Date of approval: 07/06/2011
Revision date: 01 November 2011
April 16, 2012
July 10, 2013
September 18, 2013
October 22, 2014
Ectetinib Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Ectetinib Hydrochloride Tablets
Trade name: Kemena®
English name: Icotinib Hydrochloride Tablets
Hanyu Pinyin：Yansuan Aiketini Pian
Ingredients
The main ingredient of this product is Ectatinib Hydrochloride.
Chemical name: 4-[(3-ethynylphenyl)amino]-quinazolinolo[6,7-b]-12-crown-4 hydrochloride.
Chemical structure formula.
Molecular formula: C22H21N3O4-HCl
Molecular weight: 427.88
Properties
This product is brown-red film-coated tablets, appearing off-white after removing the coating.
Indications
This product is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitive mutations in the epidermal growth factor receptor (EGFR) gene. (See [Clinical Trials])
This product alone may be tried for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen, with prior chemotherapy being primarily platinum-based combination chemotherapy.
This product is not recommended for patients with EGFR wild-type non-small cell lung cancer.
Specification】125mg/tablet.
Dosage]
The recommended dose of this product is 125mg (1 tablet) three times a day. Take orally, on an empty stomach or with food. High-calorie foods may significantly increase the absorption of the drug (see [clinical trials]).
Dose adjustment: When patients experience intolerable rash, diarrhea, or other adverse reactions, dosing may be suspended (1-2 weeks) until symptoms resolve or disappear; subsequently, the dose of 125 mg (1 tablet) three times daily may be resumed; patients with mildly elevated transaminases (ALT [alanine aminotransferase] and AST [aspartate aminotransferase] below 100 IU/L) may continue to take the drug but should be Patients with elevated aminotransferases (ALT and AST above 100 IU/L) may be suspended and closely monitored, and may resume dosing when aminotransferases recover (ALT and AST are below 100 IU/L, or normal) (see [Adverse Reactions]).
Analysis of blood concentration data in patients of different ages and genders showed that the blood concentration of patients was not affected by age and gender, so dose adjustment according to age and gender is not recommended.
Special Populations: No clinical studies are available for children or pregnant women. Clinical studies for elderly patients and patients with hepatic and renal insufficiency are in progress.
[Adverse Reactions].
The safety assessment of erlotinib is based on safety information collected in Phase III clinical trials supporting registration (ICOGEN) and post-marketing Phase IV clinical trials. Overall, erlotinib was well tolerated.
Phase III Clinical Trials
The ICOGEN study was a randomized, double-blind, controlled, multicenter study in patients with locally advanced (stage IIIB or IV) or metastatic non-small cell lung cancer (NSCLC) who had failed one or two prior chemotherapies. 399 subjects were randomized 1:1 to receive either erlotinib hydrochloride tablets 125 mg three times daily or gefitinib 150 mg once daily administration. The most frequently reported adverse reactions were rash (40.0%), diarrhea (18.5%) and elevated transaminases (8.0%), the vast majority of which were grade I-II, generally seen within 1-3 weeks of dosing, usually reversible and resolved spontaneously without specific management. Table 1 lists the common adverse reactions reported in the ICOGEN trial and their severity.
Table 1 ICOGEN study adverse reactions (≥5.0%)
Body Organ System
Adverse reactions Ectetinib group N=200 Gefitinib group N=199 NCI-CTC classification NCI-CTC classification All classifications % Grade III % Grade IV % All classifications % Grade III % Grade IV % Skin and its adnexa
Rash
40.0
0.5
0
49.2
1.0
0 Digestive system
Diarrhea
Mouth ulcers
Nausea
18.5
3.5
3.0
0
0
0.5
0
0
0
27.6
5.0
5.0
2.0
0
0
0
0
0 Metabolism and nutrition
Elevated transaminases
abnormal liver function
8.0
4.5
0.5
0.5
0.5
0
12.6
5.0
1.0
0
0
0 Blood and lymphatic system
Leukocyte decline 3.0 005.0 00
Another single-arm, multicenter, phase III extension study (BD-IC-IV01) with the same study population and dosing regimen as the ICOGEN study in the erlotinib group. A total of 127 patients entered the safety analysis set, with an overall adverse reaction rate of 48.8%. The most common adverse reactions were rash (26.0%), elevated transaminases (14.2%) and diarrhea (11.8%), consistent with the results of the ICOGEN study.
