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Tovorafenib (DAY101)

RAF-altered pediatric low-grade glioma requiring first-line systemic therapy

Also known as TAK-580
Regulatory submission
Not announced
Launch
Not announced
Last updated
155 sources

Product information and disease descriptionPlace of product in therapyDisease description

Clinical presentation - signs and symptoms

14 evidence topics · 9 sources

Tumor location as the determinant of presentation: anatomical distribution

“At the population-level, tumors were distributed equally between the diencephalon (n=313, 32%; n=124, 13% were from Neurofibromatosis Type 1 [NF1] patients), cerebral hemispheres (n=265, 27%) and the cerebellum (n=252, 26%), whereas pure brainstem (n=92, 9.4%), spinal cord (n=41, 4.2%) and extensively disseminated tumors (n=13, 1.3%) were less frequent (Figure 1A).” (opens the source at this quote in a new tab)

“The median age of diagnosis was 7.6 years (range 0–18.7 years)” (opens the source at this quote in a new tab)

“Anatomically implicated were 31.6% cerebellum, 24.6% chiasma/hypothalamus, 16.0% cerebral hemispheres, 9.9% brain stem, 6.1% other supratentorial midline structures, 5.9% optic nerve only, 4.5% spinal cord, and 1.4% others.” (opens the source at this quote in a new tab)

Raised intracranial pressure and posterior fossa symptoms: headache, vomiting, ataxia, and papilloedema

“nausea and vomiting (75%), headache (67%), abnormal gait and coordination (60%), and papilloedema (34%) for posterior fossa tumours” (opens the source at this quote in a new tab)

“Symptoms of raised intracranial pressure were absent in more than half of children with brain tumours.” (opens the source at this quote in a new tab)

“macrocephaly (41%), nausea and vomiting (30%), irritability (24%), and lethargy (21%) for children aged under 4 years with intracranial tumours” (opens the source at this quote in a new tab)

“These symptoms can include headaches, nausea, vomiting, lethargy, sixth cranial nerve palsies, seizures and behavioral changes, depending on tumor location.” (opens the source at this quote in a new tab)

Visual symptoms: optic pathway glioma

“reduced visual acuity (41%), exophthalmia (16%), and optic atrophy (15%) for children with an intracranial tumour and neurofibromatosis” (opens the source at this quote in a new tab)

“headache (49%), abnormal eye movements (21%), squint (21%), and nausea and vomiting (19%) for central brain tumours” (opens the source at this quote in a new tab)

“Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic.” (opens the source at this quote in a new tab)

“In a study of 57 children with NF1-OPG, only 32 (59%) had signs or symptoms attributable to their tumor at diagnosis” (opens the source at this quote in a new tab)

“Because vision deficits due to NF1-OPG may go unnoticed and even precede a diagnosis of OPG, ophthalmologic abnormalities found at tumor presentation and thought to be chronic may not require therapy.” (opens the source at this quote in a new tab)

Endocrine symptoms: precocious puberty, growth failure, and hypothalamic dysfunction

“Other features noted were weight loss, growth failure, and precocious puberty.” (opens the source at this quote in a new tab)

“Precocious puberty or changes in growth hormone related to NF1-OPG are not indications for treatment with chemotherapy.” (opens the source at this quote in a new tab)

Nutritional symptoms: diencephalic syndrome in infants with hypothalamic-chiasmatic glioma

“DS typically manifests in the first year of life with profound cachexia, normal or increased appetite, preserved height velocity, and characteristic features including hyperactivity, euphorism, and visual pathway involvement. Low-grade gliomas of the hypothalamic–chiasmatic region, particularly pilocytic astrocytomas, represent the predominant underlying pathology.” (opens the source at this quote in a new tab)

“Diagnostic delays averaging 11 months contribute to irreversible complications.” (opens the source at this quote in a new tab)

“By clinical definition, 28 children had DS, with hypothalamic-chiasmatic glioma (26/28) and a high frequency of primary dissemination (6/28). Their median age at diagnosis was 6.5 months (range, 2.4–27.1 mo; 23/28 <1 y).” (opens the source at this quote in a new tab)

