Introduction: This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated... Show moreIntroduction: This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd.Methods: Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/ pneumonitis are summarized.Results: The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/ pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years.Conclusions: In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all. Show less
Aims Human epidermal growth factor receptor 2 (HER2) amplification in endometrial cancer (EC) is almost completely confined to the p53-abnormal (p53abn) molecular subtype and independent of... Show moreAims Human epidermal growth factor receptor 2 (HER2) amplification in endometrial cancer (EC) is almost completely confined to the p53-abnormal (p53abn) molecular subtype and independent of histological subtype. HER2 testing should therefore be molecular subtype-directed. However, the most optimal approach for HER2 testing in EC has not been fully established. Therefore, we developed an EC-specific HER2 immunohistochemistry (IHC) scoring method and evaluated its reproducibility and performance to establish an optimal diagnostic HER2 testing algorithm for p53abn EC. Methods and results HER2 IHC slides of 78 p53abn EC were scored by six gynaecopathologists according to predefined EC-specific IHC scoring criteria. Interobserver agreement was calculated using Fleiss' kappa and the first-order agreement coefficient (AC1). The consensus IHC score was compared with HER2 dual in-situ hybridisation (DISH) results. Sensitivity and specificity were calculated. A substantial interobserver agreement was found using three- or two-tiered scoring [kappa = 0.675, 95% confidence interval (CI) = 0.633-0.717; AC1 = 0.723, 95% CI = 0.643-0.804 and kappa = 0.771, 95% CI = 0.714-0.828; AC1 = 0.774, 95% CI = 0.684-0.865, respectively]. Sensitivity and specificity for the identification of HER2-positive EC was 100 and 97%, respectively, using a HER2 testing algorithm that recommends DISH in all cases with moderate membranous staining in >10% of the tumour (IHC+). Performing DISH on all IHC-2+ and -3+ cases yields a sensitivity and specificity of 100%. Conclusions Our EC-specific HER2 IHC scoring method is reproducible. A screening strategy based on IHC scoring on all cases with subsequent DISH testing on IHC-2+/-3+ cases has perfect test accuracy for identifying HER2-positive EC. Show less
In this thesis, we aim to shed light on the diverse and often opposing roles of integrin α3β1 in cancer. Our work highlights that the role of α3β1 in cancer depends on time and place: the nature of... Show moreIn this thesis, we aim to shed light on the diverse and often opposing roles of integrin α3β1 in cancer. Our work highlights that the role of α3β1 in cancer depends on time and place: the nature of the cell environment (such as extracellular matrix composition), type of cancer and its driving mechanism, as well as the stage of the disease. We provide a new insight into the mechanisms behind the role of α3β1 in HER2-driven breast cancer and in DMBA/TPA-induced non-melanoma skin tumorigenesis. Show less
Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB... Show moreSince several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies.Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations.Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC. Show less
Antibody drug conjugates (ADCs) are emerging as powerful anti-cancer treatments. They are designed to combine the tumor specificity, pharmacokinetics and biodistribution properties of antibodies... Show moreAntibody drug conjugates (ADCs) are emerging as powerful anti-cancer treatments. They are designed to combine the tumor specificity, pharmacokinetics and biodistribution properties of antibodies with the potent cell-killing activity of small molecules. The approval of brentuximab vedotin (Adcetris) for the treatment of Hodgkin lymphoma and trastuzumab emtansine (Kadcyla) for the treatment of metastatic breast cancer has spurred clinical development of ADCs. As the field of ADCs is rapidly emerging, a better understanding of the requirements needed for optimal intracellular delivery of ADCs seems mandatory. The aim of this thesis was to better understand the antibody and antigen requirements that are needed for effective ADC treatment. Different tumor antigens and targeting antibodies were compared for their capacity to deliver a cytotoxic payload to tumor cells, uncovering general mechanisms. In the course of this work, TF was identified as an excellent ADC target because of its rapid internalization and lysosomal targeting characteristics. Furthermore we have explored a novel Ab platform that improves the intracellular delivery of cytotoxic payloads. These findings provide a better insight in the Ab and antigen requirements needed for optimal payload delivery and support the development of novel and further improved ADCs for the treatment of cancer. Show less
Rouwendal, G.J.A.; Lee, M.M. van der; Meyer, S.; Reiding, K.R.; Schouten, J.; Roo, G. de; ... ; Ubink, R. 2016
