CN113730572A - Combination comprising anti-EGFR antibody or fragment thereof - Google Patents
Combination comprising anti-EGFR antibody or fragment thereof Download PDFInfo
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- CN113730572A CN113730572A CN202110590493.9A CN202110590493A CN113730572A CN 113730572 A CN113730572 A CN 113730572A CN 202110590493 A CN202110590493 A CN 202110590493A CN 113730572 A CN113730572 A CN 113730572A
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Abstract
The invention provides a combination containing an anti-EGFR antibody or a fragment thereof, which is used for preventing or treating cancer, the combination comprises the anti-EGFR antibody or the fragment thereof and an EGFR small-molecule tyrosine kinase inhibitor, especially afatinib or a salt thereof/oxitinib or a salt thereof, and application of the combination in preparing a medicament for treating cancer. In particular, it was found that an anti-EGFR antibody or fragment thereof has a beneficial synergistic effect when administered in combination with an EGFR small molecule tyrosine kinase inhibitor, especially afatinib or its salt/oxitinib or its salt, for the treatment of cancer.
Description
Technical Field
The present invention relates to the field of biopharmaceuticals, more specifically to the use of an anti-EGFR antibody or fragment thereof for the treatment of cancer, in particular the use of such antibody or fragment in a combination medicament.
Background
Cancer refers to a large group of diseases characterized by abnormal cell differentiation and proliferation, uncontrolled growth, infiltrative and metastatic properties, and unregulated cell division may lead to the formation of malignant tumors or cells invading adjacent tissues and may be transferred to distant parts of the body through the lymphatic system or blood stream, and the occurrence of the diseases is a multi-factor and multi-step complex process which is divided into three processes of carcinogenesis, carcinogenesis and evolution, and is closely related to smoking, infection, occupational exposure, environmental pollution, unreasonable diet and genetic factors. Cancers include various types, and are generally classified into two main types, primary and secondary, according to the organ parts which occur: lung cancer, gastric cancer, breast cancer, nasopharyngeal carcinoma, liver cancer, intestinal cancer, and prostate cancer. Cancer is classified according to the tissue system in which it occurs: digestive system cancer, respiratory system cancer, genitourinary system cancer, hematological system cancer, and the like. The body part is divided into: head and neck cancer, breast, abdominal, pelvic cancer, etc. The cell sources are divided into: adenocarcinoma, squamous cell carcinoma and undifferentiated carcinoma, and the incidence probability and the severity of each cancer are different.
The lung cancer is a malignant tumor with the highest morbidity and mortality in China and worldwide, the clinical symptoms are more hidden, cough, expectoration, hemoptysis and emaciation are mainly shown, X-ray imaging is mainly shown as pulmonary nodules, mass images and the like, most patients are diagnosed late, the survival rate in 5 years is low, the disease burden is heavy, and the health of the Chinese is seriously threatened. The etiology and pathogenesis of lung cancer are not clear so far, and about 85-90% of lung cancers are caused by active or passive smoking, and there is evidence that the lung cancers are related to occupational carcinogens (asbestos, arsenic, chromium nickel, polycyclic aromatic hydrocarbons and the like), air pollution, ionizing radiation, diet, physical activity, heredity and genetic changes. Lung cancer can be classified by histological features into non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC). Among them, NSCLC accounts for about 85% of the total number of lung cancers, and molecular mechanisms such as mutations and abnormal expression of various genes are currently confirmed to be related to the onset of NSCLC, wherein Epidermal Growth Factor Receptor (EGFR) is one of the major driving genes of lung cancer. Tyrosine phosphorylation of the intracellular domain of EGFR, in turn, activates second messenger transduction, inducing activation of extracellular signals through the MAPK pathway (kinases Erk1 and Erk 2); activation of Akt via PI3K pathway; activation of the signal transducer and transcriptional activators of STAT3, STAT5 by JAK 2.
With the sequential identification of the oncogene driver of the lung cancer series, targeted therapeutics greatly improve and prolong the prognosis and survival of NSCLC patients carrying the corresponding driver. The classification of lung cancer is also based on the past simple histopathological classification, further subdivided into molecular subtypes based on driver genes. The EGFR gene mutation positive rate of Asian population and NSCLC patients in China is 40-50%. The rate of EGFR mutation differs between asian and western populations. EGFR mutations mainly include 4 types: exon 19 deletion mutation, exon 21 point mutation, exon 18 point mutation, and exon20 insertion mutation. The most common EGFR mutations are exon 19 deletion mutation 19DEL and exon 21 point mutation 21L858R, both sensitive mutations to EGFR TKI, and 18 exon G719X, 20 exon S768I and 21 exon L861Q mutations. Rare mutations of EGFR account for approximately 15% to 20% of all EGFR mutations, with more than 50% of rare mutations located in exon20 of EGFR, with exon20 insertion mutations (EGFR exon20 ins) being the most common.
In EGFR mutant lung cancer patients, EGFR exon20ins is the most common mutation type in rare EGFR mutations, accounting for about 30% of rare EGFR mutations, and EGFR exon20ins accounts for 4.8% -12% of all EGFR mutations in western population, and there are 30 known EGFR exon20 ins. The EGFR exon20ins accounts for 3% -4% of EGFR mutation proportion of Chinese population, and researches show that the genetic characteristics of the EGFR exon20ins in Chinese NSCLC patients are equivalent to the genetic characteristics reported in white-breed patients, the incidence rate accounts for about 2% -3% of the total NSCLC, and the genetic characteristics comprise most of unique mutations and most of common co-mutations.
The relationship between the curative effect of the accurate targeted therapy of the advanced EGFR sensitive mutation positive NSCLC and the molecular typing has been well proven in clinical practice. EGFR small molecule tyrosine kinase inhibitors (EGFR-TKIs) have now become the first-line standard treatment for EGFR sensitive mutant non-small cell lung cancer. Among them, Afatinib (Afatinib) is the second generation EGFR-TKIs, and has been approved in China for NSCLC first-line EGFR-sensitive mutation indication. Oxitinib (Osimetinib) is the third generation EGFR-TKIs and also the first recommended drug for the first-line treatment of EGFR sensitive mutation according to various international guidelines. The drug has been approved at home for two indications of NSCLC with front-line EGFR sensitive mutation and rear-line T790M positive.
However, insensitivity of EGFR exon20ins NSCLC patients to primary and secondary EGFR-TKI treatment has been demonstrated by several clinical studies. According to the combination analysis of LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 after marketing, EGFR exon20ins patients received the least benefit of afatinib treatment than other mutant patients, 23 EGFR exon20ins patients received the first-line treatment of afatinib with ORR of 8.7%, median PFS of 2.7 months, median OS of 9.2 months and the shortest of all EGFR mutant patients, suggesting that the effect of afatinib single drug on EGFR exon20ins NSCLC is limited. Research shows that when the first generation EGFR-TKIs are used for treatment, the ORR of EGFR exon20ins NSCLC patients is 0% -11%, mPFS is 2-3 months, and OS is similar to wild type EGFR patients. The National Comprehensive Cancer Network (NCCN) NSCLC guidelines also point out: most EGFR exon20ins are predictive of TKI resistance in the clinic.
The annual meeting of the european society for oncology in 2018 (ESMO) published preliminary data from phase ii clinical trials (NCT 03191149) on an axitinib-treated advanced stage EGFR exon20ins NSCLC patient in the united states, with a median of 1 prior systemic treatment line count (ranging from 0 to 3), and only 1 partial remission was observed in 17 patients receiving axitinib treatment, with an ORR of 6%, an mPFS of 3.7 months, and a Disease Control Rate (Disease Control Rate, DCR) of 35% (6/17), concluding that axitinib has limited antitumor activity against EGFR exon20ins NSCLC patients. ESMO published another korean phase ii clinical trial preliminary data (NCT03414814) evaluating the efficacy of oxitinib in advanced EGFR exon20ins NSCLC patients after failure of standard chemotherapy, and during the period from 1 month to 2 months 2019, 15 patients received oxitinib as second-line therapy (20%, n ═ 3) and more than three-line (including three-line) therapy (n ═ 12) in the first phase, with ORR of 0%, most stable disease (46.7%, n ═ 7%), mPFS of 3.5 months (95% CI 1.6-NR), mOS not reached (1 year OS rate 56.3%), and DCR of 31.1% at 6 months. The most common adverse events (all grades) were nausea (20%, n ═ 3), vomiting (20%, n ═ 3), anemia (13.3%, n ═ 2) and fever (13.3%, n ═ 2), concluding that ocitinib is well tolerated, but with limited efficacy in EGFR exon20ins NSCLC patients after failure of standard chemotherapy.
