DISCUSSION
There is a critical need for novel agents to treat
refractory/progressive brain tumors in children and adolescents.
Palbociclib represents an intriguing candidate as it is a highly
specific CDK4/6 inhibitor that is already FDA approved for adult breast
cancer patients. This was the first study to test the safety and
tolerability of palbociclib in pediatric patients. The MTD was
75mg/m2 for Stratum I and II patients.
Myelosuppression was the primary toxicity, among which grade 3/4
neutropenia and leukopenia were found to be significantly associated
with higher palbociclib exposure. A similar exposure-toxicity
association was also characterized in adult
patients.19
No previous pharmacokinetic parameters have been reported for
palbociclib in children with cancer. In this patient population,
palbociclib displayed a similar pharmacokinetic profile as seen in
healthy adults and adults with solid tumors.20,21Palbociclib Tmax, Cmax, and
AUC0-Tlast observed in this study were similar to the
values previously reported in adults following 100 and 125 mg
palbociclib doses.20 The mean half-life
(~15.6 h) observed in this study was slightly lower that
reported in adults (23-26 h); however this might be explained by the
shorter sampling design used in this trial.20 A
population-based pharmacokinetic analysis will be performed to further
characterize the disposition of palbociclib in this population, quantify
the inter-individual variability, and determine the potential influence
of patient covariates.
Although palbociclib has been confirmed in vitro and in vivo to be a
substrate for CYP3A genes,22-24 no associations
were found between palbociclib pharmacokinetics and variants fromCYP3A4 and CYP3A5 genes in our pediatric population.
Multiple associations were found with SULT2A1 gene which is
predominantly involved in palbociclib sulfonation,23and with genes coding for known drug transporters. Due to the small
sample size, no multivariate analysis was performed, and p-values were
not adjusted for multiplicity. Thus, these associations will need to be
confirmed by further studies.
Only a few patients proceeded beyond 2 courses of therapy, and no
patients had an objective response to palbociclib on this study. A
similar lack of efficacy was reported in a recent phase 2 study of adult
patients with recurrent, Rb-positive glioblastoma.25Notably, a subset of these patients were treated with palbociclib prior
to surgery, and the tumor concentration of palbociclib was greater than
the 0.06 µM concentration felt to be biologically
effective.25 Thus palbociclib was able to cross the
brain-tumor barrier in selected patients. The authors concluded that
palbociclib is not likely to be effective as monotherapy in pretreated
patients, but it may have a role earlier in therapy in patients with
distinct mutational events or in combination with radiation or other
biological agents.25 There are ongoing clinical trials
in adult breast cancer patients with CNS metastases to better elucidate
the role of palbociclib and other CDK4/6 inhibitors in that clinical
context; data to-date are sparse.26
CDK4/6 is central to cell cycle control in cells with intact Rb, but
enhanced vulnerability to CDK4/6 inhibition may be seen in tumors with
genetic mutations that increase signaling though the cyclin D-CDK4/6-Rb
pathway. Examples include amplification of CCND1 , CCND2 ,CCND3 , CDK4 , or CDK6 , or deletion of CDKN2A .
One might expect enhanced efficacy of palbociclib in a patient
population enriched with tumors harboring such mutations. The National
Cancer Institute-Children’s Oncology Group Pediatric MATCH Screening
Trial (NCT NCT03155620) is conducting such a study for refractory
pediatric tumors in a tissue-agnostic fashion. The MTD of palbociclib in
this study will inform the dose for the MATCH study and similar studies
in the future.
Additionally, there is a growing recognition that CDK4/6 inhibitors such
as palbociclib are maximally effective in combination with other
agents.27 Notably, palbociclib was FDA-approved in
combination with anti-estrogen agents for the treatment of patients with
breast cancer patients.6,7 Preclinical studies are
required to elucidate palbociclib resistance mechanisms that can
exploited in individual cancer types. For example,
mTOR28 and c-Met/Trk29 represent
intriguing targets for intervention in glioblastoma.
In summary, we describe the MTD, toxicity, pharmacokinetic and
pharmacogenomic data for palbociclib in children and adolescents. There
was no notable antitumor activity efficacy seen for
progressive/refractory brain tumors in this trial, but the cyclin
D-CDK4/6-Rb pathway remains an intriguing target for future
investigations. Future studies will strive to identify subsets of
patients with enhanced vulnerability to CDK4/6 inhibition and agents
that can be combined with palbociclib for synergy.