Sustained response to larotrectinib in a pediatric patient with recurrent STRN3::NTRK2 fusion-positive pilocytic astrocytoma

Recently, I was discussing the treatment of a pediatric patient who had gliomatosis cerebri. A pediatric neuro-oncologist, one of my respectable friends, insisted on chemotherapy with temozolomide. Because the histologic type was anaplastic astrocytoma (as determined by open biopsy), many would consider radiotherapy the primary option; thus, there was an exciting discussion. On another occasion, the same colleague and I were discussing a pediatric patient with a symptomatic diffuse astrocytoma of the posterior thalamus; this time as well, he insisted on a trial of chemotherapy with carboplatin and vincristine. My colleague's philosophy is that because pediatric gliomas are different from adult gliomas, chemotherapy to defer or avoid radiotherapy is reasonable in cases of low-grade and sometimes even high-grade glioma. Maybe my colleague is right regarding the difference between pediatric and adult gliomas. There have been numerous reports showing substantial differences in the molecular features underlying pediatric and adult high-grade gliomas. Pediatric and adult glioblastomas were shown to be clearly distinguished by frequent gain of chromosome 1q and lower frequency of chromosome 7 gain and 10q loss in the pediatric form. Platelet-derived growth factor receptor-α (PDGFR-α) was found to be the predominant gene subject to focal amplification in childhood high-grade gliomas.1,2 Among the pediatric low-grade gliomas, pilocytic astrocytoma is the predominant histologic type and diffuse astrocytomas are quite rare. In this issue of Neuro-Oncology, Stokland et al. from the Children's Brain Tumour Research Centre, University of Nottingham, UK, report on 639 pediatric patients with low-grade gliomas, 63.7% of which were pilocytic astrocytomas and only 5.9% of which were diffuse fibrillary astrocytomas.3 The predominance of the former type is consistent with other evidence. For instance, in the Brain Tumor Registry of Japan, the incidence of pilocytic astrocytomas peaks in patients between 5 and 9 years old, while that of diffuse astrocytomas peaks in patients between 40 and 44 years old. In the Central Brain Tumor Registry of the United States (CBTRUS), 1,834 pediatric patients (those between 0 and 19 years old) with pilocytic astrocytomas are registered, while only 101 cases of diffuse astrocytoma are found in the pediatric population. Therefore, pediatric low-grade gliomas are mostly pilocytic astrocytomas, and adult low-grade gliomas are mostly diffuse astrocytomas. Pilocytic astrocytomas and diffuse astrocytomas are classified as WHO grades I and II, respectively. However, pilocytic astrocytoma is not a precursor of diffuse astrocytoma, as there is a distinct difference between the molecular features of the two. There appears to be no role for either TP53 mutations or aberrant PDGF signaling in the development of pilocytic astrocytomas, in contrast to the role of TP53 mutations and increased expression of PDGF-A and PDGFR-α as common, early events in the formation of diffuse astrocytomas.4 Pilocytic astrocytomas also differ from diffuse astrocytomas in their altered and increased expression of immune response genes. Hierarchical clustering analysis using a set of 1,176 genes distinguished pilocytic astrocytomas from diffuse astrocytomas and oligodendrogliomas.5 Pilocytic astrocytomas are also different from the diffuse astrocytomas clinically, as evidenced by the fact that histology is one prognostic factor in pediatric low-grade gliomas.3 Fear of radiation-induced adverse effects has been used to justify the use of chemotherapy for unresectable pilocytic astrocytomas. A number of chemotherapy regimens have been used to delay the need for radiotherapy, including carboplatin and vincristine. A recent randomized trial, Children's Oncology Group A9952, compared the combination of carboplatin and vincristine with the combination of procarbazine, thioguanine, lomustine, and vincristine and reported 5-year event-free survival rates of 40%-50%. More than 400 low-grade gliomas were registered, and 83% of them were pilocytic astrocytomas.6 However, although a small study is under way, the role of chemotherapy in the management of pediatric diffuse astrocytomas remains unclear. In adult diffuse astrocytomas, a randomized study comparing radiotherapy and temozolomide is now ongoing in Europe and North America. Yes, pediatric and adult gliomas are different. Pediatric and adult high-grade gliomas are biologically different. On the other hand, differences between pediatric and adult low-grade gliomas are mainly due to the difference in their histologies. Whether pediatric diffuse astrocytomas are chemosensitive remains unproven. The UK study reported in this issue also suggests that, because of the small number of diffuse astrocytomas in the pediatric population, international cooperation will be needed to address the issue of the optimal management of this entity.

