Raadpleeg ook onze literatuurlijst van niet-toxische middelen en behandelingen, samengesteld door arts-bioloog drs. Engelbert Valstar specifiek bij longkanker

9 februari 2020: lees ook dit artikel:

https://kanker-actueel.nl/giotrifafatinib-gevolgd-door-osimertinib-laat-mediane-algehele-overleving-zien-van-bijna-vier-jaar-bij-patienten-met-egfr-t790m-positieve-niet-kleincellige-longkanker-nsclc-en-del19-mutatie.html

9 februari 2020: wellicht is deze meta-analyse interessant eens te raadplegenEfficacy and safety of osimertinib in treating EGFR‐mutated advanced NSCLC: A meta‐analysis

Abstract staat onderaan artikel:

13 augustus 2018: Bron: JAMA Oncol. Published online August 2, 2018

Osimertinib is een zogeheten EGFR medicijn, een gericht medicijn (targeted therapy), gericht met name op bepaalde EGFR mutaties bij niet-kleincellige longkanker. EGFR medicijnen kunnen bij patiënten met de juiste mutatie vaak voor beduidend langere progressievrije ziekte zorgen. Maar vaak ook treedt bij EGFR medicijnen snel resistentie op. (zie bv dit studierapport over osimertinib: Treating EGFR mutation resistance in non-small cell lung cancer – role of osimertinib (Abstract staat onderaan artikel)

Dit zijn de bekendste EGFR-TKI medicijnen die dus vaak al snel resistentie vertonen en dus ook bij  osimertinib:

https://www.dovepress.com/cr_data/article_fulltext/s103000/103471/img/TACG-103471_T001.jpg

En dit zijn de meest voorkomende mutaties bij resistentie tegen een EGFR-TKI:

https://www.dovepress.com/cr_data/article_fulltext/s103000/103471/img/TACG-103471_F001.jpg

Zo ook wordt dus osimertinib ingezet bij niet-kleincellige longkanker. Uit een heel specifieke studie blijkt nu dat met het verdwijnen van een bepaalde EGFR mutatie, de EGFR T790M mutatie, er snel resistentie ontstaat en ook nieuwe andere mutaties ontstaan. (zie schema hierboven)

Conclusie uit de reviewstudie:

Optredende resistentie is een van de belangrijkste beperkingen bij de behandeling van longkanker. Ondanks een eerste effectieve behandeling voor gerichte behandelingen, worden nagenoeg alle patiënten op een bepaald moment ongevoelig voor hun medicatie. Identificatie van mechanismen die betrokken zijn bij resistentie tegen geneesmiddelen is dus essentieel om de beste behandelstrategie voor elke patiënt op maat te maken (personalised medicin. Dit is de reden waarom identificatie van biomarkers moet worden aangemoedigd en een geschikt weefselmonster of plasmabepaling essentieel is voor biologische karakterisering. Falen van momenteel beschikbare gerichte behandelingen suggereert dat 1 enkel middel mogelijk niet voldoende is om resistentie tegen geneesmiddelen te overwinnen. Nieuwe strategieën, inclusief combinatiebehandelingen, worden momenteel onderzocht om nieuwe behandelmogelijkheden te identificeren.

Het belangrijkste uit de studie met patiënten die osimertinib gebruikten was het volgende:

In deze cohortstudie van 143 patiënten met gevorderde niet-kleincellige longkanker (NSCLC) waarbij na een behandeling een nieuw receptoren- en genenonderzoek werd gedaan  (tumorsequentiëring van de volgende generatie), was het verdwijnen van de EGFR T790M-mutatie heel vaak te zien in relatie tot resistentie tegen osimertinib en werd geassocieerd met vroegtijdig falen van de behandeling en de ontwikkeling van een reeks andere mutaties (resistentiemechanismen), waarvan sommige werden verwacht (MET amplification, small cell transformation) en sommige nieuwe (acquired KRAS mutations, targetable gene fusions) zich voordeden. Vroege veranderingen in plasma EGFR-mutatie niveaus kunnen wijzen op waarschijnlijke resistentiepatronen / mechanismes.

De onderzoekers pleiten dan ook voor betere strategieën voor het detecteren van meerdere coëxistente resistentiemechanismen en daarop gerichte behandelingen zullen nodig zijn om een meer duurzame beheersing van resistentie tegen geneesmiddelen bij EGFR-mutante longkanker te bereiken.

