Approval Date.
Pyrrolitinib Maleate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Pyrrolitinib Maleate Tablets
English name: Pyrotinib Maleate Tablets
Hanyu Pinyin: Malaisuan Biluotini Pian
Trade Name: Ariane
Ingredients
The active ingredient of this product is pyrrolotinib maleate, whose chemical name is: (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide maleate (1:2).
Its chemical structure formula is
Molecular formula: C32H31ClN6O3-2C4H4O4
Molecular weight: 815.22
Properties
This product is a film-coated tablet, which shows yellow after removing the coating.
Indications
This product, in combination with capecitabine, is indicated for the treatment of patients with recurrent or metastatic breast cancer who are epidermal growth factor receptor 2 (HER2)-positive and have not previously received or have received trastuzumab. Patients should have received anthracycline- or paclitaxel-based chemotherapy prior to the use of this product.
This indication was granted conditional approval based on the results of a Phase II clinical trial that included 128 patients with recurrent or metastatic breast cancer who had or had not received prior trastuzumab treatment. Full approval for this indication will be contingent upon ongoing confirmatory trials confirming the clinical benefit of this product in this population. (See [Clinical Trials])
Specification
C32H31ClN6O3 (1) 80 mg; (2) 160 mg.
Dosage]
This product should be started under the guidance of a physician experienced in antineoplastic drug therapy.
HER2 test
Prior to treatment with this product, HER2 status should be tested using a well-validated assay. Pyrrolitinib should only be used in HER2-positive breast cancer patients.
Recommended dose and dosing method
The recommended dose of pyrrolitinib is 400 mg orally once daily, within 30 minutes after a meal, at the same time each day. It is to be taken continuously in cycles of 21 days. If a patient misses a dose of pyrrolitinib on a particular day, there is no need to make up the dose; the next dose will be taken as scheduled.
The recommended dose of capecitabine is 1000 mg/m2 orally twice daily (once in the morning and once in the evening, for a total daily dose of 2000 mg/m2), taken within 30 minutes of a meal (once in the morning with pyrrolizidine), for 14 days with a 7-day break, in 21-day cycles. For more information on the dosing of capecitabine, please refer to the drug insert for capecitabine.
Therapeutic dosing should be continued until disease progression or intolerable toxic effects occur.
Dose Adjustments
Dose Adjustment Due to Adverse Drug Reactions
If patients experience adverse reactions during treatment, they may be managed by suspending dosing, reducing the dose, or discontinuing dosing. For diarrhea and skin reactions, symptomatic treatment can be administered first and closely observed. Adverse reactions that do not resolve after symptomatic treatment may be managed by suspending dosing or/and dose downward adjustment of pyrrolitinib/capecitabine with reference to the principles in Table 1. For dose adjustment of pyrrolitinib, see Table 2. Management of common adverse reactions to pyrrolitinib can be referred to [Precautions]. Some persistent Grade 2 adverse events may also require multiple dose suspensions and/or downward dose adjustments. Each suspension should be resumed after the adverse event has returned to grade 0 to 1 and the complication has resolved. The duration of each consecutive suspension and the cumulative duration of each cycle of pyrrolizidine should not exceed 14 days. If a subject continues to have a clinically uncontrollable (i.e., persistent after ≤14 days of clinical treatment or observation with ≥2 occurrences) adverse event after suspension of dosing, the dose should be reduced by one level upon resumption of dosing after suspension, with pyrrolitinib allowing a minimum dose reduction of 240 mg.
Capecitabine should be dose delayed and/or dose reduced according to its current instructions.
Table 1 Recommended dose adjustment principles for pyrrolitinib/capecitabine in response to adverse reactions
Adverse reactions CTCAE level Dose adjustment for resumption of pyrrolitinib after dosing regimen adjustment suspension* Diarrhea grade 3.
