A Single-center, Real-world Study Aimed At Evaluating the Efficacy and Safety of 240 Mg/d Furmonertinib Combined with Bevacizumab and Pemetrexed in the Treatment of Advanced NSCLC with EGFRm and Leptomeningeal Metastasis.

Leptomeningeal metastasis (LM) is a fatal complication of advanced lung cancer. In recent years, with the rapid advancement of precision therapy for lung cancer, the survival time of patients with advanced lung cancer has significantly increased, leading to a rapid rise in the incidence of LM. It is reported that the incidence of LM in patients with advanced non-small cell lung cancer (NSCLC) reaches 3%-5%, and as high as 9.4% among patients with epidermal growth factor receptor (EGFR) mutations. The prognosis of NSCLC patients with LM is extremely poor, with a median overall survival (OS) of only 4-6 weeks without treatment[1]. Due to the presence of the blood-brain barrier (BBB), which limits drug penetration, as well as the efflux mechanisms of transport proteins on the BBB, effectively treating patients with LM remains a significant challenge.

For brain or leptomeningeal metastases driven by genetic mutations, both the Lung Cancer Brain (Leptomeningeal) Metastasis Diagnosis and Treatment Consensus (2017) and the 2024 NCCN Guidelines recommend tyrosine kinase inhibitors (TKIs) as the first-line treatment. Most studies on first- and second-generation EGFR-TKIs for leptomeningeal metastasis are retrospective and show relatively limited efficacy. Pulse dosing of erlotinib appears to achieve relatively longer overall survival (OS), but both studies included only a few patients. In two prospective studies on afatinib and gefitinib, OS did not exceed four months. The BLOOM study included 41 patients with CSF-confirmed EGFR-mutant NSCLC with leptomeningeal metastasis who received osimertinib at a dose of 160 mg/d. The LM objective response rate (ORR) was 62%, progression-free survival (PFS) was 8.6 months, and OS was 11.0 months. While the overall efficacy showed room for improvement, safety concerns were notable: 66% of patients experienced grade 3 or higher adverse events, 51% experienced serious adverse events (SAEs), 22% discontinued treatment due to adverse events, and 12% required dose reduction. In summary, improving clinical outcomes for patients with EGFR-mutant NSCLC with LM, while reducing toxicity, remains a key area for further exploration.

Furmonertinib (brand name: Aifisha, formerly known as alflutinib/AST2818) is a third-generation EGFR TKI independently developed by Shanghai Allist Pharmaceuticals. Furmonertinib has demonstrated strong antitumor activity and manageable safety characteristics in advanced patients with EGFR exon 20 T790M point mutations (T790M-positive). It was approved by the NMPA in March 2020. In June 2022, furmonertinib received approval from the National Medical Products Administration (NMPA) for first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

In the Phase I-IIa study, furmonertinib demonstrated good tolerability, with no dose-related toxic reactions observed across the dose groups ranging from 20 mg to 240 mg. At a dose of 240 mg/day, the safety and tolerability were favorable, with an incidence of ≥ Grade 3 adverse events (AEs) at 11%, and serious adverse events occurring in 11% of patients. Dose reduction due to AEs occurred in 6% of patients, and no patients discontinued treatment due to AEs. The most common adverse reactions included diarrhea (33%), rash (33%), decreased white blood cell count (28%), elevated serum creatinine (22%), and proteinuria (22%), all of which were Grade 1-2. The most frequent ≥ Grade 3 AE was elevated ALT (6%). Overall, the drug was well-tolerated, and adverse events were relatively manageable.

An Ib phase clinical study named FAVOUR enrolled 30 patients with advanced NSCLC harboring EGFR Exon20ins mutations, who received furmonertinib at doses of 160 mg/day or 240 mg/day. Data from the initial treatment cohort of 10 patients receiving 240 mg/day of furmonertinib have been released. The results showed that the objective response rate (ORR) assessed by independent review committee (IRC) reached 60%, the disease control rate (DCR) was 100%, and progression-free survival (PFS) has not yet been reached. Additionally, safety was favorable, with no reports of ≥ Grade 3 adverse events, suggesting that high-dose furmonertinib holds promise for the treatment of patients with EGFR uncommon mutations.