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 raadplegen: Efficacy 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:

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

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

Geoffrey R. Oxnard, MD^1,2; Yuebi Hu, AB¹; Kathryn F. Mileham, MD³; et al Hatim Husain, MD⁴; Daniel B. Costa, MD, PhD⁵; Philip Tracy, BA^1,6; Nora Feeney, BSc⁷; Lynette M. Sholl, MD⁸; Suzanne E. Dahlberg, PhD¹; Amanda J. Redig, MD, PhD^1,2; David J. Kwiatkowski, MD, PhD^1,2; Michael S. Rabin, MD^1,2; Cloud P. Paweletz, PhD⁷; Kenneth S. Thress, PhD⁹; Pasi A. Jänne, MD, PhD^1,2,7

Author Affiliations

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 Cappuzzo^1,2

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 EGFR^T790M+ 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.

References

1.		Landi L, Cappuzzo F. Irreversible EGFR-TKIs: dreaming perfection. Transl Lung Cancer Res. 2013;2(1):40–49.
2.		Romanidou Ou, Landi L, Cappuzzo F, Califano R. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer. Ther Adv Med Oncol. 2016; 8(3):176–187.
3.		NCCN Guidelines. Non-small cell lung cancer (Version 4); 2016. Available from 1) https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed July 12, 2017.
4.		Cappuzzo F. Guide to Targeted Therapies: Treatment Resistance in Lung Cancer. Adis-Springer, Switzerland; 2015.
5.		Jänne PA, James Chih-Hsin Yang, Dong-Wan Kim. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015; 372:1689–1699.
6.		Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study Phase II extension component. J Clin Oncol. 2017;35(12):1288–1296.
7.		Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. J Thorac Oncol. 2015;10(9 Suppl 2):S320 (n.d.).
8.		Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–640.
9.		Jackman D, Pao W, Riely G, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010;28(2):357–360.
10.		Yu Ha, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancer. Clin Cancer Res. 2013;19(8):2240–2247.
11.		Chabon JJ, Simmons AD, Lovejoy AF, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanism in lung cancer patients. Nat Commun. 2016;7:11815.
12.		Rosell R, Karachaliou N. Implications of blood-based T790M genotyping and beyond in epidermal growth factor receptor-mutant non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3361–3362.
13.		Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3375–3382.
14.		Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–1061.
15.		Jänne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–1699.
16.		Khozin S, Weinstock C, Blumenthal GM, et al. Osimertinib for the treatment of metastatic epidermal growth factor T790M positive non-small cell lung cancer. Clin Cancer Res. 2017;23(9).
17.		Omuro AM, Kris MG, Miller VA, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005;103:2344–2348.
18.		Jamal-Hanjani M, Spicer J. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer metastatic to the brain. Clin Cancer Res. 2012;18(4):938–944.
19.		Ballard P, Yates JW, Yang Z, et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016;22(20):5130–5140.
20.		Yang JC-H, Kim D-W, Kim S-W, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from nonsmall cell lung cancer (NSCLC): updated results from BLOOM, a phase I study. J Clin Oncol. 2016;34(Suppl):9002.
21.		Ramalingam S, Rukazenkov Y, Thomaset K, et al. A randomized, phase III study (FLAURA) of AZD9291, a novel EGFR-TKI, versus gefitinib or erlotinib in treatment-naïve patients with advanced non-small cell lung cancer and an EGFR-TKI-sensitizing mutation. Abstract. Meetinglibrary.asco.org. ASCO Annual Meeting; 2015. Abstract number TPS8102.
22.		Oxnard GR, Ramalingam SS, Ahn M-J, et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. ASCO Meeting Abstracts; 2015;33:2509.
23.		Liao BC, Lin CC, Lee JH, Chih-Hsin Yang. Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptors tyrosine kinase inhibitors. J Biomed Sci. 2016;23:86.
24.		Broderick J M. Clovis ends development of rociletinib in lung cancer. OncLive.com. Published Online: Friday, May 6, 2016. Available from http://www.onclive.com/web-exclusives/clovis-ends-development-of-rociletinib-in-lung-cancer. Accessed July 18, 2017.
25.		Clovis Oncology announces regulatory update for rociletinib NDA filing. Business Wire. November 16, 2015. Available from http://www.businesswire.com/news/home/20151116005513/en/Clovis-Oncology-Announces-Regulatory-Update-Rociletinib-NDA. Accessed July 18, 2017.
26.		Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9:34.
27.		Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–1639.
28.		Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135.
29.		Herbst RS, Baas P, Kim DW, et al. Pembrolizumabversus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet. 2016;387:1540–1550.
30.		Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387:1837–1846.
31.		Barlesi F, Park K, Ciardello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Ann Oncol. 2016;27(Suppl. 6):vi552–vi587.
32.		Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–1833.
33.		Lin K, Cheng J, Yang T, Li Y, Zhu B. EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-kB. Biochem Biophys Res Commun. 2015;463:95–101.
34.		Rizvi NA, Chow LQM, Borghaei H, et al. Safety and response with nivolumab (anti-PD1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. Vol. 32. ASCO Meeting Abstracts; 2014:8022.
35.		Creelan BC, Chow LQ, Kim DW, et al. Safety and tolerability results from a phase I study of MEDI4736, a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC). Vol. 33. ASCO Meeting Abstracts; 2015:3047.
36.		Remon J, Besse B. Unravelling signal escape through maintained EGFR activation in advanced non-small cell lung cancer (NSCLC): new treatment options. ESMO Open. 2016;1(4):e000081.
37.		Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 2016;9:47.
38.		Sonia JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16:990–998.
39.		Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7:1807–1814.
40.		Eskens FA, Mom CH, Planting AS, et al. A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer. 2008;98:80–85.
41.		Janjigian YY, Smith EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4:1036–1045.
42.		Wang S, Song Y, Liu D. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017;385:51–54.
43.		Yu HA, Tian SK, Drilon AE, et al. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol. 2015;1(7):982–984.
44.		Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–562.
45.		Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–2294.
46.		Wang S, Tsui ST, Liu C, Song Y, Liu D. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol. 2016;9:59.
47.		Lee YJ, Choi HJ, Kim SK, et al. Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patient with nonsmall-cell lung cancer. Cancer. 2010;116:1336–1343.
48.		Hellman MD, Gettinger SN, Goldman JW, et al. Checkmate 012: safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC. ASCO Meeting Abstracts; 2016;34(15_suppl):3001.
49.		Antonia S., Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299–308.
50.		Dholaria B, Hammond W, Shreders A, Lou Y. Emerging therapeutic agents for lung cancer. J Hematol Oncol. 2016;9:138.
51.		Mok TS, Wu YI, Thongprasert S, et al. Gefitinib or Carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957.
52.		Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122–1128.
53.		Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–128.
54.		Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388.
55.		Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first line treatment for patients with advanced EGFR mutation-positive non-small cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–74.2
56.		Rosell R, Carceremy E, Gervais R, et al. Erlotinib versus standard chemotherapy as first line treatment for European patients with advanced EGFR-mutation positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13:239–246.
57.		Wu YL, Liam CK, Zhou C, et al. First-line erlotinib versus cisplatin/gemcitabine (GP) in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC): interim analyses from the phase 3, open-label, ENSURE study. J Thorac Oncol. 2013;8:s603 (Suppl.2).
58.		Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334.
59.		Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutation (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213–222.

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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 Zhang corresponding author

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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

niet-kleincellige longkanker, EGFR medicijnen, EGFR T790M-mutatie, resistentie, overall overleving, progressievrije ziekte, osimertinib