or grade 1-2 with co-morbidities
(≥ grade 2 nausea or vomiting, fever, neutropenia, blood in stool, or dehydration) may be suspended first, and if the suspension of capecitabine is not relieved after 3 days, pyrrolizidine will be suspended again until resumption to ≤ grade 1 first time: 400mg
Second: 320mg Grade 4 permanent discontinuation – Hand-foot syndrome Grade 2 can be suspended first capecitabine, if 14 days after suspension of capecitabine still can not be remitted, then suspend pyrrolizidine until the return to ≤ 1 grade first: 400mg
Second: 320mg Grade 3 may be suspended with capecitabine and then pyrrolizidine until recovery to ≤ grade 1 if no remission after 14 days of capecitabine suspension, and permanently discontinue 320mg if recovery does not occur in 14 days with severe progressive maculopapular rash or mucosal lesions – Left ventricular ejection fraction ( LVEF) decline LVEF below the lower limit of normal, or onset of ≥ grade 2 (at least 10-19% decline from baseline) LVEF decline with associated symptoms Suspend pyrrolizidine until LVEF returns to within normal range and less than 10% decline from baseline, with associated symptoms recovering 320mg Abnormal liver function ≥ grade 3 ALT or AST elevation (>5×ULN) with total bilirubin ≤2×ULN suspend pyrrolitinib until recovery to ≤Grade 1 first time: 400mg
Second: 320mg ≥ Grade 2 ALT or AST elevation (>3×ULN) with total bilirubin elevation >2×ULN Permanent discontinuation – Other adverse reactions ≥ Grade 2 non-hematologic adverse reactions and ≥ Grade 3 hematologic adverse reactions Suspend pyrrolizidine or capecitabine until return to ≤ Grade 1 First. 400 mg
Second: 320 mg graded according to CTCAE version 4.0. CTCAE = Common Terminology Criteria for Adverse Events. AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal.
*Refer to Table 2 for dose reduction methodology.
Table 2 Pyrrolitinib dose adjustment method
Dose recommendation Initial dose 400 mg/day First reduced dose 320 mg/day Second reduced dose 240 mg/day **Limited efficacy data for 240 mg/day dose. If further dose reductions below 240 mg/day are required, treatment will be discontinued.
Dose adjustment due to drug interactions
In vivo studies evaluating interactions between pyrrolitinib and other drugs have not been conducted. If strong inhibitors of CYP3A4 and strong inducers are combined, close monitoring should be performed and dose adjustment should be considered in conjunction with clinical observations (see [Drug Interactions]).
Use in Special Populations
Pediatric Patients.
Data on the safety and efficacy of pyrrolizidine in pediatric and adolescent patients under the age of 18 years are lacking. It is not recommended for use in patients under 18 years of age.
Geriatric Patients.
There is limited experience with the use of pyrrolitinib in elderly patients and it is recommended that in patients over 65 years of age, caution should be exercised and dose adjustments made under the direction of a physician based on clinical conditions and laboratory test indices (see [Geriatric Use]).
Patients with hepatic insufficiency.
No studies have been conducted in patients with hepatic insufficiency, and no dosing data are available for patients with moderate or severe hepatic insufficiency. Because this product is primarily metabolized by the liver, it is not recommended for patients with moderate to severe hepatic insufficiency.
Patients with renal insufficiency.
No pharmacokinetic studies have been conducted in patients with renal insufficiency and no clinical dosing data are available for patients with renal insufficiency. Less than 2% of the radioactivity was excreted via urine after oral administration of [14C]-labeled pyrrolitinib in healthy subjects, suggesting that renal insufficiency has a very limited effect on pyrrolitinib exposure. Patients with renal insufficiency should still use pyrrolitinib with caution under the guidance of a physician.
[Adverse Reactions].
This instruction describes the adverse reactions observed in clinical trials judged to be possibly caused by pyrrolitinib and their approximate incidence. Because conditions in each clinical trial vary, the incidence of adverse reactions observed in one clinical trial cannot be directly compared with the incidence of adverse reactions observed in another clinical trial and may not fully reflect the actual incidence in clinical practice.
Overview of safety characteristics
Approximately 564 subjects received pyrrolitinib alone or in combination in clinical trials, of which approximately 186 were treated with pyrrolitinib in a blinded fashion. The safety of pyrrolitinib alone or in combination with capecitabine at different doses has been evaluated in 131 subjects with HER2-positive recurrent or metastatic breast cancer. The safety data for the combination of pyrrolitinib and capecitabine were primarily derived from a phase II trial including 128 patients with recurrent or metastatic breast cancer previously treated and not treated with trastuzumab, in which 65 patients were treated with pyrrolitinib (400 mg once daily) in combination with capecitabine (1000 mg/m2 twice daily) for a median drug duration The median duration of drug treatment was 14.3 months (range: February-21 months). 10.8% of patients were on reduced doses of pyrrolitinib.
