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

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/m2) 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.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Flow-chart of patients included in the CABONE study.

Note: 5 Ewing sarcoma patients not eligible (protocol deviations: ECOG performance status equal to 2 at baseline [n=1], no measurable target lesion according to RECIST at baseline [n=2], invalid or not available laboratory parameters at baseline [n=3]. One Osteosarcoma not eligible (Protocol deviation: laboratory parameters not available at baseline).

Figure 2:. Waterfall plot of best overall response in Ewing sarcoma (A) and osteosarcoma patients (B) treated with cabozantinib (Response based on central review assessment according to RECIST 1.1).

Note: Two Ewing sarcoma patients had no tumor assessment due to early discontinuation of treatment because of end of treatment after cycle 1 of Cabozantinib, for disease progression and toxicity respectively. One osteosarcoma patient had not tumor assessment due to early treatment discontinuation because of toxicity. These three patients are classified “Not evaluable” as per RECIST 1.1. Despite tumor shrinkage one osteosarcoma patient (ID = 37) had progressive disease as best overall response. This patient had a single tumor assessment during treatment; although shrinkage of target lesion was observed, a new lesion was identified. He was as such classified as progressive disease as per RECIST 1.1.

Figure 3.. Kaplan-Meier curves of progression-free survival (A, C) and overall survival (B,D) in Ewing sarcoma (A, B) and osteosarcoma patients (C, D)

Note: For overall survival, 26 eligible and assessable patients with Ewing sarcoma (B) and 32 eligible and assessable patients with osteosarcoma (D) died during the course of the trial. For progression-free survival, 34 eligible and assessable patients with Ewing sarcoma (A) and 40 eligible and assessable patients with osteosarcoma (C) had progressive disease or died during the course of the trial.