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The risk of drug–drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment. We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software. One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p

Background The occurrence of severe, acute limiting toxicity in patients receiving anti–programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. Methods From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). Results In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 μg/mL (interquartile range = 11.8–21.0). In multivariate analysis, hypoalbuminaemia ( Conclusions Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.

AIMS Cytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this interindividual variability. METHODS From December 2014 to November 2015, 183 patients were prospectively included. Serum CDA activity, biological and clinical characteristics as well as five common single nucleotide polymorphisms (SNPs) in the CDA gene (c.-451C > T, c.-92A > G, c.-33_-31delC, c.79A > C, c.435 T > C) were analysed. Associations between clinical characteristics, pharmacogenetic variants and CDA activity were univariately tested. P

Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug–drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods Five consecutive ACC patients treated with platinum etoposide (120–150 mg/m2 day 1–2–3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04). Conclusion A drug–drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.

Oral targeted therapies are a growing class of medication. After clinical trials conducted on a selected population, these molecules are usually approved at a fixed dose. However, oral tyrosine kinase inhibitors are characterized by a large intra and inter-individual pharmacokinetic variability, and a narrow therapeutic index. Hence, their prescription is hazardous and unsafe in non-selected people from daily clinical practice. The increasing number of available targeted therapies point out new challenges. These challenges should especially concern prescription for out of the ordinary patients, rules for dose adjustment according to factors of frailty. The ultimate goal is to ensure a safe and individualized prescription. Moreover, many of these molecules are metabolized by the CYP3A4, leading to a serious risk of drug interaction. These interactions might involve not only conventional medicine but also alternative and complementary medicines. These latter are more and more common but oncologists often lack experience about them. Finally, the oral route raises the issues of adherence, and the question of its assessment should now become a permanent part of patients care.

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55&ndash, 109) vs. 658 days (222-not reached), HR: 4.12 (1.95&ndash, 8.71), p = 0.0002) and OS (HR: 3.99(1.63&ndash, 9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17&ndash, 6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive, therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30&ndash, 0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21&ndash, 0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) of five tyrosine kinase inhibitors (afatinib, crizotinib, osimertinib, erlotinib and nintedanib) used in the treatment of non-small cell lung cancer (NSCLC) was developed and validated in human plasma. Separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1% (v/v) formic acid (A) and acetonitrile containing 0.1% (v/v) formic acid (B) at a flow rate of 500 μL/min. The analytes were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with heated electrospray interface. After addition of three isotopically labeled internal standards, plasma pretreatment consisted in a simple protein precipitation. This method presented satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-assay coefficient of variation from 2.6% to 10.6%), accuracy (from 96.1% to 108.5%), recovery and matrix effects. The lower limit of quantification and the linearity of these five tyrosine kinases inhibitors are suitable with the expected concentrations in clinical practice. This new bioanalytical method can be used in daily clinical practice for therapeutic drug monitoring of these tyrosine kinase inhibitors in NSCLC patients.

Tyrosine kinase inhibitors (TKIs) used in the treatment of metastatic renal cell carcinoma present high interindividual variability in clinical response and toxicity. In addition, high interindividual variability in pharmacokinetics (PK) of TKIs is observed which could explain therapeutic failure or elevated toxicity in some patients. Monitoring of plasma concentrations of TKIs and PK-guided dose adjustment could help to achieve plasma therapeutic levels in all the patients. The key step for applying PK-guided dosing is an established and stable over time exposure–response relationship. In this review, the current data about PK and PK/PD relationships of TKIs used in the treatment of metastatic renal cell carcinoma: axitinib, pazopanib, sunitinib and sorafenib are discussed with emphasis to reported factors of interindividual variability in plasma exposure (food intake, genetic background, biological and demographical variables and drug–drug interactions). In addition, this review provides recommendations about individualized dosing strategies based on exposure–response findings reported in the recent literature.

