Mobocertinib Plus T-DM1 Elicits Preclinical Activity in HER2 Exon 20 Insertion+ Lung Cancer Models

Mobocertinib plus ado-trastuzumab emtansine demonstrated inhibitory effects in HER2 exon 20 insertion–mutated lung cancer cell lines.

Mobocertinib (TAK-788) plus ado-trastuzumab emtansine (T-DM1; Kadcyla) demonstrated inhibitory effects in HER2 exon 20 insertion–mutated lung cancer cell lines, according to preclinical findings presented during the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.

Investigators found that adding T-DM1 to mobocertinib resulted in shrinkage of tumors with acquired resistance against mobocertinib monotherapy at around 6 weeks.

“Mobocertinib in combination with T-DM1 exhibits potent efficacy in HER2 exon 20 YVMA mutant lung cancer,” Han Han, MD, from New York University Medical Center, said during a presentation of the data.

Using a patient-derived xenograft model, mobocertinib has shown inhibition against HER2 exon 20 insertion–mutant cell lines. This was confirmed in a phase 2 clinical trial (NCT02716116) in patients with non–small cell lung cancer and mutations in HER2 exon 20 insertions.

The off-target effects on Y-type EGFR from tyrosine kinase inhibitors (TKIs) is a major contributor to adverse effects. When compared with other TKIs, mobocertinib was found to have better selectivity for HER2 exon 20 insertions, which investigators believe may result in a better safety profile on patients.

Using human lung cancer cell lines with HER2 exon 20 G776>VC deletion insertion and HER2 exon 20 YVMA mutations, which cover more than 90% of all HER2 exon 20 insertion mutations in human lung cancer, mobocertinib’s inhibitory activity against these tumors was demonstrated. However, exon 20 YVMA–mutant cell lines would become resistant after 4 to 6 weeks of treatment.

Investigators noted elevated HER2 expression by flow cytometry on H1781 and Ba/F3 YVMA cell lines with mobocertinib treatment. Additionally, upregulation of HER2 by mRNA level was recorded.

These findings led to the use of 3 candidate agents plus mobocertinib, with T-DM1 showing the best efficacy. Progression-free survival was extended with its use and was able to overcome acquired resistance with mobocertinib monotherapy.


  1. Han H, Li S, Chen T, et al. Targeting HER2 exon 20 insertion-mutant lung adenocarcinoma with a novel tyrosine kinase inhibitor-mobocertinib. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract MA11.02.