Precision Medicine in Pediatric Oncology

February 13, 2020

Dr. Theodore Laetsch, MD discusses the current status of pediatric precision oncology and different clinical scenarios in which it can be effectively applied. Laetsch also discusses safety and efficacy data of targeted agents being used for the treatment of pediatric patients with oncological malignancies.


Theodore Laetsch, MD

Associate Professor, Department of Pediatrics; Norma and Jim Smith Professor of Clinical Excellence; Eugene P. Frenkel, M.D. Scholar in Clinical Medicine; Harold C Simmons Comprehensive Cancer Center; University of Texas Southwestern Medical Center; Experimental Therapeutics Program Leader; Children’s Health; Dallas, TX


Financial Disclosure     Grant/Research Support:  Bayer, Turning Point Therapeutics, Inc.; Novartis, Pfizer Consultant: Bayer, Novartis


The staff of PER® have no relevant financial relationships with commercial interests to disclose.


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Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

  • Describe the key principles and components of precision medicine in pediatric hematology-oncology

  • Discuss the current approaches to molecular testing in the pediatric population and the genetic abnormalities that are known to be important in the setting of pediatric oncology

  • Consider safety and efficacy data of ongoing trials using tropomyosin receptor kinase (TRK) inhibitors in pediatric oncology



Release Date: February 07, 2020

Expiration Date: February 07, 2021




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Precision medicine is an emerging approach for cancer treatment that has recently taken solid steps into clinical practice. The Precision Medicine Initiative has defined it as an emerging approach for the prevention and treatment of disease that considers individual variability in environment, lifestyle, and genes.1 Molecular diagnostics techniques that can analyze the individual genetic variability of tumors have provided greater understanding and additional strategies to treat cancers.2-4 For example, MYCN amplification in a patient with neuroblastoma is associated with a poor prognosis, so identification of this defect may indicate that treatment should be changed (as when standard chemotherapy and surgery are likely to be of no value). A predictive genetic defect provides information about the likelihood of the patient’s response to a specific treatment. For instance, an ALK mutation or amplification in a patient with neuroblastoma suggests the likelihood of response to an ALK inhibitor.

The use of next-generation sequencing (NGS) has greatly facilitated the understanding of pediatric cancer and identified additional therapeutic opportunities.2 These advances have been particularly striking in the assessment and treatment of pediatric cancers that have a different genetic makeup, with a fewer number of actionable targets, than adult tumors.5 The use of NGS has led to the increased use of targeted therapies and improved survival in children with leukemia and solid tumors.2,6-8 For example, the detection of somatic mutations, fusions, and other genomic abnormalities has resulted in the use of targeted therapies in Philadelphia (Ph) chromosome–positive and Ph-like acute lymphoblastic leukemia (ALL) and ALK-mutated neuroblastoma.9,10 Somatic genomic testing has become the standard of care in a variety of pediatric cancers. Genomic profiling has become particularly important in the evaluation of central nervous system (CNS) tumors, and the use of genetic profiling has been included in the World Health Organization classification of CNS malignancy.11

In the section that follows, Theodore Laetsch, MD, discusses the current status of pediatric precision oncology and different clinical scenarios in which it can be effectively applied. He also discusses safety and efficacy data of targeted agents being used for the treatment of pediatric patients with oncological malignancies.

Q: What do you consider to be the key principles of precision medicine in the setting of pediatric hematology-oncology?

Dr Laetsch: At the most basic level, precision medicine means refining the treatment based on the individual patient and tumor characteristics, and this has been going on for a long period of time using biomarkers to define therapy. I think some of the earliest examples of this are using the patient’s age or their white blood cell count when they initially presented to define the treatment for pediatric leukemia and pediatric ALL, but more recently, it has focused on the use of genetic markers.

Thinking about BCR-ABL for pediatric ALL is a good example of how precision medicine is evolving. Initially, the presence of the Philadelphia chromosome, was used only as a prognostic biomarker for patients with ALL where those with this marker would be assigned to stem cell transplant in first complete remission. But now we’re actually able to directly target this molecular alteration using a kinase inhibitor, which has resulted in substantially better outcomes and has always been used for transplant in most of these patients.

This example reflects how the era of precision medicine is evolving to use not just molecular characterization of the tumor but actually a targeted agent to improve outcomes, and the same is now going on in leukemia, where they’re studying a variety of BCR-ABL-like leukemias, the Philadelphia-like leukemias, to see if a similar philosophy works with targeting of these fusions that are identified.