Nivolumab, an anti PD-1 monoclonal antibody, has been approved for the treatment of previously treated advanced or metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to develop and validate an ELISA method for the quantification of nivolumab in plasma from patients with NSCLC in order to perform future pharmacokinetic/pharmacodynamic (PK/PD) studies. A home-made ELISA was developed and validated according to the general recommendations for the immunoassays. Then, the ELISA method was applied to quantify plasma trough levels (Cmin) of nivolumab (3mg/kg every two weeks) in 27 NSCLC patients at days 14, 28 and 42 after start of treatment. Blood samples were collected just before the infusion on days 0 (baseline), 14, 28 and 42 after start of treatment. The dynamic calibration range for nivolumab assay was 5-100μg/mL. Within- and between-day imprecision for quality controls (5, 20 and 75μg/mL) were less than 5 and 12%, respectively. The mean (±standard deviation) nivolumab Cmin was 17.3±4.8μg/mL (coefficient of variation, CV=27.8%), 25.0±9.7μg/mL (CV=38.8%) and 33.0±12.9μg/mL (CV=39.1%) on days 14, 28 and 42, respectively. IgG (p=0.002) and ALT (p=0.041) were independently associated with plasma nivolumab Cmin at day 42. The present ELISA method for quantification of nivolumab in plasma from NSCLC patients is sensitive and accurate enough to be used for further PK/PD investigations.

Abiraterone acetate combined with prednisone improves survival in metastatic castration-resistant prostate cancer (mCRPC) patients. This oral anticancer agent may result in drug–drug interactions (DDI). We aimed to evaluate the prevalence of DDI with abiraterone and the possible determinants for the occurrence of these DDI. We performed a single centre retrospective review from electronic medical records of mCRPC patients treated with abiraterone from 2011 to 2015. Potential DDI with abiraterone were identified using Micromedex and were categorized by a 4-point scale severity. Seventy-two out of ninety-five mCRPC pts (median age: 77 years [68–82]) had comorbidities. The median number of drugs used per patient was 7 [5–9]. 66 potential DDI with abiraterone were detected in 49 patients (52%): 39 and 61% were classified as major and moderate DDI, respectively. In the univariate analysis, pain (p

Introduction Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting. Patients and Methods Trough plasma concentration (Ctrough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann–Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma Ctrough (ENZA, NDE, and composite). Results Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma Ctrough of ENZA and NDE were 12.4 ± 3.0 μg/mL and 8.8 ± 2.1 μg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma Ctrough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma Ctrough was observed compared with 18 remaining patients (16.1 ± 2.4 μg/mL vs. 11.6 ± 2.6 μg/mL, respectively; P = .027). Conclusion The low interindividual variability in ENZA and NDE Ctrough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.

Purpose Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells. Methods A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration–time data (N = 221) were analyzed by using nonlinear mixed effects modeling. Findings A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration–time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6–598.7] vs 224.6 ng/mL · h [95% CI, 117.6–421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/106 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/106cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/106 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups. Implications This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results. ClinicalTrials.gov identifier: NCT02105155 .

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Highlights • The COVID-19 pandemic causes unprecedented impact on cancer patients. • Cancer patients are greater susceptible to COVID-19 infection and intense symptoms. • A rethink of the care pathway is required to reduce the risk of contamination. • Oncologists must detect and manage drug-related problems with anti-COVID-19 drugs. • Caution is needed about interactions between anticancer and viral experimental drugs., The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75–300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug–drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small&ndash, cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman&rsquo, s rank test was used to investigate the relationship between Cmin and grade &gt, 2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 &plusmn, 6.0 &micro, g/mL (n = 76), 25.6 &plusmn, 10.2 &micro, g/mL (n = 64) and 33.4 &plusmn, 11.3 &micro, g/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02&ndash, 3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78&ndash, 36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46&ndash, 27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.

