Lapatinib (Tykerb)

Binds to intracellular ATP binding site of epidermal growth factor receptor (EGFR) and HER-2 and prevents phosphorylation and activation of these tyrosine kinase inhibitors.

A small molecule, reversible tyrosine kinase inhibitor of epidermal growth factor receptor and HER-2.

Inhibits downstream signaling through homodimers and heterodimers of the EGFR and HER-2 receptors.

Approved for the treatment of HER-2 positive, trastuzumab resistant metastatic breast cancer.thank you

Works intracellularly and directly targets the tyrosine kinase domain.

Theoretical advantage over trastuzumab since the latter targets extracellular HER-2 only.

Oral drug that targets HER2 and HER1 (EGFR) that inhibits breast cancer when given with capecitabine.

Phase three trial of capecitabine plus lapatinib vs. capecitabine alone in 399 patients with 1250 mg per day of lapatinib and 2500 mg per meter squared on days 1-14 of a 21 day cycle resulted in an improvement in the median survival time to progression of disease between 3 and 4 months, and an improvement in time to progression was observed in all patients with the combination therapy.

In a trial of 1286 postmenopausal, hormone receptor positive women with metastatic disease treated with Letrozole vs. Lapatinib plus Letrozole for frontline management (EGFEG30008 trial):HER2 positive population had a median progression free survival of 8.2 months in the combination group and only 3 month in the Letrozole group, overall response rate in the combination drug treatment was 27.9% vs. 14.6% in the Letrozole only group, and there was not difference in response rate of clinical benefit in either group for patients that were HER2 negative (Johnston).

In a randomized study evaluating Lapatinib alone or in combination with Trastuzumab in 296 patients with HER2+ metastatic breast cancer whose disease has progressed while being treated with Trastuzumab: the combination improved median progression free survival 8.4 weeks vs. 12 weeks for the combination group, but the overall survival and response rates were similar (O’Shaughnessy J).

The above study suggests the synergy of Lapatinib and Trastuzumab with improved clinical outcome inpatients who had progressive disease while receiving Trastuzumab based therapy.

It’s advantage advantages for its activity in metastatic disease, its low cardiac toxicity, and the theoretical benefit in preventing brain metastasis because it  crosses  the blood brain barrier.

It is a convenient agent because it is orally administered.

Side effects include mild to moderate diarrhea, vomiting, headache, rash and fatigue.

May be associated with hepatic toxicity (0.4%) and monitoring liver functions before initiation of treatment and every 4-6 weeks as indicated.

In hormonally refractive prostate cancer one of 21 patients had a reduction in PSA of greater than 50% and a second patient had a 47% reduction in PSA lasting more than 15 months (Whang).

Significantly improves progression free survival in HER2 positive patients that failed Trastuzumab containing regimens.

Women who developed a rash early in their treatment for HER2-positive breast cancer with lapatinib were more likely to go on to have pathologic complete response compared to those who did not get a rash.

Combination of lapatinib plus trastuzumab compared to lapatinib alone in women with HER2+ metastatic breast cancer that had progressed on multiple lines of treatment: combination superior in progression free survival compared to lapatinib alone, median overall survival in the combination arm 60.7 weeks compared to lapatinib alone at 41.4 weeks (Blackwell KL).

In a phase II study CHER-LOB trial stage II orII breast cancer patients HER2+ who received chemotherapy prior to surgery for stage II or III BC responded better to treatment with a combination of trastuzumab and tyrosine kinase inhibitor lapatinib then with treatment with either lapatinib or trastuzumab alone with chemotherapy: A complete pathological response was noted in 28% of patients in the trastuzumab only arm, 32% in the lapatinib only arm and 48% in the combination arm (Guarneri V et al).

Lapatinib is indicated in combination with letrozole for the treatment of postmenopausal women for home hormonal therapy is indicated and who have hormonal receptor positive metastatic breast cancer that over expresses the HER 2 receptor.
Lapatinib can also potentially restore tamoxifen sensitivity.

In 242 patients with HER 2 positive metastatic breast cancer and progressive brain metastases after brain radiation treated with Lapatinib had a 6% greater than 50% reduction in tumor volume and 17% had a 20% reduction in brain tumor volume: with tumor progression capecitabine was added and 20% of these patients had a 50% greater reduction in tumor volume and 40% had a 20% or greater volume tumor response. (Lin NU).

NeoAltto randomized trial evaluating neoadjuvant lapatinib and trastuzumab combination therapy in her 2 positive operable breast cancer: pCR was significantly higher in the combination group, particularly in hormonal receptor-negative tumors.

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