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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]

Purpose: To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors.Methods: In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states.Results: Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC0-t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0-t was contained within the no-effect limits (0.8-1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported.Conclusion: A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals. [ABSTRACT FROM AUTHOR]

Introduction. Treatment selection tools are needed to enhance the efficacy of targeted treatment in patients with solid malignancies. Providing a readout of aberrant signaling pathways and proteolytic events, mass spectrometry-based (MS-based) peptidomics enables identification of predictive biomarkers, whereas the serum or plasma peptidome may provide easily accessible signatures associated with response to treatment. In this systematic review, we evaluate MS-based peptide profiling in blood for prompt clinical implementation. Methods. PubMed and Embase were searched for studies using a syntax based on the following hierarchy: (a) bloodbased matrix-assisted or surface-enhanced laser desorption/ ionization time-of-flight MS peptide profiling (b) in patients with solid malignancies (c) prior to initiation of any treatment modality, (d) with availability of outcome data. Results. Thirty-eight studies were eligible for review; the majority were performed in patients with non-small cell lung cancer (NSCLC). Median classification prediction accuracy was 80% (range: 66%-93%) in 11 models from 14 studies reporting an MS-based classification model. A pooled analysis of 9 NSCLC studies revealed clinically significantmedian progressionfree survival in patients classified as “poor outcome” and “good outcome” of 2.061.06 months and 4.661.60 months, respectively; median overall survival was also clinically significant at 4.0161.60 months and 10.5263.49 months, respectively. Conclusion. Pretreatment MS-based serum and plasma peptidomics have shown promising results for prediction of treatment outcome in patients with solid tumors. Limited sample sizes and absence of signature validation in many studies have prohibited clinical implementation thus far. Our pooled analysis and recent results from the PROSE study indicate that this profiling approach enables treatment selection, but additional prospective studies are warranted. [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]

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