Exceptional Response of a Large and Symptomatic EGFR-Mutant Brain Metastasis to Osimertinib: Case Report and Review of the Literature

INTRODUCTION

Brain metastases comprise a majority of malignant brain tumors of which non–small-cell lung carcinoma (NSCLC) is the most common source.¹ Indeed, brain metastasis is a common progression of NSCLC and has been observed in up to 45% of patients after 3 years despite treatment.² Among this group, tumors with activating mutations in epidermal growth factor receptor (EGFR) are the largest targetable subtype.³ Common EGFR mutations include inframe exon 19 deletions (EGFRΔ19; approximately 45%), L858R point mutations (approximately 40%-45%), and exon 18 and 20 mutations.^4,5

EGFR tyrosine kinase inhibitors (TKIs) have shown promise in the treatment of these tumors because they can inhibit EGFRΔ19 and L858R variants, and third-generation TKIs also bind irreversibly to EGFR T790M on target resistance mutations.⁶ Although first-generation EGFR TKIs have demonstrated benefit in metastatic CNS NSCLCs in small trials, third-generation EGFR TKIs have generated additional enthusiasm for brain metastasis treatment given preclinical and clinical evidence for improved blood-brain barrier and brain-tumor barrier penetration compared with earlier-generation inhibitors.^4,7,8

Despite the success of EGFR TKIs, some 45% of surgical brain metastases remain EGFR-mutant lesions.⁹ Surgical resection is indicated for large and symptomatic brain metastases, progression despite use of CNS-active drugs, and postradiation recurrences. Generally, tumors larger than 2-2.5 cm in diameter are considered for resection given diminishing radiosensitivity and increasing risk of radiation necrosis with size.¹⁰ For large and symptomatic lesions that have not yet been treated with EGFR-TKI therapy, deferring surgery has not been advocated given a lack of data on efficacy in larger tumors or speed of response. Indeed, medical therapy has not been advocated for large and symptomatic tumors outside of a rare subset of brain tumors (eg, CNS lymphoma) on a case-by-case basis.

We report here the case of a patient with an EGFRΔ19 NSCLC with a large and symptomatic CNS metastasis who was due to undergo neurosurgical excision. Treatment with third-generation EGFR-TKI osimertinib over 15 days significantly shrank the lesion's volume by 94%, with resolution of associated symptoms and steroid dependency. The dramatic response resulted in the tumor no longer requiring surgical excision. This response was faster and in a larger brain tumor than any reported in the literature to date and suggests a role for attempted nonsurgical treatment in selected previously inhibitor-naïve EGFR-mutant patients or interval reimaging for neurologically stable patients newly on treatment and slated for surgical resection.

Case Report

A 53-year-old woman with metastatic NSCLC was found to have brain metastases on staging imaging performed to establish protocol eligibility. She was originally diagnosed 1 year earlier with stage IIIA (T1bN2) lung adenocarcinoma on the right and stage IA (T1b) in the left lung. Targeted next-generation sequencing of the lung specimen identified somatic mutations in EGFR (Δ19 p.E746_A750del, 76.9% mutant allele frequency [MAF]), TP53 (p.R249M, 24.7% MAF), and additional predicted-oncogenic mutations in RBM10 (exon 21 frameshift, 11.1% MAF), PBRM1 (exon 22 nonsense, 26.4% MAF), and PTPRT (exon 8 nonsense, 32.4% MAF).¹¹ Screening brain magnetic resonance imaging was negative for brain metastasis. Her treatment consisted of right lung and mediastinal irradiation concurrent with carboplatin or paclitaxel and left lung stereotactic body irradiation. Nine months later, positron emission tomography-computed tomography demonstrated pretracheal nodal hypermetabolism within the previous radiation treatment field, which subsequently enlarged 2 months later. On repeat brain MRI, she was found to have multiple brain metastases including a 3.1-cm inferior vermian metastasis with surrounding edema and CSF outflow impingement without frank hydrocephalus and additional subcentimeter disease (Fig 1). The enhancing tumor volume of the dominant metastasis comprised 8.94 cm³ as segmented with the BrainLAB smartbrush tool (BrainLAB AG, Munich, Germany). Osimertinib was started at 80 mg daily on the same day. In retrospect, she had been suffering from ataxia which worsened significantly in the following days, and she was referred for neurosurgical consultation where she described rapidly progressive truncal imbalance, bilateral finger hyperesthesia, nonpositional bifrontal headaches, and electric sensation with neck flexion radiating to her buttocks. She was started on dexamethasone and scheduled for craniotomy and tumor resection the following week. Planning MRI performed 15 days after the initial scan demonstrated a marked decrease in the cerebellar tumor, now 0.57 cm³, a 94% reduction in volume (Fig 1). There was near-complete resolution of surrounding edema and mass effect, and the patient's symptoms had resolved. Corticosteroids were rapidly tapered off without recrudescence. Surgery was canceled, and subsequent imaging on day 60 showed continued response, with an enhancing tumor volume of 0.3 cm³ (Fig 1).

FIG 1.

MRI scans of the inferior vermian metastasis on osimertinib. The day 15 scan showed a 94% volumetric response, whereas the day 60 scan showed continued enhancement response (97%) and complete resolution of the edema. MRI, magnetic resonance imaging.