Post-marketing Phase IV clinical trial
The trial was a multicenter, single-arm, open phase IV clinical observational study with safety observation as the primary objective. it was formally initiated in August 2011, and as of October 28, 2013, safety information was collected from 6673 evaluable patients. The overall incidence of adverse reactions was 31.0%, and the very common adverse reaction was rash with an incidence of 17.0%, and the common adverse reaction was diarrhea with an incidence of 8.3%; all were mainly mild; the incidence of Grade III adverse reactions was 0.5%, and no Grade IV adverse reactions were observed, and a total of 19 patients discontinued the drug due to intolerable toxic side effects.
Table 2 Phase IV study adverse reactions (≥5.0%)
Adverse drug reactions NCI-CTC classification All classification % Grade III % Grade IV % Not available Skin and its accessories
Rash
17.0
0.13
0
0.03 Digestive system
Diarrhea
8.30.1200.21 Safety data were collected from 219 patients with EGFR mutations treated with erlotinib in first line in the post-marketing phase IV study. The incidence of adverse reactions was 46.6%, with the most common adverse reactions being rash (25.6%), diarrhea (9.1%), and elevated transaminases (3.2%). Adverse reactions were predominantly mild to moderate, with Grade III and above adverse reactions being rare. Similar to the overall population.
All clinical studies
The following are the adverse reactions observed in patients receiving ectetinib 125 mg monotherapy in all clinical studies.
The incidence of adverse reactions was graded according to the following terms: very common (≥1/10); common (≥1/100,<1/10); rare (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); and very rare (<1/10,000), including individual case reports.
The very common adverse reactions in these studies are shown in Table 1, and the classification of other frequency adverse reactions is summarized below.
Digestive system abnormalities
Common adverse reactions: including loss of appetite, vomiting and abdominal pain.
Rare adverse reactions: constipation, oral mucositis, dry stools, black stools, dry mouth, oral erythema, vomiting of blood, gastric ulcers and gastric distention.
Rare adverse reactions: ulcerative stomatitis.
Abnormal renal function
Rare adverse reactions: elevated urine protein, proteinuria, elevated creatinine, elevated urine leukocytes, abnormal urine routine, elevated urea nitrogen, painful urination, renal impairment.
Abnormal liver function
Rare adverse reactions: elevated bilirubin and elevated glutamyl transpeptidase (GGT).
Respiratory and chest abnormalities
Rare adverse reactions: cough, nasal dryness, epistaxis, dyspnea, hemoptysis, upper respiratory tract infection, intranasal crusting, lung infection, coughing, runny nose, hoarseness, chest discomfort, pleural effusion, interstitial lung disease (ILD).
Skin and subcutaneous tissue abnormalities
Rare adverse reactions: nail fungus, pruritus, dry skin, peeling skin, hand-foot syndrome, nail changes, skin cracking, hair loss, skin reactions, acne, infections in the danger triangle of the face, skin blisters, chapped extremities, and hyperpigmentation.
Eye disorders
Rare adverse reactions: eye pain and dry eye disease.
Hematologic abnormalities
Rare adverse reactions: decreased white blood cells, neutropenia, decreased hemoglobin, decreased platelets, decreased red blood cells, anemia, and bruising on the tongue.
Rare adverse reactions: leukocytosis.
Nervous System
Rare adverse reactions: disorientation and drowsiness.
Laboratory test abnormalities
Rare adverse reactions: hyponatremia and elevated blood glucose.
