cabozantinib and Sarcoma--Ewing

Sarcomas are a diverse group of rare solid tumors with limited treatment options for patients with advanced, inoperable disease. Cabozantinib is a tyrosine kinase inhibitor currently approved for advanced renal cell, hepatocellular, and medullary thyroid carcinoma. Cabozantinib has potent activity against a variety of kinases, including MET, vascular endothelial growth factor receptor, and AXL, that are associated with sarcoma growth and development. Here we review the preclinical findings and clinical development of cabozantinib in the treatment of soft tissue sarcoma, gastrointestinal stromal tumors (GIST), osteosarcoma, and Ewing sarcoma.. In vitro, cabozantinib has shown relevant activity in inhibiting the growth and viability of soft tissue sarcoma, GIST, osteosarcoma, and Ewing sarcoma tumor cell lines. Cabozantinib also promoted the regression of GIST in various murine xenografts, including imatinib-resistant models. More than 10 prospective trials with cabozantinib that included patients with sarcomas have been completed or are currently ongoing. Clinical activity with cabozantinib has been recently reported in phase 2 clinical trials for patients with GIST and for patients with osteosarcoma or Ewing sarcoma.. Cabozantinib has shown promising activity for the treatment of various sarcomas, supporting further evaluation in this setting.

Topics: Anilides; Animals; Antineoplastic Agents; Bone Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Gastrointestinal Stromal Tumors; Humans; Osteosarcoma; Protein Kinase Inhibitors; Pyridines; Receptor Protein-Tyrosine Kinases; Sarcoma; Sarcoma, Ewing

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.. 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. 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.. 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.. Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.

Topics: Adult; Anilides; Bone Neoplasms; Case-Control Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Prognosis; Protein Kinase Inhibitors; Pyridines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Sarcoma, Ewing; Survival Rate; Young Adult

Topics: Anilides; Bone Neoplasms; Humans; Pyridines; Salvage Therapy; Sarcoma, Ewing

A 49-year-old male with Ewing sarcoma and bone, pleural, lung and mediastinal lymph node metastasis was treated with cabozantinib after four lines of previous systemic treatments. He responded objectively and subjectively well for 8 months. In this heavily pretreated patient, the daily starting dose of 60 mg had to be reduced to 30 mg because of adverse events. We conclude that treatment with cabozantinib administered in further-line was active in this particular patient with metastatic Ewing sarcoma. The underlying mechanism of action remains unclear. Because of a stable disease on a long-term treatment with pazopanib targeting an anti-angiogenic pathway common to both drugs previously administered in this patient, it is hypothesized that the action of cabozantinib could be ascribed to its action on the non-common receptors AXL and c-Met. The potential of cabozantinib should be further investigated more upfront in this disease either alone or in combination with other systemic treatments.

Topics: Anilides; Bone Neoplasms; Fatal Outcome; Humans; Lung Neoplasms; Male; Middle Aged; Pyridines; Sarcoma, Ewing

Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 μmol/L), NVP-TAE684 (IC50 0.15-0.79 μmol/L) and cabozantinib (IC50 2.69-8.27 μmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Anilides; Child; Child, Preschool; Chromosome Aberrations; Crizotinib; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Inhibitory Concentration 50; Male; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Recurrence; Sarcoma, Ewing; Tetrazolium Salts; Thiazoles; Treatment Outcome; Young Adult