Background: Larotrectinib, a selective TRKi, is now FDA approved for pediatric and adult TRK-fusion solid tumors, regardless of tumor origin. Emergent TRK kinase mutations are a common mechanism of resistance to TRKis. LOXO-195, a selective TRKi, was developed to maintain potency against multiple TRK kinase domain mutations. Methods: Patients (pts) received LOXO-195 via a Phase I study (NCT03215511, n=20) or FDA expanded access single patient protocol (SPP, n=11). Eligible pts were ≥4-weeks old with a locally identified TRK fusion and had progressed or were intolerant to at least 1 priorTRKi. Parallel 3+3 dose escalations were pursued in adults and children, with intra-patient dose escalation permitted based on tolerance and pharmacokinetics. Pts aged <12 received BSA-adjusted doses. Results: As of 03-DEC-2018, a total of 31 TRK-fusion pts (7 children, 24 adults) with 11 cancer types had been treated. Median duration on last prior TRKi was 9.5 months (range, 2-30). In the Phase 1, doses of 32 mg QD to 150mg BID were explored, and TEAEs (all grades/cause, in >3 pts) were dizziness/ataxia (65%), nausea/vomiting (50%), anemia (30%), myalgia, abdominal pain, fatigue, & lymphopenia (all 20%). Five Phase I pts (all adults) had DLTs: ataxia/dizziness (4), and ataxia/vomiting (1). For the SPPs: 1 pt dose-reduced and none discontinued for a TEAE. Cmax at doses ≥50 mg exceeded the predicted IC50 for TRK kinase mutations. Pretreatment tissue and/or plasma, as available, defined TRK kinase mutation status. Preliminary efficacy overall, and by TRK kinase mutation status, is shown in the Table. Discussion: LOXO-195 had preliminary efficacy in pts with resistance to prior TRKi mediated by TRK kinase mutations. The subset of pts who develop TRK-independent resistance are unlikely to benefit from LOXO-195. Dose selection is ongoing in both children and adults. Confirmed best overall response, all dose levels, investigator assessed per RECIST 1.1 (n=29≠)Patient CohortTotal Patients,nCR/PR, nStable Disease, nPD, nNon- evaluable, †nORRTRK Kinase Mutation20963245% (9/20)Solvent Front14742150% (7/14)Gatekeeper4111125% (1/4)xDFG2110050% (1/2)Identified bypass300210% (0/3)Other/ Unknown*61#31117% (1/6)Overall291096434% (10/29)≠ 2 pts still on study drug and awaiting 1st response assessment not included in Table.† 4 pts non-evaluable: 1 discontinued drug for unrelated new cancer diagnosis <28 days after start of study drug and 3 withdrew within 14 days of study drug start.* Includes 1 pt with no identified TRK kinase resistance mutationor bypass alteration# and 5 pts who could not be tested.# Pt intolerant but not resistant to prior TRKi Citation Format: David Hyman, Shivaani Kummar, Anna Farago, Birgit Geoerger, Morten Mau-Sorensen, Matthew Taylor, Elena Garralda, Ramamoorthy Nagasubramanian, Michael Natheson, Lucy Song, Michael Capra, Mette Jorgensen, Alan Ho, Neerav Shukla, Steve Smith, Xin Huang, Brian Tuch, Nora Ku, Theodore W. Laetsch, Alexander Drilon, David Hong. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT127.