The most common (≥20%) adverse reactions to pyrrolitinib in combination with capecitabine in the treatment of recurrent or metastatic breast cancer included gastrointestinal reactions (diarrhea, vomiting, nausea, oral mucositis), skin reactions (hand-foot syndrome), metabolic and nutritional disorders (decreased appetite, hypokalemia), hepatobiliary disorders (elevated bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST AST), systemic reactions (malaise), and hematologic disorders (decreased hemoglobin, decreased white blood cell count, decreased neutrophil count). Grade 3 or higher adverse reactions with an incidence>2% included hand-foot syndrome, diarrhea, lowered white blood cells, lowered neutrophils, lowered hemoglobin, vomiting, rash, hypertriglyceridemia, and elevated AST. Adverse reactions that led to interruption or discontinuation of pyrrolitinib therapy included diarrhea, vomiting, elevated ALT, and rash.
Adverse Reaction List
A randomized, open, controlled phase II clinical study compared the safety and efficacy of pyrrolitinib in combination with capecitabine and lapatinib in combination with capecitabine in HER2-positive recurrent or metastatic breast cancer treated with prior anthracycline- and paclitaxel-based chemotherapy (see [Clinical Trials]). Tables 3 and 4 show the incidence of ³10% of adverse reactions and ³10% of abnormal drug-related laboratory test values in the trial group during treatment from this study, respectively.
Table 3 Incidence of ³10% of adverse drug reactions* in phase II clinical studies
System organ classification
Preferred term Pyrrolitinib + Capecitabine
(N=65) Lapatinib + Capecitabine
(N=63) All classes
(%) Grade 3 and above
(%) All grades
(%) Grade 3 and above
(%) Gastrointestinal disorders Diarrhea 96.9 15.444.4 4.8 Vomiting 46.2 4.6 20.60 Nausea 38.51.5 20.6 0 Abdominal pain 12.30 7.9 0 Oral mucositis 29.2 1.5 25.4 1.6 Skin and subcutaneous tissue disorders Hand-foot syndrome 78.524.673.020.6 Pigmentation abnormalities 16.9 0 11.1 0 Rash 13.83.142.90 Metabolic and nutritional diseases Decreased appetite 32.31.5 6.30 Weight loss 12.304.80 Infectious and infectious diseases Upper respiratory tract infections 12.31.57.90 Systemic diseases and various reactions at the site of administration Weakness 20.01.5 14.3 0 Neurological diseases Dizziness 10.809.50 Respiratory, thoracic and mediastinal Cough 10.806.30* The table lists adverse events in Phase II clinical studies that were determined by the investigator to be “definitely related”, “probably related”, “probably unrelated”, or “undetermined” to pyrrolizidine in combination with capecitabine.
This table refers to NCI CTC AE version 4.0 for adverse reaction classification.
Rash includes adverse reactions reporting the preferred terms eczema, maculopapular rash, rash, maculopapular rash, herpes, acneiform dermatitis, and pustular rash.
Oral mucositis includes adverse reactions reported in clinical trials as oral mucositis and oral ulcers.
Table 4 Abnormal drug-related laboratory test values with an incidence of ³10% in phase II clinical studies
System organ classification
Preferred term Pyrrolitinib + Capecitabine
(N=65) Lapatinib + Capecitabine
(N=63) All grades
(%) Grade 3 and above
(%) All grades
(%) Grade 3 and above
(%) Reduced white blood cell count 46.26.2 33.31.6 Reduced neutrophil count 40.07.734.91.6 Reduced hemoglobin 32.34.69.51.6 Reduced platelet count* 9.201.60 Elevated bilirubin 32.30 49.24.8 Elevated ALT 32.3 1.5 27.01.6 Elevated AST 29.2 3.1 30.23.2 Elevated blood triglycerides 18.53.120.64.8 Decreased blood potassium 20.01.57.9 1.6 Decreased blood calcium 13.807.90 *Including decreased platelet count with an incidence of less than 10%
[Contraindicated].
Pyrrolitinib is contraindicated in persons with known hypersensitivity to pyrrolitinib or any of the components of this product.
Precautions】
Diarrhea: Diarrhea was the most common adverse reaction observed in clinical trials of pyrrolitinib. 96.9% of the phase II studies of pyrrolitinib in combination with capecitabine for the treatment of recurrent or metastatic breast cancer had diarrhea, mainly grade 1 to 2, with grade 3 diarrhea occurring in 15.4% of patients and no grade 4 or higher diarrhea reported. The first diarrhea occurred early, and the first diarrhea could occur on days 1-4 of drug administration in 75% of patients. Cycle 1 was the high incidence of grade 3 diarrhea, and about 50% of the first grade 3 diarrhea could occur on days 2-15 of drug administration. Diarrhea usually lasts for 2-3 days and can be controlled in the majority of cases with suspension or downward dose adjustment and symptomatic treatment. The median cumulative duration of recurrent diarrhea during treatment was 47 days. There was a decreasing trend in the incidence of overall diarrhea with increasing treatment cycles and no increasing trend in the occurrence of grade 3 diarrhea.
