Rare but not forgotten: Therapeutic advancements for rare childhood cancers
Jacquelyn N. Crane,1,2 Urania Dagalakis,3 Robyn D. Gartrell,4 Kris Ann P. Schultz,5 and Theodore W. Laetsch1,2
1Department of Pediatrics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; 2Division of Oncology, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; 3Division of Oncology, Cancer and Blood Disorders Center, Children’s National Hospital, Washington, DC 20010, USA; 4Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; 5Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN 55404, USA
Cancers in children represent less than 1% of all new cases of cancer. While all cancers are rare during childhood, certain types are particularly rare. Multi-institutional pediatric trials and coordinated efforts between pediatric and adult groups have resulted in recent key advances in the treatment of certain rare pediatric cancers. This article reviews these advances with a focus on immunotherapies, molecularly targeted therapies, and radioligands. This includes work that led to the FDA approvals of immune checkpoint inhibitors in multiple rare pediatric tu- mor types, the NTRK inhibitors larotrectinib, entrectinib, and repotrectinib for children and adults with solid tumors with NTRK fusions, the ALK inhibitor crizotinib in children and adults with ALK-positive inflammatory myofibroblastic tu- mors, and the radioligand LUATHERA for adolescents and adults with somatostatin receptor-positive gastroenteropancre- atic neuroendocrine tumors. Additionally, key data from adult studies which have informed the management of pediatric rare cancers are reviewed. Despite these advances, the study of rare pediatric cancers faces multiple challenges including a limited number of patients for efficient and well-powered clinical trials and a dearth of financial incentives. Ongoing, coordinated ef- forts are needed to continue the advancement of novel treat- ments and improve survival and minimize late effects.
INTRODUCTION
There are approximately 1,800,000 new cases of cancer diagnosed each year in the United States and about 15,000 of these occur in chil- dren less than 20 years of age.1 Thus, pediatric cancers represent less than 1% of all cancer cases. While all childhood cancers are rare, there are varying definitions of what constitutes a “rare” pediatric cancer.2-5 This article will focus on cancers that are particularly rare in both children and adults and those that are particularly rare in children despite being common in adults. This includes but is not limited to carcinomas (nasopharyngeal carcinoma [NPC], thy- roid carcinoma, adrenocortical carcinoma [ACC], and colorectal carcinoma [CRC]), non-rhabdomyosarcoma soft tissue sarcomas (alveolar soft part sarcoma [ASPS], infantile fibrosarcoma, and syno- vial sarcoma), soft tissue tumors with intermediate biologic potential (inflammatory myofibroblastic tumors [IMT]), melanoma, neuroen- docrine tumors, and pleuropulmonary blastoma (PPB).
Survival for patients with pediatric cancers has improved over the past several decades. However, this progress has largely been restricted to the more common pediatric cancer types with modest to no improvement in many other pediatric cancer types with some important exceptions.6,7 Additionally, the morbidity of child- hood cancer and its treatments remains significant with the majority of childhood cancer survivors experiencing chronic health care con- ditions and late effects.8,9 There is great interest in novel treatment approaches to improve survival and limit long term treatment ef- fects. Fortunately, there have been several recent key advancements in the treatments of certain rare pediatric cancers. Herein, we review these advancements with a focus on treatment approaches other than conventional chemotherapy including immunotherapies, molecu- larly targeted therapies, and radioligands.
Immunotherapies
Immunotherapies have revolutionized the care of certain pediatric cancers. Notable examples include blinatumomab, a bispecific T cell-engager antibody targeting CD19, and tisagenlecleucel, a chimeric antigen receptor (CAR) T cell therapy targeting CD19, which have transformed the treatment of B cell acute lymphoblastic leukemia, one of the most common pediatric cancers.10,11 Another example is dinutuximab, a monoclonal antibody targeting GD2, which has similarly transformed the treatment of neuroblastoma, the most common extracranial solid tumor in children.12,13 Here, we will focus on two categories of immunotherapies, immune check- point inhibitors and adoptive cell therapies, in rare pediatric cancers.
Immunotherapies-immune checkpoint inhibitors Overview of immune checkpoint inhibitors and their use in
pediatric rare cancers
Immune checkpoint inhibitors (ICI) have transformed the landscape of cancer treatment although this impact has been largely restricted to adults with more limited efficacy of ICI in children.14-18 However, there are a subset of pediatric cancers, including certain rare
https://doi.org/10.1016/j.omton.2025.201084.