Q: What is the current status of precision medicine in pediatric oncology in terms of clinical practice? How much variability is there between the different centers?

Dr Laetsch: I think this is very cancer specific. For some cancers such as leukemia that I was just discussing, the approach is fairly standardized and is actually being studied in a large phase 3 study through the Children’s Oncology Group. But for other tumors, especially solid tumors, there are varying practices with different assays used at different centers, in different countries, and at different times in a patient’s disease course.

In particular, if you think about next-generation sequencing, there hasn’t been standardization to a particular assay with some centers using DNA-based assays, some using RNA-based assays, and some using a combination of these 2. I think it’s important as we think about this field moving forward, that we work to standardize these assays to make sure they all have the same sensitivity and specificity for the molecular alterations that are identified.

Q: When is molecular testing indicated? What should such testing involve?

Dr Laetsch: The indication for molecular testing depends on the diagnosis and prognosis. As I’ve discussed, for some cancers, molecular testing is absolutely standard of care at the time of diagnosis, for example, in patients with neuroblastoma and leukemia. But for others, it’s more variable.

I’ve studied soft tissue sarcomas in particular, and we found that 80% of children with undifferentiated sarcoma either had a more specific diagnosis or a therapeutic target suggested by next-generation sequencing. We’re now studying this finding more broadly across patients with soft tissue sarcomas, and molecular testing is very important in these patients. I believe that next-generation sequencing should be indicated for all children with either difficult-to-define tumors when the diagnosis isn’t clear or for those whose tumor relapses or lacks a good standard-of-care treatment option. We try to identify these molecular biomarkers that may predict response to therapy.

Q: What do you consider to be the most clinically significant molecular genetic abnormalities in pediatric cancer?

Dr Laetsch: I’ve discussed a number of these potential molecular alterations, including MYCN amplification for neuroblastoma, and more recently, a discovery of ALK-activating mutations in neuroblastoma, which are now being targeted, as well as the Philadelphia chromosome and Philadelphia-like mutation in pediatric ALL.

More recently, however, there have been discoveries of more pan-cancer molecular alterations that are relevant across pediatric tumor types. These include the presence of microsatellite instability, and mismatched-repair–deficient tumors, for which pembrolizumab was recently granted FDA approval and the identification of fusions of the NTRK 1, 2, or 3 genes TRK fusions for which larotrectinib and entrectinib have recently been granted FDA approval.

Q: Could you describe the incidence and presentation of NTRK fusion-positive solid tumors and hematologic malignancies in pediatric patients?

Dr Laetsch:NTRK fusion-positive tumors are rare overall and are thought to occur in less than 1% of cancers. However, especially in pediatric oncology, there are diseases for which transfusions are pathognomonic, and these include infantile fibrosarcoma (the most common sarcoma in children younger than 1 year of age) and congenital megaloblastic lymphoma of the cellular subtype. In both of these illnesses, the diagnosis is essentially made by the identification of an NTRK fusion.

There are other cancers in which NTRK fusions are not pathognomonic but are occurring in greater than 5% of patients, and these include papillary thyroid cancer and melanoma. More recently, TRK fusions have been identified across the range of histologic subtypes of soft tissue sarcomas and high- and low-grade gliomas, as well as some other CNS tumors.

I think also, given the number of patients who have been sequenced and the variability of the techniques for sequencing, you can’t completely exclude the presence of NTRK fusions and other tumors. This has been seen in adult cancers when some very common types of cancer, such as lung cancer and colon cancer have NTRK fusions, but at very, very low frequencies. I don’t think we can exclude this finding in pediatric cancer.

Q: What is the evidence that TRK inhibitors are effective in treating these malignancies?

Dr Laetsch: Two TRK inhibitors have recently received FDA approval for the treatment of TRK fusion–positive cancers regardless of histology: larotrectinib and entrectinib. Larotrectinib demonstrated a 75% response rate across adults and children with a wide range of histologies harboring TRK fusions and was recently reported to have a 35-month median duration of response in those patients. In children, the results have been even more impressive with a response rate greater than 90% and a median duration of response not yet reached. Entrectinib demonstrated a 57% response rate in adults with TRK fusion–positive malignancy, with a 10-month median duration of response. A pediatric phase 1-2 study of entrectinib is ongoing, but the preliminary results reported at ASCO in 2019 demonstrated a response in a high proportion of children with fusions of NTRK, ALK, or ROS1, as entrectinib targets all 3 of these genes. Both agents have also been shown to have activity in patients with CNS tumors.