Currently, EGFR mab single drug is not approved or recommended for NSCLC (including EGFR exon20ins NSCLC) by no guideline, EGFR mab single drug is not very effective, pemetrexed meso 10.3m [ 95% CI: 7.5,16.8 ]; cetuximab (Cetuximab) single drug median OS 3.5m [ 95% CI: 2.8,11.7], P ═ 0.046(BMC cancer.2014jan 4; 14: 5). The curative effect of EGFR monoclonal antibody combined chemotherapy on NSCLC is poor, although the scheme of anti-rituximab (Necitumumab) combined gemcitabine and cisplatin has been approved for lung cancer indications, the NCCN guidelines delete the recommendation of the therapy due to the problems of curative effect, toxicity and cost (Lancet Oncology,2015,16(7): 763-; the NCCN guideline in 2015 deleted the recommendations related to cetuximab (first line therapy of cetuximab/cisplatin/vinorelbine (class 2B), the benefit of the cetuximab/cisplatin/vinorelbine regimen was considered to be very slight, a difficult to administer regimen and less tolerable than the other regimen (Lancet 2009; 373: 1525-charge 1531), a randomized control trial revealed that Panitumumab (Panitumumab) combined with standard therapy (pemetrexed + platinoid) for NSCLC did not benefit and the data more supported standard therapy (Clinical Lung Cancer,2015,16(6): 447-charge 456).
Currently, the curative effect of afatinib or oxitinib single drug on EGFR exon20ins NSCLC is limited, the first-line standard treatment of patients is chemotherapy at present, the systemic chemotherapy ORR is only 20% -40% (J Clin Oncol 2003; 21(16): 3016-3024; J Clin Oncol 2008; 26: 3543-3551; Cancer 2003; 98: 542-553; Ann Oncol 2007; 18:317-323), the curative effect is poor, and EGFR exon20ins NSCLC has no targeted drug approval to be on the market at present, and no treatment scheme is recommended in clinical guidelines at home and abroad, part of drugs are in clinical test stages, and EGFR exon20ins NSCLC treatment has unmet clinical requirements. It is therefore highly desirable to develop more effective agents targeting EGFR exon20ins NSCLC to accurately treat these patients. More particularly, it would be beneficial if anti-EGFR antibodies could be developed to better treat EGFR exon20ins NSCLC, such as to enhance tumor remission, reduce the likelihood or frequency of recurrence, prolong survival, reduce toxic side effects, etc., in combination with other lung cancer therapies, particularly non-small cell lung cancer therapies.
CN103772504A (the contents of which are incorporated herein in their entirety) discloses a series of anti-EGFR antibodies or antigen-binding portions thereof, the sequence of heavy chain CDR1 of which is selected from the group consisting of the sequences set forth in SEQ ID NO:1 and SEQ ID NO:39 or derivatives thereof, the sequence of CDR2 of which is the sequence set forth in SEQ ID NO:4 or derivatives thereof, and the sequence of CDR3 of which is selected from the group consisting of the sequences set forth in SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:40 or derivatives thereof; the light chain CDR1 has the sequence shown in SEQ ID No. 11 or its derivative, the CDR2 has the sequence shown in SEQ ID No. 12 or its derivative, and the CDR3 is selected from the sequence shown in SEQ ID No. 9, SEQ ID No. 10 or SEQ ID No. 41 or its derivative.
Disclosure of Invention
The invention provides a combined medicament for preventing or treating cancer, which comprises an anti-EGFR antibody or a fragment thereof and an EGFR small-molecule tyrosine kinase inhibitor, especially afatinib (including afatinib salt)/oxitinib (including oxitinib salt), and application of the combined medicament in preparing a medicament for treating cancer. In particular, it was found that an anti-EGFR antibody or fragment thereof has a beneficial synergistic effect when administered in combination with an EGFR small molecule tyrosine kinase inhibitor, especially afatinib (including afatinib salts)/oxitinib (including oxitinib salts), for the treatment of lung cancer, especially EGFR exon20ins NSCLC.
In particular, the invention provides a combination comprising an anti-EGFR antibody or fragment thereof and an EGFR small molecule tyrosine kinase inhibitor for simultaneous or separate administration for the prevention or treatment of lung cancer.
Preferably, the cancer is selected from lung cancer, gastric cancer, liver cancer, breast cancer, esophageal cancer, kidney cancer, bladder cancer, cervical cancer, colorectal cancer, and lymphoma, preferably lung cancer; the lung cancer is selected from small cell carcinoma and non-small cell lung cancer, preferably non-small cell carcinoma, and more preferably EGFR exon20ins non-small cell lung cancer.
The anti-EGFR antibody or fragment thereof of the present invention preferably has 6 CDR sequences of the heavy and light chains of Cetuximab (Cetuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), and Nimotuzumab (Netuzumab), and more preferably, the anti-EGFR antibody or fragment thereof of the present invention comprises the heavy chain CDR1 sequence shown in SEQ ID NO:1 or SEQ ID NO:2, the heavy chain CDR2 sequence shown in SEQ ID NO:3, and the heavy chain CDR3 sequence shown in SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6, and/or the light chain CDR1 sequence shown in SEQ ID NO:7, the light chain CDR2 sequence shown in SEQ ID NO:8, and the light chain CDR3 sequence shown in SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO: 11. Further, the anti-EGFR antibody or a fragment thereof preferably comprises the heavy chain CDR1 sequence shown in SEQ ID NO. 1, the heavy chain CDR2 sequence shown in SEQ ID NO. 3 and the heavy chain CDR3 sequence shown in SEQ ID NO. 4, and/or the light chain CDR1 sequence shown in SEQ ID NO. 7, the light chain CDR2 sequence shown in SEQ ID NO. 8 and the light chain CDR3 sequence shown in SEQ ID NO. 9. Preferably, the anti-EGFR antibody or fragment thereof comprises the heavy chain variable region shown in SEQ ID NO. 12 and/or the light chain variable region shown in SEQ ID NO. 13. The anti-EGFR antibody fragment may be a single chain antibody (scFv), a chimeric antibody, a diabody, an scFv-Fc bivalent molecule, a dAb, a Fab fragment, a Fab 'fragment, an Fv, or a F (ab')2And (3) fragment. Preferably, the anti-EGFR antibody or fragment thereof is a full-length anti-EGFR antibody. Further, the anti-EGFR antibody has a human IgG1 heavy chain constant region and/or a human kappa light chain constant region. Preferably, the anti-EGFR antibody is a humanized antibody.
The EGFR small-molecule tyrosine kinase inhibitor in the invention is preferably afatinib (including afatinib salt) or oxitinib (including oxitinib salt).
The invention also provides application of the combined medicine in preparing a medicine for treating cancer.
The invention also provides the use of an anti-EGFR antibody or fragment thereof in the manufacture of a medicament for the treatment of cancer in combination with an EGFR small molecule tyrosine kinase inhibitor.
Preferably, the cancer is selected from lung cancer, gastric cancer, liver cancer, breast cancer, esophageal cancer, renal cancer, bladder cancer, cervical cancer, colorectal cancer and lymph cancer, preferably lung cancer; the lung cancer is selected from small cell carcinoma and non-small cell lung cancer, preferably non-small cell carcinoma, and more preferably EGFR exon20ins non-small cell lung cancer.
In the invention, the combined medicine is used for preparing the second-line and above treatment of the non-small cell lung cancer carrying EGFR exon20ins, and more preferably, the combined medicine is used for preparing the second-line and above treatment of the non-small cell lung cancer carrying EGFR exon20ins which has received at least one systemic chemotherapy.
In the present invention, the anti-EGFR antibody for use or combination is formulated for administration before, simultaneously with or after the EGFR small molecule tyrosine kinase inhibitor.
In the present invention, the anti-EGFR antibody is administered at a dose of 4mg/kg to 10mg/kg, preferably 4mg/kg, 4.8mg/kg, 6mg/kg, 8mg/kg and 10mg/kg, more preferably 6mg/kg, when the subject is a human; the administration is performed once every 1 to 4 weeks, preferably once every 1 week, once every 2 weeks, once every 3 weeks for 1 or 4 weeks, and more preferably once every 2 weeks.
In the invention, when the EGFR small molecule tyrosine kinase inhibitor is afatinib or salt thereof, the administration dosage is preferably 20 mg/day to 50 mg/day, preferably 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and more preferably 30 mg/day.
In the invention, when the EGFR small molecule tyrosine kinase inhibitor is oxitinib or salt thereof, the administration dosage is preferably 40-160 mg/day, preferably 40 mg/day, 80 mg/day, 120 mg/day, 160 mg/day, and more preferably 160 mg/day.
In the present invention, it is preferable that the anti-EGFR antibody is first infused, the EGFR small molecule tyrosine kinase inhibitor is administered within 12 hours, then the EGFR small molecule tyrosine kinase inhibitor is administered daily, the anti-EGFR antibody is administered after 1 to 4 weeks (preferably 1 week, 2 weeks, 3 weeks or 4 weeks) apart, the EGFR small molecule tyrosine kinase inhibitor is administered within 12 hours, then the EGFR small molecule tyrosine kinase inhibitor is administered daily, and more preferably the administration regimen is a cyclic cycle of 2 weeks. Cycles are performed according to the above dosing regimen until the disease progresses, toxicity is not tolerated or the patient is assessed to be unable to benefit from treatment, whichever comes first.
