Emerging targeted therapeutics
Targeted therapies are under investigation for recurrent ES and OS but are not standard of care at this time. Trial accrual for AYAs has traditionally been poor, especially in the 20-29y age group and correlates with modest gains in survival.133 Greater efforts are unfolding internationally to increase access to specialist centers and clinical trials, particularly of novel agents with age inclusion criteria across the AYA spectrum,134 and supported by multi-stakeholder platforms such as ACCELERATE135 to include adolescents >12yo, as evidenced by the novel agent trials in Table II.
Multitargeted tyrosine kinase small molecule inhibitorsinvestigated in OS and ES demonstrate single agent activity. Antiangiogenic TKIs, often multitargeted to various receptors such as VEGFR are accessible through phase 1 and 2 clinical trials for AYAs with relapsed or refractory ES and OS. They have been used either as a single agent or in combination with sarcoma responsive chemotherapy: regorafenib,136-139 carbozatinib,140apatinib,141 lenvatinib,142(summarized in Table II). Lenvatinib has been demonstrated to be tolerated in combination with ifosfamide and etoposide in patients with relapsed OS and is the subject of an ongoing randomized phase II trial.142 The challenge is how best to investigate these agents in the adjuvant setting and integrate them into intensive combination therapy regimens.
Poly-ADP-ribose polymerase 1 (PARP1) inhibitors are under clinical evaluation in ES, based on promising preclinical activity and evidence that PARP1 inhibitors induced DNA damage in tumors deficient in DNA repair mechanisms.143 Olaparib trialled as a single agent in a prospective phase II trial was disappointing with no objective responses in heavily pre-treated ES,144however potentiation of activity in combination with chemotherapeutic agents, especially temozolomide and or irinotecan in preclinical studies led to combination clinical trials of talazoparib and niraparib.145-147 These demonstrated varied efficacy in pediatric and AYA patients with refractory/ recurrent ES with toxicity limiting dose intensity, Table II. Additional trials are ongoing. Pre-clinical programmes are currently evaluating PARP inhibition as a therapeutic target in OS based on potential evidence of a “BRCAness” phenotype that may lead to increased sensitivity to these agents, although validation using patient-derived models is required before embarking on clinical trials.148-150
The role for immunotherapy in ES and OS is currently limited with little evidence of efficacy in initial trials of checkpoint inhibition, particularly for ES which has a low mutation burden. Further work and trials are ongoing to determine biomarkers to identify subsets of patients or combination therapy that may be of more benefit.151-154 Disialogangliosides, GD2 is a potential cell surface target expressed by ES and OS.155,156 Current phase 1 clinical trials investigating anti-GD2 monoclonal antibodies with immunoadjuvants are recruiting AYAs with relapsed solid tumors including ES and OS, (NCT00743496 at https://ClinicalTrials.gov/). There is support for the utility of dinutuximab in combination with irinotecan and temozolomide in neuroblastoma,157 cytotoxic agents also used in bone sarcoma and we await results of early phase clinical trials evaluating anti-GD2-CART cells in OS, (NCT02107963 at https://ClinicalTrials.gov/).
Targeting the FET-ETS translocation is challenging as the EWSR1-FLI fusion protein lacks enzymatic activity and binding sites for small molecules.16 TK-216, a clinical derivative of YK-4-279 is a novel small molecule that inhibits EWS-FLI1 transcription by blocking co-immunoprecipitation with RNA helicase A;158 this is under evaluation in a phase 1 clinical trial in combination with vincristine based on synergistic anti-tumor activity demonstrated by YK-4-279.159 Very early interim trial analyses (NCT02657005, https://ClinicalTrials.gov/) report two pronounced clinical responses for more than 24 and 18 months following treatment with TK216 in relapsed/ refractory ES.160