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BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Background: There is ongoing controversy regarding the outcome of COVID-19 in cancer patients This is one of few registries on the impact of COVID-19 in cancer patients in a country severly affected by the pandemic Methods: This cohort study is collecting data on symptomatic Sars-CoV-2 infected patients with a cancer diagnosis from 23 Swiss sites, starting March 1, 2020 The main objective of the study is to assess the outcome of COVID-19 infection in patients with solid and hematological malignancies, while the main secondary objective is to define prognostic factors of COVID-19 outcome Results: With a cutoff date of July 16, 2020, 357 patients with a diagnosis of cancer and symptomatic COVID-19 were included into this first analysis The most frequent malignancies were breast in 63 cases (18%), lung in 40 cases (11%), prostate cancer in 24 cases (7%) and myeloma in 16 cases (5%), with 104 (38%) patients having non-curative disease Anticancer treatment within 3 months prior to the diagnosis of COVID-19 included chemotherapy in 65 patients (18%), targeted therapy in 54 patients (15%), steroids in 39 (11%), checkpoint inhibitors in 22 (6%) or no anticancer treatment in 155 patients (43%) 230 patients (65%) were hospitalized for COVID-19 or were already in hospital;167 of the hospitalized patients (73%) required oxygen treatment, 43 patients (19%) intensive care, 31 (14%) invasive ventilation 63 patients died from COVID-19 infection, resulting in a mortality rate of 18% Significant risk factors for death included age ≥65 versus

Background Nivolumab is currently administered in a weight-based or fixed-flat dosing regimen. Approved fixed-flat dosing regimens have been solely based on simulations from dose-finding clinical trials. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported, suggesting that nivolumab dosing needs further optimization. In this study, we determined nivolumab pharmacokinetics (PK) and assessed the relationship between nivolumab clearance (CL) and tumor response in patients with NSCLC, melanoma, and renal cell cancer (RCC). Methods In this prospective observational cohort study (MULTOMAB trial; Dutch Trial Registry NL6828), individual estimates of nivolumab CL and the impact of baseline covariates were determined using population-PK (PPK) modeling. The study was approved by the independent ethics committee (MEC 16-011). All patients provided written informed consent. Stratified by tumor type, CL was related to best overall response (RECIST v1.1) using ANOVA and post-hoc samples t-test. Results In total 1,715 nivolumab serum concentrations were analyzed from 221 patients who were treated with monotherapy nivolumab (NSCLC n = 158; melanoma n = 48; RCC n = 14; mesothelioma n = 1). The baseline parameters gender, body surface area (BSA), and serum albumin had a significant effect on nivolumab CL and were internally validated in the PPK model. Women had 22% lower CL than men, Patients with BSA > 2.2 m2 or with baseline albumin 20% higher CL than the population mean. For NSCLC, CL was 42% higher in patients with progressive disease (mean: 0.24; 95%CI: 0.22-0.27 L/day) compared to patients with partial/complete response (0.17; 0.15-0.19). Although a similar trend was observed in RCC, no CL-response relationship was observed in melanoma patients. Conclusions We generated the first real-world PPK model of nivolumab, in which covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab CL. A significant CL-response relationship was observed in patients with NSCLC, but not in patients with melanoma. Individualized dosing regimens might therefore increase nivolumab efficacy in patients with NSCLC. Clinical trial identification MULTOMAB trial; Dutch Trial Registry NL6828. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A.A.M. Van der Veldt: Advisory / Consultancy: BMS. J.G. Aerts: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.