In vitro studies prove that after the anti-EGFR antibody is combined with afatinib (including afatinib salt) or oxitinib (including oxitinib salt), the Ba/F3 EGFR exon20ins ASV cell proliferation inhibition activity of the afatinib (including afatinib salt) or oxitinib (including oxitinib salt) is respectively improved.
It is to be understood that the specific examples and embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention, and that various further modifications or changes included within the spirit and scope of the present application are intended to be included within the scope of the present disclosure.
In the present invention, the anti-EGFR antibody having the heavy chain amino acid sequence shown in SEQ ID NO. 14 and the light chain amino acid sequence shown in SEQ ID NO. 15 is designated JMT 101.
Drawings
Fig. 1-2: the tested medicine has the function of inhibiting the proliferation of Ba/F3 EGFR-Exon 20V769_ D770insASV cells.
FIG. 3: tumor growth curves, where data points represent mean tumor volume within the group and error bars represent standard mean error (SEM).
FIG. 4: tumor volume histograms at day 14 of dosing, with data points representing mean tumor volume within the group, error bars representing standard mean error (SEM) (. p) 0.01, (. p) 0.001.
FIG. 5: end-point tumor weight histograms after day 14 of dosing, with data points representing mean tumor weight error bars within the group representing standard mean error (SEM) (# p < 0.01) (# p < 0.001).
Examples
EXAMPLE 1 Experimental study of cell proliferation
The effect of the drug on the proliferation of Ba/F3 EGFR-Exon 20V769_ D770insASV cells was examined.
1. Experimental Material
1.1 medicaments
Afatinib (Afatinib), oxitinib (Osimertinib) and JMT101 injection (201906071).
1.2 cells
Ba/F3 EGFR-Exon 20V769_ D770ins ASV cells.
2. Experimental procedure
2.1 pharmaceutical formulation
Preheating compounds Afatinib and Osimetinib at room temperature, completely dissolving the compounds Afatinib and Osimetinib to 10mM by using DMSO, and then diluting 0.5mM working solution; JMT101 was diluted to 100. mu.g/ml working solution in RPMI1640 complete medium.
2.2 cell plating and Compound treatment
1) And starting the ultraviolet lamp of the biological safety cabinet, and counting down for 30 min. In a 37 degree water bath, RPMI1640 complete medium (RPMI 1640+ 10% FBS) was preheated.
2) And after the ultraviolet irradiation is finished, opening the biological safety cabinet. Pre-warmed RPMI1640 complete medium and 384-well plates were wiped with alcohol and placed in a biosafety cabinet, and 3 cell T75 flasks were removed from the incubator and placed in a biosafety cabinet.
3) Transfer all 3 cell suspensions to 50ml centrifuge tubes with a pipette, screw the caps tightly and centrifuge (800rpm, 5 min).
4) The supernatant was centrifuged off, 50ml of complete medium was added for resuspension, and 1ml of cell suspension was taken out and counted using a cell viability counter.
5) Add 45. mu.l of the above cell suspension plate to each well, 3000 cells per well.
6) The 384 well plates were plated in column 2 and 23 with 50. mu.l RPMI1640 + 10% FBS medium and 50. mu.l PBS around the plate.
7) The cells were incubated in an incubator (37 ℃ C., 5% CO2) for 4 hours.
8) Transfer 5. mu.l of 100. mu.g/ml JMT101 solution to cell plates H3-H11, I3-I11, J3-J11 and K3-K11.
9) After 3-fold dilution of 100. mu.g/ml JMT101 solution in 384-well plates, 5. mu.l JMT101 solution was transferred from dilution plates B1-B9 to cell plates L3-L11 and M3-M11.
10) Transfer 5. mu.l of complete medium to columns 12-22 of the cell plate.
11) Other compounds, Afatinib, Osimertinib, were added using Tecan HP D300 e.
12) The DMSO content in each well of the cell plate was 0.2% by volume.
13) Centrifuging at 800rpm for 30 s, placing in an incubator (37 deg.C, 5% CO)2) The culture was carried out for 72 hours.
14) The plate was read after 72 hours of drug incubation to obtain data.
Taking out the Cell-Titer Glo reagent and the Cell plate, standing for room temperature balance for 30min, separating 25 mu L of Cell-Titer Glo reagent in each hole into 384-hole plate cells by using a Multi-drop liquid separator, shaking at medium speed for 2min, centrifuging at 1000rpm for 1min, and stabilizing a luminescent signal for 10 min; envision read plate, Luminescence.
3. Data analysis and results
IC50The results were analyzed by XLFIT5 from IDBS corporation.
TABLE 1 IC in Ba/F3 EGFR-Exon 20V769_ D770insASV cell line50Value of
Medicine | Ab IC50μM | Re IC50μM |
Afatinib | 0.038 | 0.039 |
Afatinib+JMT101(10μg/ml) | 0.0052 | 0.0078 |
Osimertinib | 0.072 | 0.073 |
Osimertinib+JMT101(10μg/ml) | 0.016 | 0.028 |
JMT101 10μg/ml | >10 | >10 |
Note: ab IC50Namely absolute IC50Re IC, concentration of the compound at 50% inhibition50Namely opposite IC50The values are the drug concentrations corresponding to the half-times of the maximum and minimum inhibition rates.
The results show that the IC of the Ba/F3 EGFR-Exon 20V769_ D770insASV cells is when Afatinib or Osimetinib is combined with JMT101 monoclonal antibody50Obviously lower than the IC of the Afatinib or the Osimetinib when used alone50As shown in fig. 1 and 2.
In the cell proliferation experiment of the Ba/F3 EGFR-Exon 20V769_ D770insASV cell line, JMT101 is combined with afatinib or oxitinib, and the obvious synergistic effect is achieved.
Example 2 in vivo drug efficacy assessment
JMT101 was evaluated for in vivo efficacy in a BaF3 EGFR exon20V769_ D770insASV tumor subcutaneously transplanted female BALB/c nude mouse model, either as single drug or in combination with afatinib or oxitinib.
EGFR exon20V769_ D770insASV refers to the insertion of three amino acids ASV between amino acid V (Val, valine) at position 769 and amino acid D (Asp, aspartic acid) at position 770 of exon20 (exon 20) on EGFR.
1. Experimental Material
1.1 Experimental animals
Female, 6-8 week old, BALB/c nude mice, purchased from Shanghai Ling Chang Biotech, Inc.
1.2 drug and Positive control information
Afatinib, manufacturer is shanghai shengde pharmaceutical science and technology limited, lot number: SEND20190925
Oxitinib, manufactured by shanghai bi pharmaceutical technology ltd, lot No.: BMW262
JMT101, provided in shanghai jinmann biotechnology limited, lot number: 201906071
Specification: 100mg/10.0 mL/bottle.
2. Experimental methods and procedures
2.1 cell culture
BaF3 EGFR exon20V769_ D770insASV cell suspension culture under the conditions of adding 10% fetal calf serum and 1% double antibody into RPMI1640 medium, 37 deg.C, 5% CO2And (5) culturing. Routinely passaged 2 times a week. When the cells are maintained in exponential growth and the cell viability is greater than 95%, the cells are harvested, counted and seeded.
2.2 tumor cell inoculation
The right dorsal cervical part of each mouse was inoculated with 5X 10 supplemented with 50% Matrigel5BaF3 EGFR exon20V769_ D770insASV cells. And 5-digit ear tag number marking is carried out on the experimental animal at the same time of inoculation, and the ear tag number is used as a confirmation mark of the subsequent experiment. The average tumor volume reaches 101mm3The grouped administration is started.
2.3 preparation of the drug
TABLE 2 pharmaceutical compounding method
Note: afatinib and oxitinib are prepared twice every week, JMT101 injection is prepared for use, and all the medicines are stored at 4 ℃.
2.4 daily Observation of Experimental animals
The protocol was developed and any modifications were approved by the institute of laboratory animals administration and use committee (IACUC) of shanghai drug minkangde new drug development, ltd. The use and welfare of the experimental animals were performed in compliance with the provisions of the international committee for evaluation and approval of experimental animals (AAALAC). Animals are monitored daily for health and mortality, and routine examinations include observations of the effects of tumor growth and drug treatment on the animal's daily performance such as behavioral activity, food intake (visual only), appearance signs, or other abnormalities.
2.5 tumor measurement and Experimental indices
The experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. Tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
The tumor suppressor therapeutic effect of the compound was evaluated as TGI (%) or relative tumor proliferation rate T/C (%). TGI (%), reflecting the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) [ (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment of the solvent control group-average tumor volume at the start of treatment of the solvent control group) ] × 100.
Relative tumor proliferation rate T/C (%): the calculation formula is as follows: T/C (%) ═ TRTV/CRTV×100(TRTV: treatment group RTV; cRTV: negative control group RTV). Calculating Relative Tumor Volume (RTV) according to the measured tumor result, wherein the calculation formula is RTV [% ] [ (- ]) V [ (- ])t/V0X 100, wherein V0When administered in groups (i.e. d)0) Measurement of the mean tumor volume, VtMean tumor volume at a certain measurement, TRTVAnd CRTVThe same day data was taken.
