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The article discusses the potential use of therapeutic drug monitoring (TDM) for oral oncology drugs. TDM is a strategy that can be used to optimize drug dosing, but its usefulness and potential harm in the context of oral oncology drugs are uncertain. The article argues that individualizing dosing for these drugs is premature due to the lack of randomized dose-ranging trials. The authors propose criteria for identifying drugs that may be suitable for TDM, but the article raises concerns about the reliability of exposure-response analyses and the potential dangers of TDM in certain cases. Overall, the article suggests that the promotion of TDM for oral oncology drugs is premature and not supported by current evidence. [Extracted from the article]

Atezolizumab, a humanized monoclonal antibody against programmed cell death ligand 1 (PD‐L1), was initially approved in 2016, around the same time that the sponsor published the minimum serum concentration to maintain the saturation of receptor occupancy (6 μg/mL). The initially approved dose regimen of 1200 mg every 3 weeks (q3w) was subsequently modified to 840 mg q2w or 1680 mg q4w through pharmacokinetic simulations. Yet, each standard regimen yields steady‐state trough concentrations (CMIN,SS) far exceeding (≈ 40‐fold) the stated target concentration. Additionally, the steady‐state area under the plasma drug concentration–time curve (AUCSS) at 1200 mg q3w was significantly (P =.027) correlated with the probability of adverse events of special interest (AESIs) in patients with non‐small cell lung cancer (NSCLC) and, coupled with excess exposure, this provides incentive to explore alternative dose regimens to lower the exposure burden while maintaining an effective CMIN,SS. In this study, we first identified 840 mg q6w as an extended‐interval regimen that could robustly maintain a serum concentration of 6 μg/mL (≥99% of virtual patients simulated, n = 1000), then applied this regimen to an approach that administers 2 "loading doses" of standard‐interval regimens for a future clinical trial aiming to personalize dose regimens. Each standard dose was simulated for 2 loading doses, then 840 mg q6w thereafter; all yielded cycle‐7 CMIN,SS values of >6 μg/mL in >99% of virtual patients. Further, the AUCSS from 840 mg q6w resulted in a flattening (P =.63) of the exposure–response relationship with adverse events of special interest (AESIs). We next aim to verify this in a clinical trial seeking to validate extended‐interval dosing in a personalized approach using therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Research biopsies included in cancer clinical trials have the goal of advancing scientific understanding of the biological bases of cancer and its treatments, but may offer no prospect of direct benefit to participants and often pose more than minimal risk. The research community is examining the ethics of research biopsies increasingly often, especially when they are mandatory for study participation but do not support primary study objectives and thus are "nonintegral" to the study. Ethical concerns center on the limited scientific justification supporting some biopsies, risks to research participants, and the potential for coercion and therapeutic misconception during the informed consent process. There is also a lack of comprehensive oversight of research biopsies by regulatory agencies and institutions. This paper reviews these ethical concerns, discusses the scope of federal oversight, and suggests that institutional review boards (IRBs) should assume a larger role in ensuring the ethical conduct of research biopsies. It concludes with guidance to IRBs on how to weigh the risks, benefits, and acceptability of such biopsies in different contexts that is based on a framework the American Society of Clinical Oncology developed for the inclusion of research biopsies in oncology clinical trials. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care. METHODS: Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5‐fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab‐govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high‐risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies. RESULTS: Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high‐risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one‐third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype. CONCLUSIONS: These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling. LAY SUMMARY: Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others.Pharmacogenomics is the study of how genetic variations affect an individual's response to medications.In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy.By analyzing the genetic results of >1500 patients, it was found that nearly one‐third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given.Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care. Nearly one‐third of individuals have actionable germline genetic variants that may impact the choice or dosing of common anticancer therapies. Preemptive germline genotyping to help guide personalized oncologic prescribing during cancer care may complement widespread somatic profiling to improve treatment selection and tolerability. [ABSTRACT FROM AUTHOR]

Nivolumab and pembrolizumab, anti–programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half‐lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that >95% of patients maintained ≥1.5 μg/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in >95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that >95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy‐driven comparative trial. [ABSTRACT FROM AUTHOR]

