Management of Recurrent Ewing Sarcoma: Challenges and Approaches

There are two other features of the TEM/IRN combination that deserve mention. The first is the possibility for oral administration, in which the intravenous preparation is mixed with cran-grape juice and given orally at least 1 hour after oral administration of temozolomide. Oral administration of irinotecan in this fashion has been studied in multiple trials to date (reviewed in reference³²). Importantly, the standard intravenous dose of irinotecan 50 mg/m²/day must be adjusted for poor oral bioavailability. Oral administration of irinotecan 90 mg/m²/day results in exposures of the active metabolite SN-38 similar to those achieved with standard intravenous dosing. Although there have been no direct comparisons between oral and intravenous irinotecan, the similar pharmacokinetics, incidence of grade 3–4 toxicities, and response rate of several tumor types suggest that these dosing strategies are roughly equivalent. Oral administration may reduce the cost of treatment by fivefold, as well as substantially improve patient convenience.³² For these reasons, several ongoing trials are now utilizing orally administered irinotecan, with the addition of prophylactic cephalosporins to reduce irinotecan-associated diarrhea.³³

Second, because TEM/IRN generally is the least myelosuppressive of these four regimens, it has been more commonly used as a backbone on which to add investigational agents. Given that single-agent targeted therapy is unlikely to be curative, coupling novel drugs with a standard well-tolerated backbone is attractive and would likely reflect how newer agents would eventually be used for upfront therapy. TEM/IRN has been used in this fashion in recently completed studies combining this regimen with bevacizumab³⁴ and temsirolimus,³⁵ as well as ongoing clinical trials adding in metformin [NCT01528046], palbociclib [NCT03709680], PARP inhibitors [NCT01858168, NCT02044120], and immunotherapy [NCT03495921].

Finally, other regimens have also been reported to have activity in relapsed Ewing sarcoma. For example, the combination of intravenous etoposide with either cisplatin or carboplatin showed an encouraging response rate and PFS in a retrospective review of patients mostly in first relapse from five European sarcoma centers,³⁶ consistent with an earlier report about the use of ifosfamide, carboplatin, and etoposide (ICE).³⁷ Less intensive options include the use of oral etoposide given on a protracted metronomic schedule.³⁸

The optimal number of chemotherapy cycles for relapsed patients is not established and depends in part on response as well as tolerance of therapy. Many physicians try to administer at least six to eight cycles of therapy in responding patients, as suggested by the rEECur study design in which most patients receive six planned cycles of therapy. However, the length of treatment often needs to be customized to the patient. Cumulative toxicity of therapy, both physical and psychological, can limit continued therapy in some adolescent and young adult patients, especially given that salvage therapy is often not curative and treatment decisions must factor in quality of life considerations.

Which clinical trials may be the most well suited for recurrent Ewing sarcoma patients?

Clinical trials of new strategies for treating patients with recurrent Ewing sarcoma will be essential for improving outcomes. Available clinical trials can be divided into three general categories, including 1) general cytotoxic chemotherapy, 2) agents targeting pathways specific to tumor cells, and 3) immunotherapy. Examples of each group are discussed below; however, this list is not exhaustive.

General cytotoxic chemotherapy

The microtubule inhibitor eribulin has received regulatory approval for adult soft tissue sarcoma and has shown preclinical activity against mouse models of Ewing sarcoma,³⁹ as well as a response in the recently completed pediatric Phase I trial.⁴⁰ Ewing sarcoma is one of the target tumors included in an ongoing single-agent Phase II trial of eribulin [NCT03441360], as well as in combination with irinotecan [NCT03245450]. New formulations of older cytotoxic agents are also being studied for Ewing sarcoma, including the nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) either alone⁴¹ or in combination with gemcitabine [NCT02945800], based on preclinical reports of additive activity of these agents⁴² as well as past responses seen with gemcitabine/taxane combinations.²⁶ Finally, a nanoliposomal preparation of irinotecan (MM-398; Onivyde^®, Ipsen Biopharmaceuticals, Inc., Cambridge, MA, USA) may yield higher plasma and tissue concentrations of SN-38 and has shown in vivo activity against Ewing sarcoma xenografts.⁴³ This drug is now being studied in combination with cyclophosphamide [NCT02013336].

