Evicenter
P&T meetings

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 therapyApproaches to treatment

Heterogeneity of treatment effect

13 evidence topics · 15 sources

Summary: factors that modify treatment effect

Molecular subgroup modifies outcomes with both chemotherapy and targeted therapy. BRAF V600E pLGG had a 10-year PFS of 27% after chemotherapy or radiation therapy versus 60.2% for wild-type tumors, and CDKN2A deletion independently predicted poor outcome; in a 1,000-tumor cohort, BRAF V600E with CDKN2A deletion had a 10-year PFS of 0%, whereas fusion-driven and NF1 tumors had a 10-year PFS of 67%. CDKN2A deletion was not associated with lack of response to BRAF inhibition. In FIREFLY-1 (relapsed or refractory), RANO-HGG objective response rate (ORR) was 69% for BRAF fusion and 50% for BRAF V600E tumors (10 evaluable participants), with a shorter median time to response for V600E tumors (2.8 versus 5.5 months by RAPNO). NF1-associated tumors were excluded from FIREFLY-1 and FIREFLY-2, and nonclinical data showed increased tumor volume in approximately 17% of NF1 model mice treated with tovorafenib; in contrast, participants with NF1 had better 5-year PFS with vinblastine (85.1% versus 42.0%) and had selumetinib response rates of 40%.

Age and tumor location also modify outcomes: younger age and tumor size greater than 3 cm2 predicted worse EFS in COG A9952, age and diencephalic syndrome predicted worse PFS and overall survival in SIOP-LGG 2004, and chemotherapy appears less effective in infants. FIREFLY-2 stratifies randomization by supratentorial midline location, fusion versus mutation, CDKN2A status, and infant chiasmatic-hypothalamic glioma. Visual outcomes after chemotherapy were poorer for sporadic than NF1-associated optic pathway glioma.

BRAF alteration type: tovorafenib response by fusion versus V600E in relapsed or refractory pLGG

“The ORR was 69% (95% CI: 56–81) in patients with tumors harboring BRAF fusions and 50% (95% CI: 19–81) in patients with tumors harboring BRAF V600E mutations. The ORR was 71% (95% CI: 54–84) in the 59% of evaluable patients who had received prior MAPK inhibitor (MAPKi) therapy and 61% (95% CI: 41–78) in those who had not.” (opens the source at this quote in a new tab)

“The median time to initial response (MR or PR) was 5.3 months (range, 1.6–11.2) overall; 2.8 months (range, 1.6–3.0) in patients with tumors harboring BRAF V600E mutations; and 5.5 months (range, 2.3–11.2) in patients with tumors harboring BRAF fusions.” (opens the source at this quote in a new tab)

“Exploratory subgroup analyses of ORR demonstrated similar response rates based on BRAF alteration (KIAA1549:BRAF fusion vs. BRAF V600E mutation), exposure to a prior MEK and/or BRAF inhibitor, and number of prior lines of therapy received.” (opens the source at this quote in a new tab)

NF1-associated tumors: exclusion and potential for tumor growth with tovorafenib

“In a neurofibromatosis type I (NF1) model without BRAF alteration, tovorafenib did not have antitumor activity, and while not statistically significant, an increase in tumor volume in ~17% of mice was observed with treatment (12).” (opens the source at this quote in a new tab)

“Although cases of patients with pLGG bearing both a BRAF alteration and loss of NF1 are rare, possible tumor growth in the context of NF-1 associated disease was considered relevant for clinician awareness (17).” (opens the source at this quote in a new tab)

NF1 status and outcomes with chemotherapy and MEK inhibition

“Patients with NF1 had a significantly better PFS (85.1%; 95% CI, 68.0% to 100%) when compared with patients without NF1 (42.0%; 95% CI, 29.1% to 60.7%; P = .012). Age< 3 years or > 10 years was not associated with poor outcome.” (opens the source at this quote in a new tab)

“In this trial, there was no correlation between BRAF alterations and outcome.” (opens the source at this quote in a new tab)

“Stratum 2: among 14 evaluable patients, there was 1 partial response (PR), 7 stable disease (SD), and 6 progressive disease (PD); the overall response rate (ORR) was 7.1%.” (opens the source at this quote in a new tab)

BRAF V600E and CDKN2A deletion: prognosis with conventional therapy and response to BRAF inhibition

“Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG.” (opens the source at this quote in a new tab)

“Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition.” (opens the source at this quote in a new tab)

Molecular risk stratification

“pLGG harboring gene fusions or germline NF1 mutations comprise the low risk group. These tumors progress less frequently and often eventually stop growing with very few progressions seen after 10 years and almost no deaths at 20 years follow-up (10-year PFS of 67% and OS of 98%, 20-year PFS and OS of 58% and 96%, respectively) (Figure 7B–C).” (opens the source at this quote in a new tab)