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta‐analysis of genome‐wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause‐specific Cox model was used to test the SNP‐OS association in both arms combined (prognostic), and the effect of SNPs‐bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta‐analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10−7, hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33‐1.86), as well as in TCGA (P =.0219, HR = 1.58, 95% CI 1.07‐2.35). In the GWAS meta‐analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10−5, HR = 1.51, 95% CI 1.25‐1.82) as well as in TCGA (P = 1.39 × 10−4, HR = 3.09, 95% CI 1.73‐5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10−5). The largest GWAS meta‐analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival. What's new? Bevacizumab improves overall survival in patients with advanced cancers, but no biomarkers are currently available to identify the patients who would benefit from treatment. In this GWAS meta‐analysis of 1,520 cancer patients treated with bevacizumab‐containing regimens, the authors provide evidence of potentially‐prognostic germline variants in the tumour suppressor genes PRUNE2 and BARD1 in advanced colorectal and ovarian cancer, respectively. They also identify a potentially‐predictive germline variant in AGAP1 that should be further evaluated as a marker affecting the response of patients to bevacizumab. [ABSTRACT FROM AUTHOR]

Aims: Rociletinib showed activity in T790M‐positive non‐small cell lung cancer patients. It undergoes amide hydrolysis to form M502, followed by N‐acetylation to M544 or amide hydrolysis to M460. We identified the enzymes responsible for rociletinib metabolism, and investigated the relationship between M544 formation and N‐acetyltransferase 2 (NAT2) polymorphisms. Methods: Rociletinib and metabolites were incubated with carboxylesterase (CES)1b, CES1c, CES2, NAT1, NAT2, arylacetamide deacetylase, inhibitors, pooled human liver microsomes (HLM) and cytosols (HLC). Cytosols (n = 107) were genotyped for NAT2 polymorphisms (rs1041983 and rs1801280) and incubated with M502. Human hepatocytes from intermediate (NAT2*6/*12A) and slow (NAT2*5B/*5B) acetylators were incubated with 10 μM rociletinib and metabolites for 24 hours. Metabolites were measured by high‐performance liquid chromatography. Results: M502 was formed from rociletinib and M544 by CES2 and HLM; M544 and N‐acetyl‐M460 were formed by NAT2 and HLC; M460 was not formed by CES or arylacetamide deacetylase. M502 formation by HLM was inhibited by bis‐(4‐nitrophenyl)phosphate and eserine (10 μM). M544 formation in HLC was inhibited by 100 μM quercetin and was associated with NAT2 genotype (P <.0001). M460 formation in HLM was inhibited by eserine, and M460 was N‐acetylated in HLC. Hepatocytes formed M502, M544 and M460. The intermediate acetylator showed higher production (range: 3.4–5.1‐fold) of N‐acetylated metabolites than the slow acetylator. Conclusions: Results indicate that NAT2 and CES2 are involved in rociletinib metabolism, and polymorphic NAT2 could alter drug exposure in patients. Slow NAT2 acetylators would have higher exposure to M502 and M460 and consequently, be at increased risk of experiencing hyperglycaemia and QTc prolongation. [ABSTRACT FROM AUTHOR]

The article presents the discussion on unintended consequences of widespread distribution of a ritonavir-containing product. Topics include coformulation of N + R enabling the maintenance of effective antiviral concentrations of nirmatrelvir over a full 24-hour period with twice-daily dosing; and patients on chronic medications for conditions predisposing to severe COVID-19 infection.

Therapeutic drug monitoring (TDM) involves frequent measurements of drug concentrations to ensure levels remain within a therapeutic window, and it is especially useful for drugs with narrow therapeutic indices or extensive interindividual pharmacokinetic variability. This technique has never been applied to immuno‐oncology drugs, but, given recent examinations of clinical data (both exposure and response) on a number of these drugs, further investigations into TDM may be justified to reduce costs as well as potentially reducing the severity and/or duration of immune‐related adverse events. Specifically, all but one of the approved PD‐1 and PD‐L1 inhibitors (pembrolizumab, nivolumab, cemiplimab‐rwlc, atezolizumab, avelumab, durvalumab) have been shown to exhibit a plateaued exposure‐response (E‐R) curve at doses evaluated extensively to date, as well as time‐dependent changes in drug exposure. Furthermore, responders have a greater decrease in drug clearance over time and would, therefore, have supratherapeutic serum concentrations. With frequent trough measurements, it is possible to use pharmacokinetic modelling and simulation to estimate drug clearance via Bayesian methods. Based on patient‐specific estimates for clearance, optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels, especially as the clearance of the drug decreases over time. This review will comprehensively discuss each of the FDA approved PD‐1, PD‐L1/2 and CTLA‐4 inhibitors regarding their indications and current recommended dosing, with evidence supporting the investigation of these types of TDM strategies. [ABSTRACT FROM AUTHOR]