Correspondence: Jacquelyn N. Crane, Department of Pediatrics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
E-mail: cranej2@chop.edu
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Antigen- presenting cell
B7 ligands CTLA-4
Tremelimumab Ipilimumab
T cell
Gal-3 LSECtin
Nivolumab Pembrolizumab Cemiplimab
T cell receptor therapy
PD-1
Relatimab
LAG3
PD-L1
Atezolizumab Durvalumab
Synovial sarcoma
Immune checkpoint inhibitors
ACC, ASPS, Melanoma, MSI-high tumors, NPC
pediatric cancers, for which ICI has shown promising efficacy.14 Im- mune checkpoint proteins provide inhibitory signals to T cells, al- lowing cancer cells to evade detection. ICIs block signaling of im- mune checkpoint proteins, allowing re-activation of T cells to promote an anti-tumor immune response. As shown in Figure 1, there are four main targets of ICIs in current clinical use: pro- grammed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG3).19 Several biomarkers of response to ICI have been evaluated but their utility is not univer- sal.2º Microsatellite instability (MSI)-high designation or mismatch repair (MMR) deficiency (MMRD) are commonly used as bio- markers predictive of clinical benefit of ICI.21 While the acute and chronic side effect profile of ICIs are different than those of cytotoxic therapies, off target immune-mediated inflammation in various parts of the body can occur and occasionally results in life threatening or- gan dysfunction or long-term endocrinopathies and/or autoimmune conditions.22,23
ICI in pediatric MSI-high cancers and MMRD
MSI is defined by the hypermutability of short tandem repeats in DNA (microsatellites) caused by impaired DNA mismatch repair. These microsatellites consist of 1-6 base pair repeat motifs and can be assessed by polymerase chain reaction assays, next generation sequencing, or immunohistochemical analysis. High MSI (MSI-H) is generally defined by instability in ≥30% of tested loci.24 MSI-H is rare in pediatric cancers, except in patients with constitutional MMRD (CMMRD), a cancer predisposition syndrome caused by biallelic germline pathogenic variants in mismatch repair genes asso- ciated with increased risk of hematologic, brain and intestinal can- cers.25,26 Among this patient population, the most common MSI-H tumors include high grade gliomas, colorectal cancer, leuke- mia/lymphoma and small bowel/duodenal adenocarcinoma.27 ICIs have important therapeutic potential in the rare pediatric patient
Figure 1. Immunotherapy in pediatric rare tumors Immune checkpoints, immune checkpoint inhibitors, and T cell receptor therapy and the corresponding pediatric rare tumor types for which these therapies have efficacy or are being actively investigated. Abbreviations: ACC = adrenal cortical carcinoma; ASPS = alveolar soft part sarcoma; MSI = microsatellite instability. (Created in biorender. Crane, J. (2025) https://BioRender.com/ urn14uc).
with MSI-H or MMRD cancers. The FDA approval for pembrolizumab in MSI-H or MMRD cancers was supported by five trials, which included 149 adult and pediatric pa- tients with MSI-H/MMRD non-colorectal can- cers with an objective response rate (ORR) of 39.6%.28 A study of 45 tumors, including CNS tumors, gastrointestinal tumors, urothe- lial cancer, and leukemia/lymphomas, from 38 pediatric patients with MMRD or Lynch syndrome, reported MSI-H was correlated with a durable response to PD-1 inhibitors with a 41% three-year survival.29 Patients with CMMRD require robust screening protocols for early detection and consideration of initiation of ICI for better patient outcomes.
ICI in pediatric melanoma
Melanoma in children accounts for less than 1% of all cases of mela- noma. There are three main subtypes of melanoma in children including conventional or adult-type melanoma, Spitzoid melanoma, and melanoma arising in a congenital melanocytic nevus.30 The rec- ommended approach to pediatric melanoma is largely extrapolated from the adult experience and includes surgical excision, when feasible, and immunotherapy and/or targeted therapies in advanced disease.31-33 The ICIs-ipilimumab, nivolumab and pembrolizu- mab-are each FDA approved for the treatment of adolescents and adults with melanoma based on multiple trials which demonstrated a survival benefit.34 Adolescents were eligible for several of the pivotal trials of ICI in melanoma but, due to the rarity of melanoma in this population, very few adolescents were enrolled and there is a dearth of pediatric-specific clinical trial data evaluating ICIs for melanoma.31 The phase 2 CA184-178 study was a pediatric specific trial which enrolled 12 adolescents (aged 12 to <18 years old) with unresectable stage III or IV advanced melanoma with ipilimumab and demon- strated a 1-year overall survival rate of 75% in the 3 mg/kg cohort and 62.5% in the 10 mg/kg cohort with two partial responses.35 This trial was stopped early due to slow accrual. The ongoing KEYNOTE-051 trial is evaluating pembrolizumab in children (6 months-17 years old) with advanced melanoma or PD-L1 positive relapsed/refractory solid tumors. In an interim analysis, there were no responses among eight patients with melanoma but half were 3 years or younger and given concern for different biology in very young chil- dren versus adolescents and adults, the melanoma cohort remained open and final results are pending.16 Existing data support the role