I think it’s important to note when describing these results that these are nonrandomized studies, so cross-study comparisons are not possible with the data, and additional long-term data will be needed to evaluate the efficacy and safety of both of these drugs.

There’s also ongoing pediatric studies of next-generation TRK inhibitors, which may overcome some of the resistance that develops in the first-generation drugs. These include selitrectinib (LOXO-195) as well as repotrectinib.

Q: What is the safety profile of the TRK inhibitors?

Dr Laetsch: The TRK inhibitors are generally well tolerated. Larotrectinib has shown some on-target neurologic toxicity, including fatigue and dizziness, some gastrointestinal side effects, including hepatotoxicity elevations in liver function tests, and typically mild cytopenias. Entrectinib has also shown CNS toxicity, including vision disorders and has warnings for the presence of congestive heart failure, skeletal fractures, hepatotoxicity, hyperuricemia and QT prolongation, and both agents have a risk for fetal toxicity. It’s also important to note that each of these agents has only recently been developed, so long-term toxicity in developing children remains unknown with both drugs.

Q: What are the ongoing trials regarding TRK inhibitors that a pediatric hematologist-oncologist should be aware of?

Dr Laetsch: There are several ongoing clinical trials. These include a frontline study testing larotrectinib for children with newly diagnosed TRK fusion–positive solid tumors that I lead through the Children’s Oncology Group and the pediatric match, which is an NCI Children’s Oncology Group study evaluating larotrectinib for children with TRK fusion–positive tumors that relapse. As I mentioned earlier, there are ongoing studies of at least 2 next-generation TRK inhibitors that are evaluating the ability of these drugs to treat patients who may develop resistance to the first-generation drugs. There are also industry-sponsored long-term follow-up studies evaluating the safety of larotrectinib in children, to find additional long-term safety data.

Q: What advice can you offer to pediatric hematologist-oncologists in the community about the use of TRK inhibitors?

Dr Laetsch: I think there are now multiple TRK inhibitors FDA approved for the treatment of children. It’s notable that entrectinib is approved for patients 12 and older and the pediatric phase 1 study is ongoing. Larotrectinib is approved for children of any age, and there is a liquid formulation available that enables dosing of young children in whom these TRK fusions are common. I think that it’s important to think through the timing of testing of these patients because without identification, patients won’t have access to these drugs. At the time of relapse or progression, this is especially important. It is also important in patients with high-frequency tumors at initial diagnosis to identify whether they may be candidates for either of these ongoing clinical trials or commercial use of 1 of these agents.

Q: What role do you think targeted therapies will have in pediatric oncology in the future?

Dr Laetsch: The use of targeted therapy in pediatric oncology is increasing very rapidly. I think there’s still a large portion of patients for whom we can’t identify an effective targeted therapy. There are, however, a number of ongoing clinical trials of both TRK inhibitors that we’ve discussed and also other drugs targeting other particular kinases that are activated in pediatric cancer. These are in phase 3 clinical trials or are currently in commercial use. So, I think this is a field that will continue to grow as we gain additional understanding about the genomics of pediatric cancer and which tumors are targetable.






















1. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793-795.

2. Ahmed AA, Vundamati DS, Farooqi MS, Guest E. Precision medicine in pediatric cancer: current applications and future prospects. High Throughput. 2018;7(4):E39.

3. Kalia M. Personalized oncology: recent advances and future challenges. Metabolism. 2013;62(suppl 1):S11-S14.

4. Garraway LA, Verweij J, Ballman KV. Precision oncology: an overview. J Clin Oncol. 2013;31(15):1803-1805.

5. Rahal Z, Abdulhai F, Kadara H, et al. Genomics of adult and pediatric tumors. Am J Cancer Res. 2018;8(8):1356-1386.

6. Caporalini C, Moscardi S, Tamburini A, et al. Inflammatory myofibroblastic tumor of the tongue. report of a pediatric case and review of the literature. Fetal Pediatr Pathol. 2018;37(2):117-125.

7. Tsui PC, Lee YF, Liu ZWY, et al. An update on genomic-guided therapies for pediatric solid tumors. Future Oncol. 2017;13(15):1345-1358.

8. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739.

9. Bresler SC, Weiser DA, Huwe PJ, et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014;26(5):682-694.

10. Maese L, Tasian SK, Raetz EA. How is the Ph-like signature being incorporated into ALL therapies? Best Pract Res Clin Hematol. 2017;30(3):222-228.

11. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803-820.

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