Application of ametinib or vomitinib, endol and oral vinorelbine in preparation of medicine for treating IV-stage non-small cell lung cancer patient carrying EGFR sensitive mutation

Abstract

The invention discloses an application of ametinib or vomitinib, endol and oral vinorelbine in preparation of a medicine for treating a IV-stage non-small cell lung cancer patient carrying EGFR sensitive mutation, and belongs to the technical field of biological medicines. Wherein the bit progression-free lifetime (PFS) is up to 32.3 months. The composition is superior to third-generation EGFR-TKI single-drug treatment in the prior art and is also superior to most reported combined schemes. In addition, the PFS rates of 1 year, 2 years and 3 years are respectively as high as 91.7%, 66.7% and 41.7%, indicating that the scheme in the invention can provide lasting and stable disease control.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to the use of amitinib or vometinib, endostar, and oral vinorelbine in the preparation of a medicament for treating patients with stage IV non-small cell lung cancer carrying EGFR-sensitive mutations. Background Technology

[0002] Lung cancer is one of the leading causes of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 80–85% of all lung cancers. In Asian populations with lung adenocarcinoma, epidermal growth factor receptor (EGFR) gene mutations are among the most common driver gene alterations, with a detection rate as high as 40–50%. Third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib, amitinib, and vormetinib have become key drugs for treating EGFR-mutant advanced NSCLC, significantly prolonging progression-free survival (PFS).

[0003] However, third-generation EGFR-TKI monotherapy still faces clinical challenges, namely acquired resistance. Patients typically experience disease progression after 10.9–20.8 months of treatment, with resistance mechanisms including EGFR T790M / C797S mutations and bypass activation. To overcome resistance and further improve efficacy, clinical practice has begun to explore combination therapy strategies involving third-generation EGFR-TKIs with other drugs with different mechanisms of action.

[0004] Currently, the main combination therapies include combinations with anti-angiogenic drugs or chemotherapy drugs. On the one hand, although first-generation EGFR-TKIs combined with anti-angiogenic drugs have been shown to prolong progression-free survival (PFS), the combination of third-generation EGFR-TKIs with bevacizumab has not clearly shown significant benefits in PFS or overall survival (OS) in large studies. On the other hand, while third-generation EGFR-TKIs combined with platinum-based doublet chemotherapy can significantly improve PFS, their toxicity is significant, with ≥ grade 3 adverse events occurring in 64% to 89.6% of studies, mainly chemotherapy-related hematological toxicities. This limits their application in real-world patient populations such as the elderly, those with poor physical condition, or those with underlying diseases.

[0005] Therefore, there is a need to find a new third-generation EGFR-TKI combination therapy that can effectively overcome drug resistance, prolong disease control time, and also has good safety and tolerability. Amitinib and vometinib are third-generation EGFR-TKIs independently developed in my country, Endostar is an anti-angiogenic drug independently developed in my country, and oral vinorelbine, as an easily managed metronidazole chemotherapy drug, provides a possibility for constructing an efficient and low-toxicity combination regimen. However, to date, there is a lack of systematic real-world efficacy and safety evaluation evidence for the combination of amitinib or vometinib with Endostar and vinorelbine. Therefore, we propose the use of amitinib or vometinib, Endostar, and oral vinorelbine in the preparation of drugs for the treatment of patients with stage IV non-small cell lung cancer carrying EGFR-sensitive mutations, in order to address the problems mentioned above.

[0006] The information disclosed above in this background section is only for enhancing the understanding of the background section of this invention, and therefore may include prior art that is not known to those skilled in the art. Summary of the Invention

[0007] The purpose of this invention is to provide the use of amitinib or vometinib, endostar, and oral vinorelbine in the preparation of a drug for treating patients with stage IV non-small cell lung cancer carrying EGFR-sensitive mutations, in order to solve the problems mentioned in the background art that currently available third-generation EGFR-TKI monotherapy is prone to drug resistance, and the efficacy of combination therapy with bevacizumab is unclear, and the toxicity of combination therapy with platinum-based doublet chemotherapy is too high.