The role of the pediatrician is crucial in both the diagnosis and management of pediatric brain tumors, the most common solid tumor of childhood. Awareness of the presenting signs and symptoms of brain tumors can lead to timely diagnosis, and understanding the late effects of brain tumor treatment improves long-term management of childhood brain tumor survivors.After completing this article, readers should be able to: Recognize the presenting symptoms and physical examination findings suggestive of a childhood brain tumor and how these findings depend on tumor location.Review common brain tumor pathologies affecting children.Understand how molecular genetics plays a role in the diagnosis and treatment of childhood brain tumors.Recognize the late affects associated with the treatment of childhood brain tumors.Brain tumors are the most common solid malignancy in children and represent the leading cause of pediatric cancer-related deaths. Five thousand new brain tumors are diagnosed yearly in the United States in children ages 0 to 19 years, with an incidence of approximately 6 per 100,000 children. (1) Childhood brain tumors, more than half of which are malignant, vary in terms of biology, prognosis and treatment. Presenting signs and symptoms depend on tumor location, growth rate, and presence of obstructive hydrocephalus. Making the initial diagnosis of a brain tumor can be difficult because early symptoms, such as headaches or vomiting, are nonspecific to brain tumors and more frequently are associated with other etiologies, leading to delays in diagnosis. The pediatrician plays a crucial role in the timely diagnosis of patients with brain tumors as well as recognizing late effects resulting from tumor therapies. This review summarizes the presenting features on history and physical examination, tumor classification of common tumor types, genetic brain tumor predisposition syndromes, general management strategy, and late effects of therapy.Signs and symptoms of a pediatric brain tumor can be nonspecific, insidious, intermittent, and dependent on location within the central nervous system (CNS) and the anatomical pathways affected. Although headache is the most common presenting complaint overall, it is present in only approximately one-third of the children presenting with brain tumors, and, in the absence of other symptoms or physical examination findings, is not in itself predictive of a brain tumor. Elevated intracranial pressure (ICP) is present in approximately half of all children with brain tumors. In addition to headache, it can cause nausea/vomiting, abnormalities of gait and coordination, and papilledema. Vital sign abnormalities associated with increased ICP, known as the Cushing triad (bradycardia, hypertension, abnormal respirations), are late signs of acutely increased ICP but can be absent in those with chronically elevated ICP. In young children with an open fontanelle, macrocephaly, especially when progressive, can be suggestive of hydrocephalus and a potential mass-occupying lesion. (2)Presenting symptoms depend on tumor location (Fig 1), and certain constellations of symptoms can point to specific lesion locations. Table 1 lists commonly overlooked signs and symptoms that can lead to a delayed diagnosis. Wilne et al analyzed presenting features of more than 4,000 childhood brain tumors and found that for posterior fossa tumors, three-quarters presented with nausea and vomiting, two-thirds with headache, three-fifths with abnormal gait and coordination, and one-third with papilledema. (2) In contrast, headache, nausea, and vomiting were rare in patients presenting with supratentorial tumors. Instead, seizures were present in one-third of patients, along with focal neurologic deficits such as weakness or sensory deficits on the contralateral side if there is involvement of the cortical motor or sensory regions, respectively. (2) In cases of brainstem tumors, children can present with crossed findings of ipsilateral facial weakness and contralateral hemiparesis. More than 75% of patients with brainstem tumors present with abnormal gait and coordination, whereas cranial nerve (CN) palsies are present in more than half. Headache, however, is not common in patients with brainstem tumors and is present in less than one-quarter at the time of diagnosis. Thalamic tumors can cause coordination and motor difficulties or hemiplegia. (2)Patients with pituitary tumors or optic pathway tumors often present with visual deficits. It is not uncommon for even severe visual deficits in children to go unrecognized by the patient, parents, or pediatrician. (3) Because patients with neurofibromatosis (NF) type 1 are at increased risk for optic pathway glioma, they should have yearly ophthalmology evaluations. Children with pituitary or hypothalamic tumors often present with endocrine abnormalities, such as failure to thrive, excessive thirst, or central obesity.Children with spinal cord tumors most commonly present with back pain, present at diagnosis in approximately two-thirds of cases. Spinal cord tumors may occur in extradural, intramedullary, and extramedullary intradural locations. Although some children may present with scoliosis, most will not. Spinal cord compression causes signs such as gait and coordination abnormalities, focal weakness, or bowel and bladder dysfunction. (2)A comprehensive neurologic examination (summarized in Table 2) is crucial to identify abnormalities that might be suggestive of a CNS tumor. A normal neurologic examination does not exclude the diagnosis of a brain or spinal cord tumor and must be correlated with symptoms.Patients with acute hydrocephalus can display dramatic changes in their mental status, with increased sleepiness, decreased energy, and decreased responsiveness. However, those with chronic hydrocephalus might show only subtle signs, such as slowly declining school performance.A fundoscopic examination of the optic nerve, CN II, is crucial to assess for papilledema and optic nerve pallor, which can reveal information about hydrocephalus or tumors along the optic pathways. A fundoscopic examination can be difficult in young or uncooperative children, warranting referral to ophthalmology for a dilated examination. Vision should be assessed by confrontation in the 4 quadrants of each eye because different patterns of visual field deficits will suggest varying tumor locations. In younger children, assessment of visual fields can be performed using a colorful object for central fixation and introducing a second object in the periphery and watching for the eyes to track to that object.Eye movements are controlled by CNs III, IV, and VI. The nuclei of CNs III and IV are located in the midbrain, whereas the nucleus of CN VI is in the pons, and brainstem tumors can lead to abnormalities of extraocular movements. Large pineal tumors can cause Parinaud syndrome, characterized by upgaze palsy, convergence-retraction nystagmus, and poorly reactive pupils due to compression of the rostral midbrain. Nystagmus can also be seen in patients with cerebellar tumors or optic pathway tumors.CN V, the trigeminal nerve, has 3 divisions that give sensation to the face. The trigeminal nucleus is located in the pons, as is the nucleus of CN VII (the facial nerve), which controls facial movement. Facial asymmetry or decreased facial sensation should raise concern for a mass in this region. Hearing in each ear should be assessed to look for CN VIII dysfunction.The lower CNs (CNs IX, X, XII) exit from the medulla and are involved in phonation, swallowing, and tongue movement. Palatal asymmetry, change in voice quality, or unilateral glossal atrophy raises suspicion for a medullary lesion. CN XI, the accessory nerve, has the most distal nucleus, also in the medulla, and innervates the trapezius and sternocleidomastoid musculature.Motor function, sensation, and reflexes should be assessed with special attention to comparison with the contralateral findings. Asymmetry can indicate a lesion affecting corticospinal tracts (motor), spinothalamic tracts (temperature, pain, light touch), or dorsal columns (proprioception, vibratory sense). Asymmetrical hyporeflexia can indicate lower motor neuron injury, whereas hyperreflexia and the presence of a Babinski reflex are indicative of upper motor neuron dysfunction. In acute upper motor neuron injury, reflexes may be absent.Patients with cerebellar tumors can present with a wide-based ataxic gait and difficulty with tandem gait. A hemiparetic gait can suggest a tumor involving cortical motor areas, the thalamus, or the brain stem. Patients with cerebellar or brainstem tumors may exhibit abnormal coordination, elicited by testing rapid alternating movements, finger to nose testing, or finger (pointer to thumb) and toe tapping (on the floor) or asking a child to mirror the examiner's finger as the examiner moves the finger laterally and/or vertically.Although not technically part of the neurologic examination, a skin examination is important to assess for dermatologic manifestations of underlying tumor predispositions such as NF type 1 (predisposed to low-grade gliomas [LGGs], especially in optic pathways), NF type 2 (predisposed to acoustic schwannomas and meningiomas), tuberous sclerosis complex (predisposed to subependymal giant cell tumors), or, more rarely, constitutional mismatch repair deficiency syndrome. Patients with constitutional mismatch repair deficiency syndrome have a genetic defect in genes responsible for repairing a specific type of DNA damage known as mismatch repair. Abnormalities in these genes (MLH1, MSH2, MSH5, PMS2) make it more difficult for the body to repair normally occurring DNA damage, leading to mutations and predisposing these patients to many types of cancers at an early age, including brain tumors, most commonly high-grade gliomas (HGGs). (4)The child with a suspected brain tumor might require urgent interventions. Those with unstable vital signs, altered mental status, or concern for increased ICP warrant expedited evaluation, best managed initially in the emergency department. Although magnetic resonance imaging (MRI) with and without contrast is the gold standard imaging technique for optimal visualization for brain tumors and is often needed for neurosurgical planning, in the unstable child, a computed tomographic (CT) scan may be the best initial imaging choice. CT scans can provide information regarding acute hydrocephalus, impending herniation, or acute hemorrhage, all of which represent neurosurgical emergencies. They can also show the anatomical location of a mass, lesion size, presence of hydrocephalus, and whether the mass is compressing other brain structures, thereby helping to triage and plan a timeline for MRI, surgery, or other sedated procedures. When choosing the optimal initial imaging study for a young child who would require anesthesia to complete an MRI, the relative risks of anesthesia compared with the risk of exposure to ionizing radiation from a CT scan, which could be completed without sedation, must be weighed while taking into account the degree of suspicion for an abnormality and individual risk factors specific to that patient. (5)MRI with and without contrast is generally the preferred imaging modality for diagnosis and follow-up of brain tumors. MRI allows for more detailed characterization of the tumor itself and the surrounding anatomy, with more specialized sequences for visualization of edema, relationship to CNs, blood vessels, and perfusion. Furthermore, MRI does not expose children to ionizing radiation so is preferred over CT for repeated studies, as would be needed to follow a brain tumor. Most patients with a brain tumor require a spinal MRI to evaluate for evidence of leptomeningeal disease.When a diagnosis of a brain tumor is made based on imaging, in the absence of a neurosurgical emergency, patients should be managed in concert with neuro-oncology teams preoperatively. Early neuro-oncology consultation allows for additional baseline neurologic examination, can help inform surgical planning based on the working differential diagnosis and postoperative treatment options, and facilitates an opportunity for clinical trial enrollment where presurgical consent may be required.The care of the pediatric neuro-oncology patient requires a multidisciplinary team–based approach. In addition to an excellent primary care pediatrician, this team includes neuro-oncology, neuro-surgery, neurology, neuro-radiology, radiation oncology, genetics, endocrinology, ophthalmology, audiology, neuropsychology, physical