco, José; Tsao, Anne S.

doi:10.1016/s2213-2600(19)30139-0

Cited by 129 publications

(95 citation statements)

References 26 publications

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“…Unfortunately, there was no difference in PFS between the two arms (HR = 1·01; 95% CI: 0·79-1·30; p = 0·91) with a median PFS of 6.8 months in the nintedanib arm and 7.0 months in the placebo arm. The HR for OS was 1·12 (95% CI: 0·79-1·58, p = 0·538), with a median survival of 14.4 months in the nintedanib arm and 16.1 months in the placebo arm; there were no new adverse safety signals (71).…”

Section: Nintedanib and The Lume-meso Clinical Trialsmentioning

confidence: 97%

Antiangiogeneic Strategies in Mesothelioma

et al. 2020

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There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.

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Section: Nintedanib and The Lume-meso Clinical Trialsmentioning

confidence: 97%

Antiangiogeneic Strategies in Mesothelioma

et al. 2020

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“…A doubleblind, randomized, placebo-controlled phase III study, the LUME-Meso trial of CDDP and PEM with or without nintedanib, a multikinase inhibitor for unresectable epithelioid MPM, showed that the primary endpoint, PFS, was not met. 47 Even with such an aggressive chemotherapy, OS for unresectable mesothelioma remains ≤12 months. 48 Given the limitations in the efficacy of existing cytotoxic chemotherapy in MPM and recent advances in tumor immunology across various malignancies, ICIs have been investigated for the treatment of unresectable mesothelioma.…”

Section: Icis In the First-line Settingsmentioning

confidence: 99%

Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma

Hotta

Fujimoto

2020

J Immunother Cancer

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Platinum-based chemotherapy is commonly used as the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM). However, in recent times, immune-checkpoint inhibitors (ICIs) have led to a paradigm shift. Herein, we review relevant literature and ongoing trials of ICIs used as both first-line and salvage therapies. Specifically, in the Japanese single-arm, phase II trial, the MERIT trial, nivolumab, an antiprogrammed cell death 1 (PD-1) antibody showed favorable efficacy when used as a salvage therapy. Currently, multiple ICI monotherapy or combination therapy trials have been conducted, which could provide further evidence. Among available ICIs, the anti-PD-1 antibody is promising for unresectable MPM, despite the limited efficacy of anti-CTLA4 monotherapy. Ongoing studies will further confirm the potential efficacy of ICIs for MPM, as observed across other malignancies. It is also crucial to identify any clinically useful predictive biomarkers that could reveal ICIs with maximal effects in MPM.

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“…Nintedanib is an inhibitor of three (triplet regimen) different growth factor receptors (VEGFR, PDFGR, and FGFR) and its administration in combination with CT improved the objective response rate (ORR) from 44 to 57% and the median PFS (9.7 vs. 5.7 months) compared to placebo in the LUME-Meso trial (42). Data from the phase III LUME-Meso trial (NCT01907100) have recently been published, and the primary PFS endpoint failed, not confirming the previous phase II trial results (43). Other TKIs, such as the anti-VEGFR axitinib (44) or the multi-target inhibitor of VEGFR1/2/3, FGFR-1, PDGFR-β, and RAF/cKit pathway sorafenib failed to improve median OS and PFS in chemonaive or CT-pretreated MPM patients (45,46).…”

Section: Angiogenesis Inhibitorsmentioning

confidence: 86%

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

et al. 2020

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Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the pleural surface associated with asbestos exposure. The median survival of MPM patients is a mere 8-14 months, and there are few biomarkers and no cure available. It is hoped that, eventually, the incidence of MPM will drop and remain low and constant, given that most nations have banned the use of asbestos, but in the meantime, the incidence in Europe is still growing. The exact molecular mechanisms that explain the carcinogenicity of asbestos are not known. Standard therapeutic strategies for MPM include surgery, often coupled with chemotherapy and/or radiotherapy, in a small percentage of eligible patients and chemotherapy in tumors considered unresectable with or without adjuvant radiotherapy. In recent years, several new therapeutic avenues are being explored. These include angiogenesis inhibitors, synthetic lethal treatment, miRNA replacement, oncoviral therapies, and the fast-growing field of immunotherapy alone or in combination with chemotherapy. Of particular promise are the multiple options offered by immunotherapy: immune checkpoint inhibitors, tumor vaccines, and therapies taking advantage of tumor-specific antigens, such as specific therapeutic antibodies or advanced cell-based therapies exemplified by the CART cells. This review comprehensively presents both old and new therapeutic options in MPM, focusing on the results of the numerous recent and ongoing clinical trials in the field, including the latest data presented at international meetings (AACR, ASCO, and ESMO) this year, and concludes that more work has to be done in the framework of tailored therapies to identify reliable targets and novel biomarkers to impact MPM management.

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Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial

Cited by 129 publications

References 26 publications

Antiangiogeneic Strategies in Mesothelioma

Antiangiogeneic Strategies in Mesothelioma

Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

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