Cancer care's sustainability is challenged by drug expenditures. In the absence of systemic change, innovation is needed to curtail drug costs. Interventional pharmacoeconomics (IVPE) utilizes clinical research to identify safe, efficacious, cost‐conscious dosing regimens to extract maximum value from expensive therapies. Strategies include de‐escalation of dosage, treatment duration and administration frequency, and substitution with therapeutic alternatives. In this review, we discuss how IVPE strategies have been successfully used and could be implemented going forward. [ABSTRACT FROM AUTHOR]

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose‐limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA‐induced PN. A meta‐analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause‐specific risk of PN were meta‐analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine‐1‐phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254–0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334–1.053); PMETA = 3.62 × 10−7) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell‐derived human sensory neurons shows partial protection against paclitaxel‐induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA‐induced neuropathy. [ABSTRACT FROM AUTHOR]

Poor adherence is associated with worse disease outcomes. Pharmacogenomics provides a possible intervention to address adherence. We hypothesized that pharmacogenomic‐informed care could increase adherence. Patients in a prospective case‐control study underwent preemptive pharmacogenomic genotyping with results available for provider use at the point of care; controls (not genotyped) were treated by the same providers. Over 6,000 e‐prescriptions for 39 medications with actionable pharmacogenomic information were analyzed. Composite adherence, measured by modified proportion of days covered (mPDC), was compared between cases/controls and genomically concordant vs. genomically higher‐risk medications. Overall, 536 patients were included. No difference in mean mPDC was observed due to availability of pharmacogenomic guidance. However, case patients prescribed high‐risk pharmacogenomic medications were more than twice as likely to have low mPDC for these medications compared with genomically concordant prescriptions (odds ratio = 2.4 (1.03–5.74), P < 0.05). This study is the first to show that composite pharmacogenomic information predicts adherence. [ABSTRACT FROM AUTHOR]

Expression quantitative trait locus (eQTL) studies in human liver are crucial for elucidating how genetic variation influences variability in disease risk and therapeutic outcomes and may help guide strategies to obtain maximal efficacy and safety of clinical interventions. Associations between expression microarray and genome‐wide genotype data from four human liver eQTL studies (n = 1,183) were analyzed. More than 2.3 million cis‐eQTLs for 15,668 genes were identified. When eQTLs were filtered against a list of 1,496 drug response genes, 187,829 cis‐eQTLs for 1,191 genes were identified. Additionally, 1,683 sex‐biased cis‐eQTLs were identified, as well as 49 and 73 cis‐eQTLs that colocalized with genome‐wide association study signals for blood metabolite or lipid levels, respectively. Translational relevance of these results is evidenced by linking DPYD eQTLs to differences in safety of chemotherapy, linking the sex‐biased regulation of PCSK9 expression to anti‐lipid therapy, and identifying the G‐protein coupled receptor GPR180 as a novel drug target for hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Chemotherapy‐induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient‐reported outcome and (2) propose a dose‐adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose‐neuropathy model was developed using dosing and patient‐reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin–bound paclitaxel or ixabepilone as first‐line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose‐adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin–bound paclitaxel, and ixabepilone, simulations with the proposed dose‐adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient‐reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies. [ABSTRACT FROM AUTHOR]

