A novel cabozantinib formulation with reduced pharmacokinetic variability and the potential to improve safety in patients with renal cell carcinoma.

Abstract

512 Background: Cabozantinib is a standard treatment for advanced renal cell carcinoma (RCC) which exhibits substantial pharmacokinetic (PK) variability and high rates of dose modification (>75% of patients) and treatment interruption. A novel cabozantinib formulation comprising an alternate salt form, has been developed to provide pH-independent solubility and reduced PK variability while achieving equivalent average systemic exposure. Methods: Two single-dose clinical studies in healthy participants evaluated bioequivalence and impact of food on a novel cabozantinib formulation compared to a reference formulation of cabozantinib 60 mg. Population PK models were developed using these data for a novel cabozantinib formulation and the reference cabozantinib formulation and applied to predict steady-state concentration (C avg,ss ) in a virtual cohort of 2,000 RCC patients with demographics and dose reduction patterns for the reference formulation consistent with the METEOR trial. Hazard ratios (HR) for clinically relevant safety endpoints were derived for the virtual population based on model-predicted exposure and published exposure-response relationships. Results: A novel cabozantinib formulation achieved bioequivalent systemic exposure to cabozantinib (34.5 mg ≈ 60 mg) with no food effect and reduced inter-subject variability relative to the reference formulation. Correspondingly, the distribution of simulated C avg,ss was narrower for a novel cabozantinib formulation, with fewer patients exceeding the toxicity threshold (>1,350 ng/mL). This reduced variability in exposure translates to reduced HRs for key safety endpoints comparing high exposure patients (90 th percentile) to median exposure patients (50 th percentile) for a novel cabozantinib formulation 34.5 mg relative to cabozantinib 60 mg. Conclusions: A novel cabozantinib formulation demonstrates bioequivalence to cabozantinib with reduced PK variability and no impact of food on exposure. Modeling predicts lower risk of exposure-related toxicities among high exposure patients, which has the potential to maximize dose intensity and long-term outcomes by improving safety and treatment continuity reducing the risk of compromising dose interruptions and reductions. Model-predicted hazard ratios for clinically relevant safety endpoints in high exposure patients (90 th percentile) relative to median exposure patients. Adverse Event Hazard RatiosNovel Cabozantinib Formulation 34.5 mg Hazard RatiosCabozantinib 60 mg % HR Comparison Reduction Palmar-plantar erythrodysesthesia (PPE) 2.46 7.08 65% Diarrhea 1.92 4.11 53% Hypertension 2.01 4.53 56% Fatigue/Asthenia 2.21 5.59 61%