Trial Title:
Evaluating High-dose Furmonertinib With Bevacizumab and Pemetrexed for EGFRm NSCLC With Leptomeningeal Metastasis
NCT ID:
NCT06643000
Condition:
Non-small Cell Lung Cancer
Leptomeningeal Metastasis
EGFR Gene Mutation
Conditions: Official terms:
Neoplasm Metastasis
Meningeal Carcinomatosis
Pemetrexed
Aflutinib
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
furmonertinib
Description:
furmonertinib (240 mg/d,po) combined with bevacizumab (15 mg/kg, every 3 weeks, ivgtt)
and pemetrexed (50 mg) intrathecal chemotherapy / pemetrexed (500 mg/m²) intravenous
chemotherapy, administered every 3 weeks.
Arm group label:
Triple therapy
Other name:
bevacizumab
Other name:
pemetrexed
Summary:
The primary objective of this clinical study is to evaluate the efficacy of high-dose
furmonertinib combined with bevacizumab and pemetrexed (triple therapy) in the treatment
of non-small cell lung cancer (NSCLC) with leptomeningeal metastasis and epidermal growth
factor receptor mutation (EGFRm) through overall survival (OS). The secondary objectives
are to further assess the efficacy of the triple therapy in patients with EGFRm and
leptomeningeal metastasis, including time to treatment failure (TTF), leptomeningeal
objective response rate (ORR-LM), and clinical response rate.The study will also evaluate
the impact of the triple therapy on quality of life using the EORTC QLQ-C30 scale and
assess the safety of the therapy in EGFRm NSCLC patients with leptomeningeal metastasis,
focusing primarily on adverse events and their severity (graded according to CTCAE v5.0),
as well as their frequency.The exploratory objectives are to assess changes in
intracranial pressure and the improvement rate of cerebrospinal fluid (CSF) before and
after the triple therapy treatment. Additionally, the study will compare the genomic and
epigenomic profile changes in circulating tumor DNA (ctDNA) from peripheral blood and
cell-free DNA (cfDNA) from cerebrospinal fluid before and after treatment, and analyze
their correlation with clinical outcomes, drug efficacy, and other clinical indicators.
The primary endpoint of this study is overall survival (OS). The secondary endpoints
include time to treatment failure (TTF), leptomeningeal objective response rate (ORR-LM),
clinical response rate, and quality of life assessment (EORTC QLQ-C30).The safety
endpoints are adverse events and their severity (graded according to CTCAE v5.0), as well
as the frequency of occurrence.
A total of 60 patients are planned to be enrolled, targeting eligible advanced NSCLC
patients with EGFR mutations and leptomeningeal metastasis.
The intervention consists of furmonertinib (240 mg/d, po) combined with bevacizumab (15
mg/kg, every 3 weeks, ivgtt) and pemetrexed (50 mg) intrathecal chemotherapy / pemetrexed
(500 mg/m²) intravenous chemotherapy, administered every 3 weeks.
Detailed description:
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.
In addition to showing good efficacy in patients with advanced NSCLC harboring classic
and uncommon EGFR mutations, furmonertinib has also demonstrated promising central
nervous system (CNS) activity. Preclinical studies indicated that 24 hours after
administration in animal models, the ratio of furmonertinib's prototype drug and its
major active metabolite AST2818 in brain tissue AUC0-24h to plasma AUC0-24h was greater
than 1, suggesting that furmonertinib can penetrate the blood-brain barrier (BBB). In its
Phase IIb clinical study, furmonertinib achieved a CNS objective response rate (ORR) of
66%, CNS disease control rate (DCR) of 100%, and CNS progression-free survival (PFS) of
11.6 months in patients with EGFR T790M mutation and brain metastases. Additionally, in
its Phase I/II study, CNS efficacy increased with higher doses: the 80 mg/day dose
achieved a CNS ORR of 60% and a CNS PFS of 9.7 months, while the 160 mg/day dose resulted
in a CNS ORR of 84.6% and a CNS PFS of 19.3 months . For patients with refractory
leptomeningeal metastasis (LM), increasing the dose of furmonertinib may offer enhanced
antitumor activity.
Based on the above findings, researchers conducted a real-world study, and data analysis
revealed that furmonertinib at a dose of 240 mg/day demonstrated significant efficacy in
the treatment of leptomeningeal metastasis, with patients overall showing good
tolerability. From May 2021 to December 2023, a total of 48 patients were enrolled, of
which 35 patients had an ECOG performance status ≥3, accounting for 72.9%. Of these, 35
patients (72.9%) had previously received other third-generation EGFR-TKI treatments.
Seventeen patients (35.4%) were treated with furmonertinib monotherapy. The median
follow-up time was 15 months. The median overall survival (OS) was 8.433 months (95% CI,
5.481-11.386 months), and the median time to treatment discontinuation (TTD) was 8.267
months (95% CI, 5.395-11.138 months). The clinical response rate was 75%. According to
the RANO-LM radiological criteria, the leptomeningeal metastasis (LM) objective response
rate (ORR) and disease control rate (DCR) were 50.0% and 92.1%, respectively. The
treatment was well tolerated overall, consistent with previous reports. Twenty-two
patients (45.8%) experienced treatment-related adverse events (TRAEs), and three patients
(6.3%) experienced ≥ Grade 3 TRAEs. We found that high-dose TKI monotherapy improved
prognosis in patients with leptomeningeal metastasis, but the median OS still did not
exceed one year. Further exploration is needed to extend survival in these patients, and
more treatment modalities are currently under investigation.