Our objective was to build a mock pharmacogenomic (PGx) patient portal and assess its ability to disseminate test results and information to patients. The YourPGx Portal delivered four sample PGx results (omeprazole, simvastatin, clopidogrel, and codeine). We hosted two study groups to assess patient knowledge and perceptions of PGx before and after accessing the portal. Ten PGx‐tested and 10 traditional care participants were included (average 61 years, 60% women, 50% African American, and 55% had a bachelor's/advanced degree). Participants scored significantly higher on the post‐test compared with the pre‐test, with no significant differences between baseline scores or score change between the groups. Patient perceptions also improved after accessing the portal—more patients wanted their providers to have access to test results, and more patients would encourage family/friends to get PGx testing. Patients would share their test results with their healthcare providers, spouse/partner, and family; none would share results with their friends or social media. Almost all patients (95%) said the portal was easy to use and 65% said it was easy to understand. In this pilot study, patients' knowledge and perceptions of PGx improved after accessing the YourPGx Portal. [ABSTRACT FROM AUTHOR]

This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug‐drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady‐state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04‐1.49), 1.30 (1.11‐1.53) and 1.28 (1.11‐1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration‐time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16‐1.66), minimum plasma concentration (1.53; 1.10‐2.12) and area under the concentration‐time curve from time zero to 8 hours (1.41; 1.19‐1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients. [ABSTRACT FROM AUTHOR]

Many medications commonly used in the perioperative setting have well-known pharmacogenomic associations, and interindividual variability in responses can lead to decreased efficacy and/or adverse drug events (ADEs), resulting in devastating patient morbidity and mortality. Patient exclusion criteria include (i) patients who have undergone, or are being actively considered for, liver or kidney transplantation; (ii) patients with known active or prior leukemia; and (iii) patients who are unable to understand and give informed consent to participate. For both arms, all medications prescribed/administered will be tracked and patients will be monitored through the course of their perioperative care to determine the occurrence of pharmacogenomic-related drug toxicity and efficacy through medical record review. Each summary will employ our traffic light iconography - red "warning", yellow "caution", and green "favorable" lights - to provide physicians patient-specific recommendations of each drug-gene pair. [Extracted from the article]

Effect of doxorubicin plus olaratumab vs doxorubicin plus placebo on survival in patients with advanced soft tissue sarcomas: the ANNOUNCE randomized clinical trial. ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. [Extracted from the article]

Genome‐wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods, such as elastic net regularization, have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression‐free survival (PFS) of 468 patients with advanced breast cancer in a clinical trial of paclitaxel, nab‐paclitaxel, and ixabepilone. A final model included 13 single nucleotide polymorphisms (SNPs) in addition to clinical covariates (prior taxane status, hormone receptor status, disease‐free interval, and presence of visceral metastases) with an area under the curve (AUC) integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting PFS with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) can be seen as a model for biomedical studies: it includes all disease areas of interest and spans in vitro studies to clinical trials, while focusing on the relationships between genes and drugs and the resulting phenotypes. This review will examine different characteristics of PGx study publications and provide examples of excellence in framing PGx questions and reporting their resulting data in a way that maximizes the knowledge that can be built on them. [ABSTRACT FROM AUTHOR]

Background: Two germ line Fc‐γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab‐treated chemotherapy‐refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log‐rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results: Of 592 wild‐type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/‐ genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double‐variant R/R + V/V genotype. Progression‐free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild‐type KRAS, cetuximab‐treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients. FCGR2A genotype was associated with efficacy but not with toxicity in wild‐type KRAS, cetuximab‐treated colorectal cancer patients. FCGR2A is a promising biomarker for clinical management for these patients. [ABSTRACT FROM AUTHOR]

The global pandemic of coronavirus disease 2019 (COVID‐19) represents an emergent threat to the public health. Mitigation strategies have been employed to varying effect in many Western nations. Treatment strategies to effectively address COVID‐19 and equitably distribute resources are needed, especially in overwhelmed hospitals. [ABSTRACT FROM AUTHOR]