After the experiment was completed, animals were euthanized and tumors were removed, and tumor weights were measured and T/C was calculatedweightPercent, TweightAnd CweightThe tumor weights of the administration group and the solvent control group are respectively expressed, and the calculation formula is as follows: T/Cweight(%)=TWtreatment/TWvehicle×100。
2.6 tumor weighing and photography
All mice were euthanized at day 14 post-dose. All tumors were weighed and photographed.
2.7 statistical analysis
Statistical analysis was performed to assess differences between groups based on data obtained at the end of the experiment. The T-test was used for comparison between the two groups. All data analyses were performed using GraphPad Prism software, with significant differences considered with p < 0.05.
3. Design of experiments
TABLE 3 in vivo efficacy protocol for drugs
Note: n number of mice per group
a. Administration volume: according to the weight of the mouse, 10 mu L/g
b. If the weight loss exceeds 15%, stopping the drug temporarily, and continuing the drug administration when the weight of the mice is recovered to be less than 10% of the weight loss
c, Vehicle: and (5) solvent control.
d.IV: intravenous injection, PO: oral administration, QD: once a day, BIW: twice a week
4. Results of the experiment
4.1 tumor volume
The change over time of the mean tumor volume of the female BALB/c nude mouse model with subcutaneously implanted BaF3 EGFR exon20V769_ D770insASV tumors is shown in table 4.
TABLE 4 tumor volumes at different time points for each group
Note that a. mean. + -. standard error
4.2 tumor growth curves and end-point tumor weights
Tumor growth curves, as well as tumor volume and tumor weight, are shown in fig. 3, 4, and 5.
4.3 evaluation index of antitumor Effect
The growth inhibition rate of the test drug on the female BALB/c nude mouse model of BaF3 EGFR exon20V769_ D770insASV tumor implanted subcutaneously was calculated based on the tumor volume at day 14 after the administration (table 5). Tumor weights for all groups at day 14 are shown in table 6.
TABLE 5 evaluation of tumor-inhibiting efficacy of test drugs on a female BALB/c nude mouse model implanted subcutaneously with BaF3 EGFR exon20V769_ D770insASV tumors (calculated based on tumor volume at day 14 after administration)
a. Mean ± standard error.
b. According to the formula T/C (%) ═ TRTV/CRTVX 100 and TGI (%) - [1- (T)i-T0)/(Ci-C0)]X 100.
c. P values of each administration group and the Vehicle group are analyzed by using one-tailed T test;
analyzing the p values of the JMT101 and Afatinib combined group and the Afatinib single group by using one-tailed T test;
JMT101 in combination with Osimetinib the p-values of the combination and the individual groups were analyzed by one-tailed T test analysis.
TABLE 6 tumor weights at the end of experiment (day 14) and statistical analysis
a. Mean ± standard error.
b. According to the formula T/Cweight(%)=TW treatment/TWvehicleX 100.
c. P values of each administration group and the Vehicle group are analyzed by using one-tailed T test;
analyzing the p values of the JMT101 and Afatinib combined group and the Afatinib single group by using one-tailed T test;
JMT101 in combination with Osimetinib group p values alone were analyzed using one-tailed T test.
5. Experimental results and discussion
In this experiment, we evaluated the in vivo efficacy of the test drug in a female BALB/c nude mouse model implanted subcutaneously with BaF3 EGFR exon20V769_ D770insASV tumors. Tumor volumes measured at different time points for each experimental group are shown in FIG. 4 and tables 4-5. The tumor weight statistics are shown in table 6 and fig. 5.
The tumor volume of the mice in the solvent control group reached 1595mm 14 days after the administration3. Compared with a solvent control group, the Afatinib is 15mg/kg (TV is 1129 mm)3,TGI=31.2%,T/C=68.6%,p<0.01), Osimetinib at 25mg/kg (TV 993 mm)3,TGI=40.3%,T/C=60.3%,p<0.001) inhibits tumor growth with a uniform degree of certainty, with statistical differences. JMT101 at 50mg/kg (TV 702 mm)3,TGI=59.8%,T/C=42.3%,p<0.001) has a more significant inhibiting effect on the growth of BaF3 EGFR exon20V769_ D770insASV tumors.
Combination of Afatinib and JMT101 (271 mm TV)3,TGI=88.6%,T/C=16.5%,p<0.001) has obvious inhibiting effect on the growth of BaF3 EGFR exon20V769_ D770insASV tumor, and has statistical difference (p is a statistical difference compared with the Afatinib single-drug treatment group<0.001). Combination of Osimertinib and JMT101 (TV 57 mm)3,TGI=103.0%,T/C=3.5%,p<0.001) has obvious inhibiting effect on the growth of BaF3 EGFR exon20V769_ D770insASV tumor, and has statistical difference (p) compared with the single-drug treatment group of the Osimetinib<0.001), it can be seen that the combination of JMT101 and Afatinib or Osimetinib has a very significant synergistic inhibition effect on the growth of BaF3 EGFR exon20V769_ D770insASV tumors compared with the single drug of JMT101, Afatinib or Osimetinib.
Example 3 clinical study
Clinical trial of JMT101 in combination with afatinib or oxitinib for treating stage III B or IV non-small cell lung cancer with EGFR (epidermal growth factor receptor) exon20 insertion mutation
Design of research
The test is a multicenter, open, dose escalating phase Ib clinical study on EGFR 20 exon insertion mutated iiib or IV NSCLC patients and aims to evaluate the safety, tolerability and efficacy of JMT101 in combination with afatinib or axitinib in the treatment of EGFR 20 exon insertion mutated iiib or IV non-small cell lung cancer patients.
Study of drugs:
JMT101, specification: 100mg/10.0 mL/bottle.
2. Afatinib maleate tablets, trade name gibareil, specification: 30mg, 40 mg.
3. Oxitinib mesylate tablet, trade name tirisate, specification: 80 mg.
The study was conducted in two phases, the first phase being a dose escalation study and the second phase being a dose escalation study.
First phase dose escalation study:
the study adopted a combination treatment scheme, which was divided into A, B groups based on the differences of the combination drugs, wherein group A was treated with JMT101 in combination with afatinib, and group B was treated with JMT101 in combination with oxitinib. Each group is divided into two queues according to different administration doses, and 4 queues are set up in total, specifically as follows:
the administration scheme is as follows:
a1 queue: JMT 1016 mg/kg, intravenous drip, Q2W + afatinib 30mg, oral, QD;
a2 queue: JMT 1016 mg/kg, intravenous drip, Q2W + afatinib 40mg, oral, QD;
b1 queue: JMT 1016 mg/kg, intravenous drip, Q2W + oxitinib 80mg, oral, QD;
b2 queue: JMT 1016 mg/kg, intravenous drip, Q2W + oxitinib 160mg, oral, QD.
Dose escalation follows the "3 +3 principle" and 3-6 subjects in each cohort were observed for safety and tolerability, with subjects with no clinical symptoms of central nervous system or meningeal metastases determined by the investigator to be in group a or B, with the remaining subjects taking the form of alternating groups in sequence between A, B groups.
Cohorts a1, B1, each cohort requiring at least 3 evaluable subjects, and if 3 subjects from cohorts a1 or B1 did not observe dose-limiting toxicity (DLT) during the evaluation window period (cycle 1, days 1-28), studies from higher dose cohorts (a2 or B2) can be initiated. If 1 of 3 subjects in a cohort presented with a DLT, 3 additional subjects in the same cohort (up to 6 evaluable subjects) were required, and if no DLT occurred in the additional 3 subjects, the cohort was continued with a higher dose cohort; if 1 or more of the 3 subjects supplemented or 2 or more of the 6 total subjects had developed DLT, the originally planned higher dose cohort would no longer be developed. If 2 of 3 subjects in a cohort presented with a DLT, the originally planned higher dose cohort was no longer developed.
If subjects in the initial dose cohort (A1 or B1) were not able to tolerate, then the investigator and the sponsor were required to discuss together whether to develop a cohort of JMT101 downregulated by one dose level (i.e., JMT 1014 mg/kg Q2W, with the drug combination dose unchanged) or to stay in the initial dose cohort and continue to group subjects until excessive toxicity occurred or the group trial was terminated early. If the dose group remains well-tolerated and safe when escalated to the pre-established highest dose cohort (a2 or B2), a co-discussion of investigators and sponsors can be made to determine whether to pursue a dose-level up-regulation of JMT101 (i.e., JMT 1018 mg/kg Q2W, with the drug combination dose unchanged).
The previous dose level of dose-limiting toxicity (DLT) dose level was defined as the Maximum Tolerated Dose (MTD) and was evaluated in the MTD dose group for at least 6 subjects.
Second phase dose escalation study:
and carrying out dose amplification research on the target dose queue according to the data such as safety, tolerance and effectiveness obtained in the first stage. All cohorts with good safety and tolerability in the first phase were selected (if greater than 4 cohorts, only 4 cohorts at most) and continued inclusion in a certain number of subjects (plus the dose escalation phase subjects, no more than 12) to further explore safety, tolerability, pharmacokinetic profile and antitumor activity. Subjects with no clinical symptoms of CNS or meningeal metastases were selected by the investigator for group A or group B, with the remaining subjects in the order of their cohorts between the cohorts.