Patients should pay attention to changes in bowel movement characteristics and frequency during treatment and start antidiarrheal therapy with loperamide or montelukast as early as possible after the detection of unformed stools. In case of persistent grade 3 diarrhea, or grade 1-2 diarrhea with complications (³ grade 2 nausea, vomiting, fever, blood in stool, or dehydration), patients should contact their physician immediately and receive therapeutic instructions to start symptomatic treatment as soon as possible. Diarrhea may be managed according to dose adjustment guidelines after the occurrence of diarrhea, see [DOSAGE AND ADMINISTRATION]. Patients who experience frequent diarrhea during treatment should be alerted to the possibility of severe diarrhea.
Abnormal liver function: The incidence of abnormal liver function in phase II studies of pyrrolizidine in combination with capecitabine for the treatment of recurrent or metastatic breast cancer was 53.8% (35/65), as evidenced by elevated transaminases (including elevated AST and ALT), elevated bilirubin (including elevated total bilirubin, elevated conjugated bilirubin, and elevated unconjugated bilirubin), elevated alkaline phosphatase, and elevated gamma-glutamyl The liver function abnormalities of grade 4 and above were not reported. Liver function abnormalities may occur days or months after dosing, with the first occurrence in clinical trials occurring on average on day 41 (range: 8 – 335 days) after dosing, and only 7.7% of patients with grade 2 to 3 liver function abnormalities required dose suspension or dose adjustment of pyrrolizidine, and all recovered with dose suspension or adjustment. Liver injury due to pyrrolitinib (ALT or AST > 3 times the upper limit of normal and total bilirubin > 2 times the upper limit of normal) has not been observed in clinical trials at this time, but data on long-term exposure to pyrrolitinib in large populations are limited.
Liver function should be checked before starting pyrrolitinib therapy and should be monitored at least every 2 cycles (6 weeks) during treatment, including ALT, AST, alkaline phosphatase, and bilirubin, and more frequently if abnormal. Treatment should be discontinued if severe liver function abnormalities are detected. Moderate to severe hepatic insufficiency may be at risk of hepatotoxicity and is not recommended.
Skin reactions: Hand-foot syndrome (painful redness, blistering or rash on the palms and soles of the feet) is a common adverse reaction to pyrrolizidine and capecitabine and may interfere with daily life or work in severe cases. the incidence of hand-foot syndrome in phase II studies of pyrrolizidine in combination with capecitabine for the treatment of recurrent or metastatic breast cancer was 78.5% (51/65), mostly grade 1 to 2, with grade 3 incidence of 24.6% (16/65). If hand-foot syndrome occurs, patients should enhance daily skin care, use emollient creams or lubricants, keep the skin clean, avoid secondary infections, avoid pressure or friction, and use topical skin medications for symptomatic treatment under the guidance of physicians. The incidence of rash was 13.8% (9/65), with most rashes being grade 1 and grade 3 rash occurring in 3.1% (2/65). Note that there have been individual reports of serious cutaneous adverse reactions to similar drugs with the same mechanism of action, including erythema multiforme, Steven-Johnson syndrome (SJS), and toxic epidermolysis bullosa (TEN).
If grade 2 or greater cutaneous adverse reactions occur, they should be managed according to dose adjustment guidelines, see [Dosage].
Hematology: In phase II studies, the incidence of neutropenia, hemoglobin reduction, and platelet reduction with pyrrolizidine in combination with capecitabine for the treatment of recurrent or metastatic breast cancer was 40.0% (26/65), 32.3% (21/65), and 9.2% (6/65), respectively, and the incidence of grade 3 neutropenia, hemoglobin reduction, and platelet reduction was 7.7% (5/65), 4.6% (3/65), and 1.5% (1/65), respectively. Blood tests should be performed prior to treatment with pyrrolizidine in combination with capecitabine and should be monitored regularly during treatment.