Other
Rare adverse reactions: pain, malaise (Class I-III), fever, dizziness, chest tightness, hypersensitivity, numbness of extremities, headache, altered taste, lower extremity edema, pericardial effusion, palpitations, tooth loss, swelling of extremities, impotence, hypotension, and numbness of fingertips.
Interstitial pneumonia (ILD)
ILD is a rare but serious adverse effect of EGFR-TKI-based drug therapy. Two patients with suspected ILD were seen in the phase I clinical study of erlotinib. One of them had further pathological examination, which ruled out ILD and confirmed disease progression, unrelated to the study drug; the other case could not be ruled out yet because pathological examination results were not obtained. There were no patients with ILD in the phase III trial (ICOGEN) in either the erlotinib or gefitinib arm; one case of interstitial pneumonia occurred in the single-arm phase III study, and the patient died 1 month after discontinuation; three cases of interstitial pneumonia (ILD) were reported in the post-marketing phase IV study; two improved after discontinuation and aggressive hormonal therapy, and one patient died 5 months after discontinuation. All patients with ILD had received at least 4 cycles of prior chemotherapy, and the diagnosis was confirmed by CT, with a minimum of 1 week after dosing and a maximum of 4 months after dosing.
[Contraindicated].
Persons with known severe hypersensitivity reactions to the active substance or to any of the excipients of the product.
Precautions】
1. The incidence of interstitial lung disease in Eastern populations treated with gefitinib and erlotinib has been reported in the literature to be 2-3% and 1-2%, respectively. In the ICOGEN clinical study supporting registration, no interstitial lung disease was observed in either arm. One and three cases of interstitial pneumonia were reported in the single-arm Phase III extension study and the Phase IV study, respectively (see [Adverse Reactions] for details). Patients with interstitial lung disease typically present with acute dyspnea with cough, low-grade fever, respiratory distress, and arterial oxygen desaturation. The symptoms are rapidly progressive, severe, and can result in patient death. Radiological examination often shows pulmonary infiltrates or interstitial hairy glassy shadows.
The treating physician should closely monitor for signs of the development of interstitial lung disease during treatment, and if the patient develops a new acute attack or progressive worsening of dyspnea or cough, treatment with this product should be interrupted and relevant investigations should be performed immediately. When interstitial lung disease is confirmed, the drug should be discontinued and the patient should be treated accordingly.
High risk factors for developing interstitial lung disease have been reported in the literature to include: smoking, poor physical status (PS ≥ 2), ≤ 50% coverage of normal lung tissue on CT scan, short time to diagnosis of non-small cell lung cancer (<6 months), pre-existing interstitial pneumonia, older age (≥ 55 years), and concomitant cardiac disease. Caution should be exercised in the treatment of patients with these high-risk factors.
2. Transient elevations of hepatic transaminases have been observed in a small number of patients in clinical trials and post-marketing use (see [Adverse Reactions]). Therefore, periodic liver function checks are recommended, especially during the first month of drug administration. This product should be used with caution in patients with mildly elevated hepatic transaminases. Patients with moderate or higher aminotransferase elevation need to suspend the drug and monitor aminotransferase until the aminotransferase elevation subsides or disappears to resume the drug (see [DOSAGE AND ADMINISTRATION]).
3. Seek immediate medical attention for new acute attacks or progressive worsening of dyspnea, cough; severe or persistent diarrhea, nausea, vomiting or anorexia.
4. Effects on the ability to drive and operate machinery: During the treatment of this product, symptoms of weakness may occur, so caution should be exercised when taking the drug while driving or operating machinery.
Pregnant women and nursing mothers
1. There is no clinical data on the use of this product in women during pregnancy. Animal studies have shown that when high doses of erlotinib, which can be toxic to the mother, are given during the organogenesis period, an increased rate of stillbirths and bruising on the back of the neck or around the eyes of some fetuses was observed in rats. No abnormalities in appearance, visceral malformations, or rate of ossification were observed in rats.
