The effect of gastrectomy on regorafenib exposure and progression-free survival in patients with advanced gastrointestinal stromal tumours

Contains fulltext : 208932.pdf (publisher's version ) (Open Access)AIMS: We investigated whether major gastrectomy influences the plasma exposure of regorafenib and treatment outcome. METHODS: Efficacy and pharmacokinetic data from 133 gastrointestinal stromal tumour patients included in a phase III trial were analysed. Patients were subdivided into 2 groups according to the extent of the gastrectomy (no/nonsignificant gastrectomy and major gastrectomy). Progression-free survival (PFS) on regorafenib was measured and regorafenib and its pharmacological active metabolites plasma exposure were measured. RESULTS: A total of 133 patient were included, of whom 27 underwent major gastrectomy. In patients with no/nonsignificant gastrectomy the median PFS was 145 (interquartile range 43-281) days. The PFS in patients with a major gastrectomy was 172 (interquartile range 57-280) days. Regorafenib pharmacokinetic samples were collected in 80 patients of which 19 patients with a major gastrectomy and 61 patients with no/nonsignificant gastric surgery. The average +/- standard deviation total concentration of regorafenib including the metabolites M-2 and M-5 was 6.9 +/- 1.53 mumol/L and 6.7 +/- 1.56 mumol/L in patient with major gastrectomy and no/nonsignificant gastrectomy respectively. CONCLUSION: Our study shows that major gastrectomy did not influence plasma exposure of regorafenib and metabolites. In addition, no difference in PFS between the subgroups was seen

Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials

Purpose: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects.Experimental Design: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients.Results: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; P = 0.54 for OS).Conclusions: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy

Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Background and Objective: As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations. Methods: The decreased function alleles CYP3A4 15389 C > T (*22), ABCB1 3435 C >T, ABCG2 421 C >A, and ABCG2 34G >A were analyzed within a recently developed population-pharmacokinetic model. Results: Incorporation of CYP3A4*22 in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: − 9.7; p < 0.005). Simulated median trough concentrations of cancer patients with CYP3A4*22 with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively. Conclusion: This analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered

Lost in third space: altered tyrosine-kinase inhibitor pharmacokinetics in a patient with malignant ascites

BACKGROUND: Pazopanib and sunitinib are oral tyrosine kinase inhibitors (TKI) approved for the treatment of renal cell carcinoma. For both oncolytics, a clear target trough concentration level in plasma has been defined above which improved clinical efficacy can be expected. However, many factors can alter TKI exposure, including disease characteristics. CASE: A 79-year old male with metastatic papillary renal cell carcinoma and malignant ascites was treated with pazopanib. Initially, treatment with pazopanib at adequate trough concentrations resulted in regression of ascites. After a 6-month puncture-free interval, paracenteses were again required and the plasma trough concentration of pazopanib had decreased to 5 mg/L without any dose adjustments. Despite a dose increase, pazopanib levels remained subtherapeutic and could not prevent new paracenteses. Pazopanib concentrations in the drained ascites fluid were comparable to plasma concentrations and remained high also after treatment discontinuation. This observation suggests that the ascites compartment may act as a third space in which pazopanib accumulates. During subsequent treatment with sunitinib, a similar distribution over ascites fluid was observed. CONCLUSION: Presence of ascites or pleural effusion in patients treated with TKIs may lead to subtherapeutic plasma exposure, which may hamper treatment efficacy. Measuring TKIs plasma concentrations regularly during treatment is essential to identify patients with subtherapeutic exposure

Pressurized Intraperitoneal Aerosol Chemotherapy: The Road from Promise to Proof

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative drug delivery technique invented to be used for the treatment of peritoneal metastasis. Its application gained popularity over the past years. Several prospective clinical trials are being conducted to determine efficacy and safety. At this moment, there remain many challenges to overcome before PIPAC can be widely adopted in clinical practice.See related article by Kim et al., p. 1875