Exposure–Response Modeling and Simulation of Progression‐Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer

Abstract

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure–response relationships, including progression‐free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction‐corrected visual predictive check (pc‐VPC) was developed to show robustness of the exposure–response relationships. Time‐to‐event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose‐reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand‐foot skin reactions).

Brigatinib Dose Rationale in Anaplastic Lymphoma Kinase–Positive Non‐Small Cell Lung Cancer: Exposure–Response Analyses of Pivotal ALTA Study

“…The utility of parametric TTE modeling in exposure-efficacy modeling of oncology therapies has been previously described. 18 In the models for PFS and OS, both brigatinib exposure and baseline tumor burden were significant predictors of PFS. The observed relationship between baseline tumor burden and survival outcomes is consistent with results of the alectinib exposure-response analysis in crizotinib-refractory patients.…”

“…A time‐varying (nonstatic) exposure metric (i.e., daily time‐varying AUC) was shown to be significantly associated with time to PFS, iPFS, and OS in the longitudinal parametric TTE models. The utility of parametric TTE modeling in exposure–efficacy modeling of oncology therapies has been previously described 18 …”

Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors

“…Sorafenib exposure at steady state (C1D7) with 200 mg twice a day was higher than historical values with sorafenib alone (AUC 0-8 23,077 vs. 6,000-16,000 ng/h/mL) and might account for the higher toxicity rates we observed (35). Sorafenib PK tended to correlate with toxicity and efficacy in some studies (36). In our study, sorafenib exposure was higher among responding patients, but we did not observe definitive correlations with toxicity or survival.…”

Advancements in the treatment of differentiated thyroid cancer

“… 97 , 98 Kinase inhibitor therapy is often limited by its side-effect profile, which includes nausea, diarrhea, fatigue, weight loss, hand-foot syndrome, hypertension, and QTc prolongation, so medical comorbidities should be assessed prior to therapy. 12 , 18 , 43 , 99 , 100 Although significant, treatment-emergent hypertension in lenvatinib therapy has been correlated with improved outcomes. 101 Moreover, tumors eventually develop resistance to kinase inhibitor therapy through an escape mechanism, reducing the efficacy of therapy.…”