medicine and rehabilitation, palliative care, and social work.Upfront treatment of pediatric brain tumors generally includes surgery, radiotherapy, chemotherapy, or a combination of these modalities. For most tumor types, maximal safe surgical resection is pursued to obtain diagnosis and as the first step in definitive treatment. Some notable exceptions to this include tumors in eloquent locations where resection would result in significant morbidity or mortality. These locations include the brain stem, optic pathways, thalamus, internal capsule, sensory and motor cortices, visual cortex, or Broca and Wernicke areas, which are important for receptive and expressive language. In some cases, a small needle biopsy of these areas can be performed to obtain tissue for diagnostic purposes. For germ cell tumors, tumor markers can be diagnostic, obviating the need for upfront surgery. Some patients with low-grade–appearing lesions are followed with observation alone.Although some low-grade tumors can be treated with resection only, many low-grade and most high-grade tumors require additional postsurgical treatment. The standard of care for postsurgical management of pediatric brain tumors is constantly evolving based on emerging preclinical and clinical data. In many cases, enrollment in an open clinical trial is considered the standard of care. There are a variety of clinical trial consortia and cooperative groups with open protocols focused on pediatric brain tumors. A complete list of open clinical trials can be found on clinicaltrials.gov.There are more than 30 unique pathologies of CNS tumors in children. MRI characteristics of some common childhood brain tumors are shown in Fig 2. The advent of molecular genetics has enhanced our understanding of the biologic behavior of brain tumors, has changed tumor classification systems, and has had treatment implications.Medulloblastoma is the most common malignant brain tumor in children and is of embryonal origin. It generally presents as a posterior fossa mass and, due to its location, is often associated with obstructive hydrocephalus. Staging includes an MRI of the spine and a lumbar puncture looking for malignant cells in the cerebrospinal fluid (CSF). Histologically it is classified as classic, large cell anaplastic, or nodular desmoplastic. Overall, medulloblastoma has 5-year overall survival (OS) of approximately 70%. (6)Treatment depends on age at presentation, extent of resection, and presence of metastatic disease. Recent trials are accounting for molecular subtype in treatment decisions. Generally, treatment involves maximal tumor resection, craniospinal radiotherapy, and chemotherapy. Young patients undergo high-dose chemotherapy with autologous stem cell rescue to avoid or delay irradiation.Medulloblastoma has been classified into 4 principle molecular subgroups: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4 (Table 3). (7) WNT-driven medulloblastomas are rarely metastatic and have the best overall prognosis, with greater than 90% OS. Current clinical trials are focused on reducing therapy in this subtype. SHH-driven tumors have a bimodal distribution presenting most commonly in infants or adolescents and young adults. They have an intermediate prognosis, although association with p53 mutations portends a poor prognosis. (9) Group 3 and group 4 tumors are known as non-WNT, non-SHH medulloblastoma subtypes. Although immunohistochemical studies can differentiate WNT and SHH medulloblastoma from the non-WNT and non-SHH medulloblastoma subtypes, other molecular methods, such as methylation studies, are needed to distinguish group 3 from group 4 tumors. Group 3 tumors can present in very young children, often have MYC amplification, are commonly metastatic at presentation, and have the poorest outcomes overall of any subgroup. Recent data suggest that group 3 tumors might benefit from intensified chemotherapy concurrent with radiotherapy. Group 4 tumors are the most common subgroup overall, presenting in children and adults and, similar to group 3 tumors, more commonly present in males than in females. (7) Group 4 tumors have an intermediate prognosis.Atypical teratoid rhabdoid tumors (ATRTs) are also embryonal tumors but can present in the posterior fossa or supratentorial region. These tumors have a very poor prognosis, with 3-year OS of approximately 25%. Survival trends improve with older age at diagnosis, with those older than 3 years faring better than younger patients. (10) Histologically, the loss of INI1, encoded by SMARCB1, is pathognomonic. Up to 35% of patients with ATRT have a germline mutation in SMARCB1 (or rarely SMARCA4), which predisposes them to the development of malignant rhabdoid tumors in other locations, most commonly the kidneys. Germline variants are more common in younger patients, and approximately two-thirds are sporadic. (11)Staging includes MRI of the brain and spine and lumbar puncture for CSF cytology. Treatment involves surgical resection, radiotherapy, and chemotherapy, with or without triple tandem autologous stem cell transplant. Recent clinical trial data showed improved survival outcomes compared with historical controls achieved with a regimen including radiotherapy for patients as young as 6 months and 3 cycles of high-dose chemotherapy with autologous stem cell rescue for all patients. (12) A meta-analysis including 130 patients with ATRT saw that survival correlated most strongly when patients were treated with regimens that included high-dose chemotherapy with autologous stem cell rescue. Treatment modalities of radiotherapy and intrathecal chemotherapy also lead to a statistically significant improvement in OS in this cohort. (10)ATRT tumors have also been classified based on molecular characteristics into 3 subgroups: ATRT–tyrosine (ATRT-TYR), ATRT–sonic hedgehog (ATRT-SHH), and ATRT–myelocytomatosis oncogene (ATRT-MYC), but further research is needed to delineate the prognostic and clinical implications of these subgroups. (13)Ependymoma represents the third most common brain tumor in children and arises from the ependymal cells lining the ventricles or the central canal of the spinal cord. Two-thirds of ependymomas present in the posterior fossa, with the remainder in the supratentorial region or spinal cord. For pediatric ependymoma as a whole, OS at 10 years is approximately 64%, but cases achieving gross total resection followed by radiotherapy fare significantly better. Molecular subtype and gain of chromosome 1q has important prognostic implications as well. (14)Ependymoma is treated with maximal surgical resection followed by focal radiotherapy, except for spinal disease, in which gross total resection without adjuvant radiotherapy can be curative. The role of chemotherapy in ependymoma remains under clinical investigation. Studies have also explored the use of postoperative chemotherapy to delay or omit radiotherapy in patients younger than 3 years, but outcomes were inferior to regimens involving radiotherapy for children older than 12 months. (15)Ependymoma has been divided into 9 molecular subgroups, with 3 subgroups for each anatomical location: spinal, supratentorial, and posterior fossa. Only 6 of the molecular subtypes generally affect children. Pediatric ependymoma of the spine is divided into the subtype and the subtype spinal subtypes have a prognosis. In the posterior fossa, patients with have a prognosis than those with and in the supratentorial those with have OS than those with and are associated with OS less than and survival of approximately are a group of tumors that including tumors the most tumors as and tumors When represent the most common brain tumor in children and can present in many anatomical locations. are less to to other of the CNS than their malignant and in some cases gross total resection can be curative. However, resection is not in certain anatomical locations, such as in the brain stem or with optic pathway common in patients with NF type have a prognosis, with OS of and survival of in a study of with follow-up of when therapy is needed for the regimen of chemotherapy with or and although other chemotherapy regimens have as well. is not in the upfront management of due to for late of the molecular of has that most are by in the most commonly variants and NF type 1 have shown pediatric and have shown in tumors. contrast to pediatric have a prognosis. include high-grade tumors brainstem tumors and of pediatric is tumors may be to surgical is followed by radiotherapy and chemotherapy for these tumors, as a Group study showed improved survival when chemotherapy to radiotherapy compared with radiotherapy specific chemotherapy regimen has as a standard of care for upfront pediatric In contrast, for tumors such as glioma, chemotherapy to radiotherapy has not been shown to survival the to OS and the OS achieved with radiotherapy open based and clinical trials are patients, to improve outcomes for these patients. studies in pediatric that the of pediatric from that of mutations and in tumors, and in tumors, the of in pediatric and a poor prognosis. are from in older children, with significantly improved are more common in children younger than 1 and under are germ cell tumors represent approximately of pediatric brain tumors and are as and germ cell tumors They most commonly in the pineal region but can also present in the thalamus, or or or both or which can be in blood and/or can cause of in the CSF but not In some cases, diagnosis can be made based on CSF and tumor whereas biopsy is when tumor markers are have a better overall prognosis, with OS greater than 90% compared with to for are commonly treated with 4 cycles of chemotherapy followed by radiotherapy to the tumor and whereas are generally treated with 6 cycles of chemotherapy alternating with and craniospinal radiotherapy in many cases, although studies are whether radiotherapy can be in patients with to associated with craniospinal radiotherapy. is a tumor from the of the and solid Histologically, they are classified as tumors and are divided into and subtypes. to their location they can and treatment for is some a more neurosurgical in an to avoid radiotherapy, and an initial resection followed by upfront radiotherapy. are germline mutations that children to specific types of childhood brain tumors in the of tumor predisposition of these is important to the primary care who follow these patients In the child who presents with a brain especially in the of other history of tumors, history of tumors at a young age, or dermatologic findings, it is important to further for these predisposition Children with a known history of predisposition might require genetic for the presence of these syndromes, and specific tumor if found to of these Furthermore, the presence of certain underlying may the of therapy for the management of a brain tumor. Table 4 summarizes germline associated with specific brain tumor the treatment of different tumor types each of the commonly treatment modalities their risks and acute risks of include and damage to structures, as well as morbidity dependent on tumor For posterior fossa syndrome affects an to of patients who undergo resection of large posterior fossa tumors. fossa syndrome is characterized by a combination of or significant with and or motor occurring within 2 of cerebellar and symptoms can months to and many are with deficits. Patients with supratentorial tumors are at greater risk for postoperative seizures and are often on Children with tumors are at increased risk for postoperative visual deficits and tumors by or at a tumor to damage is over to a total to the are without mass, that when at a point to a certain they also radiation at a lower on both the and exit side of the have mass, so the radiation is to within the the of at that the that the effects of radiotherapy are due to the radiation in both and radiotherapy, patients can skin which generally over the treatment Patients intracranial radiotherapy often headache or radiotherapy can cause due to the by the body and can the growth of the resulting in loss of in younger radiotherapy is preferred over radiotherapy, for patients who require craniospinal radiotherapy, because it to important such as the and For patients focal radiotherapy, therapy may to important or result in a significantly overall radiation on tumor the radiation field and for a plan a plan can be to evaluate relative of over based on the brain that would a with each to the use of therapy are the of radiotherapy

