| Eligibility |
Inclusion Criteria:
- 1. The age is 18-70 years old;
2. According to the TNM staging of lung cancer in the 8th edition of the International
Association for the study of lung cancer and the Joint Committee on American
Classification of cancer, non squamous non-small cell lung cancer confirmed by
histology or cytology that can not be treated surgically and can not receive radical
concurrent chemoradiotherapy and locally advanced or metastatic (stage ? B, ? C or ?)
non squamous non-small cell lung cancer;
3. EGFR mutation (deletion of exon 19 and L858R mutation of exon 21) was confirmed by
tumor histology, cytology or hematology before EGFR / - TKI treatment;
4. After EGFR-TKI treatment failure (based on RECIST v1.1, disease progression
confirmed by imaging), it meets any of the following requirements:
1. In the past, the first or second generation EGFR-TKI (such as icotinib,
gefitinib, erlotinib, afatinib or other first or second generation EGFR-TKI
listed in China) failed, and the T790M mutation of EGFR 20 exon should be
confirmed by histology;
2. In the past, he received the first or second generation EGFR-TKI (e.g. icotinib,
gefitinib, erlotinib, afatinib), and the T790M mutation of EGFR 20 exon was
confirmed by histology or hematology during or after the treatment failure. Then
he received the third generation EGFR-TKI (e.g. oxitinib or other
third-generation EGFR-TKI listed in China) and failed;
3. The patients who received the third-generation EGFR-TKI (such as oxitinib or
other third-generation EGFR-TKI listed in China) at the time of initial diagnosis
of EGFR mutant NSCLC and progressed without other targeted treatment
opportunities;
5. No previous systemic anti-tumor therapy (except EGFR-TKI) for advanced non squamous
NSCLC (for those who have received platinum neoadjuvant chemotherapy or adjuvant
chemotherapy, if the disease progression occurred more than 6 months after the end of
the last treatment, they are eligible to participate in this study);
6. The life expectancy is at least 3 months;
7. ECoG score: 0-1;
8. According to recist1.1, the researcher confirmed that there was at least one
measurable lesion;
9. The function of main organs is normal, and the test results must meet the following
requirements:
1. The standard of blood routine examination should be met (no blood transfusion and
blood products within 14 days, no correction with G-CSF and other hematopoietic
stimulating factors)
A. Hemoglobin (HB) = 90 g / L;
B. Neutrophil count (ANC) = 2 × 109/L;
C. Platelet count (PLT) = 100 × 109/L;
2. Biochemical tests should meet the following standards:
A. Total bilirubin (TBIL) < 1.5 upper limit of normal (ULN);
B. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5uln,
but < 5uln for patients with liver metastasis;
C. Serum creatinine (CR) = 1.5 ULN or endogenous creatinine clearance > 60 ml /
min (Cockcroft Gault formula);
D. Urine routine test results showed that urinary protein (Upro) < 2 + or 24-hour
urinary protein < 1g;
10. Women of childbearing age must have taken reliable contraceptive measures or
conducted pregnancy test (serum or urine) within 7 days before enrollment, and the
result is negative, and they are willing to use appropriate contraceptive methods
during the test period and 60 days after the last administration of the test drug. For
men, it is necessary to agree to use appropriate contraceptive methods or surgical
sterilization during the trial period and 120 days after the last administration of
the trial drug;
11. Signed the written informed consent, and expected to have good compliance with the
research protocol.