QT interval prolongation: In phase I and II studies, 14.5% (11/76) of breast cancer patients treated with pyrrolitinib (400 mg QD) in combination with capecitabine experienced a QTcF of more than 480 ms or an increase of ³ 60 ms from baseline. based on the current results, no definite conclusion can be drawn as to whether pyrrolitinib leads to QT interval prolongation. Prolongation of the QT interval has been reported with similar drugs. Given the inherent risk of QT interval prolongation and the fact that the possibility of pyrrolitinib causing this effect cannot be ruled out, patients should be corrected for hypokalemia, hypomagnesemia, or hypocalcemia before starting pyrrolitinib. Vigilance should be exercised in the administration of pyrrolitinib in patients with: 1) underlying cardiac disease or special conditions: e.g., congestive heart failure with preexisting cumulative high-dose anthracycline therapy; 2) congenital long QT interval syndrome; 3) hypokalemia, hypocalcemia, and hypomagnesemia; 4) concomitant use of 2 or more drugs that cause prolonged QT interval.
Decreased left ventricular ejection fraction (LVEF): A decrease in LVEF to less than 50% after pyrrolitinib combined with capecitabine treatment was not reported in clinical trials. 12.3% of breast cancer patients in phase II studies experienced a grade 2 decrease in LVEF (down > 10% from baseline, < 20%). There are limited data on long-term exposure to pyrrolitinib in large populations. LVEF assessment should be performed to confirm that LVEF is within the normal range prior to initiation of this product therapy. LVEF should be monitored periodically during the course of treatment with this product to ensure that LVEF does not fall below the lower limit of normal. If a significant decrease in LVEF occurs during treatment with pyrrolitinib, it should be managed according to the dose adjustment guidelines, see [Dosage and Administration].
Pregnant women and nursing mothers
Pregnancy
There is no information on the use of pyrrolitinib in women during pregnancy. Toxicity to the embryo has been observed in animal studies. It is recommended that women of childbearing potential use the necessary contraception during and for at least 8 weeks after treatment with pyrrolitinib. If pyrrolitinib is used during pregnancy, patients should be informed of the possible hazards to the fetus, including developmental disorders and serious malformations. During pregnancy, this product should be used only if the potential benefits to the mother outweigh the risks.
Lactating women
Animal studies are ongoing to determine if this product is excreted in breast milk and it is not known if this product is excreted in human breast milk. Because many drugs are excreted in human milk, it is recommended that breastfeeding women discontinue breastfeeding during treatment with pyrrolizidine.
Pediatric Use]
There are no data on the safety and efficacy of pyrrolitinib in patients under 18 years of age.
Geriatric Use]
There is limited experience with the use of pyrrolitinib in patients 65 years of age and older. Of the 131 patients with recurrent or metastatic breast cancer treated with pyrrolitinib alone or in combination with capecitabine in phase I and II clinical trials, only 3 patients were older than 65 years of age and none were older than 70 years of age.
[Drug Interactions].
No in vivo drug-drug interaction studies have been conducted.
Based on the results of in vitro studies, pyrrolitinib is mainly metabolized by CYP3A4 enzymes, and when combined with strong inducers of CYP3A4 (e.g. dexamethasone, phenytoin sodium, carbamazepine, rifampin, rifabutin, rifapentine), it potentially affects the effect of antitumor therapy due to the possible reduction of systemic exposure of pyrrolitinib. Combination with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir, ritonavir, voriconazole, grapefruit) increases the risk of patient safety due to the potential for increased systemic exposure to pyrrolitinib. Patients with hepatic insufficiency should be particularly alert to the risk of drug interactions between pyrrolitinib and CYP3A4 inhibitors. See [DOSAGE].
Pyrrolitinib has a weak inhibitory effect on CYP2C19 (half-inhibitory concentration [IC50] = 18.52 μM), and the concomitant use of drugs metabolized by the CYP2C19 enzyme may increase the blood levels of this drug.
Based on the results of studies with structurally similar drugs, it is more likely that pyrrolitinib is a P-glycoprotein transport substrate, and drugs that inhibit P-glycoprotein may increase the blood concentration of pyrrolitinib.
Drug overdose]
No cases of pyrrolitinib drug overdose have been reported in clinical trials. The maximum tolerated dose (MTD) determined in the phase I dose creep clinical trial of pyrrolitinib was 400 mg/day, and the highest dose administered in the phase II and III clinical trials was 400 mg/day. In the phase I dose creep clinical trial of pyrrolitinib, two patients received a maximum creep dose of 480 mg/day with pyrrolitinib alone (higher than the dose of 400 mg/day used in the phase II and III trials), and two patients experienced grade 3 diarrhea on days 1 and 2, respectively, both of which were dose-limiting toxicities that recovered with antidiarrheal therapy. One patient also experienced grade 3 nausea and grade 2 vomiting.
There are no known antidotes for pyrrolitinib overdose. Treatment of pyrrolitinib overdose should include conventional supportive therapy.
[Clinical Trials].