Glial neoplasms in children comprise many heterogeneous tumors that include pilocytic and fibrillary astrocytomas, ependymomas, and the diffuse intrinsic pontine gliomas. In contrast to adults, most of whom present with high-grade fibrillary neoplasms, alternate histologies represent most cases seen in the pediatric setting. In addition, although most adult gliomas are supratentorial in location, in pediatrics infratentorial tumors (posterior fossa and brain stem) predominate. We discuss three specific tumors: diffuse intrinsic pontine gliomas; pilocytic astrocytomas; and ependymomas. Maximal surgical resection is the mainstay of therapy for both pilocytic astrocytomas and ependymomas. Failure to achieve an optimal resection often results in progression and the need for further therapy for patients with pilocytic astrocytomas, and is ultimately fatal in most children with subtotally resected ependymomas. Surgical resection has no role in the treatment of pontine gliomas. Focal radiation therapy is included routinely in the treatment of ependymomas, and it has been shown to improve event-free survival. This therapy also is used in the treatment of pontine gliomas because radiation treatment appears to slow inevitable tumor progression. Radiation therapy in pilocytic astrocytomas is generally reserved for patients who progress after an initial surgical resection or for those patients with midline tumors; these patients are poor candidates for aggressive surgical resection. The role of chemotherapy in these tumors is in evolution. Chemotherapy for pilocytic astrocytomas, particularly in young children (for whom radiation therapy is avoided), appears to be effective in the treatment of a subset of patients. Up-front chemotherapy is generally reserved for the youngest children who present with ependymoma. In the recurrence setting, chemotherapy has shown some activity, although this approach is never curative. Despite the application of various chemotherapeutics and other biologic agents, none of these therapies has improved the prognosis for patients with the uniformly lethal pontine glioma.