[0008] To achieve the above objectives, this invention provides the use of amitinib or vormetinib, endostar, and oral vinorelbine in the preparation of a medicament for treating patients with stage IV non-small cell lung cancer harboring EGFR-sensitive mutations. The amitinib or vormetinib, endostar, and oral vinorelbine are used in combination to improve progression-free survival and reduce the incidence of ≥ grade 3 treatment-related adverse events. The EGFR-sensitive mutation is an exon 19 deletion or an L858R point mutation. The patients are ≥65 years old and / or have an ECOG PS score of 2. Amitinib is administered orally at a dose of 110 mg once daily; or vormetinib is administered orally at a dose of 80 mg once daily; endostar is administered via continuous intravenous infusion at a dose of 210 mg per cycle for 5 consecutive days; and oral vinorelbine is administered orally at a dose of 20–80 mg / m². 2 The medication is administered once a week for 3 consecutive weeks, followed by a 1-week break, constituting one treatment cycle.

[0009] Compared with the prior art, the beneficial effects of the present invention are:

[0010] This invention utilizes a combination regimen to treat patients with EGFR-mutant advanced non-small cell lung cancer, achieving a median progression-free survival (PFS) of 32.3 months. This is superior to existing third-generation EGFR-TKI monotherapy and most reported combination regimens. Furthermore, the 1-year, 2-year, and 3-year PFS rates are as high as 91.7%, 66.7%, and 41.7%, respectively, indicating that the regimen of this invention provides durable and stable disease control.

[0011] The adverse reactions of the combined regimen in this invention are mainly grade 1-2, with grade 3 events being fewer and clinically manageable. No grade 4 or higher serious toxicities or new unexpected safety signals were observed. Common toxicities include hematologic toxicity, liver function impairment, and dyslipidemia. The safety profile is consistent with the known toxicities of each component, and no synergistic toxicity enhancement occurred due to combined use. This demonstrates that this invention is particularly suitable for elderly patients, those with poor physical condition, or those with underlying diseases in the real world.

[0012] Compared to third-generation EGFR-TKIs combined with platinum-based doublet chemotherapy, this invention avoids the severe hematological toxicity associated with traditional high-dose chemotherapy and improves patient tolerability. Compared to third-generation EGFR-TKIs combined with large-molecule anti-angiogenic drugs such as bevacizumab, this invention uses endostatin, an anti-angiogenic drug with a different mechanism of action, achieving excellent efficacy while offering different safety profiles, thus providing new options for clinical practice.

[0013] This invention combines the potent targeted inhibition of third-generation EGFR-TKIs, the multi-pathway anti-angiogenic effects of endorphins, and the cytotoxic effects of vinorelbine with immunomodulation to form a synergistic treatment strategy with multiple mechanisms and multiple targets.

[0014] The above overview is for illustrative purposes only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features of the invention will become readily apparent from the accompanying drawings and the following detailed description. Attached Figure Description

[0015] Figure 1 This is a Kaplan-Meier curve of progression-free survival (PFS) for the combination of ametinib and vormetinib in this invention;

[0016] Figure 2 The PFS Kaplan–Meier curves for different targeted drug groups (amitinib vs. vormetinib) in this invention are shown.

[0017] Figure 3 The PFS Kaplan–Meier curves are for different treatment lines (first-line vs. non-first-line) in this invention. Detailed Implementation

[0018] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. It should be noted that the drawings are schematic and not illustrated to scale. For clarity and convenience, the relative sizes and proportions of the parts shown in the drawings have been exaggerated or reduced in size. Any size is only illustrative and not limiting.

[0019] Example

[0020] This example is a single-center retrospective real-world study designed to evaluate the efficacy and safety of amitinib or vormetinib combined with endostar and oral vinorelbine in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). The study included patients with EGFR-mutant stage IV NSCLC who received combination therapy at our hospital between July 2022 and September 2025. The follow-up cutoff date was September 2025. Data were obtained from patients' electronic medical records, medication orders, imaging systems, and follow-up records. Statistical analysis was performed using SPSS software (version 26.0) and Rversion 4.3.3.