The effectiveness and safety of pyrrolitinib in combination with capecitabine and lapatinib in combination with capecitabine in the treatment of HER2-positive recurrent or metastatic breast cancer was compared in a randomized, open, controlled phase II study (Study 1). Patients were required to be eligible to participate in the study including: HER2-positive breast cancer patients (IHC +++ or IHC ++/FISH positive); previous treatment failure with anthracyclines and paclitaxel (both adjuvant and treatment of recurrent metastases); and no more than 2 lines of chemotherapy after recurrence/metastasis. A total of 128 patients were enrolled and randomized into 2 groups: one group was treated with pyrrolitinib 400 mg once daily (continuous application) in combination with capecitabine 1000 mg/m2 orally twice daily (1 week off after 2 weeks of treatment); the other group was treated with lapatinib 1250 mg once daily (continuous application) in combination with capecitabine 1000 mg/m2 orally twice daily (1 week off after 2 weeks of treatment). (1 week off after 2 weeks of treatment). Study treatment continued until disease progression or intolerable toxicities occurred. The primary endpoint of the study is the objective remission rate (ORR). Secondary endpoints included time to progression-free survival (PFS), time to disease progression (TTP), and duration of remission (DoR).
The 128 subjects who received at least one dose were included in the full analysis set (FAS set), and the median age of patients treated with pyrrolizidine in combination with capecitabine was 48 years, including 2 patients aged ³ 65 years; baseline ECOG physical status score of 0 (60.0%) or 1 (40.0%); and lesion site was visceral (76.9%) and non-visceral (23.1%). ER or PR positive (56.9%) and ER and PR negative (43.1%); 53.8% of patients had previous trastuzumab use. The baseline characteristics of the two groups were balanced and comparable (see Table 5 for details).
Table 5 Baseline characteristics of study 1 (full analysis set)
Pyricitinib + capecitabine
(N=65) Lapatinib + Capecitabine
(N=63) Age, years Median 48.0 49.0 <65 years 63 (96.9%) 62 (98.4%) ≥65 years 2 (3.1%) 1 (1.6%) Prior use of macromolecular antibodies targeting HER2, n (%) Yes35 (53.8%) 34 (54.0%) No30 (46.2%) 29 (46.0%) Physical status, n ( %) 039 (60.0%) 30 (47.6%) 126 (40.0%) 33 (52.4%) Site of lesion, n (%) Visceral 50 (76.9%) 48 (76.2%) Non-visceral 15 (23.1%) 15 (23.8%) Hormone receptor status, n (%) ER and PR negative 28 (43.1%) 20 (31.7%) ER or PR positive37 (56.9%)43 (68.3%) Time to recurrence/metastasis after first diagnosis (years) Median 1.92.0 Previous chemotherapy lines, n (%) Line 0 33 (50.8%) 23 (36.5%) Line 1 15 (23.1%) 27 (42.9%) Line 2 17 (26.2%) 13 (20.6%)
Treatment with pyrrolizidine in combination with capecitabine improved ORR and prolonged PFS in patients compared with lapatinib in combination with capecitabine (see Table 6 and Figure 1 for details). Patients benefited from pyrrolitinib in combination with capecitabine treatment regardless of prior trastuzumab use/non-use (see Table 7 for details). The investigator assessment was consistent with the Independent Imaging Review (IRC) findings.