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of ICIs in advanced melanoma in both children and adults but further investigation is needed to optimize the therapeutic approach for young children and for the approximately half of adolescents and adults who do not have long-lasting benefits with current ICI approaches.34
ICI in pediatric NPC
NPC accounts for <1% of childhood cancers and only about 2% of all NPC cases occur in patients less than 20 years of age.36,37 On the Children’s Oncology Group (COG) study ARAR0331, excellent out- comes were achieved for children 18 years of age or younger with NPC.38 Patients on ARAR0331 were treated with three cycles of cisplatin (CDDP) and 5-fluorouracil (5-FU) followed by dose-strat- ified radiation achieving 84.3% 5-year event free survival (EFS). However, this treatment is associated with substantial toxicity risks, raising interest in treatment approaches that can reduce toxicity. In adults with NPC, ICI alone and the combination of ICI and chemo- therapy have shown efficacy.39 This includes the KEYNOTE-028 study in which pembrolizumab resulted in an objective response rate (ORR) of 25.9% in adults with recurrent or metastatic NPC.40 Additionally, nearly all cases of pediatric NPC are associated with Epstein-Barr virus and there is evidence that ICI may be active in vi- rus-associated cancers, including NPC.41,42 On the basis of these data, there is now an ongoing COG clinical trial for NPC, ARAR2221 (NCT06064097), evaluating the addition of the anti- PD1 ICI nivolumab with gemcitabine and cisplatin during three cy- cles of induction followed by response-adapted and dose reduced ra- diation with concurrent cisplatin and nivolumab then maintenance nivolumab.43 The German Society of Pediatric Oncology and Hema- tology (GPOH) also has an ongoing trial for NPC (NCT06019130) evaluating the addition of nivolumab to three cycles of induction chemotherapy with cisplatin and 5-FU, followed by response-adapt- ed and dose-reduced radiation with concurrent cisplatin, then main- tenance interferon-B. These studies will provide important data regarding the role of ICI with chemotherapy in the treatment of pe- diatric NPC and potential to reduce radiation toxicity.43
ICI in ASPS
ASPS is a rare soft tissue sarcoma characterized by an ASPSCR1- TFE3 gene fusion. Approximately one-third of cases of ASPS occur in adolescents and young adults.44 While ASPS often has an indolent course, it has a high propensity for metastasis and responds poorly to conventional chemotherapy.44,45 However, ICIs have shown compel- ling activity in ASPS.46-50 Notably, a phase 2 study of atezolizumab in both pediatric and adult patients with ASPS demonstrated an ORR of 37% leading to the FDA approval of atezolizumab for the treatment of unresectable or metastatic ASPS in patients 2 years and older.50 ICIs, TKIs (as discussed later), or a combination of both are now the preferred first line systemic therapies for ASPS in the National Comprehensive Cancer Network (NCCN) guidelines.
ICI in ACC
In addition to the tumor types already discussed, ICI remains of in- terest for further study in other pediatric rare cancers including pe- diatric ACC. ACC accounts for 0.1% of pediatric cancers.37 Patients
with metastatic ACC have a dismal outcome and new therapies are greatly needed.51 In two trials of pembrolizumab in adults with advanced or refractory ACC, pembrolizumab resulted in ORRs of 14% and 23% with prolonged disease stabilization seen in additional patients.16,52,53 Although efficacy of ICI has been modest in most pe- diatric solid tumors, on KEYNOTE-051, a phase 1/2 clinical trial of pembrolizumab, 2 of 4 pediatric patients enrolled with ACC had an objective response.16 Further study is warranted to understand the role of ICI in pediatric ACC.
Immunotherapies-adoptive cell therapies
Adoptive cell therapies (ACT) involve the infusion of expanded or genetically engineered human lymphocytes. There are three main forms of ACT including CAR T cell therapy, tumor-infiltrating lym- phocytes (TILs), and T cell receptor (TCR) therapy. The develop- ment of CAR T cell therapies have been a remarkable advancement in the treatment of hematologic malignancies.54 However, the appli- cation of CAR-T cell therapy in solid tumors has been challenged by limited tumor-specific surface antigens, tumor heterogeneity, immu- nosuppressive tumor microenvironment, and toxicity.55 TCR ther- apy is a type of ACT in which autologous T cells are genetically modi- fied to express a specific T cell receptor, allowing them to recognize tumor-specific epitopes presented by the major histocompatibility complex (MHC) molecules on the surface of tumor cells, thus ex- panding the potential targets beyond membrane proteins with CAR T cell therapies. One challenge with TCR therapy is that the an- tigen recognition for TCR T cells is human leukocyte antigen (HLA) restricted so only patients with specific HLA types can benefit from a particular TCR therapy.56 As shown in Figure 1, the use of specific TCR therapies has been shown to be efficacious in solid tumors, spe- cifically in adults with synovial sarcoma and evaluation in children is ongoing.