[0021] Inclusion criteria for study participants: ① Pathologically or cytologically diagnosed NSCLC, clinically stage IV; ② Molecular testing confirms the presence of EGFR-sensitive mutations, including exon 19 deletion (19del) and exon 21 L858R mutation; ③ Received ≥1 treatment cycle of third-generation EGFR-TKI (amitinib or vormetinib) combined with endostar and oral vinorelbine; ④ Possess baseline imaging data and at least one follow-up imaging data that meets the requirements for efficacy assessment.

[0022] Exclusion criteria for study participants: ① other active malignancies; ② missing baseline data or key follow-up information; ③ concurrently enrolled in interventional clinical trials or receiving initial treatment with immune checkpoint inhibitors.

[0023] As shown in Table 1, a total of 12 patients were included in the study, and their specific baseline characteristics are as follows:

[0024] Gender and age: 11 cases were female, accounting for 91.67%; 1 case was male, accounting for 8.33%; the median age was 67.8 years, of which 5 cases were ≤65 years old, accounting for 41.67%; and 7 cases were >65 years old, accounting for 58.33%.

[0025] Physical fitness score: The ECOGPS score was used. 6 cases scored 0-1, accounting for 50.00%, and 6 cases scored 2, accounting for 50.00%.

[0026] Metastasis status: 8 patients had only 1 metastasis site, accounting for 66.67%; 1 patient had 2 metastasis sites, accounting for 8.33%; 3 patients had 3 metastasis sites, accounting for 25.00%; the most common metastasis sites were bone (7 cases, 58.33%), brain (3 cases, 25.00%), contralateral lung (3 cases, 25.00%), and liver (2 cases, 16.67%); less common metastasis sites were intestine, pericardium, and adrenal gland (1 case each, 8.33%).

[0027] Smoking history: Only 1 case had a smoking history, accounting for 8.33%; 11 cases had no smoking history, accounting for 91.67%.

[0028] Targeted therapy selection: 5 patients received ametinib treatment, accounting for 41.67%; 7 patients received vormetinib treatment, accounting for 58.33%.

[0029] Underlying diseases: 6 cases had no obvious underlying diseases, accounting for 50.00%; 4 cases had hypertension, accounting for 33.33%; 1 case had diabetes, accounting for 8.33%; 2 cases had hyperlipidemia, accounting for 16.67%; 1 case each had coronary heart disease and hypothyroidism, accounting for 8.33%.

[0030] Previous treatment: 2 cases had previously received radiotherapy, accounting for 16.67%; 2 cases had previously received surgical treatment, accounting for 16.67%.

[0031] Initial efficacy assessment: 11 cases achieved partial remission (PR), accounting for 91.67%; 1 case had stable disease (SD), accounting for 8.33%.

[0032] feature Number of examples percentage(%) gender male 1 8.33 female 11 91.67 Age (years) ≤65 5 41.67 >65 7 58.33 Eastern Cooperative Oncology Group Performance Status Score (ECOG PS) 0-1 points 6 50.00 2 points 6 50.00 Number of transfer sites 1 8 66.67 2 1 8.33 3 3 25.00 Transfer site brain 3 25.00 bone 7 58.33 contralateral lung 3 25.00 intestinal 1 8.33 Pericardium 1 8.33 adrenal glands 1 8.33 liver 2 16.67 smoking history have 1 8.33 none 11 91.67 Targeted drug types Ametinib 5 41.67 Vometinib 7 58.33 Initial best efficacy assessment Partial remission (PR) 11 91.67 Disease stable (SD) 1 8.33 Past medical history No comorbidities 6 50.00 hypertension 4 33.33 diabetes 1 8.33 High blood lipids 2 16.67 Coronary heart disease 1 8.33 hypothyroidism 1 8.33 History of adjuvant therapy radiotherapy 2 16.67 Operation 2 16.67

