Background: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC).... Show moreBackground: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. Methods: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as >= 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C-min,C-pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 mu g/L was taken to explore the exposure-efficacy relationship. Results: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 - 19.1) months and 9.3 (95% CI: 7.2 - 11.1) months for patients with C-min,C-pred < 166 mu g/L and C-min,C-pred >= 166 mu g/L, respectively (p = 0.03). In the multivariate analysis, a C-min,C-pred < 166 mu g/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 - 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 - 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). Conclusion: In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively. Show less
Henegouwen, J.M.V.; Jebbink, M.; Hoes, L.R.; Wijngaart, H. van der; Zeverijn, L.J.; Velden, D.L. van der; ... ; Gelderblom, H. 2022
Introduction: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved... Show moreIntroduction: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.Methods: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease >= 16 weeks). Patients were enrolled using a Simonlike 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.Results: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease >= 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.Conclusion: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Dammeijer, F.; Gooijer, C.J. de; Gulijk, M. van; Lukkes, M.; Klaase, L.; Lievense, L.A.; ... ; Aerts, J.G. 2021
Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that... Show moreBackground: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma.Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS.Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4(+) T-helper, CD8(+) Tand NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS.Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies. (C) 2020 The Authors. Published by Elsevier B.V. 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