Targeted therapy

A variety of targeted therapies have been developed in the past decade, and they represent a rational and specific approach to treating relapsed Ewing sarcoma. The insulin growth factor receptor 1 (IGF-1R) is highly expressed on Ewing sarcoma tumor cells and appears to drive tumor growth.⁴⁴ Targeting IGF-1R with monoclonal antibodies produced convincing and durable responses in early trials of Ewing sarcoma patients.^45,46 However, larger studies failed to show consistently high response rates,^47,48even when combined with an mTOR inhibitor.^49–51 Disappointingly, the inability to identify biomarkers predictive of the small subset of responding patients has severely limited the use of these agents, as IGF-1R expression alone is not correlated with clinical benefit. The IGF-1R antibody ganitumab is currently being studied in combination with conventional chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma, and it is hoped that improved activity and predictive biomarkers may be identified [NCT02306161]. A second target for antibody-directed therapy is placenta growth factor (PGF), which has been implicated in the invasiveness and metastatic potential of Ewing sarcoma.⁵² A clinical trial is underway which targets PGF with the monoclonal antibody TB-403 [NCT02748135].⁵³

Targeting important tumor pathways with receptor tyrosine kinase inhibitors is another attractive strategy. Many such agents are now commercially available, and the oral route of administration is convenient for patients. Some modest success has been seen with the VEGFR inhibitor regorafenib, with a response rate of 10% in heavily pretreated adult patients (median five prior regimens, median age 32 years) with recurrent Ewing sarcoma.⁵⁴ The primary endpoint was 8-week PFS, with the observed rate of 73% exceeding the defined bar for activity of 25%. Similarly, a response rate of 28% and 6-month PFS of 24% have been described in relapsed Ewing sarcoma patients treated with cabozantinib,⁵⁵ an inhibitor of the MET protein which is expressed in 62% of Ewing tumors.⁵⁶ These drugs generally have more toxicity than monoclonal antibodies, with many patients requiring dose reductions when multiple cycles are given. As seen with IGF-1R antibodies, the identification of predictive biomarkers will be essential for more successful use of these agents.

Another focus for targeted therapy has been the DNA repair protein PARP1. Expression of this enzyme is elevated in Ewing tumors, and there is a positive feedback loop with the EWS-FLI1 fusion transcript.⁵⁷ Although mechanistically attractive, the clinical experience of PARP inhibitors as single agents has been disappointing.⁵⁸ Current trials now combine PARP inhibitors with DNA damaging agents such as temozolomide and/or irinotecan, based on preclinical demonstration of synergy.⁵⁹Results from these studies are eagerly awaited, although the doses of conventional chemotherapy may need to be substantially reduced in order to make combination regimens feasible.

Other strategies include specifically focusing on the EWS-FLI1 translocation that characterizes this disease and drives tumor growth. Although transcription factors such as the fusion product produced by this translocation have been notoriously difficult to target, Zollner et al have identified an inhibitor to the RNA helicase A which binds to EWS-FLI1 and disrupts its protein interactions, leading to activity against Ewing xenografts.⁶⁰ TK216 is now in a Phase I clinical trial, although administration requires a 7-day continuous infusion because of its short half-life [NCT02657005]. BRD4 is another factor required for the EWS-FLI1 fusion protein to function.⁶¹ BRD4 is a member of the bromodomain and extraterminal domain (BET) family of proteins that act as “readers” of chromatin to regulate gene expression. Recently, bromodomain inhibitors have been shown to negatively impact gene expression mediated by the EWS fusion protein, and the BET family of proteins represents a potential vulnerability that can be exploited by BET inhibitors as monotherapy or (more likely) in combination with other agents.^61–65 Clinical trials of bromodomain inhibitors are now open [NCT02419417, NCT03220347].

Another rational strategy is inhibition of lysine-specific demethylase 1 (LSD-1), which is highly expressed in Ewing sarcoma and represses the transcriptional activation of downstream targets of EWS/FLI1 that lead to tumor growth.⁶⁶ Two LSD-1 inhibitors are now entering clinical trials [NCT03514407, NCT03600649]. The above studies are particularly exciting because they represent efforts to directly target the specific underlying molecular biology of Ewing sarcoma. A summary of several targeted therapies currently in clinical trials is provided in Table 3.

(To view a larger version of Table 3, click here.)