Abiraterone acetate is an oral prodrug of abiraterone, a selective inhibitor of CYP17, used for patients with metastatic castration-resistant prostate cancer (mCRPC). To date, a single liquid chromatographic-tandem mass spectroscopy method has been reported to assay abiraterone concentration in plasma from mCRPC patients. The aim of this study was to develop a simple and sensitive high performance liquid chromatographic (HPLC) method with fluorescence detection for quantification of abiraterone in plasma from mCRPC patients. After protein precipitation with acetonitrile and a liquid-liquid extraction with diethyl ether, abiraterone, and hydroxy-itraconazole (internal standard) were separated on a C8 Xterra(®) MS column using a mobile phase of acetonitrile and glycine buffer 88.4 mM (pH 9.0) (60:40, v/v). Samples were eluted isocratically at a flow rate of 0.9 ml/min throughout an 11-min run. Fluorescence wavelengths' excitation and emission were 255 and 373 nm, respectively. The calibration was linear in the range 1.75-50 ng/ml. Inter- and intraday imprecision were less than 3.5 and 7%, respectively. This method is simple, sensitive, and selective. This analytical method was successfully applied to determine the steady-state plasma exposure to abiraterone in mCRPC patients. This method can be used in routine clinical practice to monitor plasma abiraterone concentrations in mCRPC patients.

Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3-4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients treated with sunitinib were prospectively monitored between days 21 and 28 of the first cycle, then monthly until disease progression. At each consultation, the composite AUCƬ,ss (sunitinib + active metabolite SU12662) was assayed. The decisions taken during each consultation were matched with AUCƬ,ss and compared to the decisional algorithm based on TDM. A total of 105 cancer patients and 288 consultations were matched with the closest AUCƬ,ss measurement. The majority (60%) of the patients had metastatic renal clear-cell carcinoma (mRCC). Fifty-five (52%) patients experienced grade 3-4 toxicity. Multivariate analysis identified composite AUCƬ,ss as a parameter independently associated with grade 3-4 toxicity (P < 0.0001). Using the ROC curve, the threshold value of composite AUCƬ,ss predicting grade ≥3 toxicity was 2150 ng/mL/h (CI 95%, 0.6-0.79%; P < 0.0001). At disease progression in patients with mRCC, AUCƬ,ss tended to be lower than the one assayed during the first cycle (1678 vs. 2004 ng/mL/h, respectively, P = 0.072). TDM could have changed the medical decision for sunitinib dosing in 30% of patients at the first cycle of treatment, and in 46% of the patients over the whole treatment course. TDM is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure at the time of disease progression.

A disintegrin and metalloproteinase 9 (ADAM9) possesses potent metastasis-inducing capacities and is highly expressed in several cancer cells. Previous work has shown that ADAM9 participates in the adhesive–invasive phenotype in lung cancer cells in vitro. In this study, we evaluated whether ADAM9 expression plays a critical role in metastatic processes in vivo and in angiogenesis. We first found that high ADAM9 expression was correlated with poor lung adenocarcinoma patient prognosis on Prognoscan data base. In vivo model based on intravenous injection in nude mice showed that a stable downregulation of ADAM9 in A549 (TrA549 A9-) cells was associated with a lower number of nodules in the lung, suggesting lower potentials for extravasation and metastasis. On a subcutaneous xenograft we showed that TrA549 A9− produced significantly smaller tumours and exhibited fewer neovessels. In addition, in vitro human umbilical vein endothelial cells exposed to supernatant from TrA549 A9− could reduce the formation of more vessel-like structures. To further understand the mechanism, a human antibody array analysis confirmed that five cytokines were downregulated in TrA549 A9− cells. Interleukin 8 was the most significantly downregulated, and its interaction with CXCR2 was implicated in angiogenesis on an in vitro model. These results emphasize the critical influence of ADAM9 on lung cancer progression and aggressiveness. ADAM9 should at least be a marker of cancer aggressiveness and a potential therapeutic target for cancer treatment.

