Abstract
Background
Several treatment options were recently added for metastatic castration-resistant prostate cancer (mCRPC). However, response to therapy is variable, and biomarkers that can guide ...treatment selection and response evaluation are lacking. Circulating RNAs are a promising source of biomarkers. We explored messenger RNAs (mRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs) as potential biomarkers in liquid biopsies of patients with mCRPC treated with enzalutamide.
Methods
Forty patients were included in this prospective multicenter observational study. Whole blood was drawn at baseline and 1, 3, and 6 months after start of therapy. Four mRNAs, 6 miRNAs, and 5 lncRNAs were analyzed by quantitative PCR. RNA levels in 30 healthy individuals were used as controls. RNA expression data were analyzed by Kaplan–Meier and Cox regression analyses, and the primary end point was progression-free survival. Clinical factors were included in the multivariable Cox regression analysis.
Results
Levels of 2 miRNAs, miR-375 and miR-3687, and 1 lncRNA, N-acetylated alpha-linked acidic dipeptidase like 2 antisense RNA 2 (NAALADL2-AS2), were more than 2-fold higher in patients with mCRPC compared with healthy volunteers. Patients with higher levels of miR-375 or miR-3687 showed a shorter time to progression. Patients with higher levels of NAALADL2-AS2 showed a longer time to progression. In the multivariable Cox regression analysis, higher miR-375, miR-3687 and serum prostate-specific antigen concentrations were shown to be independent predictors for shorter time to progression.
Conclusions
We identified miR-3687 as a novel prognostic marker for response in patients with CRPC treated with enzalutamide, and we confirmed the prognostic value of miR-375.
Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in ...the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs.
In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.
A sensitive and selective ultra‐high performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, ...i.e. olaparib and niraparib, and five tyrosine kinase inhibitors, i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib and regorafenib, plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope‐labelled internal standards were used for each analyte. A simple protein precipitation method was performed with acetonitrile. The LC–MS/MS system consisted of an Acquity H‐Class UPLC system, coupled to a Xevo TQ‐S micro tandem mass spectrometer. The compounds were separated on a Waters CORTECS UPLC C18 column (2.1 × 50 mm, 1.6 μm particle size) and eluted with a gradient elution system. The ions were detected in the multiple reaction monitoring mode. The method was validated for cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and regorafenib M2 over the ranges 6–1000, 100–5000, 10–4000, 200–2000, 200–20,000, 5000–100,000, 500–10,000 and 500–10,000 μg/L, respectively. Within‐day accuracy values for all analytes ranged from 86.8 to 115.0% with a precision of <10.4%. Between‐day accuracy values ranged between 89.7 and 111.9% with a between‐day precision of <7.4%. The developed method was successfully used for guiding therapy with therapeutic drug monitoring in cancer patients and clinical research programs in our laboratory.
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.
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.
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.
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;
= 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;
< 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;
= 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48;
= 0.54 for OS).
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.
Context:
Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib.
Objective:
The objective of the study was to ...determine the antitumor effects of sunitinib in refractory ACC.
Design:
This was a phase II, open-label trial using a two-stage accrual design.
Setting:
The study was conducted at two tertiary referral centers.
Patients:
Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study.
Intervention:
The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off).
Main Outcome Measure:
Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation).
Results:
Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35 = 14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0–33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r = −0.650; P = 0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction.
Conclusion:
Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.
All patients treated with anticancer agents should receive the most effective anti‐emetic regimen. Anti‐emetic guidelines provide recommendations but do not take into account possible drug–drug ...interactions between anti‐emetics and anticancer drugs. This study determines the clinical relevance of the potential drug–drug interaction of the neurokinin‐1 receptor antagonist, aprepitant, on the pharmacokinetics of etoposide. Aprepitant is a moderate CYP3A4 inhibitor and may increase the systemic exposure of etoposide which is partly metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). In this prospective observational study, the pharmacokinetics of etoposide with and without concomitant use of aprepitant was determined in 12 patients receiving first‐line chemotherapy for testicular cancer. The geometric mean (95% confidence interval (CI)) area under the plasma concentration‐time curve 0–24 hour (AUC0–24h) of etoposide with aprepitant was 86.2 (79.7–93.2) mg/L*hour vs. 83.7 (75.8–92.4) mg/L*hour without aprepitant. Geometric mean ratios (90% CIs) of AUC0–24h and maximum plasma concentration (Cmax) for etoposide with and without aprepitant were 1.03 (0.96–1.10) and 0.96 (0.89–1.03), respectively. This study confirms the absence of a clinically relevant interaction between etoposide and aprepitant. Both drugs can be safely combined without affecting etoposide exposure.
•Development and validation of an assay for quantifying 6 TKIs and 2 metabolites.•The combination of TKIs is unique by incorporating regorafenib and pazopanib.•Due to large differences in detection ...ranges, the assay is challenging.•The method is used to explore the value of TDM and to support IIS proposals.
A sensitive, sophisticated and practical bioanalytical assay for the simultaneous determination of six tyrosine kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib, pazopanib, regorafenib) and two active metabolites (N-desmethyl imatinib and N-desethyl sunitinib) was developed and validated. For the quantitative assay, a mixture of three stable isotopes as internal standards was added to human serum, standards and controls. Thereafter, samples were pre-treated using protein precipitation with methanol. The supernatant was diluted with water and injected into an ultra pressure liquid chromatographic system with an Acquity TQ tandem mass spectrometry detector. The compounds were separated on an Acquity BEH C18 analytical column (100mm×2.1mm ID, 1.7μm particle size) and eluted with a linear gradient system. The ions were detected in the multiple reaction monitoring mode. The lower limit of quantification and the linearity of all compounds generously met with the concentrations that are to be expected in clinical practice. The developed bioanalytical assay can be used for guiding TKI therapy in daily clinical practice as well as for investigator-initiated research.
Co‐treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH‐dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our ...study, we investigated whether a 1‐hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady‐state pazopanib trough concentration (Cmin) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non‐GAS users for both the 800 and 600 mg cohorts (23.7 mg/L 95% confidence interval CI: 21.1‐26.7 vs 28.2 mg/L 95% CI: 25.9‐30.5, P = .015 and 26.0 mg/L 95% CI: 22.4‐30.3 vs 33.5 mg/L 95% CI: 30.3‐37.1, P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non‐GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub‐analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non‐users. Our research showed that a 1‐hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.
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