Table 6 Primary efficacy results for Study 1 (full analysis set)
Investigator assessment
IRC assessment
Pyricitinib + capecitabine
(N=65) Lapatinib + Capecitabine
(N=63) Pyrrolitinib + Capecitabine
(N=63) Lapatinib + Capecitabine
(N=61) Median PFS, months (95% CI) 18.1
(13.88, NR) 7.0
(5.62, 9.75)12.6
(11.17,18.08)5.6
(4.20,7.67)Risk ratio (95% CI) 0.363 (0.228, 0.579)0.371 (0.238, 0.579)Statistic, P value 18.989, P < 0.000120.098, P < 0.0001Best outcome [n(%)] Complete remission (CR)3 (4.6%)1 (1.6% ) 9 (13.8%)2 (3.2%) Partial remission (PR) 48 (73.8%)35 (55.6%)36 (55.4%)28 (44.4%) Disease stabilization (SD)14 (21.5%)22 (34.9%)13 (20.0%)21 (33.3%) Disease progression (PD)05 (7.9%)5 (7.7%)10 ( 15.9%)Objective remission rate (CR+PR)51 (78.5%)36 (57.1%)45 (71.4%)30 (49.2%)95% CI (68.5%, 88.5%)(44.9%, 69.4%)(60.3%, 82.6%)(36.6%, 61.7%)P valueP=0.01P=0.0117CI. Confidence interval; NR: not reached
Figure 1 Kaplan-Meier curve for progression-free survival time (Study 1, full analysis set), investigator assessment
Table 7 Subgroup analysis of key efficacy outcomes for Study 1, by prior trastuzumab use or not (investigator’s assessment)
Prior trastuzumab prior trastuzumab not prior trastuzumab Piretinib + capecitabine
(N=35) lapatinib + capecitabine
(N=34)Pyrrolitinib+Capecitabine
(N=30) lapatinib + capecitabine
(N=29) Median progression-free survival (PFS), months
(95% CI) NR
(12.53, NR) 7.1
(5.72, 11.14) 18.1
(12.53, NR)5.6
(4.23, 9.72) Risk ratio (95% CI) 0.374 (0.190, 0.738) 0.366 (0.192, 0.696) Median time to disease progression (TTP), months
(95% CI) NR
(12.53, NR)7.1
(5.72, 11.14) 16.7
(12.53, NR)5.6
(4.23, 11.80)Risk ratio (95% CI) 0.342 (0.170,0.687)0.365 (0.188,0.706)Objective remission rate (ORR)n (%)24 (68.6%)20 (58.8%)27 (90%)16 (55.2%) (95% CI) 50.7%, 83.1%40.7%, 75.4%73.5%, 97.9%35.7%, 73.6% Median duration of remission (DoR), months
(95% CI) NR
(12.50, NR)8.4
(4.23, NR)16.7
(11.17, NR)5.6
(2.81, 16.23) Risk ratio (95% CI) 0.345 (0.140,0.853) 0.457 (0.205,1.021) CI: confidence interval; NR: not reached
To confirm the efficacy and safety of pyrrolitinib in combination with capecitabine in HER2-positive recurrent or metastatic breast cancer, 2 randomized, controlled, phase III clinical trials of pyrrolitinib in combination with capecitabine in HER2-positive recurrent or metastatic breast cancer are ongoing. One trial is a randomized, open, multicenter Phase III clinical study of pyrrolitinib in combination with capecitabine versus lapatinib in combination with capecitabine in HER2-positive recurrent or metastatic breast cancer with prior trastuzumab, with a planned enrollment of 240 patients. A primary analysis is expected to be completed in 2018. Another trial is a randomized, double-blind, multicenter Phase III clinical study of pyrrolizidine in combination with capecitabine versus placebo in combination with capecitabine in HER2-positive recurrent or metastatic breast cancer with prior trastuzumab, with a planned enrollment of 350 patients. The primary analysis is expected to be completed in 2020.
[Pharmacology and Toxicology].
Pharmacological effects
Pyrrolitinib is an irreversible small molecule receptor tyrosine kinase inhibitor that significantly inhibits epidermal growth factor receptor (ErbB1/EGFR) and human epidermal growth factor receptor 2 (ErbB2/HER2) with an IC50 of 5.6 nM and 8.1 nM, respectively. pyrrolitinib significantly inhibits the growth of HER2-high expressing tumor cells (breast, ovarian, gastric In a variety of transplanted tumor nude mouse models (breast, ovarian, lung), pyrrolitinib significantly inhibited HER2 factor-driven tumor growth, inhibited HER2-mediated downstream signaling pathways, and blocked tumor cells in the G1 phase of the cell cycle.
Toxicological studies
Genotoxicity: Pyrrolitinib showed negative results in the Salmonella typhimurium revertant mutation assay (AMES), the Chinese hamster lung fibroblast chromosome aberration assay and the mouse bone marrow cell micronucleus assay.
