Improved method for quantification of intact oxaliplatin by ultra high performance liquid chromatography-inductively coupled plasma mass spectrometry: Applications to clinical and speciation studies.

Interest is increasing in the use of different liquid chromatography techniques coupled online to mass spectrometry for the quantification of platinum anticancer drugs in human plasma to inform cancer chemotherapy. We developed, validated and studied the application of a method for quantification of intact oxaliplatin in human plasma using ultra high performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (UHPLC-ICP-MS). Plasma samples were processed instantly after collection from patients to preserve oxaliplatin speciation by methanol-deproteinization, and storage of diluted supernatants (plasma:methanol 1:2 v/v) at -80 °C.

Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

Background: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown.

Objective: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables.

Ethnic differences in the characteristics of patients with newly diagnosed lung cancer in the Te Manawa Taki region of New Zealand.

Background: Māori have three times the mortality from lung cancer compared with non-Māori. The Te Manawa Taki region has a population of 900 000, of whom 30% are Māori. We have little understanding of the factors associated with developing and diagnosing lung cancer and ethnic differences in these characteristics.

Invitation methods for Indigenous New Zealand Māori in lung cancer screening: Protocol for a pragmatic cluster randomized controlled trial.

Lung cancer screening can significantly reduce mortality from lung cancer. Further evidence about how to optimize lung cancer screening for specific populations, including Aotearoa New Zealand (NZ)'s Indigenous Māori (who experience disproportionately higher rates of lung cancer), is needed to ensure it is equitable. This community-based, pragmatic cluster randomized trial aims to determine whether a lung cancer screening invitation from a patient's primary care physician, compared to from a centralized screening service, will optimize screening uptake for Māori.

Performance of cardiovascular disease risk prediction equations in more than 14 000 survivors of cancer in New Zealand primary care: a validation study.

Background: People with cancer have an increased risk of cardiovascular disease. Risk prediction equations developed in New Zealand accurately predict 5-year cardiovascular disease risk in a general primary care population in the country. We assessed the performance of these equations for survivors of cancer in New Zealand.

Cancer of the nasopharynx in Aotearoa New Zealand from 1994 to 2018: Incidence and survival in a population-based, national registry cohort study.

Background: Cancer of the nasopharynx has remarkable geographic and ethnic variation in incidence and outcomes globally. Recent advances in diagnostic and therapeutic technologies provide new opportunities for early detection and improved outcomes. This study aimed to determine the incidence, demographics, outcomes and time trends of cancer of the nasopharynx in Aotearoa New Zealand over the last 25 years.

ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges.

Purpose: Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges.

Patients And Methods: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve).

Population-based incidence rates and increased risk of EGFR mutated non-small cell lung cancer in Māori and Pacifica in New Zealand.

Background: Non-squamous non-small cell lung cancer (NSCLC) patients with Epidermal Growth Factor Receptor (EGFR) mutation benefit from targeted treatments. Previous studies reported EGFR mutation-positive proportions among tested non-squamous NSCLC patients. However, incidence rates and population risk of EGFR mutation-positive and EGFR mutation-negative non-squamous NSCLC have not been assessed.

Factors associated with overall survival in a population-based cohort of non- squamous NSCLC patients from northern New Zealand: A comparative analysis by EGFR mutation status.

Background: Previous studies have reported inconsistent results regarding the effect of epidermal growth factor receptor (EGFR) mutations on overall survival in patients with non-squamous non-small-cell lung cancer (NSCLC). This study assesses the effect of EGFR mutation on overall survival, and how the effects of other survival predictors differ by EGFR mutation status.

Methods: The study used a population- based cohort of 1534 non-squamous NSCLC patients diagnosed in northern New Zealand between 1st February 2010 and 31st July 2017.

Development and validation of a predictive model for estimating EGFR mutation probabilities in patients with non-squamous non-small cell lung cancer in New Zealand.

Background: Targeted treatment with Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) is superior to systemic chemotherapy in non-small cell lung cancer (NSCLC) patients with EGFR gene mutations. Detection of EGFR mutations is a challenge in many patients due to the lack of suitable tumour specimens for molecular testing or for other reasons. EGFR mutations are more common in female, Asian and never smoking NSCLC patients.

Utilisation and Determinants of Epidermal Growth Factor Receptor Mutation Testing in Patients with Non-small Cell Lung Cancer in Routine Clinical Practice: A Global Systematic Review.

