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.