All subjects above, with the treatment period taking every 4 weeks (28 days) as a treatment cycle, continued until one of the following events occurred: disease progression, intolerance of toxicity, subject withdrawal required, or subject not considering the subject can no longer benefit from treatment, first responder.
During the treatment period, safety check is carried out according to the requirement of a scheme, and tumor curative effect evaluation is carried out once at the end of the 1 st cycle and every two cycles (3 rd cycle and 5 th cycle) (for example, tumor-related symptoms are aggravated, and researchers think that the time for tumor evaluation is necessary and can be shortened). After the subjects had finished the last trial drug administration, they should be followed up for survival every 8 weeks, adverse events that still existed at the end of the study visit.
DLT is defined as: one or more of the following toxic reactions occurring within cycle 1 (days 1-28) of study initiation of administration and judged to be reasonably relevant (relevant, likely relevant and likely relevant) to the study drug:
(1) non-hematologic toxicity:
a grade 4 rash or a grade 3 rash causing discontinuance of the drug for 4 weeks, or a grade 3 rash with severe infection.
Grade 4 diarrhea or grade 3 diarrhea that remained unrelieved after 2 weeks of withdrawal, or grade 3 diarrhea that reappears after appropriate supportive treatment.
Any grade 3 or more non-hematologic toxicity except rash, diarrhea (nausea/vomiting, constipation and electrolyte disturbances are still grade 3 or more after appropriate supportive treatment to be considered DLT).
Interstitial pneumonia or pulmonary fibrosis occurs.
(2) Hematological toxicity:
grade 4 neutropenia persists for more than 5 days.
Febrile neutropenia (ANC < 1.0X 10^9/L, body temperature up to 38.3 ℃ at a time (axillary temperature) or body temperature more than one hour longer than or equal to 38 ℃ at axillary temperature).
Grade 4 thrombocytopenia.
Grade 4 anemia (life threatening).
(3) Others judged that the toxic response of the study drug should be permanently discontinued.
All adverse events will be ranked according to the national cancer institute-standard of adverse event general terminology (NCI-CTCAE) version 5.0.
The test population:
and (3) inclusion standard:
1. the age is 18-75 years (inclusive) of the year of the week, with unlimited nature.
2. Histologically or cytologically confirmed stage iiib or IV NSCLC is necessary, not suitable for radical surgery or radiotherapy, and confirmed in patients with EGFR No. 20 exon insertion mutations (including repeat mutations), after primary or first-line treatment failure.
Reference is made to the international lung cancer TNM staging standard 7 th edition revision of NSCLC.
3. At least one measurable lesion exists at baseline that meets RECIST 1.1 standard definition.
ECOG performance status score: 0 or 1 point.
5. The expected survival time is more than or equal to 3 months.
6. Major organ and bone marrow function was within 7 days prior to treatment, meeting criteria listed in Table 7 (no blood transfusion, EPO, G-CSF, GM-CSF or other medical supportive treatment was received within 7 days prior to study drug administration):
TABLE 7 index criteria for organ and bone marrow function within 7 days before treatment
7. A fertile woman is negative in a blood pregnancy test within 7 days prior to the test screening; any male and female patient with fertility must agree to use an effective contraceptive method during the entire test period and within the second half of the test period at the end of the test. According to the judgment of the investigator, a patient is fertile by: he/she has biologically the ability to have children and normal sexual life. Female patients without fertility (i.e., meeting at least 1 of the following criteria):
has undergone hysterectomy or bilateral oophorectomy, or
Ovarian failure is medically confirmed, or is medically confirmed as post-menopause (with no pathological or physiological cause, at least 12 consecutive months of menopause).
8. Subjects had informed consent to the study prior to the trial and voluntarily signed a written informed consent form.
Exclusion criteria:
1. the EGFR monoclonal antibody targeted therapy has been received.
2. The study medicine is subjected to chemotherapy, biological treatment, targeted treatment, immunotherapy and other anti-tumor treatments within 4 weeks before the study medicine is used for the first time, wherein: orally administering the small molecule targeted drug 2 weeks before the study drug is first used or within 5 half-lives of known drugs (based on the long term); radiotherapy is within 2 weeks before the first use of study drug.
3. Other clinical study medications were received within 4 weeks prior to the first use of the study medication.
4. Major organ surgery (not including needle biopsy) or significant trauma occurred within 4 weeks prior to the first use of study drug.
5. Known hypersensitivity or intolerance to any component of the study protocol drug or its adjuvant.
6. Those who used potent or moderate inducers of CYP3A4, strong inducers and inhibitors of P-gp within 14 days prior to the first use of the study drug.
7. Adverse reactions of the prior anti-tumor treatment are not recovered to CTCAE grade 5.0 evaluation which is less than or equal to grade 1 (except toxicity of researchers such as alopecia and the like which judge no safety risk).
8. Central nervous system metastasis or meningeal metastasis with clinical symptoms.
9. There is a history of autoimmune disease, immunodeficiency disease, including HIV positive, or other acquired, congenital immunodeficiency disease, or a history of organ transplantation.
10. Active hepatitis B (hepatitis B virus titer > 1000 copies/ml or 200 IU/ml); hepatitis c virus, syphilis infection.
11. There is a history of serious cardiovascular disease, including but not limited to:
there is a complete left bundle branch block or a degree III atrioventricular block;
history of myocardial infarction, angioplasty, coronary artery bridging;
QT/QTc interval prolongation of the electrocardiogram at baseline (QTcF male >450ms, female >480 ms);
severe arrhythmia, and was judged by the investigator to have an effect on this trial;
baseline Echocardiography (ECHO) or multi-gated acquisition (MUGA) techniques showed a Left Ventricular Ejection Fraction (LVEF) of 50% or less;
heart failure, new york cardiology (NYHA) graded class II and above;
hypertension with poor control (BP 150/95mmHg or greater despite optimal treatment);
previous or current cardiomyopathy, and judged by the investigator to have an effect on the trial.
12. There is no way to swallow the drug orally, or there are conditions that are judged by researchers to severely affect gastrointestinal absorption.
13. Other malignancies have been diagnosed within 5 years prior to the first use of study drugs; except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or effectively resected carcinoma of the cervical and/or breast in situ.
14. There is a prior history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy, or any evidence of clinically active interstitial lung disease.
15. There is a history of other serious systemic diseases that researchers judge are not appropriate for patients to participate in clinical trials.
16. Alcohol or drug dependence is known.
17. There has been a well-established history of neurological or psychiatric disorders, including epilepsy or dementia.
18. Pregnant or lactating women.
19. The investigators considered the subjects to be unsuitable for participation in the present clinical study for other reasons.
Duration of the test:
the research comprises two stages, and the research flow of each stage mainly comprises screening, treatment, safety follow-up and survival follow-up. In the first phase up-dosing study, each subject will participate in approximately 6 months of study treatment, and 30 days (+ -3 days) after the end of treatment as prescribed by the last study protocol, subjects will receive a safety follow-up visit. This was followed by the survival follow-up portion of the study. Since the study did not clearly predict the number of specific subjects to be included at each study stage. In addition, the duration of the study may vary from subject to subject depending on whether subsequent treatment is required and the progression-free survival time. The duration of the entire study is therefore only a preliminary estimate, and will be approximately 3.5 years for subjects who completed the entire study from the first dose of test drug administration to the follow-up phase of survival.
Primary end point:
adverse events, physical examination, vital signs, laboratory examinations (including hematology, hematobiochemistry, urinalysis, blood clotting function, etc.), electrocardiograms.
Secondary endpoint:
1. the curative effect index is as follows: objective remission rate (ORR, assessed by IRC and investigator, respectively, according to RECIST 1.1 criteria), duration of remission (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS);
2. pharmacokinetic indexes are as follows: including but not limited to AUC0-t、AUC0-inf、Cmax、Tmax、t1/2And CL and the like;
3. drug-resistant and neutralizing antibody development;
4. tumor-associated biomarkers were explored and potential correlations between biomarkers and clinical outcomes were analyzed.
Sample size:
in total, a minimum of 12 subjects, a maximum of no more than 48 subjects, and a maximum of no more than 200 subjects after the protocol change were expected to be included in the group.
Statistical analysis:
analysis of population
Full analysis set (Full analysis set, FAS): all cases successfully grouped and used at least once study drug.
Protocol set (Per-protocol set, PPS): refers to the collection of cases meeting inclusion criteria, failing to meet exclusion criteria, completing a treatment regimen, i.e., the collection of all subjects who met the protocol, had good compliance, completed the prescribed treatment, and had no significant protocol deviation in the process.
Safety set (Safety set, SS): all subjects who contained at least 1 trial medication in all cases enrolled and who had a post-medication safety record were included in the safety analysis set.
