Resistance mechanisms in lung cancer patients with EGFR or ALK aberrations treated with kinase inhibitors

In dit proefschrift hebben we ons gefocust op het vinden van nieuwe resistentie mechanismen bij patiënten die behandeld zijn met afatinib indien zij een EGFR mutatie hadden en met crizotinib indien zij een ALK breuk hadden. Bij onderzoek van de literatuur vonden we voor afatinib als mechanismen van resistentie een extra mutatie in EGFR (V834I), MET en FGFR1 amplificatie, activatie van IL6R/JAK1/STAT3, Src en autofagie, en verandering van glycolyse. Bij crizotinib vonden we ALK ‘gatekeeper’ mutaties, activatie van EGFR, mutaties in KRAS, autofagie en epitheliaal-mesenchymale transitie (EMT). Deze bevindingen hebben er toe geleid dat we wilden proberen uit te zoeken of de betreffende resistentie mechanismen ook voorkomen bij patiënten die resistent zijn geworden tegen de betreffende doelgerichte therapieën. Bij de afatinib behandelde patiënten vonden we met name mutaties in de signaal transductie paden van Wnt en PI3K-AKT door DNA (exome) sequentie analyse te doen op biopten voor en na therapie. Bij de patiënten die behandeld zijn met crizotinib hebben we gebruik gemaakt van exome en RNA sequentie analyse. Hierbij vonden we bij exome sequentie analyse met name mutaties in de signaal transductie paden die betrokken zijn bij EMT. RNA sequentie analyse leverde geen nieuwe inzichten op. Het belangrijkste wat we bij crizotinib behandelde patiënten hebben gevonden, is dat wanneer er geen eiwit expressie wordt gezien in een dichotome immunohistochemische test, er geen respons op therapie wordt gezien. Patiënten met een ALK breuk bij FISH analyse, maar zonder eiwit expressie bij ALK-IHC moeten dus niet behandeld worden met crizotinib en anderzijds heeft de ALK-FISH test dus geen meerwaarde. We kunnen bij ALK testing dus volstaan met ALK-IHC

Pharmacokinetically-guided dosing to improve the efficacy of brigatinib in non-small cell lung cancer patients

Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180 mg QD; the highest tolerable dose tested in clinical trials: 240 mg QD; and two precision dosing strategies targeting the median trough concentrations following 180 mg QD, and 240 mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS) and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240 mg dosing strategy, with only a minor increase in the probability of developing toxicity

In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non–small-cell Lung Cancer

Introduction: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. Patients and methods: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. Results: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time.Conclusion: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.</p

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non-small-cell Lung Cancer

Most trials regarding tyrosine kinase inhibitors in patients with advanced epidermal growth factor receptor-mutated non-small-cell lung cancer comprised selected series from Asian populations. We found that Western European patients with epidermal growth factor receptor-mutated non-small-cell lung cancer who received first-line treatment with regular tyrosine kinase inhibitors have a median overall survival of 20.2 months in our large nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib. Background: Only a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival. Patients and Methods: Information about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals. Results: A total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and >= 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis. Conclusion: Dutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib. (C) 2020 Elsevier Inc. All rights reserved

In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non–small-cell Lung Cancer

Introduction: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. Patients and methods: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. Results: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time.Conclusion: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.</p

Prevalence of KRAS p.(G12C) in stage IV NSCLC patients in the Netherlands:a nation-wide retrospective cohort study

OBJECTIVES: The recent accelerated FDA approval of sotorasib, a highly selective KRAS G12C inhibitor, offers new opportunities for the treatment of KRAS p.(G12C)-mutated non-squamous non-small cell lung cancer (NSCLC). The objective of the current study was to the determine the prevalence of KRAS mutations in stage IV non-squamous NSCLC in The Netherlands to reveal the potential impact of upcoming KRAS targeted therapy. MATERIALS AND METHODS: All patients diagnosed with stage IV non-squamous NSCLC in 2013, 2015 and 2017 in the Netherlands were selected by linking the nation-wide Netherlands Cancer Registry (NCR) and the Dutch Pathology Registry (PALGA). Demographic and pathological variables were retrieved from the pathology reports including sex, age, KRAS mutation status, molecular test method used, and the mutation status of other genes. RESULTS: Prevalence for any KRAS mutations in codon 12/13/61/146 was 39.1%. KRAS p.(G12C) was detected in 15.5% of all non-squamous NSCLC cases representing 39.6% of all KRAS-mutant cases. National testing rate for KRAS mutations increased from 70% in 2013 to 82% in 2017. Testing techniques changed significantly over time with next generation sequencing as the main used method in 2017 (71.6%) but did not affect prevalence of KRAS mutations over time. When KRAS was tested as part of a larger panel, the KRAS p.(G12C) mutation was frequently reported with a concurrent mutation in TP53 (47.7%) or STK11 (10.3%). CONCLUSION: The high prevalence for KRAS p.(G12C) offers a promising new specific treatment option for 15% of all stage IV non-squamous NSCLC patients