Randomised phase 2 study comparing the efficacy and safety of the oral tyrosine kinase inhibitor nintedanib with single agent ifosfamide in patients with advanced, inoperable, metastatic soft tissue sarcoma after failure of first-line chemotherapy: EORTC-1506-STBSG “ANITA”

Schöffski, Patrick; Toulmonde, Maud; Estival, Anna; Marquina, Gloria; Dudzisz-Śledź, Monika; Brahmi, Mehdi; Steeghs, Neeltje; Karavasilis, Vasilios; Haan, Jacco J. de; Woźniak, Agnieszka; Cousin, Sophie; Doménech, Marta; Bovée, Judith V.M.G.; Charon-Barra, Céline; Marréaud, Sandrine; Litière, Saskia; Meulemeester, Laura De; Olungu, Christine; Gelderblom, Hans

doi:10.1016/j.ejca.2021.04.015

Cited by 12 publications

(7 citation statements)

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“…After reading the titles and abstracts, 168 studies were obtained. After reading the full text, 34 RCTs ( Richardson et al, 2018 ; Zhao et al, 2021b ; Motzer et al, 2013a ; Motzer et al, 2013b ; Sternberg et al, 2013 ; Rini et al, 2011 ; Kudo et al, 2018 ; Yang et al, 2017 ; Vilgrain et al, 2017 ; Spreafico et al, 2014 ; Sun et al, 2018 ; Symonds et al, 2015 ; Thornton et al, 2012 ; Qin et al, 2021 ; Schoffski et al, 2021 ; Sheng et al, 2019 ; Belani et al, 2014 ; Besse et al, 2017 ; Blay et al, 2020 ; Bukowski et al, 2007 ; Chi et al, 2021 ; Choueiri et al, 2020 ; Ellis et al, 2014 ; du Bois et al, 2014 ; Martin et al, 2017 ; Gravalos et al, 2018 ; Gross-Goupil et al, 2018 ; Zhou et al, 2019 ; Hall et al, 2020 ; Haas et al, 2021 ; Machiels et al, 2018 ; Langerbeins et al, 2015 ; Li et al, 2016 ; Schlumberger et al, 2015 ) were finally included ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

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Renal adverse reactions of tyrosine kinase inhibitors in the treatment of tumours: A Bayesian network meta-analysis

et al. 2022

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Objectives: Tumours remain a serious threat to human life. Following rapid progress in oncology research, tyrosine kinase inhibitors have been used to treat multiple tumour types. Given the great influence of kidneys on pharmacokinetics, renal toxicities associated with TKIs have attracted attention. However, the TKIs with the lowest risks of renal impairment are unclear. In this study, we conducted a Bayesian network meta-analysis to compare the incidence of renal impairment among different TKIs in patients with tumours.Methods and analysis: Six databases (PubMed, EMBASE, The Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Data, and China Biomedical Literature Database) were electronically searched from inception to 1 November 2021 to identify randomized controlled trials on the incidence of renal impairment for different TKIs in patients with tumours. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Then, a pairwise meta-analysis was conducted using Stata version 13, and network meta-analysis within the Bayesian framework was conducted using R software version 3.5.3 with the package “gemtc 0.8–2” recalling JAGS (version 4.3.0).Results: Overall, 34 randomized controlled trials were included in this study. Although renal toxicity was common among patients receiving TKIs, the incidence and severity greatly differed among the drugs and studies. Elevated creatinine and protein levels were the most common nephrotoxic events, whereas haematuria was relatively rare. Among TKIs, nintedanib and ripretinib carried the lowest risks of renal impairment.Conclusion: TKIs displayed different profiles of renal toxicity because of their different targets and underlying mechanisms. Clinicians should be aware of the risks of renal impairment to select the optimal treatment and improve patient adherence to treatment.Systematic Review Registration: [www.crd.york.ac.uk/prospero/], identifier [CRD42022295853].

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Section: Resultsmentioning

confidence: 99%

“…Ripretinib and nintedanib were linked to the lowest incidence of Scr elevation. Both drugs target multiple TKs such as PDGFR and VEGFR ( Dhillon, 2020 ; Schoffski et al, 2021 ). The reasons for their lower risks of adverse events are unclear.…”

Section: Discussionmentioning

confidence: 99%

Renal adverse reactions of tyrosine kinase inhibitors in the treatment of tumours: A Bayesian network meta-analysis

et al. 2022

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“…Regarding ifosfamide, a phase 2 study with two regimens of ifosfamide, as a single agent in 76 patients with STS, showed a response rate of 6-8% as a second-line treatment [29]. In a very recent randomized European Organization for Research and Treatment of Cancer (EORTC) study, we obtained a similar ORR of 5% in the ifosfamide control arm in 40 STS patients (11 of whom had DDLPS), the mPFS was 4.4 months, and the mOS was 24.1 months [36]. A study by Maki et al [37] demonstrated that the ORR, mPFS, and mOS were higher with a gemcitabine-docetaxel combination than single-agent gemcitabine (16 vs. 8%, 6.2 vs. 3.0 months, and 17.9 vs. 11.5 months, respectively) in 122 STS patients (20 of whom had liposarcomas).…”

Section: Second-line and Beyondmentioning

confidence: 73%

Established and Experimental Systemic Treatment Options for Advanced Liposarcoma

Schöffski

2022

Oncol Res Treat

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Background: While soft-tissue sarcomas (STSs) are rare tumors, liposarcomas are among the most common type of STS and are divided into four main subtypes: atypical lipomatous tumor/well-differentiated liposarcoma; dedifferentiated liposarcoma; myxoid/round-cell liposarcoma (MLPS); and pleomorphic liposarcoma (PLPS). The four different subtypes of liposarcomas have varying underlying molecular pathology, clinical behavior, and treatment sensitivity. Summary: Surgical resection is the mainstay of treatment for patients with localized liposarcoma. Radiotherapy is often used in conjunction with surgery for improving local control of liposarcoma, with MLPS being the most radiosensitive of the four subtypes. For unresectable, advanced, or metastatic disease, the effectiveness of chemotherapy can vary by subtype, with MLPS and PLPS being considered to be chemo-sensitive; however, median survival is low at around 2 years. Current first-line treatment options for patients with liposarcoma include local treatment with or without doxorubicin, ifosfamide, or a doxorubicin-ifosfamide combination, while second-line (and beyond) treatment options include ifosfamide, gemcitabine-based combinations, trabectedin, eribulin, and possibly pazopanib as established therapies. A number of other experimental treatment options are being evaluated, including mouse double minute 2 homolog antagonists, cyclin-dependent kinase 4/6 inhibitors, immune checkpoint modulators, nuclear export inhibitors, multi-kinase inhibitors, peroxisome proliferator-activated receptor gamma agonists, or various combination regimens. This review discusses established systemic therapies and emerging experimental treatment options for the treatment of patients with liposarcoma. Key Message: New treatments are needed to effectively treat liposarcomas. Results from trials exploring experimental therapeutic options will further define the role that these new treatments will play in the management of the different subtypes of liposarcoma.

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“…The results identified 45 prospective clinical trials published between 2000 and 2021, among which six were phase I trials, two were phase Ib/II trials, 36 were phase II trials and one was a phase III trial. All studies were single arm, with the exception of seven previous, randomized, placebo-controlled trials (13)(14)(15)(16)(17)(18)(19)(20). Moreover, 13 retrospective studies were analyzed (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Results Of the Literature Meta-analysismentioning

confidence: 99%

“…Patients had advanced, inoperable and/or metastatic STS following the failure of systemic non-oxazaphosphorine-based first-line chemotherapy. However, the trial was stopped early as nintedanib did not prove to be beneficial as a second-line therapy and resulted in a mPFS of 2.5 months compared with 4.4 months for ifosfamide (20).…”

Section: Results Of the Literature Meta-analysismentioning

confidence: 99%

Tyrosine kinase inhibitors in sarcoma treatment (Review)

et al. 2022

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Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients. Contents 1. Introduction 2. Methods 3. Results of the literature meta-analysis 4. Discussion 5. Conclusion

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Randomised phase 2 study comparing the efficacy and safety of the oral tyrosine kinase inhibitor nintedanib with single agent ifosfamide in patients with advanced, inoperable, metastatic soft tissue sarcoma after failure of first-line chemotherapy: EORTC-1506-STBSG “ANITA”

Cited by 12 publications

References 35 publications

Renal adverse reactions of tyrosine kinase inhibitors in the treatment of tumours: A Bayesian network meta-analysis

Renal adverse reactions of tyrosine kinase inhibitors in the treatment of tumours: A Bayesian network meta-analysis

Established and Experimental Systemic Treatment Options for Advanced Liposarcoma

Tyrosine kinase inhibitors in sarcoma treatment (Review)

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