OJEMDA Tablet / Oral suspension Ref.[109717] Active ingredients: Tovorafenib

Exposure Response Relationships

Tovorafenib exposure is associated with reduction in height-for-age z-scores in pediatric patients. Reduced height-for-age risk persists during treatment with tovorafenib.

Higher tovorafenib exposure is associated with increased risk of skin rash, elevated liver enzymes (AST and ALT), and elevated creatinine phosphokinase.

The exposure-response relationship for overall response rate based on RAPNO-LGG (Response Assessment in Pediatric Neuro-Oncology), and RANO-LGG (Response Assessment in Neuro-Oncology) were not clinically significant over the dosage range of 290 to 476 mg/m² (0.76-1.25 times the approved recommended dosage) [see Dosage and Administration (2.3) and Clinical Studies (14)].

Cardiac Electrophysiology

At the recommended OJEMDA dosage of 380 mg/m² orally once weekly (not to exceed 600 mg), a mean increase in the QT interval >20 milliseconds was not observed.

Tovorafenib pharmacokinetic parameters are presented as mean (CV%) unless otherwise indicated. Tovorafenib steady state maximum concentration (C_max) is 6.9 µg/mL (23%) and the area under the concentration-time curve (AUC) is 508 µg*h/mL (31%). Time to reach steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. No clinically significant tovorafenib accumulation occurs.

Absorption

Tovorafenib median (minimum, maximum) time to achieve peak plasma concentration (T_max) is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.

Effect of Food

No clinically significant differences in tovorafenib C_max and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the T_max was delayed to 6.5 hours.

Distribution

Tovorafenib apparent volume of distribution is 60 L/m² (23%). Tovorafenib is 97.5% bound to human plasma proteins in vitro.

Elimination

Tovorafenib terminal half-life is approximately 56 hours (33%) and the apparent clearance is 0.7 L/h/m² (31%).

Metabolism

Tovorafenib is primarily metabolized by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9, and CYP2C19 metabolize tovorafenib to a minor extent.

Excretion

Following a single oral dose of radiolabeled tovorafenib, 65% of the total radiolabeled dose was recovered in the feces (8.6% unchanged) and 27% of the dose was recovered in the urine (0.2% unchanged).

Specific Populations

No clinically significant differences of tovorafenib were observed based on age (range: 1 to 94 years), sex, race (White, Black, Asian), mild hepatic impairment [bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST], and mild-to-moderate renal impairment (eGFR) ≥30 mL/min/1.73 m² calculated by Schwartz equation or MDRD equation.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

CYP3A Substrates: Midazolam (CYP3A4 substrate) steady-state C_max and AUC are predicted to decrease by at least 20% following coadministration with tovorafenib.

In vitro Studies

CYP450 Enzymes: Tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19 and CYP3A, but does not inhibit CYP1A2, CYP2B6, and CYP2D6 at clinically relevant concentrations.

Tovorafenib induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19 at clinically relevant concentrations.

Transporter Systems: Tovorafenib is not a substrate of BCRP, P-glycoprotein (P-gp), OATP1B1 and OATP1B3. Tovorafenib has not been evaluated as a substrate of OAT1, OAT3, MATE1, MATE2-K and OCT2. Tovorafenib inhibits BCRP at clinically relevant concentrations.

Carcinogenicity studies with tovorafenib have not been conducted.

Tovorafenib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Tovorafenib was not genotoxic in cultured human lymphocytes without metabolic activation. Tovorafenib induced chromosomal aberrations in cultured human lymphocytes with metabolic activation at a single concentration in vitro. Tovorafenib was not genotoxic in an in vivo rat bone marrow micronucleus assay.

In a fertility and early embryonic development study in rats, animals were administered tovorafenib doses of 37.5, 75, or 150 mg/kg/day orally. Female animals, paired with untreated males, were dose for 14 days prior to pairing, during the mating period, and up to Gestation Day 6. Tovorafenib decreased the number of pregnancies, corpora lutea, and live embryos, as well as increased post-implantation losses at all doses. The dose of 37.5 mg/kg/day is approximately 0.8-fold the human exposure at the recommended dose based on AUC.

In repeat- dose toxicology studies in rats of up to 3 months duration, tovorafenib-related findings in female rats included reversible increased thickness of the vaginal mucosa, increased size and/or numbers of corpora hemorrhagicum and hemorrhage, and non-reversible cystic follicles, decreased corpora lutea, and interstitial cell hyperplasia were observed in ovaries at doses ≥50 mg/kg once every other day (approximately 0.4-fold the human exposure at the recommended dose based on AUC). In male rats, tovorafenib reduced weights of epididymis and testes, which correlated with reversible tubular degeneration/atrophy of the testes and reduced epididymal sperm at doses ≥50 mg/kg once every other day (approximately 0.3-fold the human exposure at the recommended dose based on AUC).