T cell receptor therapy in synovial sarcoma
Synovial sarcoma is a rare soft tissue sarcoma characterized by a SS18:SSX gene fusion. There are approximately 800 new cases of sy- novial sarcoma in the US per year and about one-third occur in pa- tients less than 20 years of age.57,58 Melanoma-associated antigen 4 (MAGE-A4) is expressed in multiple solid tumors, including the ma- jority of synovial sarcomas, and expression in healthy tissues is restricted to immune-privileged sites.59 Afamitresgene autoleucel (afami-cel) is an adoptive T cell therapy targeting MAGE-A4. Afami-cel was evaluated in the SPEARHEAD-1 trial and resulted in durable responses in adults with synovial sarcoma.60 Specifically, patients with synovial sarcoma had an ORR of 39% with median duration of response of 11.6 months and median progression free survival (PFS) of 3.8 months.60 The results of the SPEARHEAD-1 led to the recent FDA approval of afami-cel for treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, have MAGE-A4 tumor expression, and eligible HLA antigens. SPEARHEAD-3 (NCT05642455) is an ongoing phase 1/2 trial of afami-cel in patients 2-21 years of age who are HLA-A*02 positive (excluding HLA-A*02:05) with MAGE-A4 positive synovial sarcoma, MPNST, neuroblastoma, and osteosarcoma. Thus, data
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Crizotinib Alectinib Repotrectinib Ceritinib Entrectinib Loraltinib
Selpercatinib Pralsetinib Sorafenib Lenvatinib Cabozantinib Vandetanib
Larotrectinib Repotrectinib Entrectinib
Axitinib Cabozantinib Imatinib Pazopanib Regorafenib Ripretinib Sunitinib Andavapritinib
ALK
EGFR
RET
TrkA
TrkB
TrkC
IMT
RAS
Thyroid Cancer
Dabrafenib Encorafenib Vemurafenib Tovorafenib
Infantile fibrosarcoma Other sarcomas Thyroid cancer CMN
Raf
Trametinib Binimetinib Cobimetinib
Melanoma Thyroid Cancer Sarcomas
MEK1/2
ERK1/2
Targets, respective therapies, and pediatric rare tumor indications. Abbreviations: ASPS = alveolar soft part sarcoma; CMN = congenital mesoblastic nephroma; GIST = gastrointestinal stromal tumor; IMT = inflamma- tory myofibroblastic tumor. (Created in biorender. Crane, J. (2025) https://BioRender.com/kqu0joy).
with ALK-positive IMT had an ORR of 66.7%.65 On the basis of these studies, crizotinib Other receptor tyrosine kinases (e.g. VEGFR, c-MET, c-KIT, PDGFR) was FDA approved for the treatment of patients 1 year of age and older with unresectable, recur- rent, or refractory ALK-positive IMT. Addi- tional studies are either completed or are Thyroid Cancer ASPS Sarcomas GIST ongoing to evaluate other ALK-targeted thera- pies in children with ALK-altered tumors including alectinib (NCT04774718), repotrecti- nib (NCT04094610), ceritinib, entrectinib, and loraltinib. While there are compelling results to date and repotrectinib is FDA approved for adolescent and adults with NTRK fusion posi- tive solid tumors, there is not yet FDA approval for an ALK-alteration related pediatric specific indication for these other drugs.66-68
from SPEARHEAD-3 is expected to result in critical information to guide the use of afami-cel in those pediatric cancers.
Molecular therapies
Advances in the molecular characterization of cancers have enabled the development of molecular therapies for multiple rare pediatric cancers. The main targets for which therapies have been developed in rare pediatric cancers include ALK, NTRK, RET, BRAF/MEK, and other receptor tyrosine kinases (RTKs), as is summarized in Figure 2 and discussed in further detail herein.
ALK inhibitors in rare pediatric cancers
Multiple pediatric and adult cancer types have alterations in the anaplastic lymphoma kinase (ALK) gene, a receptor tyrosine kinase, including a subset of inflammatory myofibroblastic tumors (IMT), neuroblastomas, non-Hodgkin’s lymphomas, and non-small cell lung cancer (NSCLC).61 IMT is a rare tumor with approximately 150-200 new cases per year in the United States and most commonly occurs in children and young adults.61 It is classified as a mesen- chymal neoplasm of intermediate biological potential, rarely metasta- sizing.62 Complete surgical resection has been the standard of care for IMTs, when feasible. However, there was no standard therapy approach for unresectable or metastatic IMTs until recently. Approx- imately 50% of IMTs have an ALK gene rearrangement and a smaller proportion have alterations in other kinases including ROS1, RET, and NTRK.63 The COG trial ADVL0912 evaluated the ALK inhibitor crizotinib in patients 1-21 years of age with relapsed/refractory ALK- positive anaplastic large cell lymphomas and metastatic or inoperable ALK-positive IMT. On this study, 12 of the 14 (86%) patients with an ALK-positive IMT had an objective response to crizotinib.64 Addi- tionally, on the PROFILE 1013 trial of crizotinib in adults, patients
Trk inhibitors in rare pediatric cancers
Multiple cancer type have fusions involving the NTRK1, NTRK2, or NTRK3 (NTRK) genes including, but not limited to, the rare pediat- ric cancers infantile fibrosarcoma, thyroid carcinomas, cellular congenital mesoblastic nephroma, and undifferentiated sarcomas.69 Infantile fibrosarcoma is a rare soft tissue sarcoma and nearly all cases are associated with an NTRK fusion, most commonly an ETV6:NTRK3 fusion. Surgery is the cornerstone of treatment for in- fantile fibrosarcoma and unresectable or metastatic cases have tradi- tionally been treated with vincristine and dactinomycin based chemotherapy. Recently, however, Trk inhibitors have changed the landscape of treatment of infantile fibrosarcoma and other tumors with NTRK fusions.70,71