Background: Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. The authors hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities.Methods: In total, 125 oncology drugs were analyzed for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically relevant outcomes, statistical rigor, and evidence of drug-gene effects. Associations from studies of high methodologic quality were deemed potentially clinically actionable, and translational summaries were written as point-of-care clinical decision support (CDS) tools and formally evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.Results: The authors identified germline pharmacogenomic results for 56 of 125 oncology drugs (45%) across 173 publications. Actionable associations were detected for 12 drugs, including 6 that had germline pharmacogenomic information within US Food and Drug Administration labels or published guidelines (capecitabine/fluorouracil/dihydropyrimidine dehydrogenase [DPYD], irinotecan/uridine diphosphate glucuronosyltransferase family 1 member A1 [UGT1A1], mercaptopurine/thioguanine/thiopurine S-methyltransferase [TPMT], tamoxifen/cytochrome P450 [CYP] family 2 subfamily D member 6 [CYP2D6]), and 6 others were novel (asparaginase/nuclear factor of activated T-cells 2 [NFATC2]/human leukocyte antigen D-related β1 [HLA-DRB1], cisplatin/acylphosphatase 2 [ACYP2], doxorubicin/adenosine triphosphate-binding cassette subfamily C member 2/Rac family small guanosine triphosphatase 2/neutrophil cytosolic factor 4 [ABCC2/RAC2/NCF4], lapatinib/human leukocyte antigen DQ α1 [HLA-DQA1], sunitinib/cytochrome P450 family 3 subfamily A member 5 [CYP3A5], vincristine/centrosomal protein 72 [CEP72]). By using AGREE II, the developed CDS summaries had high mean ± standard deviation scores (maximum score, 100) for scope and purpose (92.7 ± 5.1) and rigour of development (87.6 ± 7.4) and moderate yet robust scores for clarity of presentation (58.6 ± 25.1) and applicability (55.9 ± 24.6). The overall mean guideline quality score was 5.2 ± 1.0 (maximum score, 7). Germline pharmacogenomic CDS summaries for these 12 drugs were recommended for implementation.Conclusions: Several oncology drugs have actionable germline pharmacogenomic information, justifying their delivery through institutional pharmacogenomic implementations to determine clinical utility. Cancer 2018;124:3052-65. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Tamoxifen is biotransformed by CYP2D6 to 4‐hydroxytamoxifen and 4‐hydroxy N‐desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype. [ABSTRACT FROM AUTHOR]

Finally, it is highly likely that if lorlatinib were being considered for approval today, the US Food and Drug Administration (FDA) would require dose optimization prior to initiating a registration trial, probably through a randomized dose-ranging trial, aiming to maximize the anticancer activity and minimize the off-target metabolic liabilities. To start with, Chen I et al i . confirm the absence of a relationship between administered lorlatinib dose and plasma exposure, as expressed by log (maximum concentration [C SB max event sb ]), at the tested doses. Sotorasib lacks even a dose-concentration relationship, while simultaneously possessing a dose-toxicity relationship and lacking a dose-efficacy relationship.4 Like sotorasib, lorlatinib is very likely overdosed, leading to marginal increases in clinical toxicity not compensated for by any increased efficacy. [Extracted from the article]

Background: Cancer and its treatment lead to increased financial distress for patients. To the authors' knowledge, to date, no standardized patient-reported outcome measure has been validated to assess this distress.Methods: Patients with AJCC Stage IV solid tumors receiving chemotherapy for at least 2 months were recruited. Financial toxicity was measured by the COmprehensive Score for financial Toxicity (COST) measure. The authors collected data regarding patient characteristics, clinical trial participation, health care use, willingness to discuss costs, psychological distress (Brief Profile of Mood States [POMS]), and health-related quality of life (HRQOL) as measured by the Functional Assessment of Cancer Therapy: General (FACT-G) and the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires. Test-retest reliability, internal consistency, and validity of the COST measure were assessed using standard-scale construction techniques. Associations between the resulting factors and other variables were assessed using multivariable analyses.Results: A total of 375 patients with advanced cancer were approached, 233 of whom (62.1%) agreed to participate. The COST measure demonstrated high internal consistency and test-retest reliability. Factor analyses revealed a coherent, single, latent variable (financial toxicity). COST values were found to be correlated with income (correlation coefficient [r] = 0.28; P<.001), psychosocial distress (r = -0.26; P<.001), and HRQOL, as measured by the FACT-G (r = 0.42; P<.001) and by the EORTC QOL instruments (r = 0.33; P<.001). Independent factors found to be associated with financial toxicity were race (P = .04), employment status (P<.001), income (P = .003), number of inpatient admissions (P = .01), and psychological distress (P = .003). Willingness to discuss costs was not found to be associated with the degree of financial distress (P = .49).Conclusions: The COST measure demonstrated reliability and validity in measuring financial toxicity. Its correlation with HRQOL indicates that financial toxicity is a clinically relevant patient-centered outcome. Cancer 2017;123:476-484. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Converting the tumor microenvironment (TME) from "cold" to "hot" represents the next step in immunotherapy's evolution. Achievement of this second step - the tumor T-cell-inflamed phenotype - is necessary but not sufficient to sensitize a tumor to immunotherapy's effects. Despite caffeine's central role in the origination of A2AR antagonists, the large, prospective, randomized controlled trials seemingly neither asked subjects about dietary caffeine intake nor performed laboratory assessments for caffeine, let alone stratified subjects by dietary caffeine consumption, excluded heavy caffeine consumers, or required "washout" from caffeine use, whereas early phase studies of A2AR antagonists often had caffeine-related exclusion criteria (e.g., NCT02253745 and NCT02764892). [Extracted from the article]

