Identification of protein biomarkers for prediction of response to platinum-based treatment regimens in patients with non-small cell lung cancer

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.</p

Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer

Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (&lt;20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; &gt;271 ng/mL) had shorter PFS compared to a low Cmin,SS (&lt;163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.</p

Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer

Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

BACKGROUND: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated ( EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. METHODS: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. FINDINGS: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). INTERPRETATION: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. FUNDING: No funding was received for this trial

Administration of crizotinib via jejunostomy tube:A case report

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors

I.AM. archive containing long-range tossing experiments for Trajectory Based Parameter Identification of Box012

I.AM. archive as part of the Impact-Aware Robotics Archives Collection. This archive contains recordings of experiments that are executed under the scenario of TOSS. In these recordings, Box012 is manually tossed on a stationary conveyor belt. The purpose of these experiments is to obtain data for trajectory based parameter identification as part of a modeling framework. This modeling framework is used within the H2020 I.AM. project (www.i-am-project.eu) to predict the end pose of a certain box on a conveyor belt, after it is tossed. This means that the involved contact is between the object and the environment, which in these recordings are Box012 and a conveyor, respectively. All the recordings in the archive were performed at the Innovation Lab of Vanderlande, located within the TU/e campus. More information can be found on https://impact-aware-robotics-database.tue.nl/

I.AM. archive containing long-range tossing experiments for Trajectory Based Parameter Identification of Box009

I.AM. archive as part of the Impact-Aware Robotics Archives Collection. This archive contains recordings of experiments that are executed under the scenario of TOSS. In these recordings, Box009 is manually tossed on a stationary conveyor belt. The purpose of these experiments is to obtain data for trajectory based parameter identification as part of a modeling framework. This modeling framework is used within the H2020 I.AM. project (www.i-am-project.eu) to predict the end pose of a certain box on a conveyor belt, after it is tossed. This means that the involved contact is between the object and the environment, which in these recordings are Box009 and a conveyor, respectively. All the recordings in the archive were performed at the Innovation Lab of Vanderlande, located within the TU/e campus. More information can be found on https://impact-aware-robotics-database.tue.nl/

Impact Aware Manipulation (I.AM.) archive containing box-drop experiments for Parameter Identification of Box006

I.AM. archive as part of the Impact-Aware Robotics Archives Collection. This archive contains recordings of experiments that are executed under the scenario of TOSS. In these recordings, a UR10 robot is used to toss and drop Box006 on a conveyor belt. The purpose of these experiments is to obtain data for Parameter Identification as part of a modeling framework. This modeling framework is used within the H2020 I.AM. project (www.i-am-project.eu) to predict the end pose of a certain box on a conveyor belt, after it is tossed. This means that the involved contact is between the object and the environment, which in these recordings are Box006 and a conveyor, respectively. All the recordings in the archive were performed at the Innovation Lab of Vanderlande, located within the TU/e campus. More information can be found on https://impact-aware-robotics-database.tue.nl/

I.AM. archive containing long-range tossing experiments for Trajectory Based Parameter Identification of Box009

I.AM. archive as part of the Impact-Aware Robotics Archives Collection. This archive contains recordings of experiments that are executed under the scenario of TOSS. In these recordings, Box009 is manually tossed on a stationary conveyor belt. The purpose of these experiments is to obtain data for trajectory based parameter identification as part of a modeling framework. This modeling framework is used within the H2020 I.AM. project (www.i-am-project.eu) to predict the end pose of a certain box on a conveyor belt, after it is tossed. This means that the involved contact is between the object and the environment, which in these recordings are Box009 and a conveyor, respectively. All the recordings in the archive were performed at the Innovation Lab of Vanderlande, located within the TU/e campus. More information can be found on https://impact-aware-robotics-database.tue.nl/

I.AM. archive containing box-drop experiments for Velocity Based Parameter Identification of Box007

I.AM. archive as part of the Impact-Aware Robotics Archives Collection. This archive contains recordings of experiments that are executed under the scenario of TOSS. In these recordings, a UR10 robot is used to toss and drop Box007 on a conveyor belt. The purpose of these experiments is to obtain data for velocity based parameter identification as part of a modeling framework. This modeling framework is used within the H2020 I.AM. project (www.i-am-project.eu) to predict the end pose of a certain box on a conveyor belt, after it is tossed. This means that the involved contact is between the object and the environment, which in these recordings are Box007 and a conveyor, respectively. All the recordings in the archive were performed at the Innovation Lab of Vanderlande, located within the TU/e campus. More information can be found on https://impact-aware-robotics-database.tue.nl/