Larotrectinib is a highly selective oral Trk inhibitor.72 Larotrectinib was evaluated in children and adults with NTRK fusion-positive can- cers, many of whom had refractory or relapsed disease, and resulted in a high response rate.73,74 These results led to the FDA approval of larotrectinib for children and adults with NTRK fusion-positive solid tumors. Recently, the COG study ADVL1823 reported the results of larotrectinib in children and young adults with newly diagnosed NTRK fusion-positive solid tumors. Patients with infantile fibrosar- coma had an ORR and 2-year EFS of 100% and 82.2%, respectively, and patients with other solid tumor types had an ORR and 2-year EFS of 73% and 80%, respectively.72
Repotrectinib is an oral tyrosine kinase inhibitor (TKI) with selective and potent activity against Trk, ROS1, ALK.75 The phase 1/2
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TRIDENT-1 trial of repotrectinib in adults with NTRK fusion-posi- tive solid tumors and ROS1 fusion-positive non-small cell lung can- cer (NSCLC) showed that patients had an ORR of 58% and 79%, respectively, in the TKI-naïve group and 50% and 38%, respectively, in the TKI-pretreated group.76,77 The ongoing CARE study (NCT04094610) is evaluating repotrectinib in children and young adults with malignancies with ALK, ROS1, or NTRK alterations. The interim results of these two ongoing trials led to the FDA approval of repotrectinib in patients 12 years and older with NTRK fusion-positive solid tumors. Further data from these trials will expand our knowledge about repotrectinib in younger children.
Entrectinib is an oral TKI with activity against TRK, ROS1, and ALK. In three phase 1 or 2 trials, ALKA-372-001, STARTRK-1, and STARTRK-2, adults with metastatic or locally advanced NTRK fusion-positive solid tumors received entrectinib at a dose of at least 600 mg once per day (the recommended phase 2 dose) and 31 of 54 (57%) patients had an objective response with median duration of response of 10 months.78 On the basis of these results, entrectinib was FDA approved for patients 12 years and older with NTRK fusion-positive solid tumors. The STARTRK-NG trial was a multi- center, international, phase 1/2 trial of entrectinib for patients <22 years of age with solid tumors with an ORR of 60% among patients with NTRK fusion-positive tumors and provided safety data in younger children.67
RET inhibitors in rare pediatric cancers
Alterations of the RET gene, an RTK, are seen in multiple pediatric cancer types and most notably in thyroid cancer.79 Papillary thyroid cancer (PTC) is a type of differentiated thyroid cancer (DTC) and approximately 10%-40% of cases have an RET alteration.79-81 While PTC is relatively uncommon in children, its incidence is increasing in both children and adults and it accounts for approximately 90% of cases of all thyroid cancer in children.82,83 The standard therapy for PTC cancer includes surgery, radioactive iodine (RAI) therapy, and thyroid hormone suppression.81 While survival outcomes of PTC are excellent, children with PTC more often present with advanced disease compared to adults and the majority of patients with lung metastases do not achieve a complete response with initial therapies.81,84 This has fueled interest in other therapies. RET alter- ations are also found in other follicular cell-derived thyroid cancers and in the vast majority of medullary thyroid cancers (MTC) although these account for few cases of thyroid cancer in children compared to PTC.
There are several drugs with activity against RET which are used in thyroid cancer. Multi-kinase inhibitors with RET activity were the initial drugs evaluated and approved in the treatment of thyroid can- cer with RET alterations. This includes sorafenib, lenvatinib, and ca- bozantinib which were FDA approved for the treatment of radioac- tive iodine refractory DTC and vandetanib which was FDA approved for progressive advanced MTC on the basis of trials which showed each of these agents resulted in improved PFS compared to pla- cebo.85-89 These FDA approved indications are limited to adults
with the exception of cabozantinib (which is approved in patients 12 years or older) although there is pediatric safety data for each of these agents.90-92 Additional multi-target kinase inhibitors, such as axitinib, pazopanib, regorafenib, and sunitinib have also showed ef- ficacy in thyroid cancer.80 However, agents with increased selectivity for RET may be more effective and have less toxicity. The LIBERTTO-001 phase 1/2 clinical trial evaluated the selective RET inhibitor selpercatinib in patients 12 years and older and resulted in an ORR and 1-year PFS 79% and 64%, respectively, in previously treated RET-fusion positive DTC.93 The phase 1/2 LIBRETTO-121 study evaluated selpercatinib in pediatric and adolescent patients and resulted in extension of FDA approval of selpercatinib to pa- tients 2 years and older with RET-altered thyroid cancer.94 There is an ongoing study evaluating selpercatinib prior to RAI therapy in children and adults with differentiated thyroid cancers with RET fusions (NCT06458036). Results of the phase 1/2 ARROW study of pralsetinib, another selective RET inhibitor, led to its FDA approval for patients 12 and older with radioactive iodine refractory RET-fusion positive thyroid cancer.95,96
BRAF/MEK inhibitors in rare pediatric cancers
BRAF alterations occur in melanoma and thyroid cancer and are also seen in other rare pediatric tumors including a subset of soft tissue tumors, gliomas, and Langerhans cell histiocytosis.97-101 Here, we focus on melanoma, thyroid cancer, and sarcomas. BRAF V600E mutations are seen in the majority of pediatric conventional mela- noma and BRAF fusions occur in Spitzoid melanomas.30,102 The treatment of melanoma in children with conventional melanoma is largely extrapolated from the adult experience. BRAF inhibitors have shown impressive efficacy in adults with BRAF V600E positive advanced melanoma and are given in combination with MEK inhib- itors to overcome resistance pathways. The combinations of dabra- fenib plus trametinib, encorafenib plus binimetinib, and vemurafe- nib plus cobimetinib are FDA approved for adults with unresectable or metastatic melanoma containing a BRAF V600E mu- tation.103-105 Additionally, approximately 30% of pediatric PTC have a BRAF V600E mutation.106,107 BRAF inhibitors and BRAF/MEK in- hibitor combinations have shown efficacy in BRAF V600E positive PTC and anaplastic thyroid cancer.108,109 The combination of dabra- fenib plus trametinib is FDA approved for children and adults 6 years and older with unresectable or metastatic solid tumors with a BRAF V600E mutation and BRAF/MEK inhibitors are often used in chil- dren with melanoma and thyroid cancers with BRAF mutations based on adult efficacy data and pediatric safety and dosing data.110