Background About 20% of breast cancer (BC) patients do not attain tamoxifen’s (TAM) active metabolite endoxifen (ENDX) target concentrations when receiving 20 mg TAM once daily (q.d.). Thus, individualised dosing of up to 120 mg TAM q.d. for ENDX target attainment (TA) has been proposed. Combining concentrations and antiestrogenic activities of ENDX and its 3 precursors, the antiestrogenic activity score (AAS) has been developed as alternative TA metric. We aimed to integrate experimental and clinical data from diverse sources in an innovative modelling approach to identify patient groups at risk of treatment failure and to assess whether ENDX- or AAS-guided dosing would be more favourable for TA applying in silico simulation. Methods In vitro data from enzyme kinetic experiments, pharmacokinetic (PK) parameters from previous clinical studies and in vivo data from three clinical trials were synthesised into a minimal nonlinear mixed-effects physiologically-based pharmacokinetic (NLME-PBPK) model. Using simulation, lowest doses needed for TA, applying either the ENDX (≥5.97 ng/mL) or the AAS (≥1798) threshold, were investigated in a representative virtual BC population with various CYP2D6 activity scores (AS) and age. Results The developed NLME-PBPK model captured individual TAM and 3 metabolite concentration profiles from 406 BC patients well. Bioactivation to ENDX was 4.5-fold higher in CYP2D6 normal (NM) than in poor metabolisers (PM). Patients with low CYP2D6 activity and young age showed highest risks for ENDX non-TA. Among all patients, 76% received the same dose irrespective of the TA metric used. For the remaining 23% with different dose selections, applying the AAS instead of the ENDX target, TA increased in NM and intermediate metabolisers (IM) (+21.7% and +6.9%, respectively), while TA decreased in PM (-11.7%). Conclusions Our modelling approach combined pharmacogenetic factors, physiological changes and variability on PK parameters in a quantitative manner and allowed to translate PK information on TAM and its three major metabolites into individualised dosing. While ENDX-guided dosing was preferable for PM in our simulation, AAS-guided dosing was superior for NM and IM. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure L. Klopp-Schulze: Full / Part-time employment: Merck Healthcare KGaA. S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Servier. C. Kloft: Research grant / Funding (institution), Grants received outside the submitted work: DDMoRe; Research grant / Funding (institution), Grants received outside the submitted work: Industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Gruenenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and SANOFI); Research grant / Funding (institution), Grants received outside the submitted work: Federal Ministry of Education and Research; Research grant / Funding (institution), Grants received outside the submitted work: Diurnal Ltd. All other authors have declared no conflicts of interest.

Drug hypersensitivity reactions (HSR) are adverse events resembling allergy which occur at therapeutic doses. Both anticancer chemotherapeutics and monoclonal antibodies have the potential for acute HSR. all infusion reactions involve the immune system; however, some (anaphylactic) are allergic in nature and usually are mediated by immunoglobulin E (IgE), whereas others (anaphylactoid) are not true allergic reactions and are not mediated by IgE. although HSR can be allergic or nonallergic, the clinical manifestations are the same and require prompt, accurate assessment and management to avoid severe adverse events, including fatality. Monoclonal antibodies have a unique side-effect profile that includes the potential for nonallergic HSR caused by cytokine release. Chemotherapeutic agents with the highest potential for acute HSR include the platinum salts, taxanes, procarbazine, asparaginase and the epipodophyllotoxins. From all anticancer agents, rituximab causes the majority of HSR (27%), followed by paclitaxel (10%). The most frequent symptoms in patients experiencing acute HSR include chest pain, dyspnea, wheezing and exanthema for the taxanes, dyspnea and exanthema for platinum salts, chills and rigor for antibodies. Patients with mild-to-moderate acute HSR can be rechallenged following intensified prophylaxis, but rechallenge is usually not recommended following severe HSR.

Background: Adding cetuximab to standard chemotherapy results in a moderate increase of overall survival in patients with advanced non-small-cell lung cancer (NSCLC), but the cost-effectiveness is unknown. Materials and methods: A Markov model was constructed based on the results of the First-Line ErbituX in lung cancer randomized trial, adding cetuximab to cisplatin-vinorelbine first-line chemotherapy in patients with advanced NSCLC. The primary outcome was the incremental cost-effectiveness ratio (ICER) of adding cetuximab, expressed as cost per quality-adjusted life year (QALY) gained, and relative to a willingness-to-pay threshold of €60 000/QALY. The impact of cetuximab intermittent dosing schedules on the ICER was also evaluated. Results: Adding cetuximab to standard chemotherapy leads to a gain of 0.07 QALYs per patient at an additional cost of €26 088. The ICER for adding cetuximab to chemotherapy was €376 205 per QALY gained. Intermittent cetuximab dosing schedules resulted in ICERs per QALY gained between €31 300 and €83 100, under the assumption of equal efficacy. Conclusions: From a health economic perspective, the addition of cetuximab to standard first-line chemotherapy in patients with epidermal growth factor receptor-expressing advanced NSCLC cannot be recommended to date, due to a high ICER compared with other health care interventions. Treatment schedules resulting in more favorable cost-utility ratios should be evaluated