Seizures: supratentorial and hemispheric tumors

“unspecified symptoms and signs of raised intracranial pressure (47%), seizures (38%), and papilloedema (21%) for supratentorial tumours” (opens the source at this quote in a new tab)

Brainstem and spinal cord symptoms: cranial nerve palsies, gait disturbance, and back pain

“abnormal gait and coordination (78%), cranial nerve palsies (52%), pyramidal signs (33%), headache (23%), and squint (19%) for brainstem tumours” (opens the source at this quote in a new tab)

“back pain (67%), abnormalities of gait and coordination (42%), spinal deformity (39%), focal weakness (21%), and sphincter disturbance (20%) for spinal-cord tumours” (opens the source at this quote in a new tab)

Symptoms prompting nonsurgical treatment at diagnosis

“Indications for immediate therapy were severe neurologic symptoms (67), visual impairment (74), and risk for tumor progression at a critical site (10)” (opens the source at this quote in a new tab)

“Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions.” (opens the source at this quote in a new tab)

Ranked symptoms and signs in children with neurofibromatosis type 1 and an intracranial tumour

“The ranked symptoms and signs were reduced visual acuity (41%), exophthalmia (16%), optic atrophy (15%), squint (13%), headache (9%), unspecified symptoms of raised intracranial pressure (8%), precocious puberty (8%), abnormal gait or coordination difficulties (7%), voice abnormalities (6%), developmental delay (5%), papilloedema (5%), and reduced visual fields (5%; figure 2).” (opens the source at this quote in a new tab)

Ranked symptoms and signs at diagnosis in children younger than 4 years

“Ranked symptoms and signs at diagnosis were: macrocephaly (41%), nausea and vomiting (30%), irritability (24%), lethargy (21%), abnormal gait and coordination difficulties (19%), weight loss (14%), clinically apparent hydrocephalus (bulging fontanelle, splayed sutures; 13%), seizures (10%), papilloedema (10%), headache (10%), unspecified focal neurological signs (10%), unspecified symptoms of raised intracranial pressure (9%), focal motor weakness (7%), head tilt (7%), altered level of consciousness (7%), squint (6%), abnormal eye movements (6%), developmental delay (5%), and hemiplegia (5%; figure 2)” (opens the source at this quote in a new tab)

Interval between symptom onset and diagnosis

“The reported median symptom interval ranges from 1 to 27 months.” (opens the source at this quote in a new tab)

“Increasing awareness of the varied and complex symptomatology that often occurs with CNS tumours could help tumour diagnosis and reduce the extended symptom interval experienced by many children.” (opens the source at this quote in a new tab)

Representation of low-grade astrocytoma in the pooled presentation data

“Apart from optic pathway gliomas, these astrocytomas were under-represented in the studies identified.” (opens the source at this quote in a new tab)

“Despite this result, the distribution of tumour location in the studies identified here was similar to that seen in clinical practice (56% infratentorial, 23% hemispheric, 21% central), lending support to the analysis results.” (opens the source at this quote in a new tab)

Under-recording of behavioural change and school difficulties at presentation

“In the meta-analysis, the frequency of change in behaviour or school performance (7% in all brain tumours, and 9% for central tumours) was lower than that reported by many individual studies. Several large cohorts reported a frequency of school difficulties and behavioural changes of 22-72%.” (opens the source at this quote in a new tab)

“Adults with brain tumours are often not asked about behavioural change, and similar reporting errors probably occur in children.” (opens the source at this quote in a new tab)

“The assumption was made that if a symptom or sign was not described in a study, it did not occur in that population.” (opens the source at this quote in a new tab)

Presenting features in a sporadic optic pathway glioma cohort

“Exactly half of patients presented with vision loss, and most (66%) presented with optic pallor. Nystagmus (45%), strabismus (32%), and hydrocephalus (29%) were also common.” (opens the source at this quote in a new tab)