Alternative dosing regimens for atezolizumab: right dose, wrong frequency. In a similar approach our group took for reoptimizing nivolumab and pembrolizumab, dose regimen simulation12 is the initial step to identify potential modified regimens, which can then be evaluated prospectively in a clinical trial,13 aiming to achieve the therapeutic concentration identified by Genentech. The recent publication by Felip et al1 describing the dose optimization of subcutaneous atezolizumab concerns us due to the continued missed opportunity to lower an unnecessarily high atezolizumab dose.2 Felip et al cite the 2016 article by Genentech authors that identified a target clinical serum concentration of 6 g/mL (4 g/mL without bevacizumab).3 Yet at the currently approved intravenous dose of 1200 mg every 3 weeks (equivalent to 15 mg/kg every 3 weeks), the steady-state trough concentration is approximately 140 g/mL, which is >20-fold higher than the stated target trough of 6 g/mL.4 Furthermore, doses as low as 1 mg/kg have been demonstrated to have clinical activity.5,6 Calls for dose reoptimization are not limited to individuals or small groups. [Extracted from the article]

The magnitude of interindividual pharmacokinetic variability (IIV) of a drug and the factors responsible for this variability are intensively studied before—and sometimes after—registration as crucial information in anticipating and understanding variability in toxicity and efficacy. However, there has been much less attention paid to intraindividual variability, reflecting random or systematic changes in an individual's pharmacokinetics over time. We have chosen to focus on small‐molecule kinase inhibitors (SMKIs). [ABSTRACT FROM AUTHOR]

BACKGROUND Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401. METHODS Patients with metastatic, castration-resistant prostate cancer were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses. RESULTS Of 1008 randomized patients, the odds of experiencing grade ≥3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥3 VTE (odds ratio, 0.60; P = .08). In the multivariable analysis, bevacizumab treatment (hazard ratio [HR], 3.00; P = .01) and age (HR, 1.06; P = .02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; P = .01) and VTE risk score (HR, 1.83; P = .03) were significantly associated with the risk of VTE. CONCLUSIONS Bevacizumab was significantly associated with a greater risk of ATE in patients with metastatic, castration-resistant prostate cancer, but it was not significantly associated with the risk of VTE. Understanding clinical factors that increase the risk for experiencing ATE/VTE is essential to mitigate the risks and reduce the burden of these prevalent complications in cancer care. Cancer 2015;121:1025-1031. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

AIMS Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. The objective was to characterize the population PK and time-dependent change in vatalanib clearance and assess exposure-toxicity relationship in patients with myelodysplastic syndrome (MDS). METHODS This was an open-label phase II study of vatalanib in MDS patients receiving 750-1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using NONMEM 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check. METHODS This was an open-label phase II study of vatalanib in MDS patients receiving 750-1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using NONMEM 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check. RESULTS Pharmacokinetic data were complete for 137 patients (86 M, 51 F), of median age 70 years (range 20-91). A one-compartment model with lagged first-order absorption and time-dependent change in oral clearance was fitted to the vatalanib plasma concentration versus time data. The population means for pre-induction and post-induction oral clearance were 24.1 l h-1 (range: 9.6-45.5) and 54.9 l h-1 (range: 39.8-75.6), respectively. The apparent oral clearance increased 2.3-fold, (range: 1.7-4.1-fold) from first dose to steady state. Our data did not identify a significant relationship of the predefined covariates with vatalanib pharmacokinetics, although power to detect such a relationship was limited. CONCLUSIONS Vatalanib pharmacokinetics were highly variable and the extent of auto induction was not determined to correlate with any of the pre-defined covariates. [ABSTRACT FROM AUTHOR]

