HER2 exon 20 inhibitor (BI 1810631)

HER2 exon 20 inhibitor (BI 1810631)

HER2 exon 20 inhibitor

BI 1810631: HER2 exon 20 inhibitor

BI 1810631* is a human epidermal growth factor receptor 2 (HER2) exon 20 inhibitor that selectively and covalently binds to the tyrosine kinase domain of both wild type and mutated HER2 receptors, including those with an exon 20 insertion.1

Clinical Trials: A global Phase I trial is underway to evaluate BI 1810631 in the treatment of advanced or metastatic solid tumors with HER2 aberrations.2

Role of HER2

HER2 (ErbB2) is a member of the ErbB family of receptor tyrosine kinases, which also includes epidermal growth factor receptor (EGFR), ErbB3, and HER4.3 HER2 is the preferred dimerization partner for ErbB family receptors, despite being the only member that lacks a ligand-binding domain.3,4 Ligand binding and dimerization of these receptors activate signaling pathways that promote cell proliferation and survival.4,5

Mutations in HER2 can lead to overexpression or overactivation, which results in uncontrolled cell proliferation, inhibition of apoptosis, and promotion of tumor growth and spread.4,6,7 HER2 exon 20 insertions are seen across a number of different cancer types, with a high prevalence in non-small cell lung cancer (NSCLC), where more than 90% of HER2 mutations may be exon 20 insertions.8,9 

Of note, none of the currently approved EGFR tyrosine kinase inhibitors (TKIs) have demonstrated sustainable clinical activity against HER2 exon 20-driven tumors, resulting in a significant unmet medical need for new agents.10 

About BI 1810631

Mechanism of action

BI 1810631 selectively and covalently binds to the tyrosine kinase domain of mutated HER2 receptors with an exon 20 insertion.1 Selective binding blocks aberrant downstream signaling, while sparing wild-type EGFR signaling, thereby avoiding wild-type EGFR-associated toxicity.1 This could result in better tolerability and the potential for more effective dosing, compared to current second-generation TKIs.1 

BI 1810631 mechanism of action1

HER2 exon 20 inhibitor mechanism of action
EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; WT, wild type.

Clinical development

The efficacy and tolerability of BI 1810631 were observed in a HER2-mutant lung cancer xenograft model at clinically relevant doses.1

BI 1810631 is currently undergoing clinical investigation as a monotherapy in patients that had previously unsuccessful treatment for advanced or metastatic solid tumours.2

More information about Boehringer Ingelheim oncology clinical trials can be found on the MyStudyWindow website. Relevant trials for BI 1810631 include: BI 1479-0001.

HER2 exon 20 inhibitor (BI 1810631) clinical trials

HER, human epidermal growth factor receptor; NSCLC, non-small cell lung cancer.
Trial number Phase Treatment Patient population Status

NCT04886804 (1479-0001)2

I

BI 1810631

Advanced or metastatic solid tumours with HER2 aberrations (dose escalation phase); NSCLC with HER2 exon 20 mutation (dose expansion phase)

Recruiting

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References

1

Boehringer Ingelheim. Data on file.

2

 ClinicalTrials.gov. NCT04886804. https://clinicaltrials.gov/ct2/show/NCT04886804 (Accessed September 2021).

3

Cocco E, et al. Pharmacol Ther 2019;199:188–196. 

4

Tai W, et al. J Control Release 2010;146(3):264–75.

5

Hynes NE, et al. Nat Rev Cancer 2005;5(5):341-54.

6

Gazdar AF. Cancer Metastasis Rev 2010;29(1):37-48.

7

Connell CM, Doherty GJ. ESMO Open 2017;2(5):e000279.

8

Mishra R, et al. Oncotarget 2017;8(69):114371–92.

9

Vyse S, Huang PH. Signal Transduct Target Ther 2019;4:5.

10

Baraibar I, et al. Crit Rev Oncol Hematol 2020;148:102906.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

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Page last updated: September 2021