[0033] Table 1. Baseline characteristics of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC)

[0034] Treatment regimen: All patients received combination therapy with a third-generation EGFR-TKI (amitinib or vormetinib), endostar, and oral vinorelbine, with specific administration methods and dosages as follows:

[0035] Ametinib is administered orally at a dose of 110 mg once daily. Vometinib is administered orally at a dose of 80 mg once daily. Endostar is administered via infusion pump at a dose of 210 mg for 5 consecutive days. Vinorelbine is administered orally at a dose of 20-80 mg / m². 2 The medication is administered once weekly for three consecutive weeks, followed by a one-week break, constituting one treatment cycle. The dosage and duration of treatment may be adjusted based on treatment-related adverse events (TRAEs) and clinical assessment results, and any adjustments should be recorded accurately.

[0036] Efficacy assessment criteria: Efficacy was assessed according to the RECIST v1.1 criteria, categorized as complete response (CR), partial response (PR), stable disease (SD), and disease progression (PD). The primary endpoint was progression-free survival (PFS); the secondary endpoint was objective response rate (ORR). The routine recommendation for assessment was imaging evaluation after every two treatment cycles, but the specific frequency depended on clinical practice.

[0037] Safety assessment criteria: TRAEs are classified according to the CTCAEv5.0 standard (levels 1-5). Assessment indicators include recording the type of TRAE, its incidence, and the proportion of TRAEs ≥ level 3, with a focus on common adverse reactions such as hematological toxicity, liver function impairment, and dyslipidemia.

[0038] PFS was estimated using the Kaplan-Meier method, and the Log-rank test was used to compare PFS differences between different subgroups (amitinib vs. vormetinib, first-line vs. non-first-line treatment). Univariate Cox proportional hazards regression analysis was used to assess prognostic factors (including clinically significant variables such as age, ECOGPS, and treatment regimen), and hazard ratios (HR) and their 95% confidence intervals (CI) were calculated. P < 0.05 was considered statistically significant.

[0039] Research findings:

[0040] ORR: Of the 12 patients, 11 achieved PR (partial response), accounting for 91.67%; 1 patient had SD (stable disease), accounting for 8.33%; the ORR was 91.67%.

[0041] PFS: As of the follow-up cutoff date, 8 out of 12 patients experienced disease progression or death, accounting for 66.7%, with a median follow-up time of 33.5 months; the median PFS in the overall population was 32.3 months (95% CI: 27.5 – not reached), and the 1-year, 2-year, and 3-year PFS rates were 91.7%, 66.7%, and 41.7%, respectively. (See attached) Figure 1 As shown.

[0042] In subgroup efficacy analysis, ametinib vs. vormetinib: there was no statistically significant difference in PFS curves between the two groups (Log-rank P = 0.710), and Cox regression analysis showed HR = 1.357 (95% CI: 0.270–6.812). (See attached...) Figure 2 As shown.

[0043] First-line vs. non-first-line treatment: There was no statistically significant difference in PFS between the two groups (Log-rank P = 0.948), and Cox regression analysis showed HR = 0.944 (95% CI: 0.168–5.306). (See attached...) Figure 3 As shown.

[0044] Safety results:

[0045] Grade 1-2 TRAE: 5 cases of leukopenia, 6 cases of decreased hemoglobin, 5 cases of neutropenia, 5 cases of dyslipidemia, 6 cases of liver function impairment, 2 cases of kidney function impairment, 1 case of rash, and 2 cases of diarrhea; no grade 1-2 thrombocytopenia occurred.

[0046] Grade 3 TRAEs: 1 case of decreased hemoglobin, 1 case of thrombocytopenia, and 2 cases of liver function impairment; no Grade 4 or higher TRAEs were observed, and no new safety signals were detected. See Table 3.