BACKGROUND Considering patients' experience is essential for optimal decision-making. However, despite increasing recognition of the impact of costs on oncology care, there is no patient-reported outcome measure (PROM) that specifically describes the financial distress experienced by patients. METHODS The content for a comprehensive score for financial toxicity (COST) was developed with a stepwise approach: step 1) a literature review and semistructured, qualitative interviews with patients for content generation; step 2) patients' assessment of the items for importance to their quality of life; step 3) pilot testing assessing interitem (IIC) and item-total (ITC) correlations to identify redundancy (Spearman rho, >0.7) and statistically unrelated content ( P > .05); and step 4) exploratory factor analysis. Sociodemographic data were collected. RESULTS In total, 155 patients with advanced cancer who were receiving treatment (20 patients in step 1, 35 patients in step 2, and 100 patients in steps 3 and 4) participated in the PROM development. In step 1, the literature was reviewed, and 20 patients generated 147 items, which were reduced to 58 items because of redundancy. In step 2, 35 patients rated the 58 items on importance, and 30 items were retained. In step 3, 46 patients assessed the 30 items, 14 items were excluded because of high IIC, and 3 were excluded because of nonsignificant ITC. In step 4, 2 items were discarded because of poor loadings in a factor analysis of 100 patients, resulting in an 11-item PROM. CONCLUSIONS The content for a financial toxicity PROM was developed in 155 patients. The provisional COST measure demonstrated face and content validity as well as internal consistency and should be validated in larger samples. Cancer 2014;120:3245-3253. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

However, unlike with nivolumab, there has never been a randomized dose-ranging study that included any dose less than 2 mg/kg every 3 weeks, and there has never been any demonstration of a dose-response relationship for any PD-1 inhibitor at doses administered to patients. Given that an excessive dose of a PD-1 (or PD-L1) inhibitor could lead to prolonged and/or severe immune-related adverse events, we continue to advocate for randomized dose-ranging studies of pembrolizumab that explore lower doses and/or less frequent administration. The starting dose of nivolumab was 0.1 mg/kg, which resulted in essentially complete PD-1 receptor occupancy in peripheral blood (in all but one patient) over a dose range 0.1-10 mg/kg.2 Furthermore, a prospective randomized trial across a 33-fold dose range (0.3-10 mg/kg) in metastatic renal cell cancer showed a lack of dose-response, implying that the maximally effective dose of nivolumab is <=0.3 mg/kg every 3 weeks.3 The development of pembrolizumab lagged that of nivolumab. [Extracted from the article]

Abstract: Pharmacogenomics is the study of genetic factors determining drug response or toxicity. The use of pharmacogenomics is especially desirable in oncology because the therapeutic index of oncology drugs is often narrow, the need for favorable drug response is often acute, and the consequences of drug toxicity can be life-threatening. In this review, we examine the state of pharmacogenomics in oncology, focusing only on germline pharmacogenomic variants. We consider several critical points when assessing the quality of pharmacogenomic findings and their relevance to clinical use, and discuss potential confounding factors limiting interpretation and implementation. Several of the most extensively studied drug–gene pairs (irinotecan and UGT1A1; tamoxifen and CYP2D6; 5-fluorouracil and DPYD) are inspected in depth as illustrations of both the state of advancement—and the current limitations of—present knowledge. We argue that there will likely soon be a critical mass of important germline pharmacogenomic biomarkers in oncology which deserve clinical implementation to provide optimal, personalized oncologic care. We conclude with a vision of how routine clinical testing of such germline markers could one day change the paradigm for cancer care. [Copyright &y& Elsevier]

