Lapatinib
Overview
Lapatinib is an oral small molecule dual tyrosine kinase inhibitor that targets both HER2, also known as ErbB2, and epidermal growth factor receptor pathways. It is primarily indicated for use in combination with either capecitabine or letrozole in the treatment of advanced or metastatic HER2-positive breast cancer. This includes patients whose disease has progressed following prior therapy with trastuzumab, anthracyclines, or taxanes. Lapatinib works by blocking intracellular kinase activity, thereby inhibiting tumor cell proliferation and survival signals. It has demonstrated benefits in prolonging progression-free survival and is valued in cases where resistance to trastuzumab has developed. Safety monitoring is important, particularly for liver function and cardiac performance, as these are known risk areas associated with treatment.
Background and Date of Approval
Lapatinib, also referred to as lapatinib ditosylate and marketed under the brand names Tykerb and Tyverb, received its first approval from the United States Food and Drug Administration in March 2007 for the treatment of advanced HER2-positive breast cancer in combination with capecitabine. Clinical trials demonstrated that this combination significantly improved median time to progression compared to capecitabine alone, supporting its place in therapy for resistant cases. Regulatory approvals were later expanded to include postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer in combination with letrozole. The drug has also been explored for orphan indications such as HER2-positive gastric or esophageal cancers, though these uses are not widely approved.
Uses
Lapatinib is approved for the treatment of advanced or metastatic HER2-positive breast cancer in patients who have previously been treated with an anthracycline, a taxane, and trastuzumab, in combination with capecitabine. It is also approved for use in postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer in combination with letrozole. In some clinical contexts, it has been studied for other HER2-overexpressing solid tumors, although these applications remain investigational.
Administration
When used with capecitabine, the recommended dose of lapatinib is 1250 milligrams taken orally once daily on days one to twenty-one of a repeating twenty-one-day cycle, together with capecitabine at a total daily dose of 2000 milligrams per square meter divided into two doses on days one to fourteen. When used with letrozole, the recommended lapatinib dose is 1500 milligrams orally once daily on a continuous schedule along with 2.5 milligrams of letrozole daily. Lapatinib should be taken at least one hour before or one hour after a meal, while capecitabine should be taken with food or within thirty minutes after eating. Dose adjustments may be necessary in patients with reduced liver function, when used with strong CYP3A4 inhibitors or inducers, or when significant toxicities occur. Cardiac toxicity, severe diarrhea, or other grade two or higher adverse events may require temporary interruption and resumption at a reduced dose.
Side Effects
Commonly observed side effects with lapatinib therapy include diarrhea, nausea, vomiting, fatigue, rash, hand-foot syndrome, decreased appetite, dry skin, nail changes, mouth sores, headache, and musculoskeletal discomfort. Many of these side effects are manageable with supportive care, but persistent or severe reactions should prompt reassessment of therapy.
Warnings
Serious risks associated with lapatinib include severe hepatotoxicity, which in rare cases can be fatal. Monitoring of liver enzymes before and during treatment is essential. Cardiac toxicity, including decreases in left ventricular ejection fraction, can occur, and periodic cardiac monitoring is advised. Severe dermatologic reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis have been reported. QT prolongation and ventricular arrhythmias including torsades de pointes are possible, necessitating caution in patients with pre-existing heart rhythm disorders. Lapatinib may cause fetal harm when administered during pregnancy, so effective contraception is required. Cases of interstitial lung disease and pneumonitis have also been documented.
Precautions
Lapatinib is metabolized mainly by CYP3A4 and also involves CYP2C8 and CYP2C19 pathways. Concomitant use with strong inhibitors or inducers of these enzymes can significantly alter lapatinib blood concentrations. The drug can also inhibit CYP3A4, CYP2C8, and P-glycoprotein, potentially affecting the pharmacokinetics of co-administered medicines. Regular monitoring of liver and cardiac function, electrocardiographic evaluation, and observation for respiratory or skin symptoms is recommended throughout treatment.
Expert Tips
Before initiating therapy, ensure baseline liver function tests and left ventricular ejection fraction assessments are completed, and repeat them periodically. Educate patients on the importance of strict adherence to timing relative to meals to optimize absorption and reduce variability. Promptly address diarrhea to prevent complications, and counsel patients to report any signs of jaundice, chest discomfort, or new respiratory symptoms. Review all concurrent medications to minimize interactions, and advise on effective contraception during treatment and for a period after completion. Provide proactive skin and gastrointestinal supportive measures to enhance patient comfort and adherence.