Trial Title:
The Efficacy of Double-dose Furmonertinib in the Treatment of Patients With Slow Osimertinib-resistant NSCLC
NCT ID:
NCT06117644
Condition:
Non Small Cell Lung Cancer
EGFR Gene Mutation
Non Small Cell Lung Cancer Stage IIIA
Non-small Cell Lung Cancer Stage IV
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Aflutinib
Conditions: Keywords:
Non Small Cell Lung Cancer
EGFR Gene Mutation
Furmonertinib
Drug Resistance
Study type:
Observational
Overall status:
Not yet recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Drug
Intervention name:
Furmonertinib
Description:
Furmonertinib 40 mg/tablet, 4 tablets, QD
Arm group label:
Furmonertinib
Summary:
This study is a single-center, prospective, single-arm study of the efficacy of
double-dose Furmonertinib in the treatment of patients with slow Osimertinib-resistant
non-small cell lung cancer, mainly in patients with advanced non-small cell lung cancer
with EGFR-sensitive mutations in stage IIIB or IV, slow drug resistance after treatment
with Osimertinib, and no therapeutic target was found by secondary biopsy after drug
resistance.
Detailed description:
According to the latest data released by the National Cancer Center in 2022, the
incidence and mortality of cancer in China are increasing year by year. There are 4.064
million new cancer patients in China in 2016, with a total of 2.414 million cancer
deaths. Among them, 824000 were new cases of lung cancer, accounting for 20.4%, and the
number of lung cancer deaths was 657000, accounting for 27.2%. The morbidity and
mortality of lung cancer ranked first among all malignant tumors. Non-small cell lung
cancer (NSCLC) accounts for about 80% of all lung cancer types, of which epidermal factor
growth receptor (EGFR) mutation is the most common driving gene for NSCLC. About 50% of
Chinese patients carry this gene mutation. Exon 19 deletion mutation (19Del) and exon 21
L858R point mutation (L858R) are called "classical mutations", accounting for about 90%
of all mutation types.
With the third generation of EGFR-TKI gradually entering the clinic, the survival
benefits of patients with EGFR classical mutation positive NSCLC have been continuously
broken through. FLAURA study showed that the median progression-free survival time (mPFS)
of Osimertinib was significantly better than that of gefitinib in the first-line
treatment of advanced NSCLC patients with positive EGFR mutation (18.9 months VS 10.2
months, HR 0.46 (P < 0.001). In addition, the third-generation domestic EGFR-TKI
ametinib, vometenil and so on, have also been listed in China in recent years. No matter
in terms of survival time or quality of life, the third generation of EGFR-TKI has
brought clinically significant improvement to patients. At present, both foreign NCCN
guidelines and domestic CSCO guidelines have taken the third generation of EGFR-TKI as
the standard scheme for first-line treatment of EGFR classic mutation positive patients.
However, with the wide application of the third generation EGFR-TKI, the problem of drug
resistance of the third generation TKI is becoming more and more obvious. The time of the
third-generation TKI listing and application in China is concentrated around 2021, while
the mPFS of the third-generation EGFR-TKI is concentrated between 18-22 months.
Therefore, it can be expected that the problem of drug resistance in the third generation
of TKI may continue to intensify in the next few years. At present, after the third
generation-TKI resistance or progress, there is no standard and unified treatment plan.
The third generation of TKI drug resistance has become a very urgent and huge clinical
problem. Therefore, there is an urgent need to carry out clinical or real-world studies
related to the third-generation TKI drug resistance to explore more or better solutions
after the third-generation TKI drug resistance, so as to bring more potential treatment
options for the third-generation TKI drug-resistant patients.
At present, the exploration direction of the third generation TKI drug resistance therapy
includes immune combination therapy (such as Xindimazumab + chemotherapy +
anti-angiogenic drugs), precision targeted combination therapy (EGFR-TKI combined with
MET-TKI,EGFR-TK combined with RET-TKI, etc.), antibody coupling drugs (ADC), bispecific
antibodies, fourth generation-EGFR-TKI and so on. However, the above treatments may face
problems such as insufficient drug accessibility, excessive adverse reactions, or less
than expected survival time. In addition to the above direction, after the
third-generation-TKI resistance, the challenge of using the third-generation TKI with
increased dose is also one of the options that may be used in clinical practice, which
also shows preliminary clinical value in the real world.