There is a recently recognized subset of pediatric mesenchymal neo- plasms with kinase alterations, including BRAF gene fusions.97,99-101 BRAF fusions are typically not responsive to first generation BRAF inhibitors.97 Thus, targeted therapy for these tumors typically in- volves MEK inhibitors which have shown efficacy although the number of cases are small.100,111 Next generation (paradox-breaking) and pan-RAF inhibitors have shown pre-clinical efficacy.112,113 Additionally, the pan-RAF inhibitor tovorafenib is being evaluated in children and young adults with advanced solid tumors with an
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activating RAF fusion in the ongoing FIREFLY-1 trial (NCT04775485). Arm 1 of the FIREFLY-1 trial included patients with relapsed/refractory BRAF-altered pediatric low grade glioma who had an ORR of 51% and these results led to the FDA approval of tovorafenib for patients 6 months and older with this diagnosis.114 When available, further results of this trial will provide key safety and efficacy data for tovorafenib in other RAF-fusion positive pediatric tumors.
Multi-target tyrosine kinase inhibitors in rare pediatric cancers
Multi-target tyrosine kinase inhibitors (MTKIs) are used in the treat- ment of multiple adult and pediatric cancer types. As discussed pre- viously, MTKIs have been used in thyroid cancer although there has been a more recent shift toward the study and use of selective kinase inhibitors in thyroid cancer. As also mentioned, several MTKIs have demonstrated clinical activity in ASPS including axitinib in combi- nation with pembrolizumab, pazopanib, sunitinib, and cabozanti- nib.49,115-126 These MTKIs are often used in the treatment of chil- dren with ASPS based on studies mainly limited to adults with ASPS and pediatric safety and dosing data in other cancer types.127-131 Furthering our understanding of the biology of ASPS would allow for better prioritization of TKIs in this disease. The MTKI pazopanib is also often used in the treatment of children with other non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) subtypes, typically in the setting of relapsed disease. This is largely based on pediatric safety and dosing data in various cancers and the results of the phase 3 PALETTE trial, which showed that pazopa- nib resulted a significantly improved median PFS compared to pla- cebo in adults with advanced soft tissue sarcoma (STS), which led to its FDA approval for this indication.127,132
MTKIs have been a key advancement in the treatment of gastrointes- tinal stromal tumors (GISTs). GISTs are mesenchymal neoplasms of the gastrointestinal tract which most commonly occur in older adults.133 About 1%-2% of cases of GISTs occur in children.134 The clinical presentation, biology, and behavior of pediatric and adult GISTs appear distinct. In adults, approximately 90% of cases of GISTs are associated with activating KIT or PDGFRA variants and a smaller proportion have what is referred to as wild-type GIST with inactivation of succinate dehydrogenase (SDH) (termed SDH-deficient) or other alterations including in BRAF and NTRK.135 In contrast, activating variants in KIT or PDGFRA are un- common in pediatric GISTs and pediatric GISTs are more commonly SDH-deficient.136 SDH downregulation often occurs via hypermethylation of the SDHC gene or inactivating mutations of SDHA, SDHB, SDHC, or SDHD and these distinct mechanisms may have potential therapeutic implications.137 Children have a higher frequency of multifocal gastric tumors and metastatic disease although often have an indolent disease course.134,138 Given the rar- ity of pediatric GIST, treatment is informed by the adult literature and recognition of the unique features of pediatric GISTs. The treat- ment of GIST includes surgery and systemic therapy may be indi- cated is based on risk of recurrence, presence of advanced or meta- static disease, and the molecular profile of the tumor.134,135 Children
with KIT- or PDGFRA-altered GIST for whom systemic therapy is indicated are treated similar to adults with imatinib as first line, su- nitinib as second line, regorafenib as third line, ripretinib as forth line for most patients and avapritinib for those with as PDGFRA D842V mutations.134,135 When indicated, the optimal approach to systemic treatment for SDH-deficient pediatric GIST is not clear although sunitinib may be considered as frontline.134,139
Combination immune checkpoint inhibitors and molecular therapies
Several trials have evaluated triple combinations of BRAF/MEK in- hibitors and ICI in adults with melanoma and the combination of atezolizumab, cobimetinib, and vemurafenib is FDA approved in adults with unresectable or metastatic melanoma.140 These ap- proaches may be of particular consideration in certain subsets of pa- tients with melanoma such as those at risk of rapid disease progres- sion. However, data on triple combination therapy is lacking in pediatrics and it is critical to enroll pediatric patients on triple com- bination trials to assess their efficacy and toxicity profiles in children and elucidate their role in children with melanoma.
