4 Discussion
This study is the first combination trial of cabozantinib, topotecan and cyclophosphamide in patients with relapsed or refractory Ewing sarcoma or osteosarcoma. Concomitant therapy was not tolerable but an interrupted schedule was tolerable. The recommended phase 2 schedule administers cabozantinib only on days 8-21 of each cycle. Most patients had stable disease with this combination, including three patients with disease control for more than 4 months. One partial response was observed in a patient with Ewing sarcoma. Decreasing ctDNA levels were observed in patients with stable disease.
Discontinuous dosing of cabozantinib was necessary with this combination based upon the observed toxicity profile with concomitant dosing. Previous studies involving mTKIs and cytotoxic therapies in pediatric patients with solid tumors have shown mixed results with regard to schedule. A phase 1 study of pazopanib in combination with irinotecan and temozolomide in relapsed/refractory sarcomas found concomitant dosing was not tolerable[19]. Likewise, in a phase 1 study of regorafenib in combination with vincristine/irinotecan, concomitant dosing of regorafenib with the cytotoxic backbone was discontinued due to toxicity. Discontinuous administration of regorafenib during weeks without vincristine/irinotecan was the recommended phase 2 schedule[20]. In contrast, a randomized phase 2 study of pazopanib added to doxorubicin and ifosfamide for patients with soft tissue sarcoma found concomitant dosing to be tolerable. While grade 3/4 toxicity rates were higher in the pazopanib arm and 60% of patients on the pazopanib arm experienced a pazopanib-related serious adverse event, the regimen met predefined feasibility rules[21]. A phase 2 study of lenvatinib in combination with ifosfamide and etoposide for patients with relapsed or refractory osteosarcoma also found that concomitant dosing was feasible[22]. Our results add to this growing body of literature that suggest that considerations for scheduling mTKIs around chemotherapy is likely dependent upon the specific chemotherapy regimen and specific mTKI. In prior adult studies, concomitant cabozantinib was tolerable with temozolomide but not with gemcitabine[14, 15]. It now seems clear that it should not be assumed that mTKIs can simply be added to backbone chemotherapy.
Previous studies have demonstrated efficacy of cabozantinib monotherapy and separately of the topotecan plus cyclophosphamide regimen in this same population. The primary objective of this phase 1 trial was safety and the study was not designed to evaluate efficacy. Further, as both cabozantinib monotherapy and topotecan plus cyclophosphamide have shown activity in this patient population, the individual contribution or possible synergy of the agents is unclear. In particular, prior experience with topotecan/cyclophosphamide in Ewing sarcoma demonstrated ~20-30% response rate compared to the 14% observed in the current dose finding study [17] [23]. Nevertheless, this novel combination may warrant further exploration given the observed disease control, including stable disease for >4 months in 3 patients. In addition, several patients with stable disease had reductions in ctDNA burden by ULP-WGS and TranSS-Seq, suggesting possible benefit in these patients.
A limitation to this study was the lack of long-term efficacy and adverse effects data. Given that all agents were commercially available, multiple patients opted to come off trial once their dose was established to be treated as per this regimen at an institution closer to home, limiting our ability to report on longer term toxicity or disease control. An additional limitation of this trial was the lack adequate sample size within each disease group to assess efficacy. However, a strength is establishing a dose that is applicable to both relapsed Ewing sarcoma and osteosarcoma.
In summary, we demonstrate the safety and tolerability of interrupted dosing cabozantinib, cyclophosphamide and topotecan for patients with relapsed Ewing sarcoma and osteosarcoma. Combinations of mTKIs with chemotherapy are either being studied or under development as part of front-line therapy for newly diagnosed Ewing sarcoma and osteosarcoma.