DISCUSSION
toxicity, fusion‐positive sarcomas, thyroid eye disease, neutropenia
COLORECTAL CANCER, METASTATIC TUMORS, PRIMARY TUMORS, NEUTROPENIA, BREAST CANCER, DISEASE, SOLID TUMORS, THYROID EYE DISEASE
The primary objectives of this study were to determine the objective response rate to palbociclib and ganitumab in patients with relapsed EWS and to determine the safety of giving this treatment combination. No patients met the RECIST definition of objective response. The combination therapy, which was based on palbociclib dosing established in patients with breast cancer, required dose reduction in this heavily pretreated population. While two patients had prolonged stable disease, without further work to define biomarkers of sensitivity, the combination of IGF‐1R and CDK4/6 inhibition does not warrant further testing in this population.Numerous preclinical studies have identified the IGF‐1 pathway as a potential vulnerability in EWS. Multiple prior early phase studies of IGF‐1R inhibitors in solid tumors, as well as in EWS specifically, have demonstrated an approximately 10% response rate. A recent randomized phase 3 study compared interval compressed vincristine/doxorucibin/cyclophosphamide and ifosfamide/etoposide with and without ganitumab and demonstrated no benefit from the addition of ganitumab. In the context of lack of benefit from combining IGF‐1R inhibition with conventional chemotherapy in metastatic EWS, the current study was developed after additional preclinical data demonstrated synergistic effects between CDK4/6 inhibition and IGF‐1R inhibition. Our study demonstrated a 6‐month PFS of 30%, which compares favorably with a recent analysis of seven COG phase 2 studies in EWS, which demonstrated a 6‐month PFS of 13%.The reasons for the lack of response in this study are not clear. The most likely fundamental explanation is that the dependency on the combination of CDK4 and IGF‐1R activity in laboratory models is not present in patients with advanced EWS. This could be due to redundant signaling in both the CDK4 and IGF‐1R pathways, or only heterogeneous expression of the IGF‐1R receptor in advanced EWS. In colorectal cancer, nuclear localization of IGF‐1R increased in metastatic tumors compared to primary tumors and was associated with chemotherapy and IGF‐1R targeted therapy resistance.Our study advances the use of ctDNA in clinical trials of EWS and other fusion‐positive sarcomas. Multiple studies have previously demonstrated the feasibility of quantifying ctDNA through fusion detection in EWS and that baseline ctDNA levels are prognostic in patients with newly diagnosed disease.The initial planned palbociclib dosing in our study was established based on previously used dosing in patients with advanced breast cancer. Two patients experienced dose‐limiting neutropenia at that dose, triggering predefined study stopping rules. Given this toxicity was thought most likely related to CDK4/6 inhibition, the starting dose of palbociclib was reduced to 100 mg for 21 days of a 28‐day cycle. This revised dosing was tolerable for most patients. This toxicity experience highlights the importance of re‐assessing tolerability of an established dosing strategy being applied to a new population.Our study was terminated early due to unanticipated inability to extend the expiration of the remaining available supply of ganitumab. At time of closure, 0/10 patients had an objective response. It is a limitation that the study was closed early, and we were therefore unable to assess 15 evaluable patients. However, it is unlikely that we would have seen four objective responses in the remaining five patients. An additional limitation of our study was that multiple correlative samples could not be collected for two patients who enrolled early in the COVID‐19 pandemic. Nevertheless, one of those patients was able to safely remain on therapy for a full 12 cycles of treatment with stable disease and minimal toxicity. This speaks to the ability of study teams to ensure that clinical trials remained available for patients during the pandemic. Most notably, this impacted baseline ctDNA collection for the patient with the most prolonged stable disease. Finally, the ctDNA assays used in our study were customized for identifying EWS fusions. More extensive ctDNA sequencing to identify mechanisms of resistance (e.g., IGF‐1R inhibitors have now been tested as monotherapy, in combination with standard chemotherapy and now in combination with another targeted therapy. Despite strong preclinical evidence, there remains minimal clinical activity of these agents for patients with EWS. Since the start of this study, teprotumumab was approved for the treatment of thyroid eye disease and remains the only FDA‐approved IGF‐1R inhibitor.