EGFR TKI have been approved as first-line treatment in NSCLC patients harboring EGFR
mutation. However, the acquired resistance of EGFR-TKI occurs almost constantly. Anlotinib is
a novel oral multitarget tyrosine kinase inhibitor and primary targeted to Vascular
Endothelial Growth Factor Receptor (VEGFR), fibroblast growth factor receptor (FGFR) ,
platelet-derived growth factor receptor (PDGFR) and c-Kit. The ALTER-0303 trial showed that
patients with advanced non-small cell lung cancer (NSCLC) who received anlotinib as
third-line or further therapy had more survival benefit. The Single-arm, multicenter study
evaluate the safety and efficacy of Anlotinib Hydrochloride combined with EGFR TKIs in
treating Advanced NSCLC With acquired Resistance to EGFR TKIs
- Patients voluntarily participate in this study, signed and dated informed consent with
good compliance and follow-up;
- Males or females aged 18 Years to 75 Years
- The patients should be confirmed with EGFR mutation [e.g., T 790 M , exon 19 deletion,
L 858 R, etc],
- Cytologically or histologically confirmed locally advanced and / or metastatic
non-small cell lung cancer (NSCLC).
- Patients should be using the EGFR TKI monotherapy as the first line treatment and meet
the following criteria:
1. Patients who showed objective clinical benefit from treatment with an EGFR
TKI as defined by either:
- Patients who showed complete (CR) or partial response (PR) ≥ 4 months, or
- Patients who maintained stable disease (SD) status ≥ 6 months
2. Patients who showed 1. risk of recurrence and progression, 2. gradual progression
or local progression while on continuous treatment with EGFR TKI within the last
28 days prior to enrollment.( For recurrent diseases, patients can be accepted
with adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy
plus adjuvant chemotherapy in the past, and 3. relapse occurs 6 months after the
end of treatment).
2. Gradual progression: Disease control lasting ≥6 months with EGFR-TKI
treatment, Compared with the previous assessment, no significant increment
of tumor burden and progressive involvement of non-target lesions with a
score less than 2, and Symptom scored ≤1. Local progression: Disease control
lasting more than 3 months with EGFR-TKI treatment, Progressive disease (PD)
due to solitary extracranial lesion or limitation in intracranial lesions
(covered by a radiation field),and symptom scored ≤1
3. Evidence of imaging or clinical progression is required if progression of
disease occurs during the treatment or after the last treatment.
- At least one measurable lesion meet the requirements of the standard Response
Evaluation Criteria In Solid Tumors（RESCIST）version 1.1
- Life expectancy is at least 3 months;
- Eastern Cooperative Oncology Group（ECOG）Performance Status（PS）:0-2.;
- The main organs function meet following criteria:
- Blood routine examination criteria (no blood transfusion and blood products
within 14 days, no correction by Granulocyte Colony-Stimulating Factor (G-CSF)
and other hematopoietic stimuli): i) hemoglobin (HB) ≥90g/L ii) Absolute
neutrophils count (ANC) ≥1.5×109/L iii) platelet (PLT) ≥80×109/L
- Biochemical tests meet the following criteria i) total bilirubin (TBIL) ≤1.5
times of upper limit of normal (ULN); ii) alanine aminotransferase (ALT) and
aspartate aminotransferase (AST)≤2.5 ULN, if liver metastasis occurred, ALT and
AST ≤5 ULN; iii) serum creatinine (Cr) ≤1.25 ULN or creatinine clearance (CCr)≥45
- Female patients of childbearing age agree that contraceptive measures must be used
within the study period and within 8 weeks after the end of the study drug treatment.
The serum or urine test indicates nonpregnant woman within 7 days prior to the study.
Male patients agree to have contraceptive use during the study period and within 8
weeks after the end of the study period or have had surgical sterilization.
- Small cell lung cancer (including Small cell lung cancer mixed with non-small cell
- Imaging (CT or MRI) showed that the distance between the lesion and the large vessels
was less than 5 mm, or there were central tumors invading the local large vessels, or
there were obvious pulmonary cavity or necrotic tumors.