Fumetinib methanesulfonate (AST2828) is the third generation irreversible TKI. At
present, NMPA has approved fumetinib for first-line treatment of locally advanced or
metastatic NSCLC patients with positive EGFR mutation (19Del/L858R), and second-line
(posterior-line) treatment for patients with disease progression with T790M mutation
during or after EGFR-TKI treatment. The results of its IIB phase clinical study showed
that for advanced NSCLC patients with positive T790M mutation, the ORR at the recommended
dose of 80mg/ days was as high as 74.1%, and the median PFS was 9.6 months. The results
of III phase FURLONG study showed that the mPFS of advanced EGFR mutation positive
(19Del/L858R) NSCLC patients treated withFurmonertinib was significantly better than that
of gefitinib (20.8months VS 11.1months, HR=0.44,P < 0.0001). In general, the conventional
dose of Furmonertinib showed a good therapeutic effect in both first-line and second-line
treatment of advanced NSCLC with classical EGFR mutation.
At the same time, in phase I and I/II clinical trials, some patients received daily doses
of 160mg (n = 53) and 240mg (n = 18), and no dose-limiting toxicity was observed.
Compared with the 80mg dose group, the main increases in the incidence of adverse
reactions were increased alanine aminotransferase (80mg 17.5% 1600240mg 35.2%), decreased
white blood cell count (80mg 13.8% 1600240mg 29.6%), decreased neutrophil count (80mg
7.8% 1600240mg 18.3%), increased serum creatinine (80mg 7.5% 1600240mg 18.3), diarrhea
(80mg 6.7% 1600240mg 15.5%). Anemia (80mg 6.0% metrology 1600240mg 23.9%). The main
increased incidence of adverse reactions in the 160-240mg dose group compared with the
80mg dose group ≥ 3 was anemia (80mg 0% meme 1600240mg 4.2%). The results of this phase
I/II study showed that increased doses of Furmonertinib maintained acceptable safety and
tolerance.
Zheng et al reported a case of successful salvage treatment with Furmonertinib 160mg/d
after Osimertinib resistance. The clinical efficacy of oxetinib in this patient lasted
only 7 months, followed by sequential use of Furmonertinib160mg/d. After two weeks of
treatment, the tumor was significantly reduced and the respiratory symptoms were
significantly improved. At the same time, the intracranial lesions of the patients were
completely relieved after 1 month of treatment. This case suggests that the use of
increased doses of Furmonertinib may be a potential treatment option for patients with
drug resistance to Osimertinib. Another real-world study explored the efficacy and safety
of 160mg/d Furmonertinib in patients with three generations of EGFR-TKI drug resistance.
In 39 patients, the median PFS and OS of Furmonertinib 160mg/d were 4.7 months and 7.53
months, respectively. Among them, it showed a better therapeutic effect for the third
generation of TKI patients with intracranial progression, with a median PFS of 5.45months
and a median OS of 9.75months. The main adverse reactions were anemia, lymphocytopenia,
diarrhea and so on. No new safety signal was observed. This real-world study
preliminarily validates the efficacy and safety of increased-doseFurmonertinib (160mg/d)
in patients with third-generation TKI drug resistance.
To sum up, the researchers predict that a higher dose of 160mg/d in third-generation
TKI-resistant patients may have a better benefit-risk ratio, which has the value of
further exploration. Therefore, this real-world study intends to collect three
generations of TKI-resistant patients who have been treated with increased doses of
Furmonertinib. To further analyze the efficacy and safety of improving the dose of
Furmonertinib in the third generation of patients with TKI drug resistance. To provide
more evidence-based medical evidence for the treatment of the third generation of
patients with drug resistance to TKI.
Criteria for eligibility:
Study pop:
Mainly targeted at IIIB or IV stage EGFR sensitive mutation advanced non-small cell lung
cancer patients with slow drug resistance after Osimertinib treatment, and no treatable
target was found by secondary biopsy after drug resistance.
Sampling method:
Probability Sample
Criteria:
Inclusion Criteria:
1. Age ≥ 18 years old;
2. EGFRm NSCLC of local progression (IIIB stage) or metastasis (IV stage);
3. previously confirmed to have EGFR (Ex19del or L858R) mutation, or T790M, received
Osimertinib treatment. According to Recist 1.1 imaging findings, the focus
progressed slowly and there was no systemic explosive progress (definition of slow
progress: disease control > 6 months, slightly increased tumor load and symptom
score ≤ 1);
4. patients who intend to use Furmonertinib (double dose, 160mg) anticancer therapy;
5. At least one tumor lesion in the patient can meet the following requirements: it has
not been irradiated in the past and can be accurately measured, the longest diameter
of the baseline phase is ≥ 10mm (in the case of lymph nodes, short axis ≥ 15mm is
required), and the measurement method can be chest CT or PET-CT, as long as repeated
measurements can be completed accurately;
6. No treatable target was found in the second biopsy after drug resistance;
7. The survival time was more than 3 months;
Exclusion Criteria:
1. Patients who have been treated with Furmonertinib;
2. Patients who intend to use anticancer therapy other than Furmonertinib recently;
3. Contraindications for the use of Furmonertinib;
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
November 1, 2023
Completion date:
October 1, 2026
Lead sponsor:
Agency:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Agency class:
Other
Source:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06117644
