Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study

Gaspar, Nathalie; Venkatramani, Rajkumar; Hecker‐Nolting, Stefanie; Melcón, Soledad Gallego; Locatelli, Franco; Bautista, Francisco; Longhi, Alessandra; Lervat, Cyril; Entz‐Werlé, Natacha; Casanova, Michela; Aerts, Isabelle; Strauss, Sandra J.; Thébaud, Estelle; Morland, Bruce; Cañete, Adela; Marec‐Bérard, Perrine; Gambart, Marion; Rössig, Claudia; Okpara, Chinyere; He, Cixin; Dutta, Lea; Campbell-Hewson, Quentin

doi:10.1016/s1470-2045(21)00387-9

Cited by 70 publications

(53 citation statements)

References 22 publications

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“…In this regard, a recent multicentre, open-label, multicohort, phase 1/2 trial has highlighted lenvatinib as a promising antitumor drug in other bone sarcoma histotypes, such as osteosarcoma, in combination with etoposide plus ifosfamide. The results showed an enhanced efficacy of chemotherapy mediated by lenvatinib, with no new safety issues in patients [ 47 ]. Furthermore, ongoing trials (NCT04784247] are assessing the role of lenvatinib and pembrolizumab in patients with advanced soft tissue sarcoma (STS) including, among all, some of the vascular sarcomas and bone sarcomas.…”

Section: Discussionmentioning

confidence: 99%

A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences

et al. 2022

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Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management.

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Section: Discussionmentioning

confidence: 99%

A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences

et al. 2022

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“…To date, the highest level of evidence for assessing the efficacy of treatments, not only for cancer, has been randomized controlled trials. In fact, of the TKIs that have efficacy data of prospective clinical trials for osteosarcoma, regorafenib, which is small in size but has shown results in randomized controlled trials, is listed in Category 1 in the NCCN guidelines [ 36 ]. Although randomized controlled trials remain important, the small number of cases makes it difficult to conduct large-scale randomized controlled trials.…”

Section: Regulatory Problems and Solutions For Investigating New Trea...mentioning

confidence: 99%

Challenges of Systemic Therapy Investigations for Bone Sarcomas

Nakano

2022

IJMS

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Bone sarcoma is a rare component of malignant solid tumors that accounts for only ~0.2% of malignancies. Bone sarcomas present various histological types, and genomic mutations differ markedly by the histological types. Although there are vast mutations in various bone sarcomas, most of them are non-actionable, and even potential targetable mutations that are actionable targets in other malignancies have not shown the appropriate responses in clinical trials for bone sarcomas. Investigations of new systemic therapy, including molecular targeted therapies for bone sarcomas, have thus not progressed like those for other solid tumors. Another problem is that high rates of pediatric/adolescent and young adult patients have bone sarcomas such as osteosarcoma, and patient recruitment for clinical trials (especially randomized trials) is challenging. For pediatric patients, evaluations of tolerability and appropriate dose modifications of new drugs are needed, as their findings could provide the threshold for investigating new drugs for bone sarcomas. To solve these problems, improvements in registry systems, real world data, and pediatric extrapolation have been attempted. We review the issues regarding targeted drug investigations for bone sarcomas, focusing on the current clinical evidence and efforts to resolve these issues.

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“…They all combine a strong anti-angiogenic component, via direct inhibition of the vascular endothelial growth factor receptors (VEGFRs), with the inhibition of key oncogenic RTKs implicated in paediatric and AYA sarcoma, including the platelet-derived growth factor receptors (PDGFRs), c-KIT, fibroblast growth factor receptors (FGFRs), RET, and/or MET. Sorafenib [ 38 ], regorafenib [ 39 , 40 ], lenvatinib [ 41 ], and anlotinib [ 42 ], all of which have activity against VEGFR, PDGFR, RET, c-KIT and FGFR, and cabozantinib [ 43 ], which has a different target profile (VEGFR, MET, AXL, and RET), have all shown some clinical benefit in sarcoma. The response rates (any response of SD, PR, or CR response) varies from 60–100% in osteosarcoma and Ewing sarcoma patients, and there are modest gains in progression-free survival (PFS) of between 3.6 and 6.7 months with these single agents.…”

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…Several studies demonstrated the increased benefit when RTK-targeted drugs were combined with chemotherapeutic agents, where particularly the combination of lenvatinib with etoposide and ifosfamide appeared remarkably effective in the clinic. This combination very recently showed an impressive median PFS and overall survival (OS) of 8.7 and 16.3 months respectively, for heavily pre-treated osteosarcoma patients between 2 and 25 years, with manageable side effects [ 41 ]. These results are incredibly encouraging, as all trials were performed on a population of heavily pre-treated patients that had exhausted all other treatment options.…”

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…There is a growing body of data to show that RTKis have immunomodulatory effects on the TME, through depletion or reprogramming of immunosuppressive cell subsets and enhancement of T cell infiltration ( Table 1 ) [ 45 ]. Interestingly, the RTKis that have shown these immunomodulatory effects are the same RTKis that have shown the most promising clinical effects in paediatric sarcoma [ 41 , 42 , 43 ]. There is evidence suggesting that for some RTKis, these effects are, at least in part, mediated through direct suppression of immune-suppressing cells [ 48 ].…”

Section: Immunomodulatory Effects Of Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

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Enhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors

et al. 2021

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Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma.

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Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study

Cited by 70 publications

References 22 publications

A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences

A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences

Challenges of Systemic Therapy Investigations for Bone Sarcomas

Enhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors

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