Successful osimertinib treatment in a patient who exhibited intramedullary spinal cord metastases of lung adenocarcinoma with an acquired EGFR T790M mutation

Abstract

Intramedullary spinal cord metastases (ISCMs) of non-small cell lung cancer (NSCLC) constitute a serious if infrequent complication, characterised by rapid progression of neurological deficits, with poor prognosis. We describe a 52-year-old man with ISCMs secondary to lung adenocarcinoma who acquired the T790M mutation of the epidermal growth factor receptor (EGFR) after previous use of a first-generation EGFR tyrosine kinase inhibitor (TKI); he was successfully treated with osimertinib. This is the first report of the use of osimertinib in ISCMs: due to its high central nervous system activity, osimertinib could be useful for treating ISCMs secondary to NSCLC in patients who exhibit the T790M mutation.

Background

Among the central nervous system (CNS) complications in systemic malignancies, intramedullary spinal cord metastases (ISCMs) are rare, comprising 4.2%–8.5% of all CNS metastases, and are characterised by poor prognosis.¹ ISCMs constitute less than 5% of all spinal metastases, including other extradural forms such as those in the vertebrae and the extradural spinal cord space.¹ Lung cancer is the most common primary malignancy leading to ISCMs (48% of cases), followed by breast cancer, melanoma and lymphoma.^{1 2} Symptoms such as weakness and paresthesia progress rapidly within a few days, and sphincter dysfunction may occur.³

In non-small-cell lung cancer (NSCLC), patients harbouring epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitising mutations are treated with EGFR-TKIs, leading to extended progression-free survival (PFS) compared with chemotherapy.^{4 5} However, most patients show acquired resistance to EGFR-TKIs, resulting in limited overall survival. The p.Thr790Met point mutation (T790M) in the EGFR gene is known to promote resistance to first- or second-generation EGFR-TKIs.^{6 7} Osimertinib, a third-generation EGFR-TKI selective for both sensitising mutations and the T790M resistance mutation, is used in advanced NSCLC, and is known to have high activity in the CNS.^{8 9}

In previous studies, ISCMs of NSCLC have been treated with radiation and chemotherapy, occasionally combined with surgery; however, the optimal treatment remains unclear.^10–12 Few reports have described the effect of EGFR-TKIs on ISCMs in NSCLC.^{13 14} Theoretically, osimertinib is expected to be effective for ISCMs, due to its high activity within the CNS. However, the use of osimertinib for ISCMs has not been previously reported. Here, we report a case of lung adenocarcinoma with ISCMs, in a patient who had acquired the T790M mutation after the previous use of a first-generation EGFR-TKI, which was successfully treated with osimertinib.

Case presentation

A 52-year-old man with lung adenocarcinoma, who had been treated with afatinib, was admitted due to a 3-day history of rapidly progressing quadriparesis and dysuria. Twelve years prior, the patient had undergone lobectomy of the right upper lobe to treat lung adenocarcinoma (pT1N2M0), followed by two courses of cisplatin and gemcitabine. Eight years prior, he had received 60 Gy radiation therapy for recurrent lymph node lesions in the mediastinum. Four years prior, his routine check-up by CT and bone scintigraphy revealed enlarged cervical and mediastinal lymph nodes, as well as multiple bone metastases in the ribs, vertebrae and pelvis, indicating the recurrence of lung adenocarcinoma. Molecular profiling of the surgical specimen by the PCR-invader method¹⁵ was negative for EGFR mutations, including T790M, and anaplastic lymphoma kinase rearrangements. He received 30 Gy radiation to the lumbar vertebrae, followed by 9 courses of chemotherapy with carboplatin, pemetrexed and bevacizumab. Three years prior, second-line erlotinib was administered for lymph node enlargement, despite the absence of EGFR mutations, because the patient exhibited favourable prognostic factors for EGFR-TKIs, including Asian ethnicity, presence of adenocarcinoma and lack of smoking history. The disease remained stable during 16 months of erlotinib therapy. Later treatment included 30 Gy radiation to the left femoral bone metastases, followed by third-line docetaxel, fourth-line S-1 and fifth-line vinorelbine. Before the fifth-line treatment, he also underwent radiation therapy for multiple brain metastases. Six months prior to admission, left pleural effusion thoracentesis revealed adenocarcinoma with the T790M EGFR mutation, as detected by the PCR-invader method, but other EGFR mutations were not detected. Sixth-line afatinib was administered because the patient had demonstrated good response to erlotinib, and osimertinib was not approved at the time.

At the time of admission, muscle strength was 2/5 in the bilateral upper and lower extremities, with enhanced deep tendon reflex, as well as paresthesia involving the upper and lower extremities and the trunk. Examination of cranial nerves did not reveal any remarkable findings. A urinary catheter was inserted due to urinary retention. Laboratory tests, including tests for electrolytes and glucose, showed no remarkable findings. CT prior to admission showed pulmonary metastases with malignant pleural effusions, mediastinal mass and multiple bone metastases, including some within the vertebrae. MRI showed no brain metastases; however, MRI of the spine revealed a T2-high spinal cord lesion at C2-Th2, indicating ISCMs (figure 1A). The patient underwent 36 Gy radiation therapy as oncological emergency treatment. By that time, osimertinib had been approved in Japan, and was thus administered.

Figure 1.