Background: Epidermal growth factor receptor (EGFR) mutation testing is recommended for selecting patients with non-squamous non-small cell lung cancer (NSCLC) for EGFR tyrosine kinase inhibitor drug treatment.

Objective: The objective of this article was to systematically review available evidence on the utilisation and determinants of EGFR mutation testing of patients with NSCLC in routine clinical practice.

Patients And Methods: Searches were made of five electronic databases (Web of Science, MEDLINE [Ovid], Science Direct, EMBASE and Scopus), bibliographies of relevant articles, studies that cited included studies and relevant cancer websites.

Osimertinib in NSCLC: Real-World Data From New Zealand.

Introduction: EGFR tyrosine kinase inhibitors (TKIs) are more effective than chemotherapy in patients with -mutant NSCLC. Disease progression on EGFR TKI therapy occurs most often owing to acquired resistance from the gain of an T790M mutation. Osimertinib, a third-generation EGFR TKI, significantly improves outcomes in patients with T790M mutation-positive NSCLC compared with platinum-pemetrexed chemotherapy.

Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC.

Introduction: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results.

Methods: Eligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted).

Transport-Mediated Oxaliplatin Resistance Associated with Endogenous Overexpression of MRP2 in Caco-2 and PANC-1 Cells.

Our recent publications showed that multidrug resistance protein 2 (MRP2, encoded by the ABCC2 gene) conferred oxaliplatin resistance in human liver cancer HepG2 cells. However, the contribution of MRP2 to oxaliplatin resistance remains unclear in colorectal and pancreatic cancer lines. We investigated the effects of silencing MRP2 by siRNA on oxaliplatin accumulation and sensitivity in human colorectal cancer Caco-2 cells and pancreatic cancer PANC-1 cells.

Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.

Introduction: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.

Methods: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.

Identification of MRP2 as a targetable factor limiting oxaliplatin accumulation and response in gastrointestinal cancer.

Oxaliplatin is important for the clinical treatment of colorectal cancer and other gastrointestinal malignancies, but tumour resistance is limiting. Several oxaliplatin transporters were previously identified but their relative contributions to determining oxaliplatin tumour responses and gastrointestinal tumour cell sensitivity to oxaliplatin remains unclear. We studied clinical associations between tumour expression of oxaliplatin transporter candidate genes and patient response to oxaliplatin, then experimentally verified associations found with MRP2 in models of human gastrointestinal cancer.

The Effects of Synthetically Modified Natural Compounds on ABC Transporters.

Multidrug resistance (MDR) is a major hurdle which must be overcome to effectively treat cancer. ATP-binding cassette transporters (ABC transporters) play pivotal roles in drug absorption and disposition, and overexpression of ABC transporters has been shown to attenuate cellular/tissue drug accumulation and thus increase MDR across a variety of cancers. Overcoming MDR is one desired approach to improving the survival rate of patients.

Lung cancer mutation testing: a clinical retesting study of agreement between a real-time PCR and a mass spectrometry test.

To investigate the clinical validity and utility of tests for detecting Epidermal Growth Factor Receptor () gene mutations in non-squamous non-small cell lung cancer patients, tumour DNA extracts from 532 patients previously tested by the cobas EGFR Mutation Test (RT-PCR test) were retested by the Sequenom/Agena Biosciences MassArray OncoFocus mass spectrometry test (MS test). Valid results from both tests were available from 470 patients (88%) for agreement analysis. Survival data were obtained for 513 patients (96%) and 77 patients (14%) were treated with EGFR tyrosine kinase inhibitors (TKIs).

Phase IB Trial of the Anti-Cancer Stem Cell DLL4-Binding Agent Demcizumab with Pemetrexed and Carboplatin as First-Line Treatment of Metastatic Non-Squamous NSCLC.

Background: Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature.

Objective: This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy.

Patients And Methods: Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design.

ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC).

Introduction: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure.

Methods: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study.

EGFR Mutation Testing of non-squamous NSCLC: Impact and Uptake during Implementation of Testing Guidelines in a Population-Based Registry Cohort from Northern New Zealand.

Background: Since 2013, clinical practice guidelines recommend EGFR mutation testing of non-squamous NSCLC to select advanced-stage patients for first-line treatment using EGFR-TKIs.

Objective: We aimed to determine population-based trends in the real-world uptake and impact in routine practice of these recently updated testing guidelines.

Patients And Methods: A population-based observational study was conducted of notifications to the New Zealand Cancer Registry of patients eligible for EGFR testing diagnosed in northern New Zealand between January 2010 and April 2014.