Mobocertinib Plus T-DM1 Combo Shows Efficacy in HER2 Exon 20 Insertion–Mutant Lung Cancer Cell Lines

Article

With the combination of mobocertinib and T-DM1, potent preclinical efficacy was observed in lung cancer cells with HER2 exon 20 insertion mutations.

Preclinical data on the use of mobocertinib (TAK-788) in combination with trastuzumab emtansine (T-DM1; Kadcyla) showed that the regimen resulted in inhibition of HER2 exon 20 insertion–mutant lung cancer call lines, according to data presented during the 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.

Reference

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.

Newsletter

Stay up to date on recent advances in the multidisciplinary approach to cancer.

Recent Videos
Success with the 177Lu-PSMA-617 radioligand therapy would be transformative for the clear cell renal cell carcinoma treatment landscape.
An ongoing phase 1 trial seeks to prove XmAb819 as an effective treatment and ENPP3 as a plausible target in patients with relapsed or refractory RCC.
“The therapy is designed to prevent both CAR T-cell inactivation and to restore the anti-tumor immunity of the white blood cells that have gotten through the tumor,” said Marasco, MD, PhD.
Ongoing studies aim to combine base immunotherapy regimens with novel agents to potentially improve outcomes among patients with kidney cancer.
Investigators have found a way to reduce liver and biliary toxicity when targeting the molecule CAIX in patients with clear cell renal cell carcinoma.
Neoantigen-targeting vaccines resulted in an absence of recurrence in 9 patients with high-risk kidney cancer, according to David A. Braun, MD, PhD.
The Kidney Cancer Research Consortium may allow collaborators to form more mechanistic and scientifically driven efforts in the field.
Wayne A. Marasco, MD, PhD, stated that by targeting 2 molecules instead of 1, higher levels of tumor cell killing can be achieved in patients with clear cell renal cell carcinoma.
Leading experts in the breast cancer field highlight the use of CDK4/6 inhibitors, antibody-drug conjugates, and other treatment modalities.
Related Content