“The intermediate risk group of pLGG includes tumors with BRAF p.V600E without CDKN2A deletion, FGFR1 SNV, IDH1 p.R132H or MET mutations. Intermediate risk tumors had a 10-year PFS and OS of 35% and 90%, respectively (Figure 7B–C).” (opens the source at this quote in a new tab)

“High risk pLGG include those with H3.3 p.K27M, or BRAF p.V600E with CDKN2A deletion. These tumors almost invariably progress (10-year PFS of 0%) and these patients often succumb to their disease (10-year OS of 41%) (Figure 7B,C).” (opens the source at this quote in a new tab)

Age, tumor size, location, and diencephalic syndrome

“On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm2. Tumor location in the thalamus was also associated with poor OS.” (opens the source at this quote in a new tab)

“Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS.” (opens the source at this quote in a new tab)

Stratification factors in LOGGIC/FIREFLY-2

“Randomization between treatment arms will be stratified by primary location of the tumor (supratentorial midline vs. other), type of genomic RAF alteration (fusion vs. mutation), CDKN2A status (deletion vs. wild-type/unknown), and infant chiasmatic-hypothalamic glioma (CHG) diagnosis (yes vs. no).” (opens the source at this quote in a new tab)

Optic pathway glioma: NF1 status and visual outcome

“Children with and without NF1 demonstrated the same rate of VA improvement, stabilisation or worsening; however, children with sporadic OPG had a poorer VA outcome. Better initial VA, older age, absence of postchiasm tumour and presence of NF1 were associated with improved or stable VA outcomes.” (opens the source at this quote in a new tab)

“The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO, and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates of 95%, 88%, and 90%, respectively.” (opens the source at this quote in a new tab)

Response by histologic subtype and CDKN2A status in first-line BRAF V600 pediatric low-grade glioma

“In addition, responses were observed across the diverse histologic types of glioma in this trial, findings that support broad use of dabrafenib plus trametinib as first-line therapy in this population.” (opens the source at this quote in a new tab)

“In addition, among the patients for whom molecular data were available, responses were observed regardless of the presence or absence of CDKN2A homozygous deletion.” (opens the source at this quote in a new tab)

Molecular subgroup and hemorrhage risk in pediatric low-grade glioma

“Six of 37 patients (16.2%) with KIAA1549::BRAF experienced a hemorrhage vs. 6 of 199 (3.0%) without known fusion” (opens the source at this quote in a new tab)

“BRAF V600E mutation showed no association (0 hemorrhages among 28 patients, p = 0.996).” (opens the source at this quote in a new tab)

“No hemorrhages occurred among patients with underlying genetic syndromes, including neurofibromatosis type 1 and tuberous sclerosis.” (opens the source at this quote in a new tab)

“Adjustment for KIAA1549::BRAF fusion substantially attenuated the apparent MAPK inhibitor effect (univariate HR 4.70 to adjusted HR 2.22, p = 0.260)” (opens the source at this quote in a new tab)

Per-eye visual acuity outcomes after chemotherapy in NF1-associated versus sporadic optic pathway glioma

“At initiation of chemotherapy, 26% and 49% of eyes in the NF1 and sporadic groups respectively had VA ≥0.7 logMAR” (opens the source at this quote in a new tab)

“At completion, in the NF1-OPG group, 49% of eyes had ≤0.2 logMAR, 23% of eyes had VA 0.30–0.60 logMAR and 28% of eyes had ≥0.70 logMAR. In the sporadic OPG group, 32% of eyes had ≤0.2 logMAR, 11% of eyes had 0.30–0.60 logMAR and 57% of eyes had ≥0.70 logMAR. Children with sporadic OPG, per eye, were significantly less likely to have a VA outcome of ≤0.60 logMAR compared with children with NF1-OPG (OR=0.30; 95% CI 0.16 to 0.56; P<0.0001).” (opens the source at this quote in a new tab)

Age and tumour location as predictors of visual outcome after chemotherapy

“Age ≤5 years (OR 25.2; 95% CI 3.02 to 209; P=0.003) and Dodge stage 3 (OR 7.14; 95% CI 2.44 to 25.0; P<0.001) at presentation were associated with VA ≥0.70 logMAR on both univariate and multivariate analysis in the NF1 group.” (opens the source at this quote in a new tab)

“In our NF1 cohort, children with Dodge stage 3 tumours were seven times more likely to experience worsening VA and a poor final VA outcome despite treatment.” (opens the source at this quote in a new tab)