International audience; BACKGROUND:Circulating tumor DNA (ctDNA) has been reported as a prognostic marker in melanoma. In BRAF V600-mutant melanoma, a plasma under-exposure to vemurafenib could favor emerging resistance but no biological data are available to support this hypothesis.OBJECTIVE:We aimed to investigate the relationship between vemurafenib plasma concentrations and the ctDNA plasma concentration during follow-up of BRAF-mutated melanoma patients.PATIENTS AND METHODS:Eleven patients treated with single-agent vemurafenib for advanced BRAF V600-mutant melanoma were analyzed in an exploratory monocentric study. The vemurafenib plasma concentration was measured by liquid chromatography. ctDNA was extracted from plasma samples and the ctDNA concentration was evaluated using picoliter droplet-based digital PCR with Taqman® detection probes targeting the BRAF p.V600E/K mutation and wild-type BRAF sequences.RESULTS:At baseline, plasma ctDNA was detectable in 72% (n = 8/11) of patients and the ctDNA concentration decreased in 88% of these patients (n = 7/8) from day (D) 0 to D15 after vemurafenib initiation. During follow-up, an increased ctDNA concentration was detected in nine patients: in five patients, the first increase in ctDNA concentrations followed a decrease in vemurafenib concentrations. More interestingly, an inverse correlation between vemurafenib concentration and ctDNA concentrations was demonstrated (p = 0.026). The ctDNA concentration at baseline was associated with overall survival (hazard ratio = 2.61, 95% CI 1.04-6.56; p = 0.04).CONCLUSIONS:This study demonstrates the relevance of vemurafenib plasma monitoring during the follow-up of metastatic melanoma patients. Plasma drug monitoring and ctDNA concentrations could be combined to monitor tumor evolution in melanoma patients treated with anti-BRAF therapies.

Background Cancer is becoming a chronic disease. Oncology patients have a higher risk of suffering medication related problems (MRPs) due to patient characteristics (ageing populations, polypharmacy and comorbidities) and the toxicity of cancer therapies. The presence of a clinical pharmacist in an oncology ward may be an effective intervention to reduce this risk, and may contribute to the optimisation of therapy and quality of services provided to patients. Purpose The aim of the study was to characterise pharmacist interventions (PIs) and report acceptance rates by physicians in order to reduce MRPs. Material and methods A satellite unit pharmacy was established in an oncology ward (27 beds) of a large teaching hospital. Clinical pharmacy services including systematic medication reviews and medication reconciliation were provided daily by the clinical pharmacist. All PIs and their acceptance rate, and MRPs were recorded during the 12 month study period (2015) according to a validated classification system (Act IP). Results Medication reviews were performed in 2080 patients and 7020 therapy forms were analysed. Detection of MRPs led to 505 PIs that were subdivided into safety PIs (60%) and medication optimisation PIs (40%). The most frequent causes of MRPs in the safety group were: excessive dosage (44%), untreated indications (17%), interactions, especially concerning cytotoxic drugs (12%), and suboptimal dosage (11%). Most common PIs in the safety group were dose modification (41%) and drug discontinuation (23%). The drug classes with more interventions were antiemetic drugs, antithrombotic agents and analgesic drugs. The most frequent cause of MRPs in the optimisation group was inadequate choice of drug related to drug formulary (40%). Medication reconciliation was performed on 210 selected high risk patients and led to 30 PIs. The most repeated medication error was omission (57%). The overall physician acceptance rate was 81% for medication reviews and conciliation processes. Conclusion Detection and resolution of potential MRPs, as well as high rates of PIs acceptance by physicians, confirm the clinical pharmacist’s role in improved patient safety in a multidisciplinary healthcare oncology team. An interesting challenge in the future will be to explore the real clinical impact of PIs. References and/or acknowledgements Thanks to all clinical pharmacists in our hospital. No conflict of interest

Drug interactions are an on-going concern in the treatment of cancer, especially when targeted therapies, such as tyrosine kinase inhibitors (TKI) or mammalian target of rapamycin (mTOR) inhibitors, are being used. The emergence of elderly patients and/or patients with both cancer and other chronic co-morbidities leads to polypharmacy. Therefore, the risk of drug-drug interactions (DDI) becomes a clinically relevant issue, all the more so as TKIs and mTOR inhibitors are essentially metabolised by cytochrome P450 enzymes. These DDIs can result in variability in anticancer drug exposure, thus favouring the selection of resistant cellular clones or the occurrence of toxicity. This review provides a comprehensive overview of DDIs that involve targeted therapies approved by the FDA for the treatment of solid tumours for more than 3 years (sorafenib, sunitinib, erlotinib, gefitinib, imatinib, lapatinib, everolimus, temsirolimus) and medicinal herb or drugs. This review also provides some guidelines to help oncologists and pharmacists in their clinical practice.