Women of childbearing potential are advised to avoid pregnancy during treatment with this product.
2. Use during lactation: There are no clinical data on the use of this product in lactating females. It is not known whether erlotinib or its metabolites are secreted into human milk.
Nursing mothers are advised to stop breastfeeding during treatment with this product.
Pediatric Use]
There is no information on the safety and efficacy of this product in pediatric or adolescent patients under the age of 18 years, so its use is not recommended.
Geriatric use]
Pharmacokinetic analysis of 25 patients receiving 125 mg Tid doses in a phase I/II study showed no significant difference in blood concentrations between patients aged 65 years or older compared to patients under 65 years, with plasma trough concentrations of 1115.8 ± 413.2 ng/ml (> 65 years) and 917.0 ± 286.3 ng/ml (> 65 years) after multiple consecutive doses, respectively. ml (<65 years), with no significant difference between them (P=0.38). In addition, plasma trough concentrations were not significantly different between the sexes (P=0.56), 1191.9 ± 588.4 ng/ml in men and 936.7 ± 132.2 ng/ml in women.
19.0% of subjects in the phase III ICOGEN study were older than 65 years. The mean duration of dosing (months) was slightly higher in patients over 65 years of age compared to subjects under 65 years of age (5.0 months vs 4.0 months), and the incidence of rash (28.9% vs 43.2%), diarrhea (15.8% vs 22.8%) and transaminase elevation (0.0% vs 6.2%) was slightly lower than in the latter group, while the efficacy was close (ORR: 28.9% vs. 27.2%; DCR: 78.9% vs. 74.1%). However, none of them were statistically different, and the results are shown in Table 3.
Table 3 Comparison of dosing and efficacy in subjects over 65 years of age versus those under 65 years of age in the ICOGEN study
Indicator Age ³ 65 years Age <65 years P-value Proportion (number of cases) 19% (38) 81% (162) Duration of medication (months) #5.04.00.80* Objective remission rate (ORR) 28.9% 27.2% 0.82* Disease control rate (DCR) 78.9% 74.1% 0.53**: none of the statistical tests were significant.
#: The average duration of medication for patients, as each patient had a certain amount of medication per day, were 3 tablets, which were basically equivalent to the dose of medication for patients.
[Drug Interactions].
No formal drug interaction studies have been conducted with exatinib. In vitro tests have shown that exatinib is mainly metabolized by CYP2C19 and CYP3A4 of the cytochrome P-450 monooxygenase system, with significant inhibition of CYP2C9 and CYP3A4, and no significant induction of rat liver P450 enzymes was found.
Therefore, attention should be paid to potential drug interactions when combined with the following drugs: CYP2C19 inducers (e.g. amiloride) and CYP3A4 inducers (e.g. nefcillin, nevirapine, phenobarbital and rifamycins); CYP2C9 substrates (e.g. warfarin) and CYP3A4 substrates (e.g. benzodiazepines, calcium channel blockers, nateglinide, ergometrine derivatives, etc.).
Drug overdose]
There are no reports of overdose of ectatinib hydrochloride, and there is no specific treatment for overdose of ectatinib. The incidence and severity of adverse reactions (mainly rash and diarrhea) increased with dose in phase I clinical trials in patients taking doses up to 625 mg three times daily. Symptomatic treatment should be given for adverse reactions caused by overdose, especially for severe diarrhea.
Clinical trials]
Phase III clinical trial (ICOGEN)
A randomized, double-blind, double-modeled, parallel-controlled (1:1), multicenter phase III clinical trial (ICOGEN) conducted at 27 clinical research institutions in China evaluated the efficacy and safety of ectatinib and gefitinib monotherapy in patients with locally advanced (stage IIIB or IV) or metastatic non-small cell lung cancer (NSCLC) who had received one or two prior chemotherapies. Subjects were randomly assigned 1:1 to receive either ectetinib 125 mg three times daily or gefitinib 250 mg once daily orally until disease progression or intolerable toxicity occurred. The primary efficacy metric was progression-free survival (PFS), and secondary efficacy metrics included overall survival (OS), objective remission rate (ORR), disease control rate (DCR), time to disease progression (TTP), and quality of life (HRQoL).
