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# HER2 tyrosine kinase inhibitors

Oral small molecules that block the HER2 kinase from inside the cell; used in HER2-positive breast cancer, often after or with trastuzumab.

Updated Nov 1, 2026

## What they are

Lapatinib (HER2 and EGFR), neratinib (irreversible HER2 and EGFR) and tucatinib (HER2-selective) inhibit the intracellular kinase domain of HER2, while antibodies such as trastuzumab bind its outside. They are combined with capecitabine, trastuzumab or endocrine therapy in HER2-positive breast cancer.

## Mechanism of action

HER2 (ERBB2) is a member of the EGFR family; when it is overexpressed it pairs with other family members and its kinase drives proliferation. These drugs occupy the ATP site of the HER2 kinase and switch the signal off. Blocking the receptor from inside complements antibodies that block it from outside.

Target: HER2 (ERBB2) tyrosine kinase, with EGFR for lapatinib and neratinib

## Key points

- Only for HER2-positive tumours.
- Diarrhoea is the common shared toxicity; hepatotoxicity can be severe.
- Lapatinib: boxed liver warning, QT prolongation and reduced heart function, less than with trastuzumab.
- Tucatinib spares EGFR, so rash is less common, and it is active in brain metastases.

## Drugs in this class

- [**Lapatinib** An oral dual HER2 and EGFR kinase inhibitor for HER2-positive breast cancer, with capecitabine or letrozole. Boxed… HER2 (ERBB2) and EGFR tyrosine kinases](https://durgical.com/en/pharmacology/lapatinib/)
- [**Tucatinib** A HER2-selective oral kinase inhibitor, with trastuzumab and capecitabine, for HER2-positive breast cancer, including… HER2 (ERBB2) tyrosine kinase](https://durgical.com/en/pharmacology/tucatinib/)

## Others in the class

- neratinib

## Test yourself

Think of the answer, then tap the question to see it.

## How do HER2 kinase inhibitors differ from trastuzumab in where they act?

They block the kinase inside the cell; trastuzumab binds the outside of the receptor.

## Which HER2 inhibitor also inhibits EGFR reversibly?

Lapatinib.

## Why does tucatinib cause less rash than lapatinib?

It is HER2-selective and barely inhibits EGFR, whose blockade causes the skin toxicity.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=L01EH) (WHO Collaborating Centre for Drug Statistics Methodology, 2026); [Tucatinib - NCI](https://www.cancer.gov/about-cancer/treatment/drugs/tucatinib) (National Cancer Institute, 2024).

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