Vemurafenib and erlotinib are two oral kinase inhibitors approved for the treatment of metastatic melanoma and advanced non-small cell lung cancer, respectively. In contrast with erlotinib, the single published method for analysis of vemurafenib in human plasma is based on mass spectrometry. The purpose of the present study was to develop an HPLC-UV method to simultaneously quantify these two drugs in plasma. Following liquid-liquid extraction, vemurafenib, erlotinib and sorafenib (internal standard) were separated isocratically on a C8 Xterra(®) MS using a mobile phase of glycine buffer (pH 9.0, 100mM)/acetonitrile (45:55, v/v). Samples were eluted at a flow rate of 0.9mL/min throughout the 12-min run. Dual UV wavelength mode was used, with vemurafenib and sorafenib monitored at 249nm, and erlotinib at 331nm. The calibration was linear in the range 1.25-100mg/L and 50-4000μg/L for vemurafenib and erlotinib, respectively. Inter- and intra-day precision was less than 6.7% and 6.6% for vemurafenib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure of these drugs in cancer patients. This accurate method can be used in routine clinical practice to monitor vemurafenib or erlotinib concentrations in plasma from cancer patients.

Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC consecutive pts. treated with erlotinib. The plasma concentration of erlotinib (Ce) was measured at steady state on day 15. We studied the relationship between age > 75 years, and Ce, using the Mann-Whitney U test and with the occurrence of acute toxicity, using a Fisher’s test. Results A total of 53 pts. were analyzed. Median age was 68 years (31–83), 56 % were female. All pts. > 75 years experienced toxicity: all grade acute adverse events were 1.6 fold more frequent (100 % vs 61 %; OR 95 % CI [1.9-INF]; p = 0.003). At day 15, Ce increased with age. Over 75 years old, the mean Ce was 1.5 fold higher: 2091 ng/mL (95 % CI [1476; 2706]) vs 1359 (95 % CI [1029; 1689]; p = 0.024). In pts. over 80 years old, the mean Ce was doubled: 2729 (95 % CI [1961; 3497]) vs 1358 ng/mL (95 % CI [1070; 1646]; p = 0.0019). Reduced lean body mass over 75 years (median 36.6 kg versus 49.1 kg) might account for these differences. Finally, the risk of early erlotinib discontinuation was increased by 11 in older pts. (33 % vs 3 % OR 17.2; 95 % CI [1.7; 892.5] p = .005). Conclusion The risk of overexposure to erlotinib increases with age. Reduced lean body mass may explain erlotinib pharmacokinetics and excessive acute toxicity in the elderly.

In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of compounds that suppressed vascular endothelial growth factor receptor-2 (VEGFR-2). As other tyrosine kinase inhibitors (TKI), pazopanib is not totally specific for one target since it also inhibits stem-cell factor receptor (cKIT), platelet-derived growth factor receptors (PDGFRα, β), VEGFR-1 and -3. Areas covered: Clinical pharmacology, drug-drug interactions and safety data published on pazopanib, between January 2006 and April 2016, are reviewed. Expert opinion: This new therapy has been shown to improve progression-free survival compared with previous approaches, in renal cell cancer and soft-tissue sarcoma. However, some specific sub-populations, such as elderly patients, patients with brain metastases or with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 or comorbidities, are poorly represented in pivotal pazopanib phase III studies. Pazopanib meets criteria defining therapies as candidates for therapeutic drug monitoring: large intra- and inter-patient pharmacokinetic variability, potential pharmacokinetic drug-drug interactions, pharmacokinetic/pharmacodynamic relationship and narrow therapeutic index. Knowledge of predictors that can be used to guide dosing regimens in the target population and in special populations needs to be improved.