DLT analysis set (DLT set): the DLT analysis set included all subjects in the DLT assessment period (1-28 d), subjects who completed the DLT assessment or who exited the trial early in the DLT assessment period due to adverse events (subjects who were not evaluable for DLT due to non-study drug dose tolerance would not be included in the DLT statistical sample). This analysis set will be used for analysis and aggregation of DLT events.
PK concentration set: at least 1 study drug treatment was received, and there were at least 1 subject with blood levels of study drug during the trial.
PK parameters analysis set: subjects who received at least 1 study drug treatment and were able to calculate the effective PK parameters for at least one study drug.
Immunogenicity analysis human cohorts: subjects who received at least 1 study drug treatment and had at least 1 sample of anti-drug antibodies.
Biomarker analysis set: subjects who received at least 1 study drug treatment and had at least 1 biomarker blood sample taken.
Statistical analysis method
General statistical principles
Statistical description of categorical variables expressed in terms of number of cases and percentages (%); the statistics of the continuous variables describe the number of use cases, the number of deletions, the mean, the standard deviation, the median, the lower quartile, the upper quartile, the minimum and the maximum. Unless otherwise stated, the confidence interval estimation of the parameters used 95% confidence intervals, assuming the test will use a two-sided test, with 0.05 as the test level.
Security analysis
Adverse events and adverse reactions:
analyzing adverse events and adverse reactions during medication period, and summarizing the number, the times and the percentage of adverse events, adverse reactions, test termination due to adverse events, death due to adverse events, serious adverse events and DLT events of all groups of subjects; comparisons between groups of incidence were made as necessary.
Performing Systematic Organ Classification (SOC) and Preferred Term (PT) coding on the adverse events and the adverse reactions according to a MedDRA dictionary, and counting the number, the times and the percentage of the adverse events and the adverse reactions according to the SOC/PT classification:
and (4) counting the number, the times and the percentage of adverse events and adverse reactions according to the SOC/PT and the severity classification. One subject's category of adverse events was counted only 1 time under the highest severity term within the same term (SOC or PT).
All adverse events (including those during non-drug periods), adverse events, severe adverse events, termination of study due to adverse event, death due to adverse event, specific attention adverse event, DLT event were individually tabulated.
Laboratory examination:
the statistical time points of the laboratory examination items comprise a base line, each visit time point after the base line and the last visit time point, and the measured values of the time points, the minimum value and the maximum value of the measured results after the base line, the last visit observed value and the change value of the last visit observed value relative to the base line are respectively counted according to the dose groups and the total.
And comparing the normal and abnormal change conditions of each index before and after the administration through a clinical judgment cross table before and after the administration.
A detailed list of the laboratory test indicators is listed by group.
Vital signs:
the statistical time points of the vital sign examination items comprise a baseline, each visit time point after the baseline and an early exit visit time point, the baseline, the visit time point after the baseline and the descriptive statistical results at the end of the research are counted according to groups and totals, and the normal abnormal change conditions (if applicable) of each index before and after the medicine is compared through a clinical judgment cross table before and after the medicine is taken.
Physical examination and electrocardiogram:
physical examination items: general, mucocutaneous, lymph nodes, head and neck, chest, abdomen, spine, musculoskeletal, nervous system and other sites. And comparing the normal abnormal change condition before and after the administration of each dosage group through a clinical judgment cross table before and after the administration of the medicament.
The electrocardiographic examination items include: heart rate, PR, QRS, QTc. And (4) carrying out statistical analysis according to dose groups and total statistics of a baseline, each visit time point after the baseline, the minimum value and the maximum value of the measurement result after the baseline, the last visit observation value and the change value of the comparison baseline. And comparing the normal abnormal change condition before and after the administration of each dosage group through a clinical judgment cross table before and after the administration of the medicament.
A detailed list of physical examinations and electrocardiographic examinations is listed by group.
And (3) effectiveness analysis:
objective remission rates will be judged according to RECIST v1.1 criteria and relevant evaluation results [ ORR: complete Remission (CR) + Partial Remission (PR), as assessed by IRC ], Disease Control Rate (DCR) (CR + PR + SD), Progression Free Survival (PFS), Overall Survival (OS).
The cases, percentages and 95% confidence intervals for ORR and DCR in each dose group and all subjects were calculated.
Median PFS, median OS and their 95% confidence intervals were estimated for all subjects and each dose group using the Kaplan-Meier method, and a survival plot was plotted.
Pharmacokinetic analysis:
(1) first phase dose escalation study
Analyzing the PK parameter analysis set data using a non-compartmental model to calculate a pharmacokinetic parameter for each subject, comprising: c after first administrationmax,AUC0-t,AUC0-inf,Tmax,Vz,t1/2,CL,%AUCextAfter multiple administrations Cmax,ss,Cmin,ss,AUC0-τ,AUC0-inf,Tmax,ss,Vss,t1/2,CL,Cav,ss,DF,Range,%AUCextAccumulation index R1ac=Cmax,ss/CmaxAccumulation index R2ac=AUC0-τ/AUC0-t. And calculating the mean and standard deviation of each parameter.
(2) Second phase dose escalation study
And sparse blood collection is carried out in the amplification stage, and the sparse blood collection is combined with other JMT101 concentration data to carry out population pharmacokinetic analysis.
Immunogenicity analysis:
the number of ADA, NABs positive cases and incidence were pooled for each dose group.
Biomarker analysis:
determining cut-off value according to the content of free DNA in plasma, determining low and high expression groups according to the cut-off value, estimating median PFS, median OS and 95% confidence interval thereof of all subjects and each dose group by adopting Kaplan-Meier method, and drawing a survival curve chart.
The test implementation state:
by 2021-2-22, 48 non-small cell lung cancer patients were enrolled in the study, with 10 cases in the a1 cohort, 4 cases in the a2 cohort, 9 cases in the B1 cohort, and 25 cases in the B2 cohort, with 1 case in each of the B1 and B2 cohorts, and the first efficacy assessment, i.e., shedding, was not obtained after dosing.
The results of the preliminary curative effect study:
1. analyzing a data set
Full analysis set (Full analysis set, FAS): all cases successfully grouped and used at least once study drug. FAS is used primarily for baseline and efficacy analysis. By 2021-2-22, in this experiment, there were a total of 48 cohorts for FAS in 4 cohorts, 10 cohorts for a1 (JMT101 in combination with afatinib 30mg), 4 cohorts for a2 (JMT101 in combination with afatinib 40mg), 9 cohorts for B1 (JMT101 in combination with axitinib 80mg), and 25 cohorts for B2 (JMT101 in combination with axitinib 160 mg).
Protocol set (Per-protocol set, PPS): refers to the collection of subjects who meet inclusion criteria, do not meet exclusion criteria, complete a treatment regimen, i.e., the collection of all subjects who meet a test regimen, have good compliance, complete a prescribed treatment regimen, and have no significant deviation from the regimen in the process. This trial is ongoing and does not ultimately discuss which subjects are unable to be enrolled in the PPS pool, so PPS is not involved in the efficacy data analysis.
2. Important demographic and baseline characteristics
Of 48 subjects in the FAS group, 16 total men accounted for 33.3% and 32 total women accounted for 66.7%; the minimum age is 26 years, the maximum age is 74 years, and the median age is 59 years; the histopathological types are adenocarcinoma, the clinical stages are stage IV when the cancer is grouped, and the number of patients with combined brain metastases in each group is about half. 13 cases were treated initially, and 35 cases were treated before the first line and above. There were 32 previous patients who received at least one systemic chemotherapy, with cohort 6 in B1 and 14 in B2.
B2 of the 25 cohorts, 15 (60%) were female and 10 (40%) were male; the minimum age is 36 years, the maximum age is 74 years, and the median age is 60 years; all are stage IV adenocarcinoma; 40% (10) cases were treated initially, 60% (15) cases had received first line and above treatment, 56% (14) cases had received at least one systemic chemotherapy; 56% (14) cases were combined with brain metastases.
3. Analysis of efficacy
The efficacy analysis was performed on the FAS set, 46 patients with at least one efficacy evaluation after baseline in 48 subjects, and 1 patient with no efficacy evaluation data in the remaining 2 subjects, which are in the queue of B1 and B2, respectively, were the first efficacy evaluation after no administration was obtained, i.e., dropped. Because the IRC evaluation data are relatively lagged, the curative effect analysis is the evaluation data of researchers. Preliminary data cleaning has been performed on the efficacy data of this study as follows.
3.1 Objective Remission Rate (ORR) and Disease Control Rate (DCR)
In FAS set, a1 queue: partial Remission (PR)3 cases, Stable Disease (SD)6 cases, Progressive Disease (PD)1 case, Objective Remission Rate (ORR) of 30.0% (3/10), Disease Control Rate (DCR) of 90% (9/10); a2 queue: partial Remission (PR)0, Stable Disease (SD)3, Progressive Disease (PD)0, unevaluated (NE)1 (cutoff time not until first efficacy assessment time), Objective Remission Rate (ORR) 0, Disease Control Rate (DCR) 75% (3/4); b1 queue: partial Remission (PR)3 cases, Stable Disease (SD)5 cases, Progressive Disease (PD)0 cases, unevaluated (NE)1 cases (shedding), Objective Remission Rate (ORR) of 33.3% (3/9), Disease Control Rate (DCR) of 88.9% (8/9); b2 queue: 11 cases of Partial Remission (PR), 12 cases of Stable Disease (SD), 1 case of disease Progression (PD) (newly added bone metastasis lesion, efficacy of target lesion evaluated as PR), 1 case of non-evaluation (NE) (shedding), Objective Remission Rate (ORR) of 44.0% (11/25), and Disease Control Rate (DCR) of 92.0% (23/25).
