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Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 121-123

Osimertinib in G719A mutated non-small cell lung cancer with leptomeningeal metastases

Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India

Date of Web Publication9-Sep-2019

Correspondence Address:
Avinash Pandey
Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_27_19

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How to cite this article:
Pandey A, Singh A, Singh S, Kumar A. Osimertinib in G719A mutated non-small cell lung cancer with leptomeningeal metastases. Cancer Res Stat Treat 2019;2:121-3

How to cite this URL:
Pandey A, Singh A, Singh S, Kumar A. Osimertinib in G719A mutated non-small cell lung cancer with leptomeningeal metastases. Cancer Res Stat Treat [serial online] 2019 [cited 2021 Jul 30];2:121-3. Available from: https://www.crstonline.com/text.asp?2019/2/1/121/266449

First-generation tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are accepted standard first-line therapies for classical sensitizing epidermal growth factor receptor (EGFR) gene mutations such as deletion 19 and L858R over chemotherapy.[1] However, about 10%–15% of EGFR mutations are non-classical, including exon 20 insertions, exon 18-point mutations, and complex mutations where sensitivity to the first-line TKIs is very low.[2] In patients with exon 18-point mutations such as G719A, gefitinib and erlotinib lead to 10%–40% response rates with 2–3 months' progression-free survival (PFS) compared to 60%–70% response rates and 7–11 months' PFS in patients with classical mutations.[2],[3] The second generation TKI, afatinib, fares much better in patients harboring rare non-classical EGFR mutations such as G719A mutation, with response rates of 70% and PFS of 13–18 months in a retrospective study and subset analyses of prospective randomized trials.[4],[5] Hence, it is considered as the preferred option in such patients. We report a patient with G719A mutation-positive metastatic adenocarcinoma lung with leptomeningeal metastasis treated with the third-generation TKI, osimertinib.

A 70-year-old male, never smoker, presented with a history of neck pain for 2 weeks with progressive right forearm tingling and numbness. Magnetic resonance imaging (MRI) of the cervical spine revealed T1 isointense and T2 hyperintense well-defined, enhancing mass of 3.4 cm × 3.1 cm destroying the vertebral bodies of the C5–C6 vertebrae with partial collapse, compression of C6–C7 nerve roots, and spinal cord compression. Prompt surgical decompression with C5–C7 corpectomy and cancellous bone graft fixation with mass cage was done to stabilize the spine. Neurological symptoms improved promptly and final histopathology after spinal decompression revealed thyroid transcription factor-1-positive metastatic adenocarcinoma from a lung primary. Positron emission tomography-computerized tomography (PET-CT) showed multiple pulmonary nodules in bilateral lungs with moderate left pleural effusion along with uptake at C5–C6 and upper dorsal vertebrae. There also were other bone metastases involving iliac bone, sternum, and lumbar vertebrae with retroperitoneal metastatic adenopathy [Figure 1]a. Sanger sequencing detected a point mutation in EGFR exon 18, G719A, which is a non-classical mutation. MRI brain suggested leptomeningeal enhancement without brain metastasis. Cerebrospinal fluid (CSF) cytology was positive for adenocarcinoma cells.
Figure 1: (a) Active hypermetabolic metastatic lytic lesions in multiple cervical (SUVmax7.4), upper dorsal vertebrae (SUVmax6.8) and sternum (SUVmax9.5) in a known case of metastatic non-small cell lung cancer. (b) After 3 months of therapy with osimertinib, reduction in hypermetabolic metastatic lytic lesion in cervical (SUVmax4.1), upper dorsal vertebrae (SUVmax2.2), and sternum (SUVmax4.3) suggestive of partial response to therapy. SUVmax: Maximum standardized update value

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The patient was started on osimertinib 80 mg once a day along with radiotherapy to the cervical spine C4–C7, 30 Gy in 10 fractions, and intravenous zoledronic acid 4 mg every 3 months. The patient tolerated osimertinib well with Grade 1 diarrhea, Grade 2 fatigue, and Grade 1 anemia in 2nd, 3rd, and 4th months, respectively, which were managed symptomatically without dose reduction or interruption in treatment. No intrathecal treatment was delivered. Response evaluation in the third month showed partial radiological and metabolic response on PET-CT [Figure 1]b. MRI brain and CSF cytology in the 3rd month of osimertinib revealed an absence of leptomeningeal enhancement and negative cytology for malignant cells, respectively. The patient continues to do well on osimertinib at with a sustained response.

