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Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial

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Italiano, Antoine, Mir, Olivier, Mathoulin-Pelissier, Simone, Penel, Nicolas, Piperno-Neumann, Sophie, Bompas, Emmanuelle, Chevreau, Christine, Duffaud, Florence +14 more·2020·The Lancet Oncology
DOI 10.1016/s1470-2045(19)30825-3PMC PMC8763616
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Abstract

Background Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma.Methods We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m 2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605.Findings Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects.Interpretation Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation.Funding Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.

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  • Objective response rates to MTKIs were low at 10-15%.

    “Objective response rates were low at 10-15%.”

    From Osteosarcoma (2022) · cites this paper as [148]

  • Prospective clinical trials evaluated sorafenib, regorafenib, cabozantinib, lenvatinib and apatinib as single agents in patients with relapsed or refractory osteosarcoma, with most enrolled patients in the adult age range.

    “Prospective clinical trials evaluated the MTKIs sorafenib, regorafenib, cabozantinib, lenvatinib and apatinib as single agents in patients with relapsed or refractory osteosarcoma, with most enrolled patients falling in the adult age range 146,147,148,149,150,151 (Table 2).”

    From Osteosarcoma (2022) · cites this paper as [148]

  • Four-month progression-free survival with MTKIs ranged from 35% to 70%.

    “Four-month progression-free survival (PFS) ranged from 35% to 70% 146,147,148,149,151 .”

    From Osteosarcoma (2022) · cites this paper as [148]

  • Dose interruptions and reductions of MTKIs have been frequent across these trials secondary to common toxic effects, including hand-foot rash syndrome, gastrointestinal toxic effects and hypertension.

    “Of note, dose interruptions and reductions of MTKIs have been frequent across these trials secondary to common toxic effects of this drug class, including hand-foot rash syndrome (palmar-plantar erythrodysesthesia), gastrointestinal toxic effects and hypertension 146,147,148,149,150,151 .”

    From Osteosarcoma (2022) · cites this paper as [148]

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Research works printed but not linked: 1

  1. [18]DuBois SG, Marina N, Glade-Bender J. Angiogenesis and vascular targeting in Ewing sarcoma: a review of preclinical and clinical data. Cancer. 2010; 116: 749– 57. 20029966 PMC2815027

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Authors
Italiano, A., Mir, O., Mathoulin-Pelissier, S., Penel, N., Piperno-Neumann, S., Bompas, E., Chevreau, C., Duffaud, F., Entz-Werlé, N., Saada, E., Ray-Coquard, I., Lervat, C., Gaspar, N., Marec-Berard, P., Pacquement, H., Wright, J., Toulmonde, M., Bessede, A., Crombe, A., Kind, M., Bellera, C., & Blay, J.-Y.
Affiliations
  • Institut Gustave Roussy (FR)
  • Université de Lille (FR)
  • Institut Curie (FR)
  • Assistance Publique Hôpitaux de Marseille (FR)
  • Centre Léon Bérard (FR)
  • National Institutes of Health (US)
  • Institut Bergonié (FR)
  • Inserm (FR)
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2020-03
Volume
21
Issue
3
Pages
446-455
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(19)30825-3
PMC
PMC8763616
OpenAlex
W3006180429
Cited by
326
References
35
Citations by year
2026: 38 · 2025: 52 · 2024: 43 · 2023: 53 · 2022: 58 · 2021: 62 · 2020: 20
FWCI
27.20
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Oncology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
Funders
  • Institut Bergonié
  • Association pour la Recherche sur le Cancer
  • Comprehensive Cancer Center, City of Hope
  • National Cancer Institute
  • Institut National Du Cancer
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Oncology › Vascular Tumors and Angiosarcomas
Keywords
cabozantinib, Ewing sarcoma, osteosarcoma, VEGFR-2 inhibition, objective response, hypophosphatemia, adverse events, oral tyrosine kinase inhibitor, angiogenesis inhibition, treatment efficacy and safety, non-small cell lung cancer
MeSH terms
Adult, Anilides, Bone Neoplasms, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Pyridines, Retrospective Studies, Sarcoma, Ewing, Osteosarcoma, Survival Rate, Case-Control Studies, Protein Kinase Inhibitors, Young Adult, Response Evaluation Criteria in Solid Tumors

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