Patient Consent

The patient has consented to the submission of the case report for submission to the journal.

DISCUSSION

Osimertinib is a third-generation EGFR TKI approved as first-line therapy in sensitizing (1) EGFR-mutant metastatic NSCLC and (2) previously treated metastatic EGFR T790M NSCLC.¹² This agent has higher CNS distribution in preclinical rodent and nonhuman primate models versus earlier-generation EGFR TKIs including erlotinib and gefitinib.¹³ Considerable clinical data support its CNS activity in both the first-line and previously treated settings.⁸

These include the extended AURA (ClinicalTrials.gov identifier: NCT01802632), AURA2 (ClinicalTrials.gov identifier: NCT02094261), and AURA3 (ClinicalTrials.gov identifier: NCT02151981) trials in previously TKI-treated patients with T790M-mutant EGFR, whereas FLAURA (ClinicalTrials.gov identifier: NCT02296125) showed efficacy in an untreated population.^14-18 Across the different trials, osimertinib demonstrated superior CNS efficacy in terms of objective response rates (ORRs), progression-free survival (PFS), and overall survival, as compared with earlier-generation EGFR TKIs or platinum-pemetrexed. Specifically, in the two phase II trials (extended AURA and AURA2),^14,17 CNS ORR was 54%; in the phase III AURA3 trial, ORR was 70%;¹⁶ and in the phase III FLAURA trial, ORR was 91% for patients with ≥ 1 measurable CNS lesions.¹⁹ The disease control rate was 92%-95% for all these trials. Moreover, in FLAURA, the probability of experiencing a CNS progression event was lower with osimertinib versus standard EGFR TKIs by approximately 52% (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014); this coincided well with the median PFS of the two groups (18.9 v 10.2 months; hazard ratio, 0.46; 95% CI, 0.37 to 0.57; P < .001).¹⁹ Although median CNS PFS was only reached in the AURA3 trial, it was reported to be 11.7 months for osimertinib compared with 5.6 months for platinum-pemetrexed in patients with measurable and/or nonmeasurable CNS lesions.¹⁶ Importantly, osimertinib response was independent of radiotherapy exposure.^16,19,20

A meta-analysis of 15 studies with 324 patients showed that the CNS ORR for EGFR-mutant metastases treated with osimertinib was 64%, whereas the CNS disease control rate was 90%.⁸ The studies included reported complete intracranial response rates of 7%-23% and a median decrease in intracranial lesion size of 40%-64%. Ongoing and recent phase III trials of osimertinib such as ADAURA (ClinicalTrials.gov identifier: NCT02511106), ASTRIS (ClinicalTrials.gov identifier: NCT02474355), and APOLLO (ClinicalTrials.gov identifier: NCT02972333) will provide additional information on effectiveness in patients with CNS metastatic disease. However, response times to osimertinib and whether there is a size dependency to any response have remained unclear.

Our case suggests that further investigation into TKI therapy as an upfront therapy may be warranted in EGFR-mutant appropriate NSCLC even with brain tumors requiring urgent palliation. The treatment mainstay for large and symptomatic metastases is palliative surgical management plus adjuvant stereotactic radiosurgery.^21,22 For smaller, asymptomatic tumors, radiation alone is recommended for most histologies although this continues to evolve as CNS-active cancer therapies are brought to market. This case illustrates a striking example of systemic drug efficacy for even a large and symptomatic brain metastasis otherwise thought to require surgical management and is the first surgical case to our knowledge where surgery was successfully avoided because of pharmacologic inhibition. This highlights a knowledge gap in the potential efficacy of systemic therapy at the extremes.

To date, the most rapid and largest brain metastasis tumor response with osimertinib was a patient with 20 brain metastases of 12 mm maximal diameter. After 5 weeks of osimertinib, all brain metastases were undetectable, and this resolution was maintained to 4 months of treatment.²³ Although individual reports do not allow for generalizable conclusions on response rapidity to osimertinib, more focused analyses will be required to better assess this and of parameters that may influence differential sensitivity, for example, by tumor size, specific EGFR alterations, and/or treatment dose.

This case illustrates the importance of timely initiation of appropriate oncologic therapy for all patients, given the potential for rapid and extraordinary disease response. In addition, for patients who are newly started on therapies known to be active in CNS tumors, consideration of reimaging before elective resective surgery should be made even at the extreme for tumors otherwise requiring surgical treatment within days or weeks if not contraindicated perioperatively.

In conclusion, we report an exceptionally rapid response of a large symptomatic EGFR-mutant NSCLC brain metastasis to third-generation EGFR inhibition within 15 days, obviating the need for surgery. To our knowledge, this is both the largest tumor and the most rapid documented precision-medicine brain tumor response and highlights the potential of nonoperative management with EGFR inhibition even for large and symptomatic tumors that do not require time-sensitive surgery.

AUTHOR CONTRIBUTIONS

Conception and design: Nelson S. Moss

Provision of study materials or patients: Juliana Eng

Collection and assembly of data: All authors

Data analysis and interpretation: Nelson S. Moss

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

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Nelson S. Moss

Consulting or Advisory Role: AstraZeneca

Research Funding: GT Medical Technologies

No other potential conflicts of interest were reported.