The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAFV600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p

// Gaёlle Noe 1,2,* , Audrey Bellesoeur 1,2,3,* , Audrey Thomas-Schoemann 1,2 , Savithri Rangarajan 4 , Faris Naji 4 , Alicja Puszkiel 1 , Olivier Huillard 3 , Nathaniel Saidu 6 , Lisa Golmard 5 , Jerome Alexandre 3,6 , Francois Goldwasser 3,6 , Benoit Blanchet 1 and Michel Vidal 1,2 1 Assistance Publique Hopitaux de Paris, Hopital Cochin, UF Pharmacocinetique et Pharmacochimie, Paris, France 2 UMR8638 CNRS, Faculte de Pharmacie, Universite Paris Descartes, PRES Sorbonne Paris Cite, Paris, France 3 Assistance Publique Hopitaux de Paris, Hopital Cochin, Service de Cancerologie Medicale, Paris, France 4 PamGene International BV, ‘s-Hertogenbosch, The Netherlands 5 Institut Curie, Departement de Biopathologie, Paris, France 6 U1016 INSERM, UMR 8104 CNRS, UMR-S1016, CARPEM, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France * These authors have contributed equally to this work Correspondence to: Benoit Blanchet, email: // Keywords : sunitinib, kinome, PBMC, renal carcinoma Received : April 14, 2016 Accepted : July 10, 2016 Published : August 29, 2016 Abstract Background: Sunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes in lymphocytes count as pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy . Thereafter, we studied the ex vivo effect of sunitinib and SU12262 (active metabolite) on PBMC from naive mRCC patients using a high throughput kinomic profiling method. Methods: The prognostic value of total lymphocytes count between Day 0 and Day 21 (expressed as a ratio D21/D0) was retrospectively investigated in 88 mRCC patients under sunitinib therapy. PTK PamChip ® microarrays were used to explore prospectively the ex vivo effect of sunitinib and SU12662 on PTK activity in PBMC from 21 naive mRCC patients. Results: In this retrospective study, D21/D0 lymphocytes ratio (Hazard Ratio, 1.83; CI95%, 1.24-2.71; p=0.0023) was independently associated with PFS. Interestingly, kinomic analysis showed that D21/D0 lymphocytes ratio and Heng prognostic model was statistically associated with the ex vivo sunitinib and SU12662 effect in PBMC. Conclusion: The present study highlights that D21/D0 total lymphocytes ratio could be a promising pharmacodynamic biomarker in mRCC patients treated with sunitinib. Additionally , it paves the way to investigate the kinomic profile in PBMC as a prognostic factor in a larger cohort of mRCC patients under sunitinib therapy.

Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients.In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 μM [CI95 0.20-0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 μM) to 30 g/L (453 μM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75-2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL.These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.

Use of complementary and alternative medicine (CAM) has been reported to be more and more frequent among cancer patients in USA. The aim of this study was to analyze among French cancer patients the prevalence of CAM use, focusing on antioxidants (AO) that could interfere with antitumor agents. Seventy-nine patients, treated by antitumor chemotherapy in oncology day care unit, participated to an interview (medium age = 60 years old). CAM use was reported by 42% of patients: mostly AO (24%) (selenium, green tea and vitamins ACE, more specifically), but also relaxation, acupuncture, hypnosis (19%) and homeopathy (15%). Among patients using CAM, 66% of them indicated that their physicians were not aware of this use and 47% of them thought that CAM use was safe. Nevertheless, for seven patients who have taken AO, previous in vitro and preclinical studies suggested interactions with antitumor chemotherapy. Therefore, CAM use and, more specifically, AO use is common among cancer patients treated by antitumor chemotherapy in France. Nevertheless, AO could generate interactions with conventional treatment. Clinical studies are warranted to evaluate these interactions, and adequate communication with patients is needed.

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF V600 -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0–6.0) and 11.0 (95% CI 7.0–16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21–1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39–15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5–5.5] vs. 4.5 [2–undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p

UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes responsible for the glucuronidation reaction. Many therapeutic classes of drugs used in solid tumors are UGT substrates, including cancer therapies.This article describes the tyrosine kinase inhibitors (TKIs) undergoing hepatic glucuronidation; its effect on transport and tissue accumulation and the clinical consequences of this particular metabolism. A PubMed search concerning the pharmacokinetics of the TKIs was performed. All are extensively metabolized by CYP450. Two TKIs, sorafenib and regorafenib, also have a major UGT-mediated metabolism and were therefore studied.The prescription of the same dose of sorafenib and regorafenib for all patients may be inappropriate since at each enzymatic step of this multistep metabolism inter-individual fluctuations exist. Having a non-exclusive CYP-mediated route of metabolism may reduce the risk of variability in drug exposure when CYP3A4 substrates are concomitantly given. Several clinical consequences derive from this pharmacokinetic particularity of sorafenib and regorafenib. Since no clear difference distinguishes TKIs in efficacy in large randomized trials, the differences for the clinical management of their toxicity is a critical aspect.