Reproductive toxicity: In SD rats, body weight gain was slowed and sperm motility was reduced in males by once-daily gavage of pyrrolitinib at 120 mg/kg; in females, body weight gain was slowed and reproductive function was reduced, with early embryotoxicity at doses of 60 and 120 mg/kg. The NOAEL for fertility and early embryonic developmental toxicity in female rats was 30 mg/kg and the NOAEL for fertility and early embryonic developmental toxicity in male rats was 60 mg/kg. 35 mg/kg/day and above given by gavage to pregnant SD rats on day 6-15 of gestation was toxic to the mother, mainly in the form of slow body weight gain, reduced food intake, and early embryotoxicity. The main effects were slow body weight gain, reduced food intake and decreased placental weight. The incidence of fetal ventricular enlargement was increased at 70 mg/kg/day, and the fetal skeletal examination did not show any significant malformation or abnormality. 140 mg/kg/day showed an increase in the incidence of ventricular enlargement and an increase in the number of fetal skeletal malformations or abnormalities, mainly in the dumbbell shape of the thoracic spine. Therefore, the NOAEL of gavage administration of pyrrolizidine to pregnant SD rats was less than 35 mg/kg/day for maternal and 35 mg/kg/day for embryonic and fetal development. Some parental, reproductive and embryotoxic effects were observed in successfully mated female New Zealand rabbits given 40 mg/kg pyrrolizidine by gavage once daily on days 6 to 18 of gestation. The progeny toxicity was mainly manifested by the decrease of body weight gain and food intake of pregnant rabbits; the reproductive toxicity was mainly manifested by the decrease of uterine weight and coefficient; the embryotoxicity was mainly manifested by the increase of fetus absorption and the decrease of live fetus number and pregnancy rate; the 10 mg/kg group only showed some embryo and fetus developmental toxicity, mainly manifested by the increase of the incidence of ossification insufficiency of the 5th-6th sternal segment of fetus rabbits. Therefore, the NOAEL of pyrrolitinib was 10 mg/kg for both parental females and reproductive toxicity, and 2.5 mg/kg for embryonic and fetal development.
Carcinogenicity: The carcinogenicity study of pyrrolitinib in rats and mice is underway.
Pharmacokinetics]
Patients with breast cancer received pyrrolitinib orally once a day continuously, and the blood concentration of pyrrolitinib reached steady state on day 8, and the accumulation ratio of area under the blood concentration-time curve (AUC) was 1.22~1.57, and no significant accumulation was observed with continuous administration.
When pyrrolitinib was combined with capecitabine, the AUC accumulation ratio of pyrrolitinib was approximated to 1 after 14 consecutive days of daily oral administration, and no significant accumulation was observed. In the dose range of 160-400 mg daily, the AUC0-24h and peak blood concentration (Cmax) of pyrrolitinib at steady state increased essentially with increasing dose administration.
Absorption
In breast cancer patients receiving oral pyrrolitinib (160-400 mg daily) in combination with capecitabine, the median time to peak blood concentration of pyrrolitinib at steady state was 4.0-5.0 hours. The mean Cmax of 400 mg daily pyrrolitinib was approximately 170 ng/mL.
Food Effects
In healthy subjects, one oral dose of 320 mg pyrrolitinib was administered after a high-fat meal and in the fasted state, respectively. Compared to the fasted state, oral administration of pyrrolitinib after a high-fat meal increased AUC0-∞ by approximately 43% and Cmax by approximately 79%.
Distribution
The mean apparent volume of distribution (Vss/F) of 400 mg pyrrolitinib daily at steady-state was 4200 L. Pyrrolitinib is hematocrit-accessible, with a whole blood/plasma concentration ratio of 1.18-1.57 for the substance of interest. In vitro Caco-2 cell assays suggest that pyrrolitinib has a low permeability profile and significant efflux on Caco-2 cells. In vitro human plasma protein binding ranged from 86.9% to 99.7% with no concentration dependence.
Metabolism
Pyrrolitinib is mainly metabolized by CYP3A4 enzymes catalyzed in the liver, and the main metabolic pathways are O-demethylpyridine (M1-2, SHR150980), O-demethylpyridine and carbonylation (M2, SHR151468), carbonylation (M7-3, SHR151136), double oxidation and dehydrogenation (M9-1, M9-2, M9-3, and M9-9), and double oxidation (M10-1).
Excretion
The mean elimination half-life at steady state of 400 mg pyrrolitinib daily was 18.2 hours and the mean clearance (CLss/F) was 141 L/h when administered in combination with capecitabine in breast cancer patients. ±0.33%. Pyrrolitinib is mainly excreted in the form of prodrug and metabolites in the feces.
Storage
Seal and store in a dry place below 25oC. It should not be kept for more than one month after opening.
Package】
This product is packed in high-density polyethylene bottle for oral solid medicine with built-in desiccant. 14 tablets/bottle (80 mg specification); 28 tablets/bottle (160 mg specification).
Expiration date
12 months.
Execution Standard
Approval number】
【Manufacturer】
Company Name: Jiangsu Hengrui Pharmaceutical Co.
Production Address: No. 38, Huanghe Road, Lianyungang Economic and Technological Development Zone, Jiangsu Province
Postal Code: 222047
Telephone number: 800-828-3900, 400-828-3900
Fax number: 0518-85453845
Web address: http://www.hrs.com.cn