Long‐term survival of a patient with epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) and untreated multiple brain metastases treated with zorifertinib: A case report

Abstract Brain metastases (BM) are common in patients with epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) and confer poor prognoses. Zorifertinib (AZD3759), an EGFR‐tyrosine kinase inhibitor (TKI) with high blood‐brain barrier penetration, has previously demonstrated promising systemic and intracranial antitumor activity in phase 1–3 studies. This is the first report of a patient with EGFR‐mutant (exon 21 L858R) NSCLC and symptomatic untreated multiple BM who achieved a long overall survival (OS) of more than 65 months after sequential treatment with zorifertinib and a third‐generation EGFR‐TKI. This new treatment paradigm offers a new treatment option and deserves further clinical exploration to prolong OS of patients with EGFR‐mutant NSCLC and untreated multiple BM.


INTRODUCTION
Brain metastases (BM) in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) are very common and confer poor prognoses. 1GFR tyrosine kinase inhibitors (EGFR-TKIs) are the systemic therapy recommended by most treatment guidelines for patients with EGFR-mutant NSCLC and BM.[1][2][3][4][5] Overall survival (OS) on first-line osimertinib monotherapy for these patients has previously been reported to be 17-26.7 months.[6][7][8][9] Zorifertinib (AZD3759), a novel EGFR-TKI inhibiting mutant EGFR (exon 19del or L858R), is not a substrate of either P-glycoprotein or breast cancer resistance protein and was designed specifically to improve blood-brain barrier (BBB) penetration 10,11 and to treat EGFR-mutant NSCLC patients with BM.2,13 This is the first report of a patient with EGFR-mutant (exon 21 L858R) NSCLC and symptomatic untreated multiple BM who achieved a long OS after sequential treatment with zorifertinib and aumolertinib.

CASE REPORT
A 65-year-old Asian, nonsmoking female was initially diagnosed with EGFR-mutant (exon 21 L858R) NSCLC and multiple BM (adenocarcinoma; T2aN0M1c, stage IVb) in June 2018.She was enrolled in a phase 1-2 clinical trial which evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of zorifertinib in Chinese patients with EGFR-mutant NSCLC and BM (NCT03360929) on July 12, 2018.There were three target lesions (24.1-34.8mm, Figure 1) with a total diameter of 93.5 mm, and multiple brain nontarget lesions at baseline.The ECOG performance status was 1.She had neurological symptoms at baseline including gait abnormalities (abnormal but walks without assistance) and decreased strength (movement present but decreased against resistance).The patient received zorifertinib as first-line treatment administered orally for 21-day cycles starting on July 23, 2018.The starting dose of zorifertinib was 250 mg twice daily, and finally maintained at 150 mg twice daily after two dose reductions (Table 1).She continued on zorifertinib as she had shown clinical benefit (only single-site metastasis without related symptoms, the intracranial lesions were still responding) when the first progressive disease (PD) in just the pleural nodules occurred on July 21, 2021.On October 26, 2022, the pleural nodules significantly progressed and the gene test using the pleural effusion showed EGFR T790M mutation.She was then prescribed the marketed third-generation EGFR-TKI aumolertinib as second-line therapy.For a timeline of diagnosis to treatment, please refer to Figure 2.
The radiographic assessments per response evaluation criteria in solid tumors version 1.1 (RECIST1.1)following zorifertinib treatment were partial response (PR) for all the intra-, extracranial, and overall tumor responses (Figure 1).The patient's neurological symptoms gradually improved and completely disappeared on October 18, 2018 after fourcycle zorifertinib therapy (without any local treatments [requirement of the NCT03360929 study protocol]); and there were no relapses thereafter.Progression-free survival (PFS) of first-line zorifertinib treatment was 3 years, while the intracranial PFS was more than 4 years.By December 25, 2023, the duration of second-line aumolertinib therapy was 13 months.The patient was still alive, and the OS was more than 65 months since the beginning of treatment with zorifertinib.

DISCUSSION
The third-generation EGFR-TKI osimertinib has not previously shown significant survival benefit in Asians (HR = 1.0, 95% confidence interval [CI]: 0.75-1.32), in patients with L858R mutation (HR = 1.0, 95% CI: 0.71-1.40)and in Chinese patients with BM (HR = 0.95, 95% CI: 0.45-1.97) in FLAURA and FLAURA China studies. 14,157][8][9] In the phase 2 APPLE trial, the sequential treatment showed more survival benefit (HR = 0.59) than upfront osimertinib in brain-metastatic patients. 16Additionally, the mechanism of acquired resistance to thirdgeneration EGFR-TKIs is very complex; optimizing the next step after PD is an ongoing challenge. 17orifertinib demonstrated 100% BBB penetration, which is much higher than that of other EGFR-TKIs (first-and second-generation EGFR-TKIs, 1.13% to 3.3%; osimertinib, 2.5% to 16%). 10,18In previous studies, first-line zorifertinib was particularly effective in controlling BM (extracranial PD is the main pattern of PD), and the main acquired resistance mutation was EGFR T790M which is subsequently treatable with third-generation EGFR-TKIs, helping to prolong OS of patients; the median OS was 34.1 months in patients subsequently treated with osimertinib in CTONG1702, and is consistent with that of the phase 3 EVEREST study (data on file). 12,13ifferent from other case reports of long OS in EGFRmutant NSCLC patients with initially asymptomatic, solitary BM or initially no BM after four-line therapies including combination with radiotherapy, or off-label use of osimertinib (double dose), 19,20 the patient in this report had more poor prognostic factors, including EGFR L858R and initially diagnosed symptomatic multiple BM.She also received only sequential treatment of zorifertinib and a third-generation EGFR-TKI without intracranial radiotherapy.Her neurological symptoms completely recovered.She achieved PR in both extra-and intracranial tumor lesions, developed EGFR T790M mutation after PD on zorifertinib, and finally achieved an OS of more than 65 months.The AEs with zorifertinib were consistent with those reported in phase 1-3 studies and other EGFR-TKIs. 10,12,13ese results demonstrate that sequential treatment of zorifertinib and third-generation EGFR-TKIs may be a better treatment option for patients with EGFR-mutant NSCLC and untreated multiple BM, as zorifertinib is a high BBB penetrant and well-validated EGFR-TKI with T790M as the main resistant mutation, which is treatable with the thirdgeneration EGFR-TKIs.This sequential treatment offers a new treatment option and deserves further clinical exploration to prolong the OS of these patients.
T A B L E 2 All treatment-related adverse events summarized by maximum severity a when the patient was taking zorifertinib.

F I G U R E 1
Image screenshots of the three target lesions.(a) Brain magnetic resonance images of the No. 1 target lesion in the left cerebellar hemisphere: it was 34.8 mm in diameter on July 18, 2018 (baseline), 1.35 mm in diameter on November 29, 2018, and 0.87 mm in diameter on November 10, 2020.(b) Brain magnetic resonance images of No. 2 target lesion in the right cerebral hemisphere: it was 24.1 mm in diameter on July 18, 2018 (baseline), 0.82 mm in diameter on November 29, 2018, and 0.67 mm in diameter on November 10, 2020.(c) Thoracic computed tomography scans of No. 3 target lesion in the right upper lung: it was 34.6 mm in diameter on June 27, 2018 (baseline) and 14.8 mm in diameter on September 18, 2019.On July 21, 2021, pleural nodules appeared.On October 26, 2022, the chest CT showed massive pleural effusion and significant progressive disease of the pleural nodules.On March 09, 2023, the pleural effusion disappeared, and the pleural nodules had shrunk significantly.

T A B L E 1
Abbreviation: BID, twice daily.a Per the requirement of the NCT03360929 study protocol, dose reduction was allowed when a treatment-related grade 3 advert event occurs.
Adverse events were graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE 4.03). a