A comparative analysis of the subjects’ demographic data and disease characteristics is shown in Table 4.
Table 4 Comparison of demographic data and disease characteristics of subjects between the two groups of the ICOGEN trial
Group Intergroup comparison Ectetinib group (%) Gefitinib group (%) (N=199) (N=196) P-value Gender Female 82 (41.2) 85 (43.4) 0.6846* Male 117 (58.8) 111 (56.6) Total 199 (100.0) 196 (100.0) Age (years) Median 57.057.0 NA range 28.0~ 75.034.0~76.0 Whether smoking history No 101(50.8)102(52.0)0.8406* Yes 98(49.2)94(48.0) Pathological diagnosis Squamous carcinoma 34(17.1)36(18.4)0.4620* Adenocarcinoma 149(74.9)150(76.5) Adenosquamous carcinoma 6(3.0)1(0.5) Large cell carcinoma 2(1.0)2(1.0) Other 8(4.0)7(3.6) History of chemotherapy was 199(100.0)196(100.0) Number of NA chemotherapy regimens 1 126(63.3)107(54.6) 0.0733* 2 72(36.2)89(45.4) 3 1(0.5)0 ECOG PS score 0.038 ( 19.1 )36 ( 18.4)0.7438*1.0135( 67.8)139( 70.9) 2.026 ( 13.1)21 ( 10.7) * Statistical tests were not significant.
Efficacy analysis was performed in all subjects who met the inclusion criteria, were randomized to the group, and had used the trial drug at least once (FAS set). For the primary efficacy measure, PFS, the risk ratio (HR) for erlotinib/gefitinib was 0.835 (0.667-1.046), with an upper 95% CI of 1.046 below the study’s non-inferiority threshold of 1.14, confirming that erlotinib was not inferior to gefitinib. No other efficacy evaluation indicators were statistically different between the two groups. Details are shown in Table 5 and and Figure 1.
Table 5 Comparison of efficacy between the erlotinib and gefitinib groups (FAS set)
Group
Indicator Exatinib group
N=199 Gefitinib group
N=196P value Objective remission rate (ORR) 27.6% 27.2% 0.91* Disease control rate (DCR) 75.4% 74.9% 0.90* Median PFS (months) (95% CI) 4.6 (3.5 to 6.3) 3.4 (2.3 to 3.8) 0.13* Median TTP (months) (95% CI) 5.2 (3.6 to 6.6) 3.7 (2.5~5.0) 0.65*Median OS (months) (95% CI) #13.3 (11.1~16.2) 13.9 (11.4~17.3) 0.57** Statistical tests were not significant.
# Statistics as of December 2011 data.
Figure 1 Survival analysis graph of PFS in the erlotinib and gefitinib groups (Kaplan-Meier)
The ICOGEN study used the Scorpions ARMS method of DxS to test a sample of 134 subjects for EGFR mutations, 68 in the erlotinib group and 66 in the gefitinib group. 29 patients in the erlotinib group tested positive, 27 reached the endpoint event, and the median PFS was 7.8 months (234 days); of the 39 patients in the wild-type, 37 Of the 39 patients with wild-type, 37 reached the endpoint event with a median PFS of 2.3 months (70 days), which was significantly higher in the mutant than in the wild-type (P=0.0053).
Analysis of OS data showed that 20 of 29 patients in the EGFR mutant group reached the endpoint event with a median OS of 20.9 months (627 days), while 36 of 39 patients in the wild-type group reached the endpoint event with a median OS of 7.8 months (233 days), which was higher in the mutant than in the wild-type group (P=0.0028).