Exclusion Criteria:
- 1. Patients with active brain metastases (for patients with stable symptoms of brain
metastases after treatment, keep stable for at least 4 weeks);
2. Previously received the following therapies: anti-PD-1, anti-PD-L1 or anti-PD-L2
drugs or drugs that stimulate or synergistically inhibit T cell receptors (e.g.,
CTLA-4, OX-40, CD137);
3. Have received systemic anti-tumor therapy (including cytotoxic chemotherapy
combined with radiotherapy) for advanced NSCLC other than EGFR-TKI in the past;
4. Immunosuppressive drugs were used within 14 days before the first use of
karelizumab, excluding nasal and inhaled corticosteroids or physiological doses of
systemic steroids (i.e. not more than 10 mg / day prednisolone or other
corticosteroids with the same physiological dose of drugs);
5. Received systemic treatment of Chinese herbal medicine with anti-tumor indications
or immunomodulatory drugs (including thymosin, interferon and interleukin, except for
local use to control pleural effusion) within 2 weeks before the first administration;
6. Received EGFR-TKI within 2 weeks before the first administration;
7. Received palliative radiotherapy within 7 days before the first administration. For
the patients who had received palliative radiotherapy 7 days before the first
administration, all the following conditions must be met before they can be enrolled:
there is no toxic reaction related to radiotherapy, glucocorticoid is not required,
and radiation pneumonia is excluded;
8. Severe cardiovascular diseases: myocardial ischemia or myocardial infarction above
grade II, poorly controlled arrhythmia (including QTc interval = 450 ms for male and =
470 MS for female); Grade ? - ? cardiac insufficiency (according to NYHA
classification of New York Heart Association, see Annex 3), or left ventricular
ejection fraction (LVEF) < 50% by echocardiography;
9. Currently participating in interventional clinical research treatment, or receiving
other research drugs or research devices within 4 weeks before the first
administration; Not fully recovered from toxicity and / or complications caused by any
intervention before the first administration (i.e., = grade 1 or baseline, excluding
fatigue or hair loss);
10. With uncontrolled pleural effusion, pericardial effusion, or ascites requiring
repeated drainage (drainage once a month or more frequently);
11. Subjects have received or plan to receive solid organ or blood system
transplantation (except corneal transplantation) during the study period;
12. Patients with active autoimmune disease or immunodeficiency, or with the above
history, including but not limited to: autoimmune hepatitis, interstitial pneumonia,
uveitis, rheumatoid arthritis, inflammatory bowel disease, hypophysitis, vasculitis,
nephritis, etc.) were not included. The following exceptions: Patients with a history
of autoimmune hypothyroidism but receiving thyroid hormone replacement therapy were
included in the study. Patients with type 1 diabetes whose blood glucose is controlled
after insulin administration can participate in this study.
13. Subjects who received systemic therapy such as bronchodilators were not satisfied
with asthma control and could not be included (those who had complete remission of
asthma in childhood and did not need any intervention in adulthood could be included).
14. Severe infection occurred within 4 weeks before the first administration (e.g.
need for intravenous drip of antibiotics, antifungal or antiviral drugs), or fever of
unknown origin > 38.5 ° C occurred during the screening period / before the first
administration; Or received major surgical treatment within 3 weeks before the first
medication;
15. Inoculate live attenuated vaccine within 30 days of the first administration or
expected during the study period;
16.16. Human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome
(AIDS), untreated active hepatitis B, hepatitis C virus (hepatitis C antibody positive, and
HCV-RNA higher than the lower limit of analysis method) or combined hepatitis B and
hepatitis C common sense;
Note: the hepatitis B subjects who met the following criteria also met the inclusion
criteria: HBV viral load must be <1000 copy /ml (200 IU/ml) before the first dose, and the
subjects should be treated with anti HBV therapy during the whole chemotherapy course to
avoid virus reactivation. For the subjects with anti HBC (+), HBsAg (-), anti HBS (-) and
HBV viral load (-), preventive anti HBV treatment is not necessary, but close monitoring of
virus reactivation is needed;
17. Patients with a clear history of allergy are known to have allergic reactions to
carrizumab, pemetrexed, carboplatin or cisplatin active ingredients and or any excipients;
18. Those who have a history of psychotropic drug abuse and can not give up or have mental
disorders;
Other conditions that increase the risk associated with participating in the study or the
study drug and, in the judgment of the investigator, may result in patients not suitable
for inclusion in the study.
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