Het volledige studierapport: Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib is tegen betaling of registratie bij JAMA in te zien.

Hier het abstract van de studie:

Loss of EGFR T790M Mutation Is Associated With Early Treatment Failure and Development of Resistance to Osimertinib

Original Investigation
August 2, 2018

Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib

JAMA Oncol. Published online August 2, 2018. doi:10.1001/jamaoncol.2018.2969
Key Points

Question  What molecular and clinical biomarkers can be used to better understand osimertinib mesylate resistance and develop treatment strategies?

Findings  In this cohort study of 143 patients who underwent tumor next-generation sequencing, loss of the EGFR T790M mutation was common on resistance to osimertinib and was associated with early treatment failure and development of a range of competing resistance mechanisms, some expected (MET amplification, small cell transformation) and some novel (acquired KRAS mutations, targetable gene fusions). Early changes in plasma EGFR mutation levels may indicate probable resistance patterns.

Meaning  Strategies to detect and target multiple coexistent resistance mechanisms will be needed to achieve more durable control of drug resistance in EGFR-mutant lung cancer.

Abstract

Importance  Osimertinib mesylate is used globally to treat EGFR-mutant non–small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.

Objective  To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.

Design, Setting, and Participants  Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.

Main Outcomes and Measures  Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.

Results  Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).

Conclusions and Relevance  Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.

Osimertinib has been approved for treatment of advanced EGFRT790M+ mutation NSCLC following progression on a prior EGFR-TKI. Occurrence of acquired resistance to osimertinib represents an urgent need for additional strategies including combination with other agents, such as other targeted therapies or checkpoint inhibitors, or development of new and more potent compounds.

Treating EGFR mutation resistance in non-small cell lung cancer – role of osimertinib

Authors Mazza V, Cappuzzo F

Received 8 February 2017

Accepted for publication 6 May 2017

Published 26 July 2017 Volume 2017:10 Pages 49—56

DOI https://doi.org/10.2147/TACG.S103471

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Martin H. Maurer


Valentina Mazza,1 Federico Cappuzzo1,2

1Department of Oncology-Hematology, 2Department of Medical Oncology, AUSL Romagna, Ravenna, Italy

Abstract: The discovery of mutations in EGFR significantly changed the treatment paradigm of patients with EGFR-mutant non-small cell lung cancer (NSCLC), a particular group of patients with different clinical characteristics and outcome to EGFR-wild-type patients. In these patients, the treatment of choice as first-line therapy is first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, or afatinib. Inevitably, after the initial response, all patients become refractory to these drugs. The most common mechanism of acquired resistance to EGFR-TKIs is the development of a second mutation in exon 20 of EGFR (T790M). Osimertinib is a third-generation EGFR-TKI designed for overcoming T790M-mediated resistance. Based on the results of efficacy and tolerability of Phase II and Phase III studies, osimertinib has been approved for treatment of advanced EGFRT790M+ mutation NSCLC following progression on a prior EGFR-TKI. Occurrence of acquired resistance to osimertinib represents an urgent need for additional strategies including combination with other agents, such as other targeted therapies or checkpoint inhibitors, or development of new and more potent compounds.

Disclosure

The authors report no conflicts of interest in this work.

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Generally, osimertinib is a favorable treatment option for previously treated T790M mutation‐positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation‐positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.

. 2019 Jul 1; 145(1): 284–294.
Published online 2019 Jan 20. doi: 10.1002/ijc.32097
PMCID: PMC6590181
PMID: 30613959

Efficacy and safety of osimertinib in treating EGFR‐mutated advanced NSCLC: A meta‐analysis

Lilan Yi, 1 , † Junsheng Fan, 1 , 2 , † Ruolan Qian, 1 , † Peng Luo,corresponding author 1 and Jian Zhangcorresponding author 1

Associated Data

Supplementary Materials

Abstract

Osimertinib is the only Food and Drug Administration‐approved third‐generation epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitor (TKI). A meta‐analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment‐naïve patients with EGFR‐TKI‐sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6‐month PFS 83% (95% CI 80–87%), and 12‐month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier‐generation EGFR‐TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6‐month PFS 63% (95% CI 58–69%), and 12‐month PFS 32% (95% CI 17–47%). EGFR‐TKI‐naïve patients with EGFR‐positive mutations tend to have longer median PFS than EGFR‐TKI‐pretreated counterparts (19.17 vs


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