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.

Pilocytic astrocytoma is the most frequent pediatric glioma. Despite its overall good prognosis, complete surgical resection is sometimes unfeasible, especially for patients with deep-seated tumors. For these patients, the identification of targetable genetic alterations such as NTRK fusions, raised as a new hope for therapy. The presence of gene fusions involving NTRK2 has been rarely reported in pilocytic astrocytoma. The aim of the present study was to investigate the frequency of NTRK2 alterations in a series of Brazilian pilocytic astrocytomas. Sixty-nine pilocytic astrocytomas, previously characterized for BRAF and FGFR1 alterations were evaluated. The analysis of NTRK2 alterations was performed using a dual color break apart fluorescence in situ hybridization (FISH) assay. NTRK2 fusions were successfully evaluated by FISH in 62 of the 69 cases. Neither evidence of NTRK2 gene rearrangements nor NTRK2 copy number alterations were found. NTRK2 alterations are uncommon genetic events in pilocytic astrocytomas, regardless of patients' clinicopathological and molecular features.

Neurotrophic tyrosine receptor kinase 1-3 (NTRK1-3) gene fusions are found in a broad range of tumor types. Clinical trials demonstrated high response rates to tropomyosin receptor kinase (TRK) inhibitors in NTRK fusion-positive cancers, but few reports have described real-world experience with these targeted agents. We evaluated the prevalence of NTRK fusions and the outcomes with TRK inhibitor therapy in a real-world population of patients in the Veterans Health Administration. Patients with NTRK fusions or rearrangements were identified from the Veterans Affairs (VA) National Precision Oncology Program (NPOP), and patients who were prescribed TRK inhibitors were identified from the Corporate Data Warehouse. Baseline data and clinical outcomes were obtained by retrospective review of medical records. A total of 33 patients with NTRK fusions or rearrangements were identified, including 25 patients comprising 0.12% of all patients with solid tumors sequenced through VA NPOP. Twelve patients with NTRK fusions or rearrangements were treated with TRK inhibitors, none of whom had objective responses. Eight patients experienced toxicities leading to drug interruption, dose reduction, or discontinuation. In this retrospective study of VA patients, NTRK fusions and rearrangements were less common than in previous studies, and objective responses to TRK inhibitors were not observed. Real-world experience with TRK inhibitors differs markedly from clinical trial findings, possibly due to differences in patient demographics, tumor types, and sequencing methods. Our findings highlight the need to study TRK inhibitors in the real-world setting and in populations underrepresented in clinical trials.

