Management of Recurrent Ewing Sarcoma: Challenges and Approaches

Immunotherapy

Previous studies in adult malignancies have suggested that widespread expression of programed death ligand-1 (PD-L1) in malignant cells, high mutational tumor burden, and extensive infiltration of tumors with CD8⁺ T cells were all associated with responses to immune checkpoint blockade.⁶⁷Although results have varied between studies, Machado et al identified PD-L1 expression in tumor cells in 19% of Ewing sarcoma samples in the largest series to date.⁶⁸ However, Ewing sarcoma has a low mutational tumor burden when compared to carcinomas or melanoma.^69–72 Further, Ewing sarcomas typically have only a low level of infiltrating T cells, identified in only 15% of tumor samples in the Machado series.⁶⁸ These laboratory findings suggest that Ewing sarcoma would be a relatively “cold” tumor in terms of responding to immunotherapy, and indeed two cooperative group clinical trials reported to date are consistent with this impression. Specifically, no responses have been reported in 13 patients treated with the anti-PD-1 antibody pembrolizumab⁷³ or in ten patients treated with the anti-PD-1 antibody nivolumab.⁷⁴ While it is hoped that combination immunotherapy regimens now under investigation will make sarcomas more “hot” and therefore responsive,⁷⁵ at present there is little evidence that checkpoint inhibitors should routinely be used as monotherapy for relapsed Ewing sarcoma.

An important caveat is the use of an innovative immunotherapy approach for Ewing sarcoma called Vigil.^76,77 This novel strategy involves administration of a vaccine that comprised autologous tumor cells to provide patient-specific tumor antigens to provoke an anti-tumor response. These cells are transfected with the rhGMCSF transgene and the RNAibi-shRNA^furin in order to recruit and activate dendritic cells while reducing local immune tolerance through the blockade of furin-mediated activation of endogenous TGF-beta1 and 2. An early trial reported a 1-year survival of 73% for patients with relapsed Ewing sarcoma treated with Vigil compared to 23% of historical controls treated with conventional chemotherapy.⁷⁸ Given the low toxicity of Vigil, a randomized Phase III trial is now underway that combines Vigil with TEM/IRN and compares this group with patients treated with TEM/IRN alone [NCT03495921]. This trial represents one of the few Phase III studies for relapsed Ewing sarcoma, and hopefully accrual of patients from both pediatric and adult sarcoma centers will allow for meaningful conclusions.

Should relapsed patients be treated with high-dose chemotherapy and autologous stem cell transplantation?

Several retrospective studies have suggested that treatment with myeloablative doses of alkylators followed by autologous stem cell transplantation may improve outcomes in patients with recurrent Ewing sarcoma.^79–81 Most patients in these studies first received conventional-dose chemotherapy, which was then followed by high-dose busulfan and melphalan. To date, no prospective randomized studies have been performed, and the difficulty in identifying a suitable control population has made interpretation of results more complicated. For example, patients who receive high-dose chemotherapy generally have recurrent tumor that is responsive to typical salvage therapy. At best, this describes only about half of relapsed patients,⁸⁰ with the majority being those with initially localized disease who often have longer survival than relapsed patients who had metastases at diagnosis. In addition, patients must remain progression-free until high-dose chemotherapy is administered, must have adequate stem cells collected, and must have no comorbidities or organ dysfunction that would preclude such intensive treatment. Finally, patients must be willing to undergo this intensive treatment, which is not always the case given that their prognosis still remains unfavorable, despite the prolonged therapy they have already received.

Taken together, the data would suggest that certain patients with favorable features at relapse may possibly have prolonged PFS with high-dose therapy. In a different clinical context, newly diagnosed patients with localized higher-risk tumors were randomized to receive either myeloablative busulfan/melpahalan with autologous stem cells or continuation of standard chemotherapy.⁸²Although patients receiving high-dose therapy had superior outcomes, it should be emphasized that the treatment backbone used in European studies of newly diagnosed patients differs from that used in North America,⁸³ and the implications of this study for relapsed patients are unclear. Moreover, a study incorporating high-dose chemotherapy in patients with responsive recurrent disease was not able to show it to be an independent variable influencing post-relapse survival.¹⁰ The analysis was complicated by the fact that high-dose chemotherapy was reserved for patients achieving a complete or partial response to IFOS, no prior history of myeloablative therapy, and willingness to undergo high-intensity treatment.¹⁰ As such, only 20/107 evaluable patients underwent treatment.¹⁰ This study illustrates some of the complexities of designing a clinical trial to rigorously demonstrate a role for high-dose therapy and autologous stem cell transplantation in the relapse setting. It is clear that this strategy is not well suited for all relapsed patients, and it remains an intensive therapy for which the unequivocal benefits have not yet been established.

What is the role of genetic testing of tumor tissue for actionable mutations in patients with recurrent Ewing sarcoma?

Apart from the characteristic EWSR1 translocations that characterize this tumor, recurring genetic changes in Ewing sarcoma are relatively infrequent. The most common mutations occur in genes such as STAG2, CDKN2A, and TP53, which have not been easily targetable.^69–71 Although potentially actionable mutations have been reported with Ewing sarcoma, these are uncommon.⁸⁴ Therefore, the likelihood of identifying a molecular change that will drive effective therapy is low but not zero. Ongoing translational studies that prospectively collect data on patients with relapsed Ewing sarcoma will be helpful to further characterize the genetic changes that may occur in these patients, especially given the potential of new targeted agents being developed. However, extensive molecular testing outside the context of a clinical trial is expensive, and decisions regarding genetic analysis should be individualized given that the cost/benefit relationship of such testing has not been clarified.

CONCLUSION

The outcome for patients with recurrent Ewing sarcoma remains poor, and the standard approach to their management has not yet been established. Many patients may initially benefit from salvage chemotherapy in terms of reducing symptoms and prolonging time to further progression, but consistent cures remain elusive. Knowledge of prognostic factors that affect survival of these patients may help guide therapy decisions. Enrollment on clinical trials should strongly be considered when feasible, as a variety of mechanistically novel Phase I to Phase III studies are currently underway and represent the best way to better understand which treatments may be beneficial in the future. In this regard, close cooperation between pediatric and adult oncology centers, as well as between continents, will help drive advances for this rare disease of adolescence and young adulthood.

Disclosure

The authors report no conflicts of interest in this work.

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David Van Mater, Lars Wagner

Department of Pediatrics, Division of Hematology/Oncology, Duke University, Durham, NC, USA.

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Source: OncoTargets and Therapy.

Originally published March 27, 2019.