Jennifer Arrondeau

Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review.

ABSTRACT Introduction: 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.

Bi-weekly very-high-dose lapatinib: an easy-to-use active option in HER-2-positive breast cancer patients with meningeal carcinomatosis.

The erbb2 gene, which encodes the growth factor receptor HER2, is amplified and overexpressed in 15–25 % of breast cancers, associated with poorer prognosis before the use of HER2 targeting agents. In patients with HER2positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel significantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplified tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal fluid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the blood–brain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. Because it has a small molecular weight and is lipophilic, we hypothesized that very high doses of lapatinib may circumvent the sanctuary effect in case of HER2-positive breast cancer with leptomeningeal metastases. We report the case of a 66-year-old woman who presented with a HER2-positive breast cancer with bone and liver synchronous metastases diagnosed in April 2012. Trastuzumab-based systemic chemotherapy resulted in a complete response of the liver. In April 2014, while being under trastuzumab and lapatinib, she presented severe headache, ataxia, and rapidly progressing dysarthria. The magnetic resonance imaging confirmed diffuse meningeal metastases. She was treated with high-dose lapatinib given once a day, twice a week, with plasma concentration monitoring. The dose was guided by clinical tolerance and efficacy with an initial dose of 5000, 6250 mg at the second intake, and 7500 mg (30 pills at once) at the third intake. The patient experienced grade 3 diarrhea lasting one day, the day after the first and third intakes. After the first administration, the headache disappeared within 2 days, and she recovered from both ataxia and dysarthria after 1 week of administration. Pre-cycle 2 and pre-cycle 3 through concentrations (Cmin) of lapatinib were 1041 and 1274 ng/ml, consistent with reported pharmacokinetic data and linear clearance of the high-dose lapatinib [5]. In August 2015, the patient is off therapy, alive and well, without neurological clinical manifestation, 16 months & P. Lavaud pernelle.lavaud@gmail.com

Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Development and validation of an ELISA method for the quantification of nivolumab in plasma from non-small-cell lung cancer patients

HIGHLIGHTSThis study describes a sensitive and accurate ELISA method for quantification of nivolumab in human plasma.Plasma concentration of nivolumab was assayed in non‐small‐cell lung cancer patients.The assay is applicable to investigate pharmacokinetics of nivolumab and its PK/PD relationship.Endogenous IgG level contributes to the interindvidual variability in nivolumab pharmacokinetics. ABSTRACT 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 (3 mg/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 5–100 &mgr;g/mL. Within‐ and between‐day imprecision for quality controls (5, 20 and 75 &mgr;g/mL) were less than 5 and 12%, respectively. The mean (± standard deviation) nivolumab Cmin was 17.3 ± 4.8 &mgr;g/mL (coefficient of variation, CV = 27.8%), 25.0 ± 9.7 &mgr;g/mL (CV = 38.8%) and 33.0 ± 12.9 &mgr;g/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.

Inhibiteurs de tyrosine kinase ciblant l’angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables

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.

SynthèseInhibiteurs de tyrosine kinase ciblant l’angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirablesTyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management

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.

TP53, STK11 and EGFR Mutations Predict Tumor Immune Profile and the Response to anti-PD-1 in Lung Adenocarcinoma

Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non–small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained. Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16–0.63, P < 0.001) was observed in anti–PD-1-treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710–23. ©2018 AACR.

Abstract P5-15-12: Clinico-biological characteristics of patients surviving more than two years with metastatic breast cancer (MBC): Results of a transversal national multicentric survey

Introduction: MBC cancer patients may have prolonged survival, and MBC cancers can be considered as a chronic disease. The main goal of the present study was to describe the clinico-biological features of patients surviving more than two years with MBC. Method: During 4 months, we conducted a national multicentric survey about patients aged ≥ 18 in metastatic setting (all solid tumors) for more than 24 months. Clinico-biological data from 200 patients were collected in 39 French centers. Preliminary results of MBC patients (N=88, 87 women/one man) are presented. Results: Most of them were ductal carcinoma (88%), expressing hormonal receptor HR (77%). 43% of tumors overexpressed HER2 (HER2+ tumors: 43%; Triple negative tumors: 6%). Median age at MBC diagnosis was 53 years [29-85]. 18% had metastatic disease at diagnosis and 82 % were localized with a disease-free survival of 65 months [4-312]. Median time of MBC disease was 4,5 years [2-20]. At the time of MBC diagnosis, 64% of patients were not single; 55% were working while 30% were retired. At data collection, 89% of non-single patients were not separated, and 43 % of working patients at diagnosis were still working. Mean number of treatment lines in advanced disease was 4.7 [1-13]. 89% of MBC patients received at least one chemotherapy, 68% hormonotherapy, 70% targeted therapy and 38% had been included in at least one clinical trial. 97% of patients had a local treatment of their primary tumor. Concerning metastasis, 23% had a surgical treatment and 40% radiotherapy treatment. 80% of patients remain with PS of 0 or 1. Only 9% of patients were followed by a palliative care team, 24% by a psychologist and 23% by a nutritionist. Conclusion: Our preliminary results of suggest that an important proportion of MBC cancer patients who live more than 2 years are young, have been treated with chemotherapy, hormonal and targeted therapy, have participated to clinical trials and still have good performance status. No change in marital status was observed. Half of working patients at MBC diagnosis continue to work. Few of them received palliative care. This study may help to better describe long-term survivors with MBC, and socio-medical burden as cancer became a chronic disease. Citation Format: Delphine Loirat, Camille Tlemsani, Jennifer Arrondeau, Audrey Bellesoeur, Christophe Le Tourneau, Benoit Rousseau. Clinico-biological characteristics of patients surviving more than two years with metastatic breast cancer (MBC): Results of a transversal national multicentric survey [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-12.

1379PCLINICO-BIOLOGICAL CHARACTERISTICS OF PATIENTS SURVIVING MORE THAN TWO YEARS WITH RECURRENT AND/OR METASTATIC (R/M) CANCER: RESULTS OF A TRANSVERSAL NATIONAL MULTICENTRIC SURVEY

ABSTRACT Aim: R/M cancer patients may have prolonged survival, and R/M cancer can be considered as a chronic disease. To our knowledge, there are few data describing these patients. The main goal of the present study was to describe the clinico-biological features of patients surviving more than two years with R/M cancer. Methods: During 4 months, we conducted a national multicentric survey about patients aged ≥ 18 with R/M cancer for more than 24 months. Clinico-biological data were collected in 39 French centers. Preliminary results of the first 200 patients are presented. Results: Most of them were women (70%) with breast cancer (44%) but a wide variety of other cancers were represented. Median age at diagnosis was 58 [range: 20-85]. Median time between primary tumor and R/M disease was 19 months [range: 0-312] with 39% of patients with a R/M disease at presentation. Median time from R/M disease was 46 months [range: 24-241]. At the time of R/M diagnosis, 72% of patients were not single; 48% were working while 37% were retired. At data collection, 88% of non-single patients were not separated, but only 32% of working patients were still working. At the time of R/M diagnosis, patients presented with good performance status (ECOG performance status of 0 or 1 in 88% of cases), without malnutrition (Body Mass Index Conclusions: Our preliminary results suggest that an important proportion of R/M cancer patients who live more than 2 years have been treated with a targeted therapy and have participated in a clinical trial. However, a majority of them have stopped their job and few of them received palliative care. Disclosure: All authors have declared no conflicts of interest.