[0047] Adverse reaction types Level 1-2 Level 3 Hematologic toxicity Leukopenia 5 0 Hemoglobin decrease 6 1 Neutropenia 5 0 Thrombocytopenia 0 1 Elevated total cholesterol (dyslipidemia) 5 0 Liver function damage 6 2 Kidney damage 2 0 rash 1 0 diarrhea 2 0

[0048] Table 3 Treatment-Related Adverse Events (TRAEs) Table

[0049] Comparing the TRAEs between the amitinib and vormetinib groups, there was no statistically significant difference in the incidence of most TRAEs (liver function impairment, kidney function impairment, hematologic toxicity (except neutropenia), dyslipidemia, rash, and diarrhea) between the two groups. A significant difference was found in the incidence of neutropenia (standardized difference = 2.89, P = 0.014, P = 0.01 after multiple correction): 4 cases (80.00%) of grade 1-2 neutropenia were observed in the amitinib group, while 1 case (14.29%) of grade 1-2 neutropenia was observed in the vormetinib group. (See Table 4).

[0050] Adverse reaction types Ametinib group Vometinib group Standardization differences p-value Liver function impairment (grading) 1.33（0.06，2.59） 0.18 None: 1 case (20.00%) None: 3 cases (42.86%) Level 1: 4 cases (80.00%) Level 1: 2 cases (28.57%) Level 3: 0 cases (0.00%) Level 3: 2 cases (28.57%) Kidney function impairment (grading) 0.15（-1.00，1.30） 0.793 None: 4 cases (80.00%) None: 6 cases (85.71%) Level 1: 1 case (20.00%) Level 1: 1 case (14.29%) Hematological toxicity (grading) 0.15（-1.00，1.30） 0.793 None: 1 case (20.00%) None: 1 case (14.29%) Yes: 4 cases (80.00%) Yes: 6 cases (85.71%) Leukopenia (graded) 0.70（-0.48，1.88） 0.516 None: 2 cases (40.00%) None: 5 cases (71.43%) Level 1: 2 cases (40.00%) Level 1: 1 case (14.29%) Level 2: 1 case (20.00%) Level 2: 1 case (14.29%) Neutropenia (graded) 2.89（1.26，4.51） 0.014 (P=0.01 after multiple test correction) None: 1 case (20.00%) None: 6 cases (85.71%) Level 1: 4 cases (80.00%) Level 1: 0 cases (0.00%) Level 2: 0 cases (0.00%) Level 2: 1 case (14.29%) Decreased hemoglobin (graded) 0.92（-0.29，2.12） 0.589 None: 3 cases (60.00%) None: 2 cases (28.57%) Level 1: 1 case (20.00%) Level 1: 1 case (14.29%) Level 2: 1 case (20.00%) Level 2: 3 cases (42.86%) Level 4: 0 cases (0.00%) Level 4: 1 case (14.29%) Thrombocytopenia (graded) 0.58（-0.59，1.75） 0.377 None: 5 cases (100.00%) None: 6 cases (85.71%) Level 3: 0 cases (0.00%) Level 3: 1 case (14.29%) Elevated total cholesterol (graded) 1.00（-0.22，2.21） 0.345 None: 2 cases (40.00%) None: 3 cases (42.86%) Level 1: 3 cases (60.00%) Level 1: 2 cases (28.57%) Level 2: 0 cases (0.00%) Level 2: 2 cases (28.57%) Rash (grading) 0.71（-0.47，1.89） 0.217 none 4 (80.00%) 7 (100.00%) Level 1 1 (20.00%) 0 (0.00%) Diarrhea (graded) 0.15(-1.00,1.30) 0.793 none 4 (80.00%) 6 (85.71%) Level 1 1 (20.00%) 1 (14.29%)

[0051] Table 4 Comparison of adverse events between the ametinib group and the vormetinib group

[0052] Univariate Cox proportional hazards regression analysis showed that age was significantly associated with PFS (β = -0.69, 95% CI: -1.24 to -0.14, P = 0.0328). ECOGPS score (2 vs 0) was significantly associated with PFS (β = -24.13, 95% CI: -41.84 to -6.43, P = 0.0256).