In vitro, tovorafenib increased phosphorylation of ERK at clinically relevant concentrations in cells with neurofibromatosis Type 1-loss of function (NF1-LOF) suggesting activation, rather than inhibition, of the MAP kinase pathway. In an NF1 genetically engineered mouse model of plexiform neurofibroma without BRAF alteration, tovorafenib did not have antitumor activity, and while not statistically significant, an increase in tumor volume was noted in 2/12 mice (approximately 17%).

The efficacy of OJEMDA was evaluated in a multicenter, open-label, single-arm clinical trial (FIREFLY-1; NCT04775485). Eligible patients (N=76) were required to have a relapsed or refractory pediatric low-grade glioma (LGG) harboring an activating BRAF alteration based on local laboratory testing. Patients were also required to have at least one measurable lesion as defined by RANO 2010 criteria. All patients had received at least one line of prior systemic therapy and had documented evidence of radiographic progression. Patients with tumors harboring additional activating molecular alteration(s) (e.g., IDH1/2 mutations, FGFR mutations, etc.) or patients with known or suspected diagnosis of neurofibromatosis type 1 (NF1) were excluded.

Patients received OJEMDA approximately 420 mg/m² orally once weekly (range: 290 to 476 mg/m², 0.76-1.25 times the approved recommended dosage) according to body surface area with a maximum dose of 600 mg until disease progression or unacceptable toxicity. Although the OJEMDA dosages administered in FIREFLY-1 were between 290 mg/m² to 476 mg/m², the recommended OJEMDA dosage is 380 mg/m² orally once weekly because this dosage was determined to be safe and effective for the treatment of patients 6 months of age and older with relapsed or refractory pediatric LGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation [see Dosage and Administration (2.3)].

Tumor assessments were performed every 12 weeks.

The major efficacy outcome measure was overall response rate (ORR), defined as the proportion of patients with complete response (CR), partial response (PR), or minor response (MR) by independent review based on RAPNO-LGG (Response Assessment in Pediatric Neuro-Oncology) criteria. Additional efficacy outcome measures were duration of response, time to response, and ORR by independent review based on RANO-LGG (2011) criteria.

The efficacy population included 76 patients who had measurable disease at baseline and who received OJEMDA. The median age was 8.5 years (range 2 to 21 years); 53% were male; 53% White, 7% Asian, 2.6% Black or African American, 3.9% multiple races, 8% other race, 26% where race was not reported; 3.9% were Hispanic or Latino, and 93% had Karnofsky/Lansky performance status of 80 to 100. Patients received a median of 3 prior systemic regimens (range: 1 to 9). Forty-five patients (59%) received prior treatment with a MAP kinase pathway inhibitor. The most common tumor locations were the optic pathway (51%), deep midline structures (12%), brain stem (8%), cerebral hemisphere and cerebellum (7% each). Fifty-six patients (74%) had a KIAA1549:BRAF fusion, twelve patients (16%) had a V600E mutation, and eight patients (11%) had a BRAF alteration classified as “other” including BRAF duplication or BRAF rearrangement. Efficacy results are shown in Table 10.

Table 10. Efficacy Results Based on Independent Review in FIREFLY-1 (Arm-1):

Abbreviations: LGG = low-grade glioma; RAPNO = Response Assessment in Pediatric Neuro-Oncology; CI = confidence interval; NE = not estimable.
^* At least one measurable lesion at baseline based on RAPNO-LGG criteria.
^a Based on Clopper-Pearson exact confidence interval.
^b Based on Kaplan-Meier estimate.

Among responders, the median time to response was 5.3 months (range 1.6, 11.2). In exploratory analyses of BRAF alteration status, the ORR was 52% among patients with BRAF fusion or rearrangement (n=64), and 50% among patients with BRAF V600E mutation (n=12), respectively. In exploratory analyses of prior therapies, the ORR was 49% among patients who had received prior MAPK-targeted therapy (n=45), and 55% among patients who had not received prior MAPK-targeted therapy (n=31).

Based on RANO-LGG (2011) criteria (n=76), the ORR was 53% [95% CI: (41, 64)], including 20 patients each with PR and MR, respectively.