TABLE 8 Objective remission/disease control Rate (investigator evaluation)
Data set: FAS
Note: ORR is objective remission rate, DCR is disease control rate, CR is complete remission, PR is partial remission, SD is stable disease, PD is disease progression, NE is not assessed, BOR is optimal time point response, and the table above counts as unidentified CR and PR because many subjects have not yet been evaluated for secondary tumor efficacy. A1 queue 3 cases PR in 1 case confirmed, 1 case unconfirmed (PD), 1 case not confirmed evaluation of curative effect; b1 queue 3 cases PR, 2 cases confirmed, 1 case has not carried on the curative effect confirmation evaluation; b2 queue 11 PR cases, 9 confirmed, 2 not yet evaluated for efficacy confirmation.
Note: ORR ═ CR + PR
Note: DCR ═ CR + PR + SD
Note: CI represents the confidence interval, 95% CI employs the Clopper-Pearson method
Note: efficacy was assessed by investigators according to RECIST v1.1
3.2 Progression Free Survival (PFS)
The study was ongoing, with 34 (70.8%) of 48 subjects remaining on dosing from the first subject group to a data cutoff of less than 8 months. Therefore, the PFS data of the curative effect analysis is not mature and is only used as a primary supplementary reference.
In the FAS set, the median PFS in the A1 cohort was 4.6 months (95% CI: 1.02-NR), the median PFS in the A2 cohort was not reached (95% CI: 2.73-NR), the median PFS in the B1 cohort was 4.6 months (95% CI: 2.73-NR), and the median PFS in the B2 cohort was not reached (95% CI: 2.50-NR).
Table 9 PFS analysis (investigator evaluation) dataset: FAS
Item | A1(N=10) | A2(N=4) | Group A (N ═ 14) | B1(N=9) | B2(N=25) | Group B (N ═ 34) |
Progression-free survival (month) | ||||||
|
10 | 4 | 14 | 9 | 25 | 34 |
Number of events n (%) | 4(40.0) | 1(25.0) | 5(35.7) | 3(33.3) | 3(12.0) | 6(17.6) |
Number of deletions n (%) | 6(60.0) | 3(75.0) | 9(64.3) | 6(66.7) | 22(88.0) | 28(82.4) |
Kaplan- |
||||||
50%(95%CI) | 4.6(1.02~.) | .(2.73~.) | 4.6(2.73~.) | 2.8(2.79~.) | .(2.50~.) | 2.9(2.76~.) |
Note: progression Free Survival (PFS) is defined as the time from the start of the study drug to the first recording of disease Progression (PD) or death from any cause. PFS (month) ═ (PFS event or deletion date-first medication date +1)/30.4375
3.3 subgroup analysis
The ORR, DCR and PFS were subjected to subgroup analysis based on the number of lines of antitumor therapy in each cohort or group of subjects and whether or not they had combined brain metastases. The target indication to be developed is locally advanced or metastatic NSCLC carrying an exon insertion mutation of EGFR 20 that has been subjected to at least one systemic chemotherapy. The treatment protocol to be used for the key trial was the B2 cohort treatment protocol: JMT 1016 mg/kg Q2W in combination with oxitinib 160mg QD.
3.3.1 first line treatment effectiveness data
Based on the results of the ORR, DCR and PFS subgroup analyses, in the study subjects treated in combination as first line therapy (i.e., treatment naive patients when included in the group), the efficacy profile for each group was: group a total of 1 case, the efficacy was Partial Remission (PR), both Objective Remission Rate (ORR) and Disease Control Rate (DCR) were 100.0% (1/1), PFS was not reached; group B consisted of 12 cases, Partial Remission (PR)5 cases, Stable Disease (SD)6 cases, disease Progression (PD)1 case (newly added bone metastasis, target lesion efficacy evaluation PR), Objective Remission Rate (ORR) 41.7% (5/12), Disease Control Rate (DCR) 91.2% (11/12), PFS not yet achieved. In a total of 48 subjects, the FAS was collected, 13 subjects were treated at the first line, 6 subjects were partially alleviated (PR), 6 subjects were Stable (SD), 1 subject was treated (new bone metastasis lesion, efficacy of target lesion was evaluated as PR), Objective Remission Rate (ORR) was 46.2% (6/13), Disease Control Rate (DCR) was 92.3% (12/13), and PFS was not achieved.
The first-line treatment efficacy data show that the combined treatment of the research has obvious efficacy in the initial treatment of patients, the efficacy is equivalent to that of the first-line standard treatment platinum-containing dual-drug chemotherapy, and the overall ORR value is increased compared with that of the platinum-containing dual-drug chemotherapy.
3.3.2 Targeted indications (which have previously received at least one systemic chemotherapy) effectiveness data
According to the results of the ORR and DCR subgroup analyses, in locally advanced or metastatic NSCLC carrying an EGFR exon20 insertion mutation, which had received at least one systemic chemotherapy for the target indication, the efficacy profile of each cohort was: the A1 queue has 9 cases: partial Remission (PR)2 cases, Stable Disease (SD)6 cases, Progressive Disease (PD)1 case, Objective Remission Rate (ORR) of 22.2% (2/9), Disease Control Rate (DCR) of 88.9% (8/9); the A2 queue has 3 cases: partial Remission (PR)0, Stable Disease (SD)2, Progressive Disease (PD)0, unevaluated (NE)1 (cutoff time not until first efficacy assessment time), Objective Remission Rate (ORR) 0, Disease Control Rate (DCR) 66.7% (2/3); total 6 cases of B1 queue: partial Remission (PR)0, Stable Disease (SD)5, Progressive Disease (PD)0, unevaluated (NE)1 (shedding), Objective Remission Rate (ORR) 0(0/6), Disease Control Rate (DCR) 83.3% (5/6); b2 queue has 14 cases: partial Remission (PR)7 cases, Stable Disease (SD)6 cases, Progressive Disease (PD)0 cases, unevaluated (NE)1 cases (shedding), Objective Remission Rate (ORR) of 50.0% (7/14), Disease Control Rate (DCR) of 92.9% (13/14). In subjects who had received at least one systemic chemotherapy, the objective remission rate in the B2 cohort was numerically significantly higher than in the other cohorts, as well as the rate of disease control.
Based on the PFS subgroup analysis, 12 cases were counted in group A (combined Afatinib-treated group) with a median PFS of 4.6 months (95% CI: 2.73-NR) in subjects who had received at least one systemic chemotherapy for the target indication. Group B (combined Oxitinib treatment group) consisted of 20 cases with a median PFS of 2.9 months (95% CI: 2.76-NR). The B1 cohort had 6 cases, the median PFS was 2.8 months (95% CI: 2.79-NR), the B2 cohort had 14 cases, and the median PFS had not yet been reached (95% CI: 2.76-NR).
The target indication has obvious curative effect under the condition that a key experiment is planned to adopt a treatment scheme and dosage
Based on the results of the subgroup analysis, the therapeutic efficacy of the critical trial in the case of locally advanced or metastatic NSCLC with EGFR exon20 insertion mutation, which had received at least one systemic chemotherapy for the target indication (i.e., the B2 cohort), under the treatment regimen and dose to be used was: in total, 14 subjects, 7 Partial Remission (PR), of which 5 were confirmed PR, the remaining 2 PR subjects had not been evaluated for efficacy confirmation, 6 Stable Disease (SD), 0 Progressive Disease (PD), 1 unevaluated (NE) (shedding before first efficacy evaluation), 50.0% Objective Remission Rate (ORR) (7/14, 95% CI: 0.230-0.770), 92.9% Disease Control Rate (DCR) (13/14, 95% CI: 0.661-0.998), and median PFS had not reached (95% CI: 2.76-NR). Cohort B2 Objective Remission Rate (ORR) was 53.8% (7/13, 95% CI: 0.251-0.808) in 13 subjects with at least one treatment evaluation. Compared with the current standard treatment docetaxel single-drug efficacy (Journal of Clinical Oncology,2000,18(12): 2354-. Compared with ORR 25% (4/12) (Journal of Clinical Oncology,2020,38(15_ suppl): 9513) -9513) reported in the literature for Clinical study of EGFR exon20ins NSCLC treated by first-line therapy and ORR 0% (0/9) (Lung cancer. 2021Feb; 152:39-48.) reported in the literature for Clinical study of EGFR exon20ins NSCLC treated by 160mg single drug, JMT101 and 160mg combination treatment protocol of Austrocic have significant synergy.
TABLE 10 ORR/DCR subgroup analysis- (investigator evaluation)
Data set: FAS
Note: ORR is the rate of objective remission and DCR is the rate of disease control
Note: ORR ═ CR + PR where CR or PR is unidentified CR or PR
Note: DCR ═ CR + PR + SD
Note: CI represents the confidence interval, 95% CI employs the Clopper-Pearson method
Note: efficacy was assessed by IRC according to RECIST v 1.1.
TABLE 11 PFS analysis subgroup analysis (investigator evaluation) _ group A
Data set: FAS
TABLE 12 PFS analysis subgroup analysis (investigator evaluation) _ group B
Data set: FAS
TABLE 13 PFS analysis subgroup analysis (investigator evaluation) _ B1 cohort
Data set: FAS
TABLE 14 PFS analysis subgroup analysis (investigator evaluation) _ B2 cohort
Data set: FAS
3.4 conclusion of therapeutic Effect
Preliminary efficacy data from this study showed that objective remission rate in the FAS set was significantly higher in the B group (combined axitinib cohort) than in the a group (combined afatinib cohort), with the highest in the B2 cohort and an ORR of 44.0%. Disease control rate group B was numerically higher than group a, with the highest data in the B2 cohort and a DCR of 92.0%. The median PFS of both the a1 and B1 queues were 4.6 months, and the median PFS of both the a2 and B2 queues had not yet been reached. Subgroup analysis suggests that first-line treatment efficacy data indicates that the combined treatment of the study has obvious efficacy in patients treated initially, the efficacy is equivalent to that of first-line standard treatment platinum-containing dual-drug chemotherapy, and the overall ORR value is higher than that of platinum-containing dual-drug chemotherapy.
In subjects who had received systemic chemotherapy at least once in the target population, the objective remission rate in the B2 cohort, which is the combination regimen and dose to be used in the key study, was numerically significantly higher than in the other cohorts, as well as the disease control rate was numerically higher than in the other cohorts: objective Remission Rate (ORR) of 50.0%, Disease Control Rate (DCR) of 92.9%; cohort B2 Objective Remission Rate (ORR) was 53.8% (7/13, 95% CI: 0.251-0.808) in 13 subjects with at least one treatment evaluation. The median PFS has not yet been reached. Preliminary curative effect data of the research show that JMT101 is orally administered together with Oxitinib 160mg QD in an intravenous drip administration mode of 6mg/kg Q2W, the curative effect of treating the local advanced or metastatic NSCLC carrying the EGFR 20 exon insertion mutation which has received at least one systemic chemotherapy is remarkable, and the potential of the treatment is remarkably superior to that of the existing treatment.
The important terms:
evaluation of therapeutic effect on target lesions:
complete Remission (CR): all target lesions disappeared and the minor axis value of any pathological lymph node (whether or not it was a target lesion) must be <10 mm.
Partial Remission (PR): the sum of all target lesion diameters is reduced by at least 30% relative to the baseline state total diameter.
Disease Progression (PD): the sum of all target lesion diameters was increased by at least 20% with reference to the smallest total lesion diameter during the study (including the sum of the lesion diameters at baseline, if it is the minimum). In addition, in addition to a relative increase of 20% in the sum of the diameters, the absolute value of the sum must also be increased by at least 5mm (note: the appearance of one or more new lesions may also be considered as progression of the disease).
Disease Stability (SD): with the sum of the minimum lesion diameters as a reference in the study, lesion shrinkage neither met PR, lesion increase nor PD.
Objective Remission Rate (ORR): defined as the proportion of Complete Remission (CR) or Partial Remission (PR) (i.e., CR + PR) at the optimal time point as assessed by the independent review board (IRC) according to the therapeutic efficacy assessment criteria (RECIST v1.1) for solid tumors from the time of study drug use initiation to study withdrawal.
Disease Control Rate (DCR): defined as the proportion of CR, PR, Stable Disease (SD) (i.e., CR + PR + SD) response at the optimal time point as assessed by RECIST 1.1 criteria from the time study drug use is initiated to the time study withdrawal.
Progression Free Survival (PFS): defined as the time between the start of study drug use and the date of first recorded disease Progression (PD) or death, depending on which occurred first.
Overall Survival (OS): defined as the time between the start of the study drug use and the death date for any cause.
Sequence listing
<110> Shanghai Jinmant Biotech Co., Ltd
<120> combination drug containing anti-EGFR antibody or fragment thereof
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<170> SIPOSequenceListing 1.0
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Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Asp Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
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Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
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Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
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Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Asp Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
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Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
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Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Trp Pro Thr
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Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 14
<211> 466
<212> PRT
<213> Artificial sequence (unknown sequence)
<400> 14
Met Arg Ala Trp Ile Phe Phe Leu Leu Cys Leu Ala Gly Arg Ala Leu
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Ala Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser
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Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn
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Tyr Asp Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
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Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe
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Thr Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
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Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Ala Leu Asp Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln
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Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
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Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
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Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
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Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
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Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
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Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
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Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
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Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
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Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
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Gly Lys
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Ala Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro
20 25 30
Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Thr
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Asn Ile His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu
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Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn Glu Trp Pro
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Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
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Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
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Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
165 170 175
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
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Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
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Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
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Ser Phe Asn Arg Gly Glu Cys
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Claims (10)
1. A combination comprising an anti-EGFR antibody or fragment thereof and an EGFR small molecule tyrosine kinase inhibitor for simultaneous or separate administration for the prevention or treatment of cancer.
2. The combination according to claim 1, wherein the cancer is selected from lung cancer, gastric cancer, liver cancer, breast cancer, esophageal cancer, kidney cancer, bladder cancer, cervical cancer, colorectal cancer, lymphatic cancer, preferably lung cancer; the lung cancer is selected from small cell carcinoma and non-small cell lung cancer, preferably non-small cell carcinoma, and more preferably EGFR exon20ins non-small cell lung cancer.
3. The combination of any one of claims 1 to 2, wherein the anti-EGFR antibody or fragment thereof comprises the heavy chain CDR1 sequence of SEQ ID No. 1 or 2, the heavy chain CDR2 sequence of SEQ ID No. 3 and the heavy chain CDR3 sequence of SEQ ID No. 4, SEQ ID No. 5 or SEQ ID No. 6, and/or the light chain CDR1 sequence of SEQ ID No. 7, the light chain CDR2 sequence of SEQ ID No. 8 and the light chain CDR3 sequence of SEQ ID No. 9, SEQ ID No. 10 and SEQ ID No. 11; preferably, the anti-EGFR antibody or fragment thereof comprises the heavy chain CDR1 sequence shown in SEQ ID NO. 1, the heavy chain CDR2 sequence shown in SEQ ID NO. 3 and the heavy chain CDR3 sequence shown in SEQ ID NO. 4, and/or the light chain CDR1 sequence shown in SEQ ID NO. 7, the light chain CDR2 sequence shown in SEQ ID NO. 8 and the light chain CDR3 sequence shown in SEQ ID NO. 9; more preferably, the anti-EGFR antibody or fragment thereof comprises the heavy chain variable region shown in SEQ ID NO. 12 and/or the light chain variable region shown in SEQ ID NO. 13.
4. A method according to any one of claims 1 to 3The combination according to item (1), wherein the anti-EGFR antibody fragment is selected from the group consisting of a single chain antibody (scFv), a chimeric antibody, a diabody, a scFv-Fc bivalent molecule, a dAb, a Fab fragment, a Fab 'fragment, a Fv and a F (ab')2And (3) fragment.
5. The combination according to any one of claims 1 to 3, wherein the anti-EGFR antibody is a full-length antibody; further, the anti-EGFR antibody includes a human IgG1 heavy chain constant region and/or a human light chain kappa constant region.
6. The combination of any one of claims 1 to 5, wherein the anti-EGFR antibody or fragment thereof is humanized.
7. The combination according to any one of claims 1 to 6, wherein the EGFR small molecule tyrosine kinase inhibitor is preferably Afatinib or a salt thereof or oxitinib or a salt thereof.
8. Use of a combination according to any one of claims 1 to 7 in the manufacture of a medicament for the prophylaxis or treatment of cancer.
9. Use according to claim 8, wherein the cancer is selected from lung cancer, gastric cancer, liver cancer, breast cancer, esophageal cancer, kidney cancer, bladder cancer, cervical cancer, colorectal cancer, lymphatic cancer, preferably lung cancer; the lung cancer is selected from small cell carcinoma and non-small cell lung cancer, preferably non-small cell carcinoma, and more preferably EGFR exon20ins non-small cell lung cancer.
10. Use of a combination according to any one of claims 1 to 7 for the preparation of a medicament for the prophylactic or second-line and above treatment of non-small cell lung cancer carrying EGFR exon20ins that has been subjected to at least one systemic chemotherapy.
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CN103772504A (en) * | 2012-10-17 | 2014-05-07 | 上海津曼特生物科技有限公司 | Humanized antibody against epidermal growth factor receptor and application thereof |
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EP3176183A1 (en) * | 2015-12-02 | 2017-06-07 | Yeda Research and Development Co. Ltd | Compositions and methods for treating cancer not resistant to a tyrosine kinase inhibitor (tki) |
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