Characterization Of The Exposure-Response Relationship Leading To Recommendations For Dosing Optimization In A New Drug Application Review.

2510 Background: On November 29 2012, the U. S. FDA approved cabozantinib (COMETRIQ) for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). Drug-related toxicity was common at a dose of 140 mg once daily across Phase 1 to Phase 3 trials submitted in this NDA. During the review of this application, these safety findings raised the question whether the optimal cabozantinib dose was selected for the treatment of MTC. Exposure-response (E-R) analyses were performed to assess the appropriateness of the cabozantinib dose. Methods: The data were obtained from an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. To account for variable exposure levels due to dose modification and inter-individual pharmacokinetic variability, average exposure (Starting Dose*Dose intensity/individual CL/F) was used as the exposure metric in the E-R analyses. The relationships between cabozantinib exposure and progression free survival (PFS), and selected safety endpoints including diarrhea, palmar-plantar erythrodysesthesia (PPE) syndrome and time to dose modification (TTDM) were evaluated. Results: Kaplan-Meier analyses of PFS for each quartile of average cabozantinib exposure suggest that patients with lower exposure and those with higher exposure may have equivalent PFS, comparatively. The multivariate Cox proportional analysis identified individual patient’s clearance as a significant covariate for prediction of TTDM with a hazard ratio of 1.95 (95% CI [1.47-2.59]), suggesting that patients with higher exposures required dose modification earlier than patients with lower exposures. The results of the E-R analyses may be difficult to interpret due to the high rate of dose modification. Nevertheless, these results indicate that a lower dose may be as effective with improved tolerability. Conclusions: The E-R analyses along with the observed safety and efficacy data in the clinical trials led to an FDA requirement to conduct a post marketing clinical trial to evaluate the safety and efficacy of a lower cabozantinib dose.