An Observational Study to Assess the Molecular Epidemiology and Direct Medical Costs of Epidermal Growth Factor Receptor (EGFR) Mutations in Patients with Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer Treated with Afatinib in Real-World Clinical Settings in Greece

Giannis Mountzios, Sofia Lampaki, Georgia-Angeliki Koliou, Athanassios Vozikis, Ioannis Kontogiorgos, Panagiotis Papantoniou, Margarita-Ioanna Koufaki, Eleni Res, Anastasios Boutis, Athina Christopoulou, Nicoleta Pastelli, Anastasios Grivas, Gerasimos Aravantinos, Efthalia Lalla, Georgios Oikonomopoulos, Anna Koumarianou, Dionisios Spyratos, Dimitrios Bafaloukos, Georgios Rigakos, Pavlos Papakotoulas, George Fountzilas, Helena Linardou, Giannis Mountzios, Sofia Lampaki, Georgia-Angeliki Koliou, Athanassios Vozikis, Ioannis Kontogiorgos, Panagiotis Papantoniou, Margarita-Ioanna Koufaki, Eleni Res, Anastasios Boutis, Athina Christopoulou, Nicoleta Pastelli, Anastasios Grivas, Gerasimos Aravantinos, Efthalia Lalla, Georgios Oikonomopoulos, Anna Koumarianou, Dionisios Spyratos, Dimitrios Bafaloukos, Georgios Rigakos, Pavlos Papakotoulas, George Fountzilas, Helena Linardou

Abstract

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking.

Materials and methods: This was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered.

Results: A total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37-91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9-51.4), the median PFS was 14.3 months (95% CI 12.2-16.4), and the median OS was 29 months (95% CI 25.6-33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5-18.5) and 28.1 months (95% CI 21.1-32.6), respectively. The mean expenditure for the treatment of each patient equals €25,333.68; with €21,865.06 being attributed to drug acquisition costs, €3325.35 to monitoring costs and €143.27 to adverse event treatment-related costs.

Conclusion: Long-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC.

Clinical trial registration: Clinicaltrials.gov NCT04640870.

Keywords: EGFR; afatinib; cost-effectiveness; epidermal growth factor receptor; lung cancer; molecular epidemiology.

Conflict of interest statement

Dr Giannis Mountzios report personal fees from Roche Hellas, personal fees from BMS Greece, personal fees from MSD Greece, personal fees from AstraZeneca Greece, personal fees from Pfizer Greece, personal fees from Takeda Greece, personal fees from Boehringer Greece, outside the submitted work; Professor Athanassios Vozikis report personal fees from BMS, personal fees from Roche, personal fees from TAKEDA, personal fees from ANGELINI, outside the submitted work; Dr Anastasios Grivas report personal fees, non-financial support from Bristol-Myers Squibb, personal fees, non-financial support from LEO Pharma, personal fees, non-financial support from Novartis Greece, personal fees, non-financial support from AstraZeneca, personal fees, non-financial support from Amgen, personal fees, non-financial support from Pierre Fabre, personal fees, non-financial support from Boehringer Ingelheim, personal fees, non-financial support from Roche, outside the submitted work; Dr Georgios Rigakos report grants from pfizer, grants from Merck, grants from roche, outside the submitted work; Professor George Fountzilas report personal fees from Pfizer, personal fees from Novartis, personal fees from Roche, personal fees from AstraZeneca, outside the submitted work; and Stock ownership: Genprex, Daiichi Sankyo, ARIAD, RFL Holdings, FORMYCON. Dr Helena Linardou report personal fees from Roche, personal fees from Astra Zeneca, personal fees from Novartis, personal fees from MSD, personal fees from BMS, personal fees from Merck, personal fees from Pfizer, personal fees from Amgen, outside the submitted work. The authors report no other conflicts of interest in this work.

© 2021 Mountzios et al.

Figures

Figure 1
Figure 1
Type of EGFR mutation detected.
Figure 2
Figure 2
Kaplan-Meier curves with respect to PFS1 and OS.
Figure 3
Figure 3
Kaplan-Meier curves based on the type of EGFR mutation with respect to (A) PFS1 and (B) OS.

References

    1. International Agency for Research on Cancer. Estimated number of new cases in 2018. Global Cancer Observatory: Cancer Today. 2020.
    1. Lung cancer statistics. World Cancer Research Fund International. Available from:. Accessed May5, 2020.
    1. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl4):iv192–iv237.
    1. 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(25):2380–2388.
    1. 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(2):121–128.
    1. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24(1):54–59.
    1. 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 mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–222.
    1. Rosell R, Carcereny 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(3):239–246.
    1. Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a Phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–589.
    1. Paz-Ares L, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28(2):270–277.
    1. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454–1466.
    1. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244–2250.
    1. Wang J, Wang B, Chu H, Yao Y. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. Onco Targets Ther. 2016;9:3711–3726.
    1. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31(31):3987–3996.
    1. Health MBulletin of revised prices for human medicines. Available from:. Accessed August12, 2021.
    1. Drug pricing provision. Tax heaven. Available from:. Accessed August12, 2021.
    1. Legislative Affairs. Government Gazette; 2017.
    1. (EOPYY) NOfHSP. Categories of Medical Practices. 2021. Available from:. Accessed August12, 2021.
    1. Legislative Affairs. Government Gazette. Vol 946/Β/27.03.2012; 2012.
    1. Kim HR, Cho BC, Shim HS, et al. Prediction for response duration to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutated never smoker lung adenocarcinoma. Lung Cancer. 2014;83(3):374–382.
    1. Levy BP, Rao P, Becker DJ, Becker K. Attacking a moving target: understanding resistance and managing progression in EGFR-positive lung cancer patients treated with tyrosine kinase inhibitors. Oncology (Williston Park). 2016;30(7):601–612.
    1. Cortot AB, Janne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014;23(133):356–366.
    1. 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 cancers. Clin Cancer Res. 2013;19(8):2240–2247.
    1. Blakely CM, Bivona TG. Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance. Cancer Discov. 2012;2(10):872–875.
    1. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
    1. Wu SG, Liu YN, Tsai MF, et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 2016;7(11):12404–12413.
    1. Takeda M, Nakagawa K. First- and second-generation EGFR-TKIs are all replaced to osimertinib in chemo-naive egfr mutation-positive non-small cell lung cancer? Int J Mol Sci. 2019;20:1.
    1. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616–1622.
    1. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–1699.
    1. Goss G, Tsai CM, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17(12):1643–1652.
    1. Chouaid C, Luciani L, LeLay K, et al. Cost-effectiveness analysis of afatinib versus gefitinib for first-line treatment of advanced EGFR-mutated advanced non-small cell lung cancers. J Thorac Oncol. 2017;12(10):1496–1502.
    1. Gu X, Zhang Q, Chu YB, et al. Cost-effectiveness of afatinib, gefitinib, erlotinib and pemetrexed-based chemotherapy as first-line treatments for advanced non-small cell lung cancer in China. Lung Cancer. 2019;127:84–89.
    1. Hochmair MJ, Morabito A, Hao D, et al. Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: final analysis of the GioTag study. Future Oncol. 2020;16(34):2799–2808.
    1. Hochmair MJ, Buder A, Schwab S, et al. Liquid-biopsy-based identification of EGFR T790M mutation-mediated resistance to afatinib treatment in patients with advanced EGFR mutation-positive NSCLC, and subsequent response to osimertinib. Target Oncol. 2019;14(1):75–83.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe