拉帕替尼（TYKERB）

【Function and indication】
Lapatinib (TYKERB) combined with capecitabine is used to treat advanced or metastatic breast cancer with ErbB-2 overexpression, which has been previously treated with anthracyclines, paclitaxel, and trastuzumab (Herceptin).

【Model and specification】
Each 250 mg tablet contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg of lapatinib free base.

【Usage and dosage】
The recommended dose is 1 250 mg, once a day, taken from the 1st to the 21st day, combined with capecitabine 2 000 mg/d, taken in 2 doses from the 1st to the 14th day. Lapatinib should be taken once a day, and divided doses are not recommended. Take 1 hour before or 2 hours after meals. If you miss 1 dose, there is no need to double the dose on the second day. Pregnancy level D, pregnant women are prohibited from using it. It is not clear whether it is secreted through breast milk, and breastfeeding women should stop breastfeeding. No significant difference was found between the use of drugs in the elderly and young patients. No clinical trials have been conducted on patients with severe renal damage and dialysis. Patients with moderate to severe liver damage should reduce the dose as appropriate.

[Clinical Research]
In a phase III clinical trial to investigate the efficacy and safety of lapatinib combined with capecitabine in the treatment of breast cancer, patients with HER2 overexpression, advanced or metastatic breast cancer, and patients who were ineffective with anthracyclines, taxanes, and trastuzumab were enrolled. Patients were randomly given lapatinib 1,250 mg once a day, and 2,500 mg/m2 per day on days 1 to 14, for a 21-day cycle. The endpoint was the time to tumor progression. 399 patients participated in the trial, with an average age of 53 years, 14% of the patients were over 65 years old, 91% were white, 97% had stage IV breast cancer, 48% of the patients were estrogen receptor positive or progesterone positive, 95% were ErbB2 IHC 3 positive and IHC 2 positive (confirmed by fluorescein in situ hybridization), and 95% of the patients had been treated with anthracyclines, taxanes, and trastuzumab. After 4 months, the time to tumor progression in the lapatinib and capecitabine combination treatment group and capecitabine alone was 27.1 and 18.6 weeks, respectively [2]. 67 patients with metastatic solid tumors were treated with lapatinib for 8 weeks and found to be effective in patients with trastuzumab resistance and to prolong the time to tumor progression in patients [3]. In clinical trials, lapatinib was well tolerated at a daily dose of 1,800 mg and was effective against various solid tumors, including breast cancer and head and neck cancer [4]. In a trial of the combined use of 5-fluorouracil, folinic acid, and irinotecan to treat tumors, 25 patients took lapatinib orally and received intravenous injections of the above three drugs at the same time. Compared with traditional chemotherapy, the drug dose was reduced by 40%. Among the 19 evaluable patients, 4 had partial responses and 9 had stable disease[5]. In a study of malignant salivary gland tumors, lapatinib was able to prolong the patient’s tumor stability period for more than 6 months and was well tolerated by patients[6].

【Precautions】
Currently available lapatinib is a 250 mg oral tablet. The US Food and Drug Administration-approved formula is a combination of lapatinib and capecitabine. The recommended dose of lapatinib is 1250 mg (five tablets) per day for 21 days as a course of treatment. The oral dose of capecitabine is 2000 mg per square meter of body surface area per day for 28 days as a course of treatment.
Lapatinib is a HER-1/HER-2 tyrosine kinase inhibitor, the second molecular targeted new drug for breast cancer after trastuzumab (Herceptin). Clinical trials of HER-1/HER-2 tyrosine kinase inhibitors have shown that it is effective for recurrent or refractory inflammatory breast cancer that overexpresses Her2, and is also effective for brain metastases of breast cancer. Its latest clinical trials became the hottest topic at the 2006 American Society of Clinical Oncology Annual Meeting.
Human ErbB receptors belong to the type I receptor tyrosine kinase (TK) family. They include ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). In cancer patients, ErbB-1 (EGFR) and ErbB-2 (HER-2) receptors are usually overexpressed or otherwise altered. It is known that human epidermal growth factor receptor-2 (ErbB-2, HER-2) is a human oncogene that is closely related to breast cancer. Its high expression in breast cancer often indicates that it is easy to have lymph node metastasis and poor tumor differentiation, and the prognosis is poor. With the in-depth study of HER-2, it has become one of the target molecules for specific treatment of breast cancer.
Lapatinib is a reversible tyrosine kinase inhibitor that can effectively inhibit the activity of ErbB1 and ErbB2 tyrosine kinases. Its mechanism of action is to inhibit the ATP site of EGFR (ErbB-1) and HER2 (ErbB-2) in cells to prevent tumor cell phosphorylation and activation, and block the downregulation signal through homo- and hetero-dimers of EGFR (ErbB-1) and HER2 (ErbB-1).
Related clinical trials:
Phase I trial:
The dual EGFR kinase inhibitor Lapatinib can induce partial response or disease stabilization in about half of the patients with advanced refractory solid tumors participating in the Phase I study. The drug is relatively non-toxic.
The researchers treated 67 patients with ErbB1-expressing and/or overexpressing ErbB2, randomly assigning them to one of five doses of lapatinib (500 to 1600 mg daily). After an initial 21-day trial period, treatment continued until patients had disease progression, treatment toxicity, or withdrawal from the trial. The results were published in the August 10, 2005, issue of the Journal of Clinical Oncology (J Clin Oncol 2005;23:5305-5313).
The drug was generally well tolerated, with 44 patients experiencing drug-related adverse events, mostly grade 1 or 2 diarrhea, rash, nausea, and fatigue, the authors noted. There were five grade 3 adverse events (abdominal pain, rash, diarrhea, and gastroesophageal reflux disease), but no drug-related grade 4 adverse events or deaths. Two patients discontinued treatment. Of the 59 patients who were evaluable for disease status, four had a partial response and 24 had stable disease. Clinical activity was observed at doses ranging from 650 to 1600 mg daily. 12 patients received lapatinib treatment for at least 6 months, and 4 patients received lapatinib treatment for more than 1 year.
Phase II trial: EGF103009 is a phase II clinical trial of lapatinib for the treatment of recurrent and/or resistant inflammatory breast cancer. 34 patients received lapatinib 1500 mg/d treatment, 22 patients were evaluable for efficacy, and 17 patients underwent pathological biopsy. The results showed that 8 of the 11 patients in the HER-2 2/3(+)IHC/FISH(+) group achieved clinical remission, while no patients in the HER-1(+)/ErbB2(-) group achieved remission. The preliminary study showed that lapatinib has an outstanding efficacy in the treatment of HER-2 positive inflammatory breast cancer.
Another trial used lapatinib as a rescue treatment for brain metastases in breast cancer patients who were treated with trastuzumab (Herceptin). A total of 39 patients were enrolled. The results showed that although only 2 patients achieved partial remission (PR) and 5 patients were stable (SD) for ≥16 weeks during systemic efficacy evaluation, the efficacy analysis of 20 patients with brain metastases based on RECIST standards found that the volume of brain metastases in 5 patients was reduced by ≥30%, and the volume of tumors in 3 patients was reduced by 15%~30%. The main adverse reactions of lapatinib are diarrhea and fatigue. The study showed that lapatinib can pass through the blood-brain barrier and has a positive effect on brain metastases of HER-2 positive breast cancer.
Phase III trial: (Reported at the 2006 ASCO Annual Meeting) An international multicenter Phase III clinical trial showed that lapatinib combined with capecitabine can improve the efficacy of patients with advanced breast cancer. The study included 321 patients with advanced breast cancer with HER-2/neu overexpression, and randomly divided them into lapatinib combined with capecitabine and capecitabine alone. The median tumor progression time of the two groups was 36.9 weeks and 19.7 weeks, respectively. The occurrence of brain metastasis in the combined group was significantly reduced, and the incidence of adverse reactions in the two groups was similar. The researchers believe that lapatinib has potential clinical value in the treatment of breast cancer. Another phase III clinical trial showed that lapatinib can prevent tumor growth and prolong the overall survival of patients with EGFR overexpression advanced renal cell carcinoma who had not responded to previous standard treatment.
The new targeted anticancer drug Tykerb (lapatinib) is on the market. The drug is used in combination with the anticancer drug capecitabine to treat patients with advanced HER2-positive breast cancer.
Tykerb is a new chemical molecular entity and a kinase inhibitor. Different from the approved humanized monoclonal antibody drug trastuzumab (Herceptin), Tykerb is effective for some HER2-positive breast cancer patients who have been treated with trastuzumab and have not been effective.
The randomized clinical trial supporting the approval of Tykerb showed that in a trial of 400 women with HER2-positive advanced or metastatic breast cancer, half of the patients used Tykerb + capecitabine, and the other half only used capecitabine. The treatment effect of the former was statistically significantly improved compared with the latter, with a higher tumor response rate (24% vs. 14%). However, the data on the improvement of patient survival is not yet mature.
Currently, the side effects associated with Tykerb include diarrhea, nausea, vomiting, rash and hand-foot syndrome, as well as numbness, tingling, redness, swelling and discomfort in the hands and feet. A small number of patients have a general reversible decline in heart function (which can cause shortness of breath).

【Adverse Reactions and Contraindications】
The adverse reactions observed in clinical trials with an incidence rate greater than 10% were mainly gastrointestinal reactions, including nausea, diarrhea, stomatitis and indigestion, dry skin, rash, and other reactions such as back pain, dyspnea and insomnia [4]. When used in combination with capecitabine, adverse reactions include nausea, diarrhea and vomiting, and poor tactile sensation of the palms and plantar muscles. Some patients may experience a decrease in left ventricular ejection fraction and interstitial pneumonia.
The most common side effects are gastrointestinal side effects, namely nausea, vomiting, diarrhea and other symptoms. Other side effects include skin redness, swelling, itching, pain, and fatigue. In addition, there are very rare but serious side effects, including those related to the heart and lungs.
When the patient has a decrease in the left ventricular ejection fraction (LVEF) of level 2 (New York Heart Association, NYHA class 2) or above, the drug must be discontinued to avoid heart failure. When the LVEF returns to normal or the patient is asymptomatic two weeks later, the drug can be resumed at a lower dose. Compared with anthracycline chemotherapy drugs, lapatinib’s cardiotoxicity is reversible. Unlike anthracycline, which is irreversible and has a lifetime maximum dosage, lapatinib does not have a lifetime maximum dosage.

[Contraindications]
Since lapatinib is a drug metabolized by the liver CYP enzyme system, when using other drugs that induce or inhibit CYP enzymes, attention must be paid to dose adjustment. Pregnant women should generally not use lapatinib because its pregnancy toxicity is classified as D. Therefore, if there is no absolute need or great benefit to the mother, it is not recommended for pregnant women or pregnant women.

[Pregnant women’s medication]
Not recommended.

[Children’s medication]
Not recommended.

[Drug interactions]
In vitro, lapatinib can inhibit CYP3A4 and CYP2C8 at therapeutic concentrations, and is mainly metabolized by CYP3A4. Drugs that inhibit the activity of this enzyme can significantly increase the blood concentration of lapatinib. Ketoconazole, 0.2 g each time, twice a day, can increase the AUC of lapatinib by 3 to 7 times after 7 days, and prolong the half-life by 1.7 times. Healthy volunteers took CYP3A4 inducers orally, 100 mg each time, twice a day, and changed to 200 mg each time, twice a day for 17 days after 3 days, and the AUC of lapatinib decreased by 72%. Lapatinib is a transporter of P-glycoprotein, and drugs that inhibit glycoprotein may increase the blood concentration of the drug.

[Storage]
Store at room temperature.

[Manufacturer]
GSK