Among patients in the EGFR mutant group, the best outcome was PR in 18 patients with an objective response rate (ORR) of 62.1% (18/29), while in the 39 patients with wild type, the best outcome was PR in 2 patients with an objective response rate (ORR) of 5.1% (2/39), which was significantly higher in mutant than wild type (P<.0001). A comparison of the efficacy of mutant and wild type is detailed in Table 6.
Table 6 Comparison of the efficacy of wild type and mutant type in the ectetinib group
Metrics Mutant Wild-type P Objective remission rate (ORR) 62.1% 5.1%<.0001 Median PFS (months) (95% CI) 7.8 (3.7 to 12.2) 2.3 (1.1 to 3.6) 0.0053 Median OS (months) (95% CI) 20.9 (16.2 to 27.2) 7.8 (5.6 to 13.3) The results of the 0.0028 COX proportional risk model analysis showed that the 4 factors of smoking or not, PS score, pathology type, and disease stage all had a significant effect on PFS: smoking/non-smoking risk ratio of 1.317 (1.043-1.662, P=0.021), PS score 2/PS score 0-1 risk ratio of 1.657 (1.102, 2.49 , P=0.015), adenocarcinoma/non-adenocarcinoma risk ratio was 0.601 (0.455, 0.794, P=0.0003), and stage IV/IIIB risk ratio was 1.45 (1.062, 1.98, P=0.019). It is suggested that stage IIIB patients who are non-smokers, have a histological type of adenocarcinoma, and are in better physical condition are more likely to benefit from treatment with this product.
Single-arm Phase III extension study
In a multicenter, single-arm, prospective phase III clinical trial, similar in design to the ICOGEN study protocol except that there was no control arm, patients enrolled in 15 study centers were treated with exatinib 125 mg three times daily in an expanded sample size to observe its effect on patients with locally advanced or metastatic NSCLC who had received one or two prior chemotherapy regimens (at least one of which contained platinum). metastatic NSCLC patients who had received one or two prior chemotherapy regimens (one of which contained platinum). The key efficacy indicators were the same as in the ICOGEN study.
A total of 128 subjects were enrolled in the study, 124 patients were evaluable, with a median progression-free survival (PFS) of 5.0 months, median time to disease progression (TTP) of 5.4 months, objective remission rate (ORR) of 25.8%, disease control rate (DCR) of 67.7%, and overall survival (OS) time data still being collected. All efficacy evaluation indicators were consistent with or better than the results of the ICOGEN study, and subgroup analysis showed more significant benefit of erlotinib hydrochloride in specific populations (adenocarcinoma, women and non-smoking patients).
Phase IV Study
A post-marketing, multi-center, single-arm, open phase IV clinical study was conducted to observe the safety of patients after dosing in an expanded sample, including adverse reactions/events, vital signs and laboratory tests. Secondary study metrics were objective remission rate (ORR) and disease control rate (DCR).
The study collected information from 7338 patients, of which 6673 (90.9%) patients received efficacy and safety evaluation information, and their baseline characteristics are shown in Table 7.
Table 7 Post-marketing phase IV study patients at baseline
Classification Number of cases (%) Age <705289 (72.1) ≥702023 (27.6) Unknown 44 (0.6) Gender Male 3705 (50.5) Female 3633 (49.5) Pathological staging Adenocarcinoma 5836 (79.5) Non-adenocarcinoma 1130 (15.4) Other 372 (5.1) Clinical stage Stage IIIB 534 (7.3) Stage IV 6497 (88.5) Stage IIIA 106 (1.4) Other 201 (2.7) Smoking status Smoking 892 (12.2) Non-smoking 4922 (67.1) Smoking quit 1514 (20.6) Not available 10 (0.1) Number of lines of Kemenah treatment First line 1607 (21.9) Second line 3346 (45.6) Third line and above 2264 (30.9 ) not available117 (1.6) Mutation detection
N=1369 wild type 343 (25.1) mutant 19-Del494 (48.1) 21-L858R485 (47.3) other 47 (4.5) Among 6673 patients evaluable for efficacy, ORR was 32.5% (2167/6673) and DCR was 81.9% (5462/6673), with overall efficacy results slightly higher than ICOGEN study.
