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