Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study

Abstract

Objectives: We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC).

Methods: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.

Results: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis.

Conclusion: Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.

Keywords: CanSaRCC; Ewing sarcoma; cabozantanib; chondrosarcoma; osteosarcoma; regorafenib.

FIGURE 1

Progression‐free survival (PFS) of 66 patients with recurrent or refractory bone tumours treated either with regorafenib (A) or with cabozantinib (B). Osteosarcoma (Blue), chondrosarcoma (Red), Ewing's sarcoma (Green) and Extra‐skeletal mesenchymal CS (Brown).

FIGURE 2

Swimmer plots and tumour response for patients treated either with regorafenib (pink bar) or with cabozantinib (light blue bar). (A) Osteosarcoma (n = 39), (B) Ewing's sarcoma (n = 18) and (C) chondrosarcoma (n = 9, ECMS—five out of nine). Bars ending with an arrow signify patients who are alive and continued response to TKI. A black square along the y‐axis signifies patients who are deceased. The x‐axis begins when the patient starts TKI and ends with patient's last follow‐up. Response start date, denoted by triangle, is the date of best response assessment. The response and date denoted by a circle is the date of treatment end. PD (progression disease); SD (stable disease); CR (complete response) can be identified within each bar and are denoted by blue, red, green and dark brown lines, respectively. For patients whose best response is PD, the response start and end date overlap.

FIGURE 3

Swimmer plots of TKI duration, line of therapy (LOT) and tumour progression of children versus adults diagnosed with osteosarcoma (A), Ewing sarcoma(B), chondrosarcoma or ECMS (C). (A,B,C—right plot) ‐ The x‐axis begins when the patient starts TKI and ends on last day the patient received TKI (denoted by circle). LOT = 1, LOT = 2 and LOT >2 can be identified within each bar and are denoted by blue, red and green, respectively. (A,B,C—Left Plot) ‐ The x‐axis begins when the patient was diagnosed with bone tumour and ends on last follow‐up. Children (Age ≤ 18) and adults (Age ≥ 18) are denoted by yellow and grey lines, respectively. TKI start can be identified by triangle and denoted by blue (LOT = 1), red (LOT = 2) and green (LOT >2).