Among 814 patients with EGFR mutation, the ORR was 51.8% (422/814) and DCR was 92.9% (756/814), and among 255 wild-type patients, the ORR was 20.4% (52/255) and DCR was 76.1% (194/255), with significantly better efficacy in mutant patients than in wild-type patients.
First-line treatment of NSCLC
There were 219 EGFR-mutated, previously untreated patients with locally advanced or metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) in the post-marketing phase IV study who received exatinib 125 mg administered orally three times daily until disease progression or intolerable toxicity occurred. The demographic data and disease characteristics of the subjects are shown in Table 8.
Table 8 Demographic data and disease characteristics of subjects receiving first-line treatment with erlotinib hydrochloride
Classification Number of cases (%) Age <70162 (74.0) ≥7057 (26.0) Gender Male 82 (37.4) Female 137 (62.6) Pathological staging Adenocarcinoma 205 (93.6) Non-adenocarcinoma 8 (6.0) Not investigated 1 (0.4) Clinical stage Stage IIIB 16 (7.3) Stage IV 180 (82.2) Other 23 (10.5) Not available 2 (0.9 ) Smoking status Smoking 17 (7.8) Non-smoking 178 (81.3) Smoking quit 24 (11.0) Mutation type 21-L858R103 (47.0) 19-Del112 (51.1) Other 4 (1.9) PS score 0-1 194 (88.6) 2 21 (9.6) 3 3 (1.4) Not available 1 (0.5) Of 219 cases 133 subjects achieved tumor remission (CR/PR) and 75 patients had stable disease (SD) with an ORR of 60.7% (133/219) and a DCR of 95.0% (208/219), which was superior to the rest of the population, as shown in Table 9.
Table 9 Comparison of the efficacy of subjects receiving each line of treatment with erlotinib hydrochloride
Number of treatment lines Number of cases CRPRSDPD/death ORRDCR First-line EGFR mutated patients 2191132751160.7%95.0% Second-line 30859964151158132.2%81.2% Third-line and above 209018567110540028.0%80.9% Other*85037301843.5% 78.8% Overall 66735316102808107830.0%80.6%* Other includes patients receiving adjuvant and neoadjuvant therapy with exatinib hydrochloride and maintenance therapy. Due to the limited number of cases, conclusions need to be interpreted with caution.
[Pharmacology and Toxicology].
Pharmacological effects
Ectatinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The half effective concentration (IC50) of ectatinib to inhibit EGFR tyrosine kinase activity is 5 nM. Among the 88 kinases tested, 500 nM concentration of ectatinib only inhibited EGFR wild type and its mutant type significantly, but not other kinases, suggesting that ectatinib is a highly selective EGFR kinase inhibitor. In vitro studies and animal studies have shown that exatinib can inhibit the proliferation of various human tumor cell lines.
Toxicological studies
Data from preclinical studies indicate that ectatinib has a favorable safety profile, with reversible toxic effects such as transaminase excursions in the 60 mg/kg dose group seen only in dogs administered multiple times for 270 days.
No genotoxic effects were observed in mutation analysis (bacterial and in vitro mammalian cells), in vitro mammalian cells and in vivo mouse micronucleus assays. Ectatinib had no significant effects on reproductive function and reproductive system in male mice and no teratogenic effects in Wistar rats. Ectatinib inhibited reproductive function and embryonic growth and development in pregnant rats. At high doses (300 mg/kg), it caused a significant decrease in live fetal rate and fetal weight, and bruising on the back of the neck or around the eyes in some fetal rats, but no abnormalities in appearance, visceral malformations or ossification rates were observed.
No carcinogenicity study has been conducted.
