Lazarus effect in a patient initially empirically treated with osimertinib for EGFR L858R mutant non-small cell lung cancer with leptomeningeal disease: a case report

Osimertinib has been shown to be effective for patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations, and these patients are at risk for leptomeningeal disease. In this report, we present a patient of East Asian descent whose initial presentation included severe, progressive leptomeningeal carcinomatosis and a small lung mass, with limited tissue available for molecular testing. She responded to empiric, urgent initiation of osimertinib, repeat tissue sampling revealed an EGFR L858R mutation, and she has experienced durable disease improvement for 18 months on osimertinib monotherapy.


INTRODUCTION
Osimertinib is a highly effective third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that is the current first line standard of care for patients with metastatic nonsmall cell lung cancer (NSCLC) with EGFR activating mutations.Importantly, osimertinib provides antitumor efficacy for patients with central nervous system (CNS) involvement, either intracranial metastases or leptomeningeal disease (LMD) [1].
Clinically, the early identification of LMD is difficult, and patients often present with diffuse, clinically debilitating LMD.Furthermore, isolation of sufficient tissue for molecular analysis in patients with LMD is a barrier to allocating patients to optimal therapy.Herein, we present the case of a patient who presented with life threatening LMD with insufficient tissue for molecular analysis, who was urgently started on empiric osimertinib with successful disease improvement for over 18 months to date on osimertinib monotherapy.

CASE REPORT
A 64-year-old woman with no smoking history and of East Asian descent presented to the emergency department with four months of headaches, one month of right eye vision loss, right lower extremity weakness, and syncope.Upon admission, she was also noted to have a spontaneous pneumothorax with an 18 mm spiculated lesion in her left upper lobe (LUL).
A non-contrast MRI of the brain and spine showed no intracranial abnormalities and no LMD was noted.Cerebrospinal fluid (CSF) cytology raised concern for malignancy with large, atypical cells.Bronchoscopy with biopsy of the LUL lesion revealed NSCLC (adenocarcinoma), and carcinomatous meningitis from NSCLC was suspected given the CSF findings.The lung tissue and CSF cytology were insufficient for molecular analysis.Peripheral blood circulating tumor DNA using a Tempus xF ® assay was assessed, and there were no pathogenic mutations identified.
Because of the high pre-test probability of this cancer being driven by an EGFR activating mutation and the patient's ongoing clinical decline from carcinomatous meningitis, osimertinib 80 mg daily was empirically started.Within two days headaches improved, and within 2 weeks she had a dramatic improvement in her functional status.Imaging after approximately one month on therapy showed slight improvement in her lung nodule (Figure 1).Repeat bronchoscopy with biopsy of the LUL lesion was completed and Tempus xT ® molecular assessment revealed an EGFR L858R activating mutation.www.oncotarget.com The patient required escalated dosing of osimertinib to 160 mg daily for progressive cranial nerve deficits from LMD six months into therapy, and she has since continued osimertinib at 160 mg daily for a total of 18 months to date with ongoing excellent disease control in the lung and CNS.

DISCUSSION
Leptomeningeal disease is characterized by CNS metastases with spread to the CSF or leptomeninges.In patients with NSCLC with EGFR activating mutations, there is an increased occurrence of LMD [2], which occurs in 9% of patients [3].
Osimertinib is an EGFR TKI that has been shown to be safe and efficacious for patients with metastatic EGFR mutant NSCLC complicated by LMD [1].Notably in the BLOOM trial, patients who had previously progressed on other TKI therapies showed clinical improvement in neurological function on osimertinib 160 mg daily [1].Current data on the use of osimertinib supports its application in previously treated or untreated patients with metastatic EGFR mutant NSCLC with LMD.
Our case demonstrates the nuances of decisionmaking in starting osimertinib in urgent clinical settings.Given our patient's progressively worsening functional status and spread of disease to her CNS upon presentation, there was a need to begin treatment imminently.Time constraints, financial constraints, and lack of sufficient tissue for analysis ultimately led to the empiric use of osimertinib.Through the urgent initiation of appropriate anti-cancer therapy, she experienced

CONCLUSION
Overall, this case supports a body of literature noting potentially dramatic clinical benefits of administering appropriate oncogene directed targeted therapy for critically ill patients with NSCLC (Table 1), and in this specific case it is noted that epidemiology can help guide empiric treatment in patients with prohibitive challenges to adequate and timely molecular assessment, an approach that has also been report on two previous occasions (Table 2).

Figure 1 :
Figure 1: Treatment timeline with chest computed tomography (CT) and brain magnetic resonance images (MRI) on osimertinib.(A) Pretreatment CT chest, demonstrating 18 mm spiculated mass in the left upper lobe (LUL).(B) CT chest following 12 days of Osimertinib treatment, showing decreased size of LUL mass.(C) Pretreatment brain MRI showing no acute abnormalities (axial).(D) Pretreatment brain MRI showing no acute abnormalities (sagittal).