(A) T2-weighted spinal MRI at the time of diagnosis reveals a T2-high intramedullary lesion at C2-Th2, indicating ISCMs (white arrow). Cervical vertebrae metastases are present at T2-low (black arrow). (B–D) Spinal MRI 2, 5 and 10 months after the diagnosis show rapid improvement of ISCMs. ISCM, intramedullary spinal cord metastasis.

Outcome and follow-up

The treatment resulted in improvement of both symptoms and ISCMs (figure 1B–D). Although the patient required the use of a wheelchair for all visits to the clinic, muscle strength of the upper and lower extremities recovered to 4/5, and rehabilitation enabled the patient to stand and urinate without a catheter. NSCLC remained stable for 14 months with osimertinib; however, the patient finally died from bacterial pneumonia.

Discussion

We reported a case of ISCMs secondary to lung adenocarcinoma in a patient who had acquired the T790M mutation in the EGFR gene after previous use of first-generation EGFR-TKI; this manifestation of ISCMs was successfully treated with osimertinib. The use of osimertinib treatment for lung adenocarcinoma with the T790M EGFR mutation was effective due to its high activity within the CNS. Moreover, the T790M mutation had been acquired in the absence of other detectable EGFR mutations. To our knowledge, this is the first reported case of the use of osimertinib to successfully treat ISCMs originating from T790M-positive NSCLC. In a previous retrospective analysis of ISCMs, neurological improvement was observed in only 15/48 (31%) patients managed with non-surgical treatment; the median survival after the ISCM diagnosis was 5 months.¹ In our case, osimertinib administration resulted in neurological improvement with long-term disease control.

Notably, only two cases of treatment of ISCMs secondary to lung adenocarcinoma with EGFR-TKIs (gefitinib or erlotinib) have been reported.^{13 14} Although neither case had EGFR mutations, including T790M, PFS after ISCM diagnosis was 7 years and 11 months, respectively. The reason for the administration of EGFR-TKI in the first case¹⁴ is unclear; however, its use in the second case¹³ was due to patient preference and favourable EGFR-TKI prognostic factors, including Asian ethnicity, presence of adenocarcinoma, female sex and lack of smoking history.¹⁶ Our case differs from these prior cases because the ISCMs appeared during the administration of EGFR-TKI (afatinib), suggesting that response to treatment with gefitinib or erlotinib would be unlikely.

Data from the AURA3 study have shown markedly high efficacy of osimertinib in the treatment of T790M-positive advanced NSCLC in the CNS, following disease progression after prior EGFR-TKI treatment.¹⁷ Few EGFR-TKIs have prospectively demonstrated CNS PFS¹⁸; however, this prospective phase 3 study demonstrated that the median CNS PFS of osimertinib was 11.7 months, longer than that of platinum-pemetrexed (5.7 months). Osimertinib is a substrate of the permeability glycoprotein and breast cancer-resistance protein efflux transporters, which has shown greater penetration of the mouse blood-brain barrier and greater brain distribution compared with gefitinib, rociletinib or afatinib.⁹ Thus, the high CNS activity of osimertinib may have resulted in the favourable response in the presence of ISCMs.

In our case, the T790M mutation was first detected 11 years after surgery, with a history of treatment with a first-generation EGFR-TKI. However, other EGFR mutations were not detected. A de novo T790M mutation was unlikely, because the surgical specimen was of sufficient quality and quantity to detect any type of mutation; moreover, the PCR-invader method is known to have high sensitivity.¹⁵ Therefore, an acquired mechanism for the T790M mutation in the presence of an underlying, under-recognised minor EGFR mutation was strongly suspected. Recent meta-analysis of de novo and acquired EGFR T790M mutations revealed worse outcomes in patients with a de novo rather than acquired T790M mutation.¹⁹ Our patient remained CNS progression-free for 18 months after the ISCM diagnosis, until he died of pneumonia; this rather favourable outcome may have been a result of the acquired nature of the T790M mutation. Regarding the lack of other EGFR mutations, we suspect that the tumour exhibited a minor EGFR mutation that was not detected by the PCR-invader method. In fact, this assay can only detect a limited number of mutations: G719A/C/S in exon 18, deletion in exon 19, S768I in exon 20, L858R and L861Q in exon 21, and the known resistance mutation T790M in exon 20.¹⁵ In East Asia, the prevalence of EGFR mutations is approximately 30%, higher than in Western countries, where it is approximately 10%–15%.²⁰ Additionally, treatment with first-generation EGFR-TKIs reportedly leads to poor response in cases of EGFR-wild-type NSCLC, compared with EGFR-mutant cases.²¹ In our case, long-term PFS with erlotinib suggests an underlying EGFR mutation.

In conclusion, we encountered a case of NSCLC with ISCMs in a patient who had acquired the T790M mutation after previous use of a first-generation EGFR-TKI; the manifestation of ISCMs was successfully treated with osimertinib. Although its effect on de novo T790M mutations remains unknown, osimertinib could be a useful treatment option for ISCMs of NSCLC in patients who exhibit this EGFR mutation.

Learning points.

• The occurrence of intramedullary spinal cord metastases (ISCMs) secondary to non-small cell lung cancer (NSCLC) is a serious if infrequent complication characterised by rapid progression of neurological deficits and poor prognosis.

• Osimertinib may be a suitable treatment option for ISCMs secondary to lung adenocarcinoma in patients with the epidermal growth factor receptor (EGFR) T790M mutation, due to its high activity in the central nervous system.

• NSCLC with an undetectable EGFR abnormality, possibly due to a rare mutation, may acquire the T790M mutation after treatment with an EGFR tyrosine kinase inhibitor.