Peptide receptor radionuclide therapy
Peptide receptor radionuclide therapy (PRRT) is a treatment that al- lows for the targeted delivery of radiation to tumor cells.141 The development of PRRT has been a key advancement in the manage- ment of gastroenteropancreatic neuroendocrine tumors (GEP- NETs). GEP-NETs are rare tumors that arise in a tubular part of the gastrointestinal system or in the pancreas and may be functional (hormone secreting) or non-functional.142 They may occur sporad- ically or in the setting of genetic predisposition syndromes, such as multiple endocrine neoplasia type 1 syndrome, von Hippel-Lindau disease, tuberous sclerosis, and neurofibromatosis.143,144 While the incidence of GEP-NETs has increased over the past several decades, they remain rare and the vast majority of cases occur in adults. 145
The PPRT LUTATHERA (177Lu-DOTATATE) is used in the treat- ment of GEP-NETs. LUTATHERA contains the radioactive beta particle emitting isotope lutetium-177, a chelating molecule DOTA, and a somatostatin analogue octreotate (TATE). After being administered intravenously, LUTATHERA binds to tumor cell membrane somatostatin receptors (SSR) allowing for its internaliza- tion and the intracellular decay of lutetium-177 which results in DNA damage and tumor cell death.146 The NETTER-1 trial was a phase 3 trial which evaluated 229 adults with advanced, progressive, somatostatin-receptor-positive (SSTR+) midgut neuroendocrine tu- mors treated with lutathera and long acting release octreotide injec- tions versus double-dose long acting release octreotide alone. This study showed statistically significant improved PFS and clinically meaningful trend for improvement in median overall survival rate in the LUTATHERA group. 147,148 The results of the NETTER-1 trial led to the FDA approval of LUTATHERA in adults with SSTR+ GEP-NETs in 2018. Subsequently, the NETTER-P trial evaluated pharmacokinetic, dosimetry, and safety of LUTATHERA in patients 12-17 years of age with GEP-NETs and paragangliomas. Based on
Review
the results of the NETTER-P study and the prior efficacy outcomes in NETTER-1, the FDA approved indication for LUTATHERA was expanded in 2024 to include patients 12 years or older with SSTR+ GEP-NETs.149
Challenges in drug development for rare pediatric cancers and potential solutions
There are several unique challenges to the study of rare pediatric can- cers. For cancer types seen in both children and adults, much may be learned from the study of adults but potential inherent differences in the biology of a disease in children versus adults may limit the appli- cability to children. In rare diseases, patient accrual can be limited and/or lengthy, making it difficult or impossible to conduct well powered and efficient studies. Additionally, limited resources may result in de-prioritizing the opening of studies which are expected to have low enrollment, further compounding patient accrual chal- lenges. While there are incentives for orphan drug development, the high cost of drug development and low return on investment in rare diseases remain key challenges.
Collaboration is critical to accelerate progress in rare pediatric can- cers and facilitate rapid and adequate patient accrual on clinical tri- als. Multi-institutional collaboration may be facilitated by large consortia such as COG which leads clinical trials for a broad spec- trum of pediatric and young adult cancers. Collaborative efforts be- tween COG and national/multinational adult consortia may facili- tate accrual in cancer types which bridge the pediatric, adolescent, and young adult populations. Examples of this include the joint COG and National Research Group (NRG) Oncology trial ARST1321 which evaluated pre-operative radiation with or without chemotherapy and/or pazopanib in children and adults with NRSTS and the forthcoming joint Alliance and COG trial, NCT06900595, which will evaluate cemiplimab and cabozantinib in adolescents and adults with metastatic or recurrent ACC. Pedi- atric consortia such as the Pediatric Neuro-oncology Consortium (PNOC) and Sunshine Project may facilitate clinical trials in spe- cific cancer subtypes.
In rare cancers, collaboration not only includes formal consortia but also collaborative efforts beyond traditional trial consortia. The Na- tional Institute of Health Pediatric and Wildtype GIST clinic is a yearly event and involves collaboration of clinicians, researchers, pa- tients and patient advocates to advance the care and knowledge or pe- diatric GIST. Groups such as the International Pediatric Adrenocor- tical Tumor Registry, the International Pleuropulmonary blastoma (PPB)/DICER1 Registry, European Cooperative Study Group for Pe- diatric Rare Tumors (EXPERT), the European Pediatric Rare Tumors Network-European Registry (PARTNER) project for very rare tu- mors in children, and the International Non-rhabdomyosarcoma Soft Tissue Sarcoma Consortium (INSTRUCT) represent key global collaborative groups advancing pediatric rare cancer research.
Given the rarity and clinical and biologic heterogeneity of certain tu- mor types/subtypes, innovative clinical trial designs such as basket or
umbrella trials may be needed. In some tumor types, additional bio- logic/molecular, risk stratification, and natural history studies may first be needed to lay the groundwork for future clinical trials. As an example, for ACC, data from the International Pediatric Adreno- cortical Tumor Registry showed distinct methylation patterns with prognostic significance which will be key to risk stratification in future clinical trials.
Pleuropulmonary blastoma (PPB) is a rare lung tumor seen primarily in infants and very young children. As mentioned previously, the In- ternational PPB (now PPB/DICER1) Registry was founded in 1987 to study this rare tumor and has led to elucidation of the genetic basis of a spectrum of pediatric tumors, development of targeted surveillance guidelines and development of preclinical models. Data from the Registry facilitated the first-ever truly prospective trial for PPB, COG trial ARAR2331 (NCT06647953), which activated in March 2025. In addition, the Registry hosts annual scientific symposia and family meetings to bring together researchers, clinicians, pa- tients, and caregivers to share research updates and strategies and educational resources for clinicians, patients, and families.
In rare and common cancers, collaboration is needed not only be- tween clinicians and researchers across institutional and oceans but also with patients and families. Strategic insights and support from patient advocates, navigators and advocacy groups are key components of both research advancements and translation to improved clinical outcomes. Involvement of patient advocates early in the development of clinical trials is critical to optimize protocol design for feasibility and to align with patient priorities and is key in facilitating patient awareness and accrual. Additionally, patient advocates play a key role in shaping healthcare policy and funding priorities.
Conclusions
Despite the challenges to drug development, there have been several recent key advances in the treatment of multiple rare pediatric cancer types. This includes the use of ICI in children with MSI-high and MMRD tumors, melanoma, and ASPS which has been largely extrapolated from the adult literature. There is an ongoing prospec- tive study of ICI with chemotherapy in pediatric NPC and encour- aging, although limited, data in ACC warranting further study. Pedi- atric focused trials have resulted in FDA approvals of the NTRK inhibitors larotrectinib, entrectinib, and repotrectinib for children and adults with solid tumors with NTRK fusions and the ALK inhib- itor crizotinib in children and adults with ALK positive IMT, chang- ing the landscape of the treatment of these diseases. The selective RET inhibitors selpercatinib and pralsetinib are now FDA approved for adolescents and adults with RET altered thyroid cancer and there is an ongoing study of selpercatinib and RAI therapy in children with RET fusion positive DTC which will generate further data to guide treatment of these patients. Finally, a clinical trial in adults followed by a pediatric-specific clinical trial led to the approval of LUTATHERA for adolescents and adults with SSTR+ GEP-NETs, a novel treatment approach for this rare tumor.
Review
Further work is needed to continue to advance our understanding of the biology of pediatric rare cancers and to develop novel treatment approaches. Successful drug development for rare tumors requires pediatric specific research efforts, collaborative studies in children and adults, and global collaborations. These efforts have been championed by organizations including the COG, rare tumor regis- tries such as the International PPB/DICER1 Registry, and patient ad- vocates who will all be critical to continued progress.
ACKNOWLEDGMENTS
J.N.C. and T.W.L. receive support from an Alex’s Lemonade Stand Foundation Center of Excellence in Childhood Cancer Drug Development grant. J.N.C. also receives support from a Penn Medicine Abramson Cancer Center Clinical Scientist Scholar grant and an Early Career Clinical Investigator Award awarded by the National Cancer Institute Coordinating Center for Clinical Trials through a supplement to P30CA016520. T.W.L. receives support from the National Cancer Institute of the National Institutes of Health award 1R50CA305079 and the US Department of Defense Translational Team Science award W81XWH-22-1-0654. K.A.P.S. receives support from National In- stitutes of Health R37CA244940. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors are deeply grateful to our patients and their families and for the opportunity to investigate rare pediatric cancers.
AUTHOR CONTRIBUTIONS
Conceptualization, supervision and project administration: T.W.L; investigation: J.N.C., U.D., and K.A.P.S .; visualization: J.N.C .; writing - original draft and review and editing: J.N.C., U.D., R.D.G., K.A.P.S., and T.W.L.
DECLARATION OF INTERESTS
T.W.L participates in consulting/advisory boards for Advanced Microbubbles, AI Ther- apeutics, Bayer, GSK, ITM Oncologics, and Jazz Pharmaceuticals, and receives research support to his institution from Bayer, Pfizer, Eli Lilly, and Exelixis.
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