In terms of systemic combination therapy, studies have shown that bevacizumab can enhance
the penetration of TKIs into cerebrospinal fluid, increasing their concentration in brain
tissue. A retrospective analysis of 27 patients receiving osimertinib combined with
bevacizumab showed that the median OS in the combination group (n=16) and the monotherapy
group (n=11) was 18.0 months and 13.7 months (p = 0.046), respectively, and intracranial
PFS (iPFS) was 10.6 months and 5.5 months (p = 0.037) . These results suggest that
osimertinib combined with bevacizumab may significantly improve the median OS and
intracranial PFS in patients with leptomeningeal metastasis compared to osimertinib
monotherapy. Additionally, combining intrathecal chemotherapy to increase local drug
concentration can improve efficacy and survival benefits. An I/II phase study showed that
intrathecal injection of pemetrexed achieved good efficacy in lung cancer patients with
leptomeningeal metastasis who had failed multiple lines of targeted therapy: the ORR was
84.6%, and the median OS was 9 months. Among patients who achieved a clinical response
(CR or PR), the median OS was 12 months, and the safety profile was significantly better
than with traditional drugs . When pemetrexed was administered intravenously in
combination with systemic therapy, patients also benefited in terms of survival. A
retrospective study of 110 patients with EGFR-mutant advanced NSCLC treated with EGFR
TKIs found that after leptomeningeal metastasis, patients who received systemic
pemetrexed chemotherapy had a longer overall survival than those who did not (13.7 vs 4.0
months, p = 0.008) .
Based on the above findings, this study aims to explore the efficacy and safety of
furmonertinib 240 mg/day combined with bevacizumab and pemetrexed in EGFR-mutant NSCLC
patients with leptomeningeal metastasis.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Have obtained written informed consent from the patient or his or her legal
representative;
2. The patient is ≥18 years old, male or female;
3. Non-small cell lung cancer confirmed by histological or cytological pathology;
4. Genetic testing confirming positive for classical or non-classical EGFR mutations;
5. After comprehensive clinical evaluation according to the "EANO-ESMO" meningeal
metastasis diagnostic criteria, the comprehensive clinical evaluation of patients
with definite meningeal metastasis included symptom evaluation, imaging evaluation,
and/or cerebrospinal fluid pathology evaluation;
6. Patients with newly diagnosed leptomeningeal metastases and those with disease
progression after previous antineoplastic therapy were eligible;
7. ECOG Performance Status 0-3;
8. Prior treatment with radiation or surgery targeting the central nervous system is
permitted;
9. Admit patients with CNS symptoms or signs, but those symptoms or signs are not life
threatening;
10. Fertile men or women with the possibility of becoming pregnant must use a highly
effective method of contraception (such as oral contraceptives, intrauterine
devices, abstinence or barrier contraception combined with spermicides) during the
course of the trial and continue contraception for 12 months after the end of
treatment.
Exclusion Criteria:
- 1)Patients currently have tumors other than NSCLC; 2)Have had or have a history of
other malignancies within the last 5 years, other than basal cell carcinoma of the
skin, carcinoma in situ of the cervix, and ductal carcinoma in situ of the breast
that have been effectively controlled; 3)Serious digestive tract diseases that
affect drug use and absorption, including but not limited to peptic ulcer,
inflammatory bowel disease, etc.
4)Evidence of any severe or uncontrolled systemic disease, including uncontrolled
hypertension, diabetes, and active bleeding, any that the investigator deems to be
detrimental to the patient's participation in the study or to adherence to the
protocol, or active infections including hepatitis B, hepatitis C, and human
immunodeficiency virus (HIV); 5)A history of interstitial lung disease, drug-induced
interstitial lung disease, prior history of radiation pneumonia requiring steroid
treatment, or any evidence of active interstitial lung disease; 6)The presence of
significant arrhythmias (such as prolonged QT interval > 500ms) or heart failure
(left ventricular ejection fraction < 50%) 7)Pregnant or lactating women; 8)Patients
who received a live vaccine within 4 weeks before treatment began; 9)Patients who
are or have been involved in another clinical study within 4 weeks; 10)Other severe
acute or chronic medical or psychiatric conditions or laboratory abnormalities that,
in the investigator's opinion, may increase the risks associated with participating
in the study or may interfere with the interpretation of the study results; Or
subjects who may not be able to complete the study or comply with the requirements
of the study (for administrative or other reasons).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Henan Cancer Hospital
Address:
City:
Zhengzhou
Country:
China
Contact:
Last name:
Wang Qiming, PI
Phone:
+86 0371 65588421
Email:
qimingwang1006@126.com
Start date:
October 2024
Completion date:
March 2025
Lead sponsor:
Agency:
Henan Cancer Hospital
Agency class:
Other
Source:
Henan Cancer Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06643000