Aim: Breast cancer (BC) is the most frequent cancer and the principal cause of cancer death for females worldwide. Triple-negative breast cancer (TNBC), carries extraordinarily poor prognosis due to its aggressive biology, fast development of drug resistance, and lack of molecular targets such as hormone receptors and HER2/Neu. Until now, chemotherapy remains the standard care for advanced TNBC, with a poor median overall survival. Recently, pharmacological aggravation of endoplasmic reticulum stress (ERS) has become an attractive strategy for cancer therapy. In our work we present evidence that pharmacological aggravation of ERS may lead to efficient killing of breast cancer preclinical models in vitro. Methods: We determined the cytotoxic activity of proteasome inhibitors (bortezomib, bzb; carfilzomib, cfz) alone and in combination with the two HIV protease inhibitors nelfinavir (nfv) and lopinavir (lpv) in five different breast cancer cell lines. To assess cytotoxicity of each drug and their combinations, the MTS assay was applied. Results: Both proteasome inhibitors moderately reduced cell survival in all BC cell lines at clinically relevant concentrations (125 nM) when applied alone (8% - 36%). Importantly, combinations with HIV protease inhibitors yielded significantly enhanced cytotoxicity in all cell lines compared with either proteasome (see table) or HIV protease inhibitors alone. Moreover, preliminary data shows that these combinations cause strong cytotoxic effects in TNBC cell lines. Conclusions: Drug combinations of the irreversible proteasome inhibitors and an HIV protease inhibitor resulted in substantial cytotoxicity in preclinical models of TNBC. The concept of pharmacological aggravation of ERS is promising in patients with TNBC, and a respective phase IB-II clinical study is in early planning. Cell Lines Bzb (125 nM) Cfz (125 nM) - Nfv Lpv - Nfv Lpv MDA-MB 468 27 ± 8 57 ± 0.1 80 ± 1 21 ± 7 65 ± 2 79 ± 4 MDA-MB 231 36 ± 8 56 ± 0.1 57 ± 2 41 ± 2 74 ± 4 78 ± 8 BT 549 23 ± 3 90 ± 1 56 ± 0.2 44 ± 3 91 ± 1 69 ± 4 BT 474 8 ± 6 28 ± 6 32 ± 3 33 ± 6 82 ± 6 61 ± 1 SK-BR-3 - - - 30 ± 2 68 ± 3 21 ± 4 Cytotoxic effects of mono and combination experiments in BC cell lines (% cell death +/- SD) Disclosure: All authors have declared no conflicts of interest.

Aim: Germline gene polymorphisms may impact clinical outcome in patients with gastrointestinal malignancies, but there are no data on the interaction between chemotherapy pharmacokinetics (PK) and gene polymorphisms, to assess their independent predictive value. Methods: Two studies prospectively assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, -M1, -T1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2, UGT2B7) by Sanger sequencing in 64 patients with advanced colorectal cancer (CRC) receiving capecitabine/oxaliplatin chemotherapy, and 76 patients with advanced gastroesophageal (GE) cancer receiving epirubicin/cisplatin/capecitabine (ECC) chemotherapy, respectively. Plasma concentrations of all anticancer drugs were sampled for up to 24 hours, analyzed using validated LC-MS/MS (capecitabine), HPLC (epirubicin) and flameless atomic absorption spectrometry (platinum), and results submitted to population PK analysis using non-linear mixed effects modeling. We calculated the association between gene polymorphisms, anticancer drug exposure, radiological tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Results: Patients with a low clearance of the active metabolite 5FU had an increased risk of neutropenia in both groups (p A and A2846T were associated with diarrhea (p Conclusions: Carriers of the TYMS high-expression genotype have a markedly inferior outcome when receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. Therapeutic targeting of this molecularly-defined subgroup of patients should be explored to improve their prognosis. Disclosure: All authors have declared no conflicts of interest.