The platelet-derived growth factor receptor (PDGFR) pathway has important functions in cell growth and, by overexpression or mutation, could also be a driver for tumor development. Moreover, PDGFR is expressed in a tumoral microenvironment and could promote tumorigenesis. With these biological considerations, the PDGFR pathway could be an interesting target for therapeutics. Currently, there are many molecules under development that target the PDGFR pathway in different types of cancer.In this review, the authors report the different molecules under development, as well as those approved albeit briefly, which inhibit the PDGFR pathway. Furthermore, the authors summarize their specificities, their toxicities, and their development.Currently, most PDGFR kinase inhibitors are multikinase inhibitors and therefore do not simply target the PDGFR pathway. The development of more specific PDGFR inhibitors could improve drug efficacy. Moreover, selecting tumors harboring mutations or amplifications of PDGFR could improve outcomes associated with the use of these molecules. The authors believe that new technologies, such as kinome arrays or pharmacologic assays, could be of benefit to understanding resistance mechanisms and develop more selective PDGFR inhibitors.

Following the articles by Verheijen and colleagues and Mir and colleagues reporting individualized pazopanib dosing strategy ([1, 2][1]), we wish to share our experience on pazopanib dose monitoring. From January 2014 to June 2017, we monitored trough pazopanib concentration ( C min) in plasma from

Introduction Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. Materials and Methods Exposure to sunitinib and SU12662 was assessed on days 10 and 21 during the first treatment cycle. Acute toxicity was graded using the NCI 4.0 CTCAE ver. 4.0. The LBM and 14 common single nucleotide polymorphisms in the CYP3A4/3A5, NR1I2, NR1I3, ABCB1, and ABCG2 genes were analyzed according to the drug exposure at day 10. Determinants (including sunitinib exposure and pharmacogenetic variants) for toxicities were assessed, as well as the relationship between drug exposure and survival in renal cancer patients. Results Ninety-two patients (60 % with renal cancer) were assessable for pharmacokinetics, toxicity and survival, and 66 for genetic analysis. The LBM (p A) (p = 0.014) were two independent parameters accounting for the variability of composite (sunitinib + SU12662) exposure. Advanced age (OR = 1.47 [1.01–2.15], p = 0.048) and high sunitinib exposure (OR = 1.16 [1.05–1.28], p = 0.005) were independently associated with any grade ≥ 3 acute toxicity, and high SU12662 exposure was associated with grade ≥ 2 thrombocytopenia (OR = 1.27 [1.03–1.57], p = 0.028). A high composite area under the curve (AUC) >1,973 ng/mL∙h at day 21 was associated with a doubled survival (35.2 vs 16.7 months; log-rank p = 0.0051) in renal cancer patients. Conclusions This study indicates that LBM and drug monitoring may be helpful in the management of sunitinib-treated patients.

Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge.Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management.The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug-drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.

The objective was to quantify the risk dynamics for the sorafenib-induced hand-foot syndrome (HFS) and to explore by simulations the dose-toxicity relationships according to different dosing regimens.Eighty-nine patients treated with sorafenib were considered: Treatment duration and regimen, and number and frequency of HFS observations were highly variable. A nonlinear mixed-effect model was built to link sorafenib administrations to the risk of each HFS score, through a latent variable model. Model evaluation was driven by goodness-of-fit and simulation-based diagnostics. Impact of sorafenib regimen on HFS dynamics was evaluated by simulations. A surrogate measure of benefit-to-risk ratio was calculated by using the concept of utility function, accounting for efficacy on tumor growth inhibition and severe HFS risk.An original pharmacokinetic-pharmacodynamic model for sorafenib-induced HFS, including the kinetics of a latent variable model, relating sorafenib administrations, per se its exposure, to HFS dynamics is proposed. From the model simulations, it appears that the more the daily dose is fractioned, the more the patients are at risk of HFS. Interestingly, the number of daily occasions was found more influential than the dose itself. Taking into account tumor growth inhibition in the utility function, the twice-daily administration schedule is favored for daily doses600 mg. This approach illustrates how understanding the dynamic relationship between drug administrations and a limiting adverse event may help to control toxicity and adequately adjust treatment modalities.

