Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer

Shigeki Nanjo, Akito Hata, Chiyuki Okuda, Reiko Kaji, Hideaki Okada, Daisuke Tamura, Kei Irie, Hiroshi Okada, Shoji Fukushima, Nobuyuki Katakami, Shigeki Nanjo, Akito Hata, Chiyuki Okuda, Reiko Kaji, Hideaki Okada, Daisuke Tamura, Kei Irie, Hiroshi Okada, Shoji Fukushima, Nobuyuki Katakami

Abstract

Background: Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose.

Methods: T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled.

Results: We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%.

Conclusions: Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.

Conflict of interest statement

AH received lecture fees from Chugai, Astra Zeneca, Boeringer Ingelheim, and Eli Lilly. NK received grants from Astra Zeneca, Eisai, Ono, Kyowa Kirin, Shionogi, Daiichi-Sankyo, Taiho, Chugai, Eli Lilly, Boeringer Ingelheim, and Merck Serono, and payment for lectures from Dainippon Sumitomo, Chugai, Boeringer Ingelheim, Astra Zeneca, Eli Lilly, Taiho, Janssen, Novartis, Pfizer, Ono, and Daiichi-Sankyo. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Treatment and CSF results. (A) Treatment timelines. (B) Cerebrospinal fluid (CSF) cytology/mutation status in definitive LM cases.
Figure 2
Figure 2
Representative magnetic resonance images before and after osimertinib (patients 2 and 10) Patient 2 (definitive case): (A) before osimertinib and (B) 2 months after osimertinib initiation. Patient 10 (possible case): (C) before osimertinib and (D) 2 months after osimertinib initiation.

References

    1. Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, Clarke JL, Lassman AB (2011) 'Pulsatile' high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 13: 1364–1369.
    1. Hata A, Kaji R, Fujita S, Katakami N (2011) High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. J Thorac Oncol 6: 653–654.
    1. Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Masago K, Fujita S, Kaji R, Imai Y, Monden K, Matsumoto T, Nagata K, Otsuka K, Tachikawa R, Tomii K, Kunimasa K, Iwasaku M, Nishiyama A, Ishida T, Nishimura Y (2015) Prognostic impact of central nervous system metastases after acquired resistance to EGFR-TKI: poorer prognosis associated with T790M-negative status and leptomeningeal metastases. Anticancer Res 35: 1025–1031.
    1. Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schütz M, Serke M, Stöhlmacher-Williams J, Märten A, Maria Huber R, Dickgreber NJ (2015) Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol 10: 156–163.
    1. Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M (2015) AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372: 1689–1699.
    1. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139.
    1. Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA AURA3 Investigators (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376: 629–640.
    1. Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, Kris MG, Chan TA, DeAngelis LM, Omuro AM (2012) Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol 7: 382–385.
    1. Nagai Y, Miyazawa H, Huqun, Tanaka T, Udagawa K, Kato M, Fukuyama S, Yokote A, Kobayashi K, Kanazawa M, Hagiwara K (2005) Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res 65, 7276-728205-0331.
    1. Nakamura T, Sueoka-Aragane N, Iwanaga K, Sato A, Komiya K, Abe T, Ureshino N, Hayashi S, Hosomi T, Hirai M, Sueoka E, Kimura S (2011) A noninvasive system for movnitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA. J Thorac Oncol 6: 1639–1648.
    1. Nanjo S, Ebi H, Arai S, Takeuchi S, Yamada T, Mochizuki S, Okada Y, Nakada M, Murakami T, Yano S (2016) High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells. Oncotarget 7: 3847–3856.
    1. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.
    1. Pareek V, Welch M, Ravera E, Zampolin RL, Sequist LV, Halmos B (2016) Marked Differences in CNS Activity among EGFR Inhibitors: Case Report and Mini-Review. J Thorac Oncol 11: e135–e139.
    1. Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, Lee JS (2012) Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 77: 556–560.
    1. Planchard D, Brown KH, Kim DW, Kim SW, Ohe Y, Felip E, Leese P, Cantarini M, Vishwanathan K, Jänne PA, Ranson M, Dickinson PA (2016) Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotalclinical studies. Cancer Chemother Pharmacol 77: 767–776.
    1. Takeda T, Itano H, Takeuchi M, Nishimi Y, Saitoh M, Takeda S (2017) Osimertinib administration via nasogastric tube in an EGFR-T790M-positive patient with leptomeningeal metastases. Respirol Case Rep 5: e00241.
    1. Yang JC, Cho B, Kim DW, Kim SW, Lee JS, Su WC, John T, Kao CH, Natale R, Goldman JW, Overend P, Vishwanathan K, Ye X, Yang Z, Ahn MJ (2017) Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from BLOOM study. J Clin Oncol 35(suppl): abstr 2020.
    1. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ (2013) 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 19: 2240–2247.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться