RASONQUE Film-coated tablet Ref.[116904] Active ingredients:

Exposure-Response Relationships

Daraxonrasib exposure-response relationships and time course of pharmacodynamic response have not been fully characterized.

Based on exposure and safety data from patients with pancreatic adenocarcinoma receiving 10 to 400 mg once daily of daraxonrasib (n = 466), higher daraxonrasib exposure was associated with higher incidence of dose interruption/reduction/discontinuation, Grade ≥ 3 adverse reactions, Grade ≥ 2 dermatologic reactions, mucositis/stomatitis, nausea/vomiting, and diarrhea.

Cardiac Electrophysiology

At the recommended dosage, a mean increase in the QTc interval > 20 msec was not observed.

The pharmacokinetics of daraxonrasib were studied in healthy subjects and patients with advanced solid tumors, including patients with pancreatic adenocarcinoma treated with 300 mg once daily, and are presented as geometric mean (geometric percent coefficient of variation), unless otherwise specified.

Daraxonrasib maximum concentration is 365 ng/mL (50%) and total systemic exposure (AUC) is 3760 ng·h/mL (46%). Daraxonrasib AUC increases in an approximately dose proportional manner whereas C_max increases in a less than dose proportional manner over the dose range of 80 mg (0.27 times the recommended dose) to 300 mg. Minimal to no accumulation was observed for AUC.

Absorption

Daraxonrasib median (min, max) time to reach maximum concentration (T_max) is approximately 2.2 hours (0.67, 8.0).

Effect of Food

No clinically significant differences in daraxonrasib pharmacokinetics were observed following administration of a high-fat, high-calorie meal (800 to 1000 calories, 50% from fat).

Distribution

Daraxonrasib apparent (oral) volume of distribution during the terminal elimination phase is 1060 L (48%).

Daraxonrasib plasma protein binding is approximately 98% in vitro and is not concentration-dependent. Daraxonrasib blood to plasma ratio is concentration-dependent and ranges from 1.7 to 2.6 in healthy subjects.

Elimination

Daraxonrasib mean (SD) terminal elimination half-life is 9.2 (±2.7) hours with an apparent (oral) clearance (CL/F) of 80.4 L/h (44%).

Metabolism

Excretion

After a single oral dose of radiolabeled daraxonrasib 220 mg to healthy subjects, approximately 93% of the dose was recovered in feces (51% unchanged) and approximately 1% was recovered in urine (1% unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of daraxonrasib were observed based on age (19 to 87 years old), sex, race (72% White, 11% Asian, 4% Black or African American), body weight (37 to 171 kg), ECOG PS (0, 1), tumor burden, CLcr 30 to 89 mL/min, or mild (total bilirubin > ULN to 1.5 × ULN or AST > ULN (with bilirubin normal)) or moderate (total bilirubin > 1.5 to 3 × ULN (with any AST level)) hepatic impairment per NCI-ODWG classification. The effects of CLcr < 30 mL/min or severe hepatic impairment (total bilirubin > 3 to 10 × ULN (with any AST level)) on daraxonrasib pharmacokinetics are unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A Inhibitors with P-gp Inhibition: Daraxonrasib AUC was observed to increase 5.1-fold following concomitant use of itraconazole 200 mg once daily (a strong CYP3A inhibitor with P-gp inhibition).

Strong CYP3A Inhibitors without P-gp Inhibition: Daraxonrasib AUC is predicted to increase 2.0-fold following concomitant use of voriconazole 200 mg twice daily (a strong CYP3A inhibitor without P-gp inhibition).

Moderate CYP3A Inhibitors with P-gp Inhibition: Daraxonrasib AUC is predicted to increase 2.6-fold following concomitant use of verapamil 80 mg three times daily (a moderate CYP3A inhibitor with P-gp inhibition).

Moderate CYP3A Inhibitors without P-gp Inhibition: Daraxonrasib AUC is predicted to increase 1.5-fold following concomitant use of fluconazole 200 mg once daily (a moderate CYP3A inhibitor without P-gp inhibition).

P-gp Inhibitors: Daraxonrasib AUC was observed to increase 1.8-fold following concomitant use of quinidine 300 mg three times daily (a P-gp inhibitor).

Strong CYP3A Inducers: Daraxonrasib AUC was observed to decrease to 50% following concomitant use of phenytoin 100 mg three times daily (a strong CYP3A inducer) and is predicted to decrease to 30% following concomitant use of rifampin 600 mg once daily (a strong CYP3A inducer).