e14096Background: Cytidine deaminase (CDA) catabolizes gemcitabine and cytosine arabinoside and its serum activity (CDA-A) has been associated with efficacy and toxicity of both treatment. CDA is a...

Introduction: Sunitinib, a potent multi-tyrosine kinase (TK) inhibitor, is a standard first-line treatment for metastatic renal cell carcinoma (mRCC). In addition to its antiangiogenic activity, sunitinib is known to have immune-modulating properties especially on regulatory T-cells and tumor-infiltrating lymphocytes. However, data is sparse about sunitinib impact on peripheral lymphocytes and new data is needed to gain insights into the angiogenesis and immunity bidirectional link. This study aims to fill such a gap by investigating the clinical and intracellular modifications of sunitinib on peripheral blood mononuclear cells (PBMC) from naïve mRCC patients. Methods: Initially, a retrospective study was conducted in 88 mRCC patients treated with first-line sunitinib therapy to assess the evolution of lymphocyte count (expressed as a ratio between Day 21 and Day 0 i.e. D21/D0) during the first cycle of treatment. A new prospective study was carried out to determine kinomic profiles in PBMC from 21 naïve mRCC patients and 12 healthy volunteers. TK activity profiles of PBMC lysates were generated on TK PamChip® microarrays. The ex vivo effect of sunitinib and its active metabolite SU12662 were also determined in PBMCs. All data were analyzed using BioNavigator software. Results: The retrospective preliminary study showed that an increased D21/D0 lymphocytes ratio was significantly associated with a shorter Progression Free Survival (PFS) in multivariate analysis (p = 0.0023). In the prospective study, the phosphorylation level in PBMCs from mRCC patients was significantly lower than in healthy volunteers for 74 peptides (p Conclusions: Our retrospective study shows a decreased lymphocyte count on D21 after sunitinib initiation is a favorable prognostic factor in mRCC patients. The kinomic analysis of TKs in PBMCs after ex vivo exposure to sunitinib correlates with both Heng prognostic score and lymphocyte D21/D0 ratio, suggesting that PBMCs could be an interesting biological matrix to seek future biomarkers regarding clinical efficacy of sunitinib. Further investigations are underway to determine the involvement of signaling pathways contributing to the inter-individual variability in kinomic profiles of PBMCs from mRCC patients treated with sunitinib. Citation Format: Audrey Bellesoeur, Gaelle Noe, Audrey Thomas-Schoemann, Olivier Huillard, Faris Naji, Savithri Rangarajan, Alicja Puszkiel, Jerome Alexandre, François Goldwasser, Benoit Blanchet, Michel Vidal. Sunitinib impact on kinome profiles of peripheral blood mononuclear cells from renal cell carcinoma patients: Do molecular effects correlate with clinical data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2038.

Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As2O3) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (Treg) numbers. As2O3 induced Treg-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As2O3 showed a significant decrease in the Treg/CD4 cell ratio and in absolute Treg count versus controls. As2O3 exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As2O3-induced Treg depletion by the NO synthase inhibitor NG-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As2O3 on Treg versus other CD4 cells may be related to differences in the cells’ redox status, as indicated by significant differences in 2′7′dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As2O3 can delay solid tumor growth by depleting Tregs through oxidative and nitrosative bursts, and suggest that As2O3 could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer.

BackgroundIdentifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors.MethodsToxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with pResultsGender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUC(cum)) was independently associated with any grade ≥ 3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥ 2 diarrhea (p = 0.015) and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUC(cum) value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018).ConclusionIn this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.

5041 Background: Abiraterone (ABI) is a standard treatment in metastatic castration-resistant prostate cancer (mCRPC). However, the large interindividual variability in ABI pharmacokinetics could c...