[0053] Gender, BMI, metastatic site (bone, brain, contralateral lung, liver), number of metastases, smoking status, treatment line, EGFR mutation site, previous radiotherapy or surgery, primary lesion location, and type of targeted drug were not statistically associated with PFS, as shown in Table 2.

[0054] variable Statistical indicators Progression-free survival (PFS) [β value (95% confidence interval) P value] Age (years) 67.83±10.30 -0.69（-1.24，-0.14） 0.0328 gender female 11 cases (91.67%) Reference group male 1 case (8.33%) -14.95（-38.10，8.19） 0.2341 Eastern Cooperative Oncology Group Performance Status Score (ECOG PS) 0 points 1 case (8.33%) Reference group 1 point 5 cases (41.67%) -9.67（-27.63，8.29） 0.3189 2 points 6 cases (50.00%) -24.13（-41.84，-6.43） 0.0256 Body Mass Index (BMI) 23.62±2.70 -1.40（-3.92，1.13） 0.3037 Transfer site bone none 5 cases (41.67%) Reference group have 7 cases (58.33%) 7.93（-5.15，21.01） 0.2623 contralateral lung none 9 cases (75.00%) Reference group have 3 cases (25.00%) -0.08（-15.99，15.83） 0.9922 brain none 9 cases (75.00%) Reference group have 3 cases (25.00%) 9.15（-5.72，24.02） 0.2556 liver none 10 cases (83.33%) Reference group have 2 cases (16.67%) -4.83（-23.07，13.42） 0.6154 Number of transfer sites 1 8 cases (66.67%) Reference group 2 1 case (8.33%) -12.43（-35.33，10.47） 0.3150 3 3 cases (25.00%) 9.23（-5.38，23.85） 0.2470 smoking history have 1 case (8.33%) Reference group none 11 cases (91.67%) 14.95（-8.19，38.10） 0.2341 First-line / Second-line treatment First line 9 cases (75.00%) Reference group Second-tier 3 cases (25.00%) 3.93（-11.79，19.66） 0.6345 mutation site L858R mutation 5 cases (41.67%) Reference group Exon 19 deletion 7 cases (58.33%) 3.76（-10.02，17.54） 0.6047 History of radiotherapy none 10 cases (83.33%) Reference group have 2 cases (16.67%) 8.23（-9.54，26.00） 0.385 Surgical history none 10 cases (83.33%) Reference group have 2 cases (16.67%) -10.37（-27.70，6.97） 0.2684 Location of the primary lesion (left / right lung) right lung 7 cases (58.33%) Reference group left lung 5 cases (41.67%) -7.30（-20.52，5.92） 0.3046 Targeted drug types Vometinib 7 cases (58.33%) Reference group Ametinib 5 cases (41.67%) 6.64（-6.71，20.00） 0.3527

[0055] Table 2. Results of Univariate Analysis of Progression-Free Survival (PFS)

[0056] Experimental Conclusions: The combined regimen of this invention demonstrates excellent anti-tumor efficacy, significantly prolonging progression-free survival and achieving a high objective response rate. Efficacy data show that the median progression-free survival (PFS) in the overall population was as high as 32.3 months, with 1-year, 2-year, and 3-year PFS rates reaching 91.7%, 66.7%, and 41.7%, respectively. This result is not only far superior to the efficacy of third-generation EGFR-TKI monotherapy (previous monotherapy median PFS was mostly between 10.9 and 20.8 months), but also superior to other reported third-generation EGFR-TKI combination regimens, fully demonstrating the synergistic advantages of multi-mechanism combination in delaying disease progression and controlling tumor burden. Simultaneously, the 91.7% objective response rate (ORR) and 100% disease control rate (DCR) indicate that this regimen can rapidly and effectively inhibit tumor growth, helping patients achieve tumor shrinkage or stabilization, improve clinical symptoms, and enhance quality of life.

