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PurposeThis review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed.MethodsA comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted.ResultsOADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy.ConclusionSub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.

Some cancer therapies damage DNA and cause mutations in both cancerous and healthy cells. Therapy-induced mutations may underlie some of the long-term and late side effects of treatments, such as mental disabilities, organ toxicity and secondary neoplasms. Nevertheless, the burden of mutation contributed by different chemotherapies has not been explored. Here we identify the mutational signatures or footprints of six widely used anticancer therapies across more than 3,500 metastatic tumors originating from different organs. These include previously known and new mutational signatures generated by platinum-based drugs as well as a previously unknown signature of nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of contributing coding and potential driver mutations in the genome. The mutational footprints identified here allow for precise assessment of the mutational risk of different cancer therapies to understand their long-term side effects. Analysis of whole-genome sequences from more than 3,500 metastatic tumors identifies mutational signatures associated with different chemotherapies and provides estimates of the relative contribution of different treatments to tumor mutational burden.

Colorectal cancers with BRAF mutations have an aggressive natural history and are often resistant to therapy. A treatment regimen that combined BRAF inhibition, MET inhibition, and blocking of EGFR signaling resulted in a response rate of 26% and a median overall survival of 9 months.

In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance. Molecular landscapes of metastatic colorectal cancers (mCRC) have often been restricted to coding regions or low numbers of patients. Here the authors present a whole-genome landscape of 429 mCRC patients, revealing the mutational impact of prior therapies and potential actionable targets.

PurposeWhile in the era of precision medicine, the right drug for each patient is selected based on molecular tumor characteristics, most novel oral targeted anticancer agents are still being administered using a one-size-fits-all fixed dosing approach. In this review, we discuss the scientific evidence for dose individualization of oral targeted therapies in oncology, based on therapeutic drug monitoring (TDM).MethodsBased on literature search and our own experiences, seven criteria for drugs to be suitable candidates for TDM will be addressed: (1) absence of an easily measurable biomarker for drug effect; (2) long-term therapy; (3) availability of a validated sensitive bioanalytical method; (4) significant variability in pharmacokinetic exposure; (5) narrow therapeutic range; (6) defined and consistent exposure-response relationships; (7) feasible dose-adaptation strategies.ResultsAll of these requirements are met for most oral targeted therapies in oncology. Also, prospective studies have already shown TDM to be feasible for imatinib, pazopanib, sunitinib, everolimus, and endoxifen.ConclusionsIn order to realize the full potential of personalized medicine in oncology, patients should not only be treated with the right drug, but also at the right dose. TDM could be a suitable tool to achieve this.

Although kinase inhibitors (KI) frequently portray large interpatient variability, a ‘one size fits all’ regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels—i.e., therapeutic drug monitoring (TDM)—could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12 −/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12 −/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups. Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.

There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations ( C trough ) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly C trough , and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.

Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.

BackgroundInterleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy.MethodsPatients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0–10.0 mg/kg) of weekly CAN04.ResultsTwenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses.ConclusionsThe IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition.Clinical trial registrationNCT03267316.