3146 Background: Approximately 15% of cancers harbor BRAF alterations, of which ~5% are BRAF fusions. BRAF fusions are class II alterations that have worse outcomes than class I V600E alterations. While prior investigational therapies for BRAF fusions had disappointing outcomes, novel therapies are in clinical trials, underscoring the need to better characterize these tumors. Methods: Data from adult and pediatric patients with BRAF fusion+ cancers identified between January 2014 and November 2022 utilizing a center-wide next generation sequencing (NGS) program of >99,000 sequenced samples were analyzed. DNA-based hybrid capture tumor NGS (MSK-IMPACT), ctDNA targeted NGS (MSK-ACCESS), and/or RNA anchored multiplex PCR tumor NGS (MSK-Fusion) were used. Fusions were manually reviewed and considered to have oncogenic potential if they had an in-frame protein fusion involving a non-BRAF partner gene and an intact BRAF kinase domain (exons 11-18). Fusions not previously reported in OncoKB, COSMIC, TCGA, NIH gene, Fusion GDB2, and PubMED were classified as novel. All cases underwent clinical data curation including baseline demographic, tumor characteristics, and treatment histories. Results: 212 patients (0.2%) with BRAF-fusion positive solid tumors were identified. 194 were identified by DNA-based tumor NGS (96 had sufficient tissue for confirmatory RNA-based NGS, all of which were positive). Six were identified by ctDNA NGS and 12 by RNA-based tumor NGS only (5 had insufficient tissue for DNA-based tumor NGS). 83 unique 5’ fusion partners were found, of which 42 were novel. The most frequent tumor types were pilocytic astrocytoma (n=30, 14%), prostate CA (n=28, 13%), melanoma (n=24, 11%), lung CA (n=21, 10%), and colon CA (n=15, 7%). 44% of patients with pilocytic astrocytoma had BRAF fusions, of which 90% were BRAF-KIAA1549. Concomitant alterations (≥10% frequency) included TP53 (24%), TERT (18%), CDKN2A deletions (13%), and CDKN2B deletions (12%). 20% (n=43) were treated with MAPK-pathway directed therapies spanning multiple histologies and lines of therapies. Of the 212 patients, 17 had acquired BRAF fusions after targeted therapy for another oncogene ( EGFR mutation (n=11), BRAF V600E (n=4), FGFR fusion (n=1), NTRK fusion (n=1)). The majority of patients with acquired BRAF fusions had EGFR-mutant lung adenocarcinoma (n=11, 76%); the median time from EGFR targeted therapy initiation to BRAF fusion detection was 25 months (range 16-38 months). Conclusions: A wide variety of adult and pediatric solid tumors harbored de novo BRAF fusions. Complementary RNA sequencing optimized fusion identification in many cases. Multiple novel fusion partners were found. Acquired BRAF fusions were identified after targeted therapy for a variety of distinct oncogenes, the majority of which were EGFR mutations.

10048 Background: NTRK gene fusions are significant oncogenic drivers in pediatric tumors (e.g. infantile fibrosarcoma). Zurletrectinib is a highly selective next-generation TRK inhibitor. Preclinical data of zurletrectinib showed strong activity against resistant mutations, e.g., G595R. Promising efficacy was observed in a phase I/II clinical trial (NCT04685226). The pivotal phase II clinical trial (NCT05745623) is currently ongoing. Here we report an integrated analysis by combining pediatric and adolescent pts from the two clinical trials. Methods: Eligible pts with locally advanced or metastatic solid tumor harboring NTRK fusions, who failed from standard of care or for whom there was currently no effective therapy were included in the efficacy analysis. Adolescent pts (12-18 years) received zurletrectinib tablet at fixed dose, and pediatric pts ( < 12 years) received zurletrectinib orally disintegrating tablet (ODT) based on body surface area (BSA). The primary endpoint was confirmed objective response rate (ORR) per independent review committee (IRC). Tumor responses were assessed by IRC and investigators per RECSIT1.1 and RANO (BM) criteria. Treatment-emergent adverse events (TEAEs) were evaluated and graded according to CTCAE v5.0. Results: As of 23 Nov 2024, 18 pts in total were enrolled, including 8 pediatric pts and 10 adolescent pts. Median age was 5.0 (range: 3-9) and 13.5 (range: 12-15) respectively. ECOG performance status was between 0-1. Among the 18 pts, 6 TRK inhibitor treatment-naïve pts with central lab confirmed NTRK+ were efficacy evaluable. The confirmed ORR assessed by IRC was 100% (95% CI 54.1, 100.0). All of the pts achieved partial response (PR) at the 1 st tumor assessment and maintained the remission as of the cutoff date. Median time to response were 1.0 month (95% CI: 0.99, NE) in adolescent pts and 0.9 (95% CI: 0.89, NE) month in pediatric pts. It is worth noting that one pediatric patient who progressed on prior first-generation TRK inhibitor achieved complete response after receiving zurletrectinib. The most common treatment related adverse events (TRAEs) were ALT increased (n = 8) and anemia (n = 6), the majority of which were Gr 1 or 2. There were no TRAEs leading to dose reduction or discontinuation, and no serious TRAEs were reported. PK results indicated that zurletrectinib PK profiles in pediatrics and adolescents at the recommended phase 2 dose (RP2D) were similar to that in adults. Conclusions: The integrated analysis demonstrated that zurletrectinib had significant efficacy and good safety profile in pediatric and adolescent pts with NTRK+ solid tumors. Zurletrectinib also showed the potential to overcome the resistance to 1 st generation TRK inhibitors. These findings support zurletrectinib is a better treatment option for NTRK+ pediatric and adolescent pts. Clinical trial information: NCT04685226 .

