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Simple Summary: Multitargeted tyrosine kinase inhibitors (TKIs) provide clinical benefit in patients with cancer when daily dosed to continuously inhibit their designated targets. Alternative dosing strategies pursuing higher tumor drug concentrations may improve their benefit by inhibiting relevant off-target kinase activity. We studied the tumor-drug exposure in a previously established safe and feasible high-dose intermittent treatment strategy of the multikinase inhibitor sunitinib in relation to its treatment benefit. Patients with advanced cancer refractory to standard treatment were treated with sunitinib at a dose of 300 mg once every week (Q1W) or 700 mg once every two weeks (Q2W). Tumor, skin and plasma concentrations were measured and immunohistochemical staining for tumor cell proliferation (TCP), microvessel density (MVD) and T-cell infiltration was performed on tumor biopsies before and after 17 days of treatment. Oral administration of 300 mg sunitinib Q1W or 700 mg Q2W resulted in 19-fold (range 5–35×) and 37-fold higher (range 10–88×) tumor drug concentrations compared to parallel maximum plasma drug concentrations, respectively. Patients with higher tumor sunitinib concentrations had favorable progression-free and overall survival than those with lower concentrations (p = 0.046 and 0.024, respectively). In addition, immunohistochemistry of tumor biopsies revealed an induction of T-cell infiltration upon treatment. These findings provide pharmacological and biological insights in the clinical benefit from high-dose intermittent sunitinib treatment. It emphasizes the potential benefit from reaching higher tumor drug concentrations and the value of measuring TKI tumor- over plasma-concentrations. The finding that reaching higher tumor drug concentrations provides most clinical benefit in patients with treatment refractory malignancies indicates that the inhibitory potency of sunitinib may be enforced by a high-dose intermittent treatment schedule. These results provide proof of concept for testing other clinically available multitargeted tyrosine kinase inhibitors in a high-dose intermittent treatment schedule. [ABSTRACT FROM AUTHOR]

Simple Summary: About 20% of patients with cancer who participate in a phase I clinical trial discontinue the trial early. Early trial discontinuation is undesirable both for the wellbeing of the patient as well as for the trial efficiency and the development of new anticancer drugs. We investigated which clinical predictors at baseline were significantly associated with early trial discontinuation of patients with cancer who participated in phase I clinical trials. The clinical predictors which were identified in this study were hyponatremia, elevated alkaline phosphatase level, performance score of 1 or higher and opioid use. Hyponatremia especially, which was the strongest predictor, should be considered to be used as an additional eligibility criterion in order to reduce the early trial discontinuation of patients with cancer who participate in phase I clinical trials. Despite stringent eligibility criteria for trial participation, early discontinuation often occurs in phase I trials. To better identify patients unlikely to benefit from phase I trials, we investigated predictors for early trial discontinuation. Data from 415 patients with solid tumors who participated in 66 trials were pooled for the current analysis. Early trial discontinuation was defined as (i) trial discontinuation within 28 days after start of treatment or (ii) discontinuation before administration of the first dosage in eligible patients. Multilevel logistic regression analyses were conducted to identify predictors for early trial discontinuation. Eighty-two participants (20%) demonstrated early trial discontinuation. Baseline sodium level below the lower limit of normal (OR = 2.95, 95%CI = 1.27–6.84), elevated alkaline phosphatase level > 2.5 times the upper limit of normal (OR = 2.72, 95%CI = 1.49–4.99), performance score ≥ 1 (OR = 2.07, 95%CI = 1.03–4.19) and opioid use (OR = 1.82, 95%CI = 1.07–3.08) were independent predictors for early trial discontinuation. Almost 50% of the patients with hyponatremia and all four patients in whom all four predictors were present together discontinued the trial early. Hyponatremia, elevated alkaline phosphatase level, performance score ≥ 1 and opioid use were identified as significant predictors for early trial discontinuation. Hyponatremia was the strongest predictor and deserves consideration for inclusion in eligibility criteria for future trials. [ABSTRACT FROM AUTHOR]

Identification of predictive biomarkers for targeted therapies requires information on drug exposure at the target site as well as its effect on the signaling context of a tumor. To obtain more insight in the clinical mechanism of action of protein kinase inhibitors (PKIs), we studied tumor drug concentrations of protein kinase inhibitors (PKIs) and their effect on the tyrosine-(pTyr)-phosphoproteome in patients with advanced cancer. Tumor biopsies were obtained from 31 patients with advanced cancer before and after 2 weeks of treatment with sorafenib (SOR), erlotinib (ERL), dasatinib (DAS), vemurafenib (VEM), sunitinib (SUN) or everolimus (EVE). Tumor concentrations were determined by LC-MS/MS. pTyr-phosphoproteomics was performed by pTyr-immunoprecipitation followed by LC-MS/MS. Median tumor concentrations were 2–10 µM for SOR, ERL, DAS, SUN, EVE and >1 mM for VEM. These were 2–178 × higher than median plasma concentrations. Unsupervised hierarchical clustering of pTyr-phosphopeptide intensities revealed patient-specific clustering of pre- and on-treatment profiles. Drug-specific alterations of peptide phosphorylation was demonstrated by marginal overlap of robustly up- and downregulated phosphopeptides. These findings demonstrate that tumor drug concentrations are higher than anticipated and result in drug specific alterations of the phosphoproteome. Further development of phosphoproteomics-based personalized medicine is warranted. [ABSTRACT FROM AUTHOR]