Moderate CYP3A Inducers: Daraxonrasib AUC is predicted to decrease to 50% to 84% following concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A inducers).

P-gp Substrates: Free dabigatran C_max and AUC are predicted to increase 2.5-fold and 2.1-fold, respectively, following concomitant use of RASONQUE 300 mg once daily. No clinically significant differences in free dabigatran pharmacokinetics are predicted when RASONQUE 300 mg once daily is given 4 hours apart from dabigatran etexilate.

Other Drugs: No clinically significant differences in daraxonrasib pharmacokinetics were observed when used concomitantly with esomeprazole (a proton pump inhibitor).

No clinically significant differences in the pharmacokinetics of the following drugs were observed or predicted when used concomitantly with RASONQUE: midazolam (a sensitive CYP3A substrate), rosuvastatin (a BCRP/OATP1B3 substrate), and pravastatin (an OATP1B3 substrate).

Carcinogenesis

Carcinogenesis studies have not been conducted with daraxonrasib.

Mutagenesis

Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.

Impairment of Fertility

No fertility studies have been conducted with daraxonrasib. In general toxicology studies in mice and monkeys, there were no remarkable findings in male or female reproductive organs.

In a 4-week toxicity study in mice, increased bone remodeling was observed at ≥ 10 mg/kg/day (exposures at or greater than the recommended dose based on AUC) and was partially reversible. The finding was characterized by increased number and size of osteoclasts (metaphyseal cut-back zone and diaphyseal periosteum) and structural bone changes (wider cortical walls, wider Haversian canals, larger osteocytes/lacunae).

The efficacy of RASONQUE was evaluated in a global, randomized, open-label, multicenter study (RASolute 302; NCT06625320). Patients were required to have metastatic pancreatic adenocarcinoma with disease progression after receiving one prior line of systemic therapy, which included either a fluoropyrimidine-based or gemcitabine-based regimen, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, investigator-assessed measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1), and documentation of locally available RAS mutation status (mutant or wild-type).

A total of 500 patients were randomized 1:1 to receive either RASONQUE 300 mg orally once daily (N = 248) or physician's choice of standard of care (SOC) chemotherapy regimens (mFOLFIRINOX, gemcitabine and nab-paclitaxel, FOLFOX, or nal-IRI+5-FU/LV) (N = 252). Patients were treated until disease progression or unacceptable toxicity. The major efficacy outcomes were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review (BICR) in patients with a RAS G12 mutation (RAS G12 population). Additional efficacy outcomes included OS and PFS as assessed by BICR in the overall population and objective response rate (ORR) as assessed by BICR in the RAS G12 population and overall population.

The baseline demographics and disease characteristics were: median age 66 years (range: 30 to 88); 45% Female; 68% White, 11% Asian, 4% Black or African American; 50% ECOG PS 1; and 70% had liver metastases. Of the 500 patients randomized in the study, 92% of patients had KRAS G12 mutations, 5% had KRAS mutations at locations other than G12 (i.e., G13 and Q61), and 3% of patients did not have a RAS mutation detected by local testing.

RASolute 302 demonstrated a statistically significant improvement in OS, PFS, and ORR for patients treated with RASONQUE compared to SOC chemotherapy in the RAS G12 population and in the overall population.

Efficacy results for the overall population are summarized in Table 6 and Figures 1 and 2.

Table 6: Efficacy Results from RASolute 302 (Overall Population)

In the RAS G12 population (n = 459), median OS was 13.2 months in the RASONQUE arm vs. 6.6 months in the SOC chemotherapy arm [HR: 0.40 (95% CI: 0.30, 0.54), p-value < 0.0001] and median PFS assessed by BICR was 7.3 months in the RASONQUE arm vs. 3.5 months in the SOC chemotherapy arm [HR: 0.45 (95% CI: 0.34, 0.59), p-value < 0.0001]. Additionally, in the RAS G12 population, ORR assessed by BICR in all randomized patients was 32% (95% CI: 26%, 38%) in the RASONQUE arm vs. 11% (95% CI: 7%, 16%) in the SOC chemotherapy arm [p-value < 0.0001].

Figure 1: Kaplan-Meier Curve of Overall Survival in RASolute 302 (Overall Population)

Figure 2: Kaplan-Meier Curve of Progression-Free Survival by BICR in RASolute 302 (Overall Population)