Clinical Utility of Functional Precision Medicine in the Management of Relapsed/Refractory Childhood Cancers

Pediatric cancers are fundamentally different from those in adults, with a lower frequency of genetic mutations and fewer options for targeted therapies. The implementation of functional precision medicine (FPM) – the integration of ex vivo drug screening and mutation profiling- can, therefore, provide better treatment options for pediatric tumor patients. In this study, we investigated the feasibility and clinical utility of FPM in the management of pediatric patients with recurrent and/or refractory cancers. We use a functional ex vivo drug screening test (DST) panel encompassed 40 formulary drugs frequently used at Nicklaus Children’s hospital and 47 non-formulary drugs approved by FDA for cancer treatment, as well as drugs from phase III and IV clinical trials. Drug sensitivity scores (DSS) were calculated for each drug based on cancer cells’ responses. DST results were then combined with results from targeted mutation profiles to match actionable mutations with selective targeted therapies. We have recruited a total of 21 patients into this ongoing clinical trial (number NCT03860376) and were able to perform drug testing and mutation profiling on 17 patients. We optimized and successfully performed DST on at least 13 different tumor types including acute myeloid leukemia, chronic lymphoblastic leukemia, ependymoma, osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, glioblastoma, medulloblastoma, astrocytoma, neuroblastoma, rhabdoid, lung, and liver. Our feasibility study, so far, has demonstrated that ex vivo DST can be performed within a clinically actionable time frame (median: 7 days). Ex vivo DST returned between 10 and 30 treatment options for each patient. These patients showed different responses to the 103 FDA-approved compounds used on the screen. More than half of the evaluated compounds were not active in any of the patients. Remarkably, DST provided valuable information to the oncologists on drug dosing and treatments that may not be effective and should be avoided. DSS synergizes with genomic data to further refine treatment recommendations. FPM-guided treatment regimens resulted in encouraging partial and complete responses as compared to progressive disease in prior regimens and physician choice regimens. Thus, our study shows the technical feasibility of integrating functional precision medicine approaches for patients with refractory/relapsed pediatric cancers. Routine clinical integration of FPM for treatment selection is technically feasible and led to improved treatment of pediatric cancer patients with refractory malignancies in an initial patient cohort, warranting further investigation.