- Patients with active brain metastasis, cancerous meningitis, spinal cord compression,
or with brain or pia mater diseases detected by CT or MRI at screening time (patients
with stable symptoms and complete treatment 14 days before enrollment may be admitted
to the group, but no symptoms of cerebral hemorrhage should be confirmed by
craniocerebral MRI, CT or venography evaluation).
- Uncontrollable hypertension (systolic blood pressure ≥ 140 mmHg, or diastolic blood
pressure ≥ 90 mmHg, despite using the optimal medical treatment;
- Patients are participating in other clinical studies, or there are less than four
weeks before the end of the previous clinical study.
- Other active malignant tumors requiring concurrent treatment;
- The patient has a history of malignant tumors. Patients with basal cell carcinoma of
skin, superficial bladder cancer, squamous cell carcinoma of skin or carcinoma of
cervix in situ who had undergone possible curative treatment and had no disease
recurrence within 5 years after the initiation of curative treatment are permitted.
- Patients had treatment related adverse reactions after previous systemic anti-tumour
therapy (except hair loss), but did not recover to NCI-CTCAE ≤ 1 grade.
- The patient has the coagulation disorders (INR > 1.5 or prothrombin time (PT) > ULN +
4 seconds or activated partial thromboplastin time (APTT) > 1.5 ULN), or bleeding
tendency, or undergoing thrombolysis or anticoagulation therapy; Note: On the premise
that the International Standardized Ratio of Prothrombin Time (INR) is less than 1.5,
low doses of heparin (0.6 million to 12,000 U per day for adults) or aspirin (less
than 100 mg per day) are allowed for preventive purposes.
- Renal insufficiency: Urinary routine indicated that urinary protein ≥ ++ or confirmed
24-hour urinary protein ≥ 1.0 g;
- Subjects who had undergone major surgery or had severe trauma had less than 14 days
- Severe acute or chronic infections requiring systemic treatment
- Severe cardiovascular diseases: grade II or above myocardial ischemia or myocardial
infarction and poor control arrhythmias (including corrected QT interval (QTc)
interval ≥ 450 ms for males and ≥ 470 ms for females); cardiac insufficiency of grade
III to IV according to New York Heart Association (NYHA) criteria, or left ventricular
ejection fraction (LVEF) < 50% by color Doppler echocardiography;
- ≥ CTCAE grade 2 peripheral neuropathy, except for trauma.
- Respiratory syndrome (≥ CTCAE grade 2 dyspnea), serous effusion (including pleural
effusion, ascites, pericardial effusion) requiring surgical treatment;
- Long-term unhealed wound or fracture;
- Decompensated diabetes mellitus or other contraindications of high-dose glucocorticoid
- There are obvious factors affecting oral drug absorption, such as inability to
swallow, chronic diarrhea and intestinal obstruction;
- Three months prior to enrollment, significant hemoptysis (more than 50 ml per day)
occurred, or significant clinical hemorrhage symptoms or defined bleeding tendency,
such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult
blood ++ or above, or suffering from vasculitis.
- Arteriovenous thrombosis events occurred within 12 months before enrollment, such as
cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage,
cerebral infarction), deep vein thrombosis and pulmonary embolism.
- Patients participated in clinical trials of other antineoplastic drugs within four
weeks prior to enrollment, or planned systemic anti-tumor therapy within four weeks
prior to enrollment or during the period of the study, including cytotoxic therapy,
signal transduction inhibitors, immunotherapy (or use of mitomycin C within six weeks
prior to the treatment of the experimental drugs). Over-extended-field radiotherapy
(EF-RT) was performed within four weeks prior to grouping or limited-field
radiotherapy to evaluate the tumor lesions was performed within two weeks prior to
- Physical and laboratory findings Untreated active hepatitis (hepatitis B: HBsAg
positive and hepatitis B virus (HBV) DNA ≥ 500 IU/mL; hepatitis C: hepatitis C virus
(HCV) RNA positive and abnormal liver function); co-infection of hepatitis B and
- According to the researcher's judgment, patients may have other factors that may lead
to the forced termination of the study, such as other serious diseases or serious
abnormal laboratory examinations or other factors that may affect the safety of the
subjects, or family or social factors such as test data and sample collection.