Osimertinib is an irreversible third-generation oral TKI approved as a first-line therapy in treatment-naive unresectable and metastatic non-squamous cell lung cancer harboring classical exon 19 deletion or L858R exon 21 mutation.[6] In the Phase III multicenter, international, double-blind FLAURA trial, osimertinib 80 mg once a day showed superior response rates and significantly longer PFS compared to first-generation gefitinib or erlotinib.[7] Among patients presenting with de novo brain metastasis, osimertinib scored better in terms of significantly higher intracranial response rates and longer intracranial PFS, median not reached versus 13.9 months (P = 0.0.14), compared to the first-generation TKIs.[8]

In patients with rare non-classical EGFR exon 18 point mutations such as G719A, response rates, and PFS to first-line TKIs are dismal.[2] When tested in cell lines, the 90% inhibitory concentrations (IC90) of the first-generation and third-generation TKIs were extremely high (11–50-fold) for exon 18 point mutations compared to classical sensitizing del 19 mutations. In contrast, the IC90 for the second generation oral TKI, afatinib, is only modestly higher (5-fold) for exon 18 point mutations in comparison to del 19 mutations.[9] This observation is supported by the clinical experience of much higher response rates and PFS of exon 18 G719A mutation with afatinib compared to gefitinib or erlotinib.[4],[5] However, in a recent, still unpublished Phase II single-arm trial among patients harboring uncommon EGFR mutations, osimertinib 80 mg once a day demonstrated over 50% response rates and 8 months of PFS in patients with exon 18-point mutation including G719A, but no information of its activity in patients with leptomeningeal or brain metastasis in the above rare cohort is yet known.[10],[11]

Our patient had presented with cervical cord compression with extensive metastatic disease from lung primary in addition to the leptomeningeal enhancement and CSF cytology positivity. As EGFR testing revealed exon 18 point mutation G719A which responds poorly to first-generation TKIs, we did not use gefitinib or erlotinib. Second-generation oral TKI, afatinib and third-generation oral TKI, osimertinib have never been compared head to head as first-line therapy in EGFR mutation non-squamous cell lung cancer in either classical sensitive or nonclassical EGFR mutations. We chose to treat our 70-year-old performance status of two patients with osimertinib 80 mg once daily as it has a better safety profile and supported with unequivocal data of it having higher blood–brain barrier penetration with better response rate and intracranial PFS in patients presenting with brain metastasis, in our case with leptomeningeal metastasis. The patient became symptom free within 3 weeks of starting osimertinib and continues to have sustained partial response at 6 months of therapy with a negative CSF cytology despite not receiving any intrathecal chemotherapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lee CK, Wu YL, Ding PN, Lord SJ, Inoue A, Zhou C, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: A meta-analysis. J Clin Oncol 2015;33:1958-65.  Back to cited text no. 1
O'Kane GM, Bradbury PA, Feld R, Leighl NB, Liu G, Pisters KM, et al. Uncommon EGFR mutations in advanced non-small cell lung cancer. Lung Cancer 2017;109:137-44.  Back to cited text no. 2
Nguyen KS, Neal JW. First-line treatment of EGFR-mutant non-small-cell lung cancer: The role of erlotinib and other tyrosine kinase inhibitors. Biologics 2012;6:337-45.  Back to cited text no. 3
Shen YC, Tseng GC, Tu CY, Chen WC, Liao WC, Chen WC, et al. Comparing the effects of afatinib with gefitinib or erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. Lung Cancer 2017;110:56-62.  Back to cited text no. 4
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-lung 2, LUX-lung 3, and LUX-lung 6. Lancet Oncol 2015;16:830-8.  Back to cited text no. 5
U.S. Food and Drug Administration: FDA Approves Osimertinib for First-Line Treatment of Metastatic NSCLC With Most Common EGFR Mutations. Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm605113.htm. [Last accessed on 2019 May 05].  Back to cited text no. 6
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non – Small-cell lung cancer. N Engl J Med 2018;378:113-25.  Back to cited text no. 7
Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, et la. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non–small-cell lung cancer. Journal of Clinical Oncology 2018;36:3290-7.  Back to cited text no. 8
Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, et al. EGFR exon 18 mutations in lung cancer: Molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs. Clin Cancer Res 2015;21:5305-13.  Back to cited text no. 9
Cho JH, Sun J, Lee S, Ahn JS, Park K, Park KU, et al. OA10. 05 an open-label, multicenter, phase II single arm trial of osimertinib in NSCLC patients with uncommon EGFR mutation (KCSG-LU15-09). J Thorac Oncol 2018;13:S344.  Back to cited text no. 10
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 11
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