229 Background: Since late 2018, 2 TRK inhibitors—larotrectinib and entrectinib—have been approved by the EMA and FDA for treating patients with advanced solid tumors harboring an NTRK fusion and progressive disease or no therapeutic alternatives. It is recommended that testing for NTRK fusions occur as early as possible after a diagnosis of advanced disease in patients with solid tumors to inform potential use of TRK inhibitors. Methods: Between April 2018 and April 2021, we conducted multiple live and online educational activities for oncology healthcare professionals (HCPs) on NTRK fusion testing and/or TRK inhibitor treatment for varied solid tumors. Each activity included polling questions designed to assess HCP knowledge and practice patterns. In this analysis, we assessed HCP responses to these questions to evaluate awareness of expert recommendations on NTRK fusion testing and the selection of TRK inhibitor therapy for appropriate patients. Results: In 6 live and online activities with data from April 2018 to April 2021, 29% of HCPs (n = 844) indicated that they ordered molecular profiling to test for NTRK fusions in all solid tumors in their current practice. Of note, low rates of testing were reported in TRK inhibitor/ NTRK testing-focused activities throughout this time period, with no significant increase over time. In assessing different patient cases across 8 activities where experts recommended TRK inhibitor therapy as optimal, many HCPs did not select a TRK inhibitor, with considerable variance by tumor type (Table). *For all cases, experts selected larotrectinib and/or entrectinib as optimal treatment. †HCP respondents. GBM, glioblastoma; GI, gastrointestinal; MSI-H, microsatellite instability-high; PD, progressive disease; PTC, papillary thyroid cancer.Conclusions: The rate of broad testing for NTRK fusions across patients with solid tumors remains low, and many HCPs lack awareness of when to consider a TRK inhibitor. Educational activities designed to address these deficiencies would be of clear benefit to HCPs treating patients with advanced solid tumors. A detailed analysis of HCP trends will be presented.[Table: see text]

ADVERTISEMENT RETURN TO ISSUEPREVPatent HighlightNEXTPROTAC Compounds Targeting TRK for Use in Cancer TherapeuticsRobert B. Kargbo*Robert B. KargboUsona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States*E-mail: [email protected]More by Robert B. Kargbohttp://orcid.org/0000-0002-5539-6343Cite this: ACS Med. Chem. Lett. 2020, 11, 6, 1090–1091Publication Date (Web):May 18, 2020Publication History Received2 May 2020Published online18 May 2020Published inissue 11 June 2020https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00235https://doi.org/10.1021/acsmedchemlett.0c00235editorialACS PublicationsCopyright © 2020 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3563Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (805 KB) Get e-AlertscloseSUBJECTS:Cancer,Inhibitors,Neurophysiology,Peptides and proteins,Receptors Get e-Alerts

Pilocytic astrocytoma, a World Health Organization grade 1 tumor, is the most common brain tumor in childrenbetween 5 and 14 years of age and the second most common in children younger than 5 and older than 14.Although classical to the cerebellum and hypothalamic regions, it can also arise in the spinal cord. Larotrectinib, aselective inhibitor of tropomyosin receptor kinase, has been effective in pediatric tumors with NTRK fusionmutations in children as young as 1-month-old. We share the case of a 9-month-old boy who presented with a 4-month history of regression of his milestones andsevere constipation who was found to have a large spinal pilocytic astrocytoma with multiple intracranialperiventricular lesions.

Spotlight on the treatment of infantile fibrosarcoma in the era of neurotrophic tropomyosin receptor kinase inhibitors: International consensus and remaining controversies

2038 Background: Pilocytic astrocytoma (PA) accounts for up to 25% of all brain tumors in children. A 75% progression-free survival rate at 5 years and overall survival rates of 95.8% at 10 years have been reported after a complete resection. However, the incidence in adults is low and the outcome less well characterized. We conducted a retrospective analysis of adult PAs identified in order to review the clinical characteristics and outcome of this neoplasm in this age group. Methods: A descriptive, cross-sectional study was undertaken in patients over 16 y.o., diagnosed with PA between January 1990 and December 2010 at our center. Clinical characteristics, date and extent of surgery, tumor location, postoperative treatment, complications and recurrences were collected from hospital records. Results: From May, 1990 to December, 2010, 18 eligible adult patients (pts) with the diagnosis of PA were identified. Median age was 25,5 (16-52) years, 72,2% female and 83,3% had an ECOG performance status ≤ 2. The most frequent tumor sites were the cerebellum (44,4%), followed by the cerebral hemispheres (38%). All patients underwent surgery as primary treatment, 72% had a complete macroscopic resection (CMR) and 28% had a partial resection (PR). Two patients received postoperative radiotherapy: one following a PR and the other after tumor relapse following a CMR. Two patients relapsed five months and 44 months after initial complete gross resection. Salvage surgery achieved CMR in both. With a median follow-up of 89 months, all patients are alive, except for one who died in the postoperative period due to fungal meningitis. Of note, none of 5 pts undergoing a partial resection progressed and 3 are alive for more than 10 years. Conclusions: As it occurs in the pediatric population, PA in adults seems to carry a similarly favorable prognosis. It is conceivable that after initial surgical resection a watch and wait type of approach is appropriate, even following partial resection. The role of upfront radiotherapy is uncertain and it should probably be left for progressive tumors.

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers