The American Society of Clinical Oncology (ASCO) Annual Meeting was held in Chicago from June 2 to June 6, 2023. Oncology Insight delves into the forefront of the conference, inviting researchers to share the most prominent Chinese research at ASCO, witnessing the advancement of China’s anti-tumor efforts on the international stage. Professor Wu Yilong from the People’s Hospital of Guangdong Province presented the results of the Phase III EVEREST study at ASCO 2023 in the form of an oral presentation. This article provides specific details of the EVEREST study and invites Professor Wu Yilong to provide an interpretation.

 

EGFR-mutant non-small cell lung cancer (NSCLC) patients often have central nervous system metastases (CNS), limited treatment options, and poor prognosis. Currently, there is a lack of head-to-head Phase III studies for patients with this condition. AZD3759 (Zorifertinib), a highly effective EGFR tyrosine kinase inhibitor (TKI) with good blood-brain barrier penetration, has shown promising systemic and intracranial antitumor activity, along with tolerable safety in preliminary data.

 

An open-label, multicenter, randomized Phase III trial reported at the 2023 ASCO Annual Meeting compared the efficacy and safety of Zorifertinib with first-generation EGFR-TKIs as first-line treatment for EGFR-mutant (L858R and/or Ex19Del) NSCLC patients with CNS metastases. From February 1, 2019, to January 12, 2021, the study randomized 439 patients with MRI-confirmed CNS metastases (asymptomatic/stable symptoms) in a 1:1 ratio. 220 patients received Zorifertinib (200 mg, twice daily) in the experimental group, while 219 entered the control group and received first-generation EGFR-TKIs (Gefitinib 250 mg or Erlotinib 150 mg, once daily). The primary endpoint was the blinded independent central review (BICR) determined progression-free survival (PFS) based on RECIST 1.1. As of July 12, 2022, the median follow-up time for both groups was 20.4 months.

All patients included in the study were of East Asian descent, with the majority being Chinese. The median age of patients in the experimental and control groups was 58 (range: 34-84) and 59 (range: 33-82), respectively. Adenocarcinoma was the predominant histological type in both groups (99.1% vs. 95.4%). Female patients accounted for 63.6% in the experimental group and 64.4% in the control group. Patients had an ECOG PS score of 0 or 1, with ECOG PS 1 patients making up 77.7% vs. 77.2% in the two treatment groups. More than half of the patients had the L858R mutation (53.6% vs. 54.8% in both groups). Over half of the patients had more than three intracranial lesions (55.5% vs. 52.1%), with 65.5% and 62.6% of patients having intracranial target lesions in the experimental and control groups, respectively.

According to BICR assessment, the experimental group’s median PFS was significantly superior to the control group, with 9.6 months (8.2–9.7) vs. 6.9 months (6.3–8.0) (HR=0.719, 95% CI: 0.580–0.893, p=0.0024). PFS benefits were consistent across subgroups, including patients with EGFR L858R mutations and those with a higher intracranial tumor burden.

The median time for brain metastasis control in the two groups was 15.2 months (12.5–19.4) and 8.3 months (8.0–9.6) (HR=0.467, 95% CI: 0.352–0.619, p<0.0001). Intracranial PFS, confirmed based on the Radiologic Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, was 17.9 months in the experimental group and 11.1 months in the control group (p=0.0018).

The objective response rate (ORR) confirmed by BICR was 68.6% in the experimental group and 58.4% in the control group (p=0.027). Compared to the control group, the experimental group showed a trend of extended median duration of response (DoR) (8.2 months vs. 6.8 months; p=0.0997). The ORR assessed by the researchers was 71.4% vs. 64.8%, with a median DoR of 9.7 months vs. 8.4 months.

The intracranial ORR, as assessed by researchers, was 75.6% in the experimental group and 62.3% in the control group, with median intracranial DoR of 13.8 months and 11.1 months, respectively. BICR-confirmed intracranial ORR was 75% vs. 64.2%, and intracranial DoR was 12.4 months vs. 7 months.

Both the intracranial lesion PFS, ORR, and DoR, whether assessed by researchers or BICR, were better in the experimental group than in the control group. Overall survival (OS) data were not mature.

 

EGFR T790M mutation, the most common resistance mutation, occurred in 33.3% of the experimental group (20.3% with Ex19Del and L858R simultaneously) and 12% of the control group (8% with Exon 19 complex mutation).

 

No new safety signals were found. The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (97.7% vs. 94%). The incidence of grade 3 or higher TRAEs was 65.9% (experimental group) and 18.3% (control group). TRAEs mainly included skin and subcutaneous tissue adverse reactions, gastrointestinal reactions, and liver function abnormalities. The incidence of rash (55.9% vs. 13.6%) and diarrhea (63.6% vs. 13.2%) was higher in the experimental group, while the incidence of alanine aminotransferase (ALT) and aspartate aminot

 

ransferase (AST) elevation was comparable between the two treatment groups. There were no safety signals related to the central nervous system. The proportion of patients in the Zorifertinib group who required dose reduction or temporary discontinuation was higher, ultimately resulting in a TRAE-related treatment discontinuation rate of 5.9%.

Compared to first-generation EGFR-TKIs, Zorifertinib used as first-line treatment for EGFR-mutant NSCLC patients with CNS metastases showed superior systemic and intracranial antitumor efficacy, significantly extending both systemic and intracranial PFS. Adverse reactions were as expected (most commonly rash, diarrhea, and liver function abnormalities) and manageable, with no new safety signals. This study provides a new, well-validated first-line treatment option for EGFR-mutant NSCLC patients with CNS metastases.

 

Expert Commentary

 

EGFR-sensitive mutant NSCLC patients with CNS metastases have always posed a clinical challenge, severely affecting patient survival and quality of life. The EVEREST study is a randomized, controlled, open-label, multicenter clinical trial specifically designed for EGFR-sensitive mutant NSCLC patients with CNS metastases. The results show that Zorifertinib used as first-line treatment for EGFR-mutant NSCLC patients with CNS metastases (asymptomatic/stable symptoms) leads to prolonged progression-free survival and intracranial progression-free survival, with intracranial PFS numerically longer than systemic PFS, indicating its advantage in controlling intracranial lesions.

 

From the initial first-generation EGFR inhibitors to the fourth-generation EGFR inhibitors currently in clinical trials, the iterative updates of EGFR-TKIs have fundamentally changed the treatment paradigm for EGFR-mutant NSCLC. Several third-generation EGFR-TKIs have demonstrated efficacy not only in treating EGFR-sensitive mutations and resistance mutations but also in controlling central nervous system lesions. We look forward to the emergence of more innovative drugs in the future to further improve the efficacy for EGFR-positive NSCLC patients with CNS metastases and enhance their survival and quality of life.

 

References: Randomized phase 3 study of first-line AZD3759 (Zorifertinib) versus gefitinib or erlotinib in EGFR-mutant non-small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. 2023 ASCO Oral Abstract Session. 9001.

Professor of Oncology, Doctoral Supervisor, IASLC Distinguished Scientist Awardee

President of the Guangdong Medical Association (GDMDA), Chief Expert of the People’s Hospital of Guangdong Province (GDPH), Honorary Director of the Guangdong Lung Cancer Institute (GLCI), and Chairman of the Chinese Thoracic Oncology Research Collaboration Group (CTONG)

2018-2022 Global Highly Cited Scientist in Clinical Medicine

Chairman of the 2020 World Conference on Lung Cancer (WCLC)

Former Chairman of the Chinese Society of Clinical Oncology, currently the Chairman of the Supervisory Committee