• Clinical cases reported that fatal acute liver failure occurred when paracetamol (acetaminophen) was co-administrated with some tyrosine kinase inhibitors (TKIs). The direct inhibition of UDP-glucuronosyltransferase activities has been identified as a mechanism of potentiation of paracetamol hepatotoxicity. However, the effects of TKIs on paracetamol glucuronidation are not known. • The TKIs, sorafenib, dasatinib and imatinib exhibited potent mixed inhibition against paracetamol glucuronidation in pooled human liver microsomes, implying a possible increase in paracetamol hepatotoxicity when they are co-administrated with paracetamol. We aimed to investigate the effects of tyrosine kinase inhibitors (TKIs) on paracetamol (acetaminophen) glucuronidation. The inhibition of nine small molecule TKIs on paracetamol glucuronidation was investigated in human liver microsomes (HLMs) and recombinant human UDP-glucuronosyltransferases (UGTs). Sorafenib, dasatinib and imatinib exhibited mixed inhibition against paracetamol glucuronidation in pooled HLMs, and potent inhibition in UGT1A9 and UGT2B15. Dasatinib and imatinib also inhibited UGT1A1-mediated paracetamol glucuronidation. Axitinib, erlotinib, gefitinib, lapatinib, nilotinib and vandetanib exhibited weak inhibition of paracetamol glucuronidation activity in HLMs. The inhibition of paracetamol glucuronidation by TKIs might be of particular concern when they are co-administered. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the metabolic processes of the anastrozole and its specific enzymes. The study uses the method of liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the characterization of anastrozole metabolism through the human liver microsomes (HLMs). The study shows that the main metabolites of anastrozole are the hydroxyanastrozole and the anastrozole glucuronide which can be measured among the plasma of breast cancer patients.

The article presents an overview on the progress of pharmocogenetics and pharmacogenomics using a five-staged architecture which includes the determination of genetics in drug response, validation of genetic markers and clinical utility assessment. It notes that the pharmacogenetics and pharmacogenomic studies have identified genetic variants that contributes to chemotherapy. Meanwhile, an illustration on the identification, validation and challenges of these markers is provided.

Recent changes to the labels of three prescription drugs--irinotecan, 6-mercaptopurine, and warfarin--include recommendations for pharmacogenetic testing in patients. Thus, clinicians are faced with determining the utility and practicality of pharmacogenetic testing in clinical practice. We illustrate the clinical implications that this testing may have using irinotecan, an agent approved for the treatment of metastatic colorectal cancer, as an example. A clinical association between the drug's active metabolite and toxicity has been found. By performing uridine diphosphate glucuronosyltransferase (UGT) 1A1 genetic testing, some studies have been able to predict which patients receiving irinotecan will experience the toxicity. Thus, irinotecan's package insert was revised to include a recommendation for such testing. In addition, the United States Food and Drug Administration approved a clinical test for the UGT1A1 *28 allele. These events demonstrate that pharmacogenetics has entered the realm of clinical practice. However, the transition from bench to bedside of these tests has distinct challenges such as population differences, test sensitivity, and the role of other genetic and nongenetic factors that influence drug toxicity. In addition, ethical and logistic implications of pharmacogenetic testing exist. [ABSTRACT FROM AUTHOR]

The variability in treatment responses and narrow therapeutic index of anticancer drugs are some of the key challenges oncologists face. The knowledge of pharmacogenetics can potentially aid in the discovery, development and ultimately individualization of anticancer drugs. The identification of genetic variations that predict for drug response is the first step towards the translation of pharmacogenetics into clinical practice. This review provides an update on the results of studies assessing the effects of germline polymorphisms and somatic mutations on therapeutic outcomes and highlights the potential applications and future challenges in pharmacogenetic research pertaining to cancer therapeutics. [ABSTRACT FROM AUTHOR]

There have been numerous publications over the past two decades regarding the decline of clinical pharmacology as a medical subspecialty[1] ( B Table b S1). In this context, a young physician is currently likely to see greater opportunity, prestige, and value in participating in a traditional medical subspecialty society, rather than ours - the American Society for Clinical Pharmacology and Therapeutics (ASCPT). [Extracted from the article]