[0057] The proposed combination regimen demonstrates good safety and tolerability, with manageable adverse reactions and no new safety signals. Safety data shows that all treatment-related adverse events (TRAEs) were predominantly grade 1-2, with a low incidence of grade 3 TRAEs (only 4 cases), and no grade 4 or higher serious adverse reactions occurred. No new safety signals were observed. Even grade 3 adverse reactions were effectively controlled with symptomatic treatment, and no patients permanently discontinued treatment or died due to adverse reactions, demonstrating the regimen's good safety profile. In particular, this regimen showed good tolerability in elderly patients and those with underlying diseases, addressing the real-world challenge of limited treatment options for elderly patients with underlying conditions. These patients often have poor physical function and cannot tolerate traditional chemotherapy or high-intensity combination therapy. This regimen, through optimized drug dosage and selection of drugs with high safety profiles, provides them with a safe and effective treatment option.

[0058] The combined regimen of this invention has broad applicability, achieving stable benefits in different subgroups. Subgroup analysis showed no statistically significant difference in progression-free survival (PFS) between the ametinib and vormetinib combination therapy groups, indicating that the two domestically produced third-generation EGFR-TKIs can be used interchangeably in combination regimens, allowing clinicians to flexibly choose based on patient drug accessibility, economic situation, and medication history. Simultaneously, there was no significant difference in PFS between the first-line and non-first-line treatment groups, indicating that patients can benefit from this regimen regardless of whether they are treatment-naïve or have progressed after previous targeted therapies, greatly expanding the clinical applicability of the regimen and providing new treatment options for EGFR-mutant advanced NSCLC patients at different treatment stages. Furthermore, prognostic factor analysis showed that, except for age and performance status, patient gender, metastatic site, mutation type, and treatment line did not affect the regimen's efficacy, further demonstrating the broad applicability of this regimen, eliminating the need for strict screening of specific patient groups and facilitating its widespread application in clinical practice.

[0059] The combined approach of this invention has good clinical applicability and accessibility. From a clinical application perspective, all the drugs in the approach are domestically produced, with high drug accessibility and more advantageous prices compared to imported drugs, which can reduce the economic burden on patients. At the same time, the oral administration method and simple dosing cycle greatly improve patients' treatment compliance. Patients do not need to be hospitalized frequently and can complete treatment and follow-up in outpatient settings, which reduces the consumption of medical resources and improves the convenience of treatment for patients.

[0060] In summary, the real-world data in this embodiment fully demonstrate that the treatment regimen of amitinib or vormetinib combined with endostar and oral vinorelbine exhibits excellent efficacy, good safety, wide applicability, and strong practicality in patients with EGFR-mutant advanced non-small cell lung cancer. In particular, it can still bring significant survival benefits in typical real-world patient groups such as the elderly and those with underlying diseases. This provides important real-world evidence for solving the problem of resistance to third-generation EGFR-TKI monotherapy and optimizing the treatment strategy for EGFR-mutant advanced NSCLC.

[0061] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of amatinib or fravitinib, endostar and oral vinorelbine in the preparation of a medicament for treating stage IV non-small cell lung cancer patients carrying EGFR sensitive mutations, characterized in that: The amatinib or volitinib, endostar and oral vinorelbine are used in combination for treatment to improve the progression-free survival and reduce the incidence of grade 3 or more treatment-related adverse events.

2. The use according to claim 1, wherein the EGFR sensitive mutation is exon 19 deletion or L858R point mutation.

3. Use according to claim 1 or 2, wherein, The patient is aged 65 years or older and / or has an ECOG PS score of 2 points.

4. Use according to any one of claims 1 to 3, wherein, The amatinib is administered orally at 110 mg each time, once a day; or the volitinib is administered orally at 80 mg each time, once a day; The endostar is administered by intravenous continuous pumping at 210 mg each time per cycle, continuously for 5 days. Oral vinorelbine is administered orally at a dose of 20-80 mg / m 2 with 1 dose per week, and 3 consecutive weeks of administration followed by 1 week of rest as 1 treatment cycle.

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