Pharmacokinetics]
The pharmacokinetics of this product was studied in 22 healthy subjects and 71 patients with advanced NSCLC at different doses of single and multiple doses, respectively; it was rapidly absorbed and widely distributed after oral administration. The mean plasma half-life was approximately 6 hours, with no significant difference between healthy volunteers and cancer patients. Exatinib reached steady-state after 7-11 days of oral administration with no significant accumulation.
Absorption
Pharmacokinetic results showed rapid absorption of exatinib after a single oral dose of 125 mg in subjects with advanced NSCLC, with a peak time of 0.5-4 hr, a mean Cmax of 1400±547.52 ng/mL, and a mean AUC0-last of 3.4±1.21 hrmg/L, respectively.
Subjects received 125 mg orally three times daily for 7-11 days to reach steady-state. After reaching steady state, subjects reached peak time after a single dose of 125 mg at 1.5hr (0-4hr); mean Cmax was 1860±721.84 ng/mL; mean AUC0-last was 5.89±2.21 hrmg/L, respectively.
In healthy subjects high calorie foods significantly increased their absorption with 59% increase in Cmax and 79% increase in AUC. However, the effect of food on absorption was not compared in patients with advanced NSCLC.
Distribution
Subjects received a single oral dose of 150 mg (fasting dose) followed by a mean CL/F of 13.3±4.78 L/hr; mean Vz/F of 115±63.26 L. The cumulative renal excretion Ae24h in the 125 mg dose group was 0.234±0.1 mg. The percentage excretion of exatinib via urine in the 125 mg dose group was 0.187%.
After reaching steady state, the cumulative renal excretion Ae8h was 0.544±0.31 mg and the percentage of urinary excretion of execitinib was 0.436% after a single dose of 125 mg in subjects.
The mean volume of distribution for fasting and postprandial doses of exatinib was 355 L and 113 L, respectively, suggesting a wide distribution in the tissues.
Metabolism
In vitro tests have shown that exatinib is metabolized mainly by CYP2C19 and CYP3A4 of the cytochrome P-450 monooxygenase system, with significant inhibition of CYP2C9 and CYP3A4, and no significant induction of rat liver P450 enzymes was detected. (See [Drug Interactions]).
The main organ of metabolism for erlotinib in humans is the liver, with 6 major metabolic pathways and 29 metabolites, including 19 phase I metabolites and 10 phase II metabolites. Ectatinib undergoes a multi-step oxidation reaction during phase I. The phase I metabolism reactions are the side chain ring opening and post-ring opening oxidation of the 4-hydroxyquinoline ring, the 15-position hydroxylation of the phenylethynyl ring and the 14-position acetylene oxidation, and the phase II metabolism reaction is the glucuronide and sulfuric acid binding reaction.
The total Cmax of the five major metabolites was 19%-29% of the original drug at single administration, and their half-lives ranged from 5-16.5 hours. After multiple sequential doses, the five major metabolites reached steady state in about 7 days with a combined Cmax and AUC of 18% of the original drug and a total trough concentration equivalent to 29% of the original drug.
Elimination
The total plasma clearance of exatinib was 46 L/hr and 22 L/hr after fasting and postprandial administration, respectively. excretion was mainly via feces and urine (79.5%), with fecal excretion accounting for 74.7%. The excreted form was mainly metabolites (81.4%,) and the prototype drug accounted for 18.6%.
Pharmacokinetic studies have not been conducted for special populations such as the elderly, children, and those with hepatic and renal impairment.
Storage】Store under shade and seal.
Package】Aluminum-plastic aluminum packaging. 21 tablets per plate, 1 plate per box.
Expiration date】48 months.
Execution Standard】YBH02142011
Approval Number】State Drug Administration H20110061
Manufacturer】 Company name: Beda Pharmaceutical Co.
Production Address: No. 589 Hongfeng Road, Yuhang Economic Development Zone, Hangzhou, Zhejiang Province
Postal Code: 311100
Telephone number: 0571-86130357
Fax number: 0571-86130266
Web address: http://www.bettapharma.com.cn