|LETTER TO EDITOR
|Year : 2019 | Volume
| Issue : 1 | Page : 121-123
Osimertinib in G719A mutated non-small cell lung cancer with leptomeningeal metastases
Avinash Pandey, Anjana Singh, Shivkant Singh, Amit Kumar
Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
|Date of Web Publication||9-Sep-2019|
Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar
Source of Support: None, Conflict of Interest: None
|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 2020 Apr 10];2:121-3. Available from: http://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. 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. 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., 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., 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. 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. 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.
In patients with rare non-classical EGFR exon 18 point mutations such as G719A, response rates, and PFS to first-line TKIs are dismal. 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. 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., 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.,
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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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