Trastuzumab Deruxtecan Shows Promising Efficacy for HER2-Mutated NSCLC

Lyudmila Bazhenova, MD, discusses targeted therapies for patients with HER2-mutated non–small cell lung cancer.

Lyudmila Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego Health, discusses targeted therapies for patients with HER2-mutated non–small cell lung cancer (NSCLC).

HER2, which is a common biomarker in other disease types such as breast cancer, can be targeted in patients with lung cancer. Agents that targeted the HER2 exon 20 insertion mutations have been investigated in clinical trials, including trastuzumab deruxtecan (Enhertu), poziotinib, pyrotinib, and neratinib (Nerlynx).

Investigators in the phase 2 DESTINY-Lung01 trial (NCT03505710) of trastuzumab deruxtecan observed an objective response rate (ORR) of 55%, median progression-free survival (PFS) of 8.2 months, and median overall survival (OS) of 17.8 months. Bazhenova notes that pneumonitis was reported as an adverse event (AE) in 26% of patients in the trial. Trastuzumab deruxtecan has been approved for patients with breast cancer and has been granted priority review for patients with NSCLC.

Other agents have shown efficacy, but not to the degree of trastuzumab deruxtecan, according to Bazhenova. In the phase 2 ZENITH20 study (NCT03318939), poziotinib showed a 27.8% ORR, while pyrotinib had an ORR of 19.2%, median PFS of 5.6 months, and median OS of 10.5 months in a phase 2 trial (ChiCTR1800020262). Neratinib plus temsirolimus had an ORR of 19% in the phase 2 PUMA-NER-4201 trial (NCT01827267).


0:08 | There are several HER2 perturbations you can find in lung cancer. HER2 can be overexpressed, amplified, or mutated. Currently, the majority of the [patients with HER2-mutated lung cancer] actually have mutations in HER2 called exon 20 insertions. And for this we have the efficacy of trastuzumab deruxtecan, which was recently published in the New England Journal of Medicine, showing ORR of 55%, median PFS of 8.2 months, and median OS of 17 months.

[What is] important to note is that one of the AEs of trastuzumab deruxtecan is pneumonitis, which was seen in approximately 26% of the patients. So once, if the drug gets approved and we start using it in lung cancer, it is very important to be aware of the pneumonitis as [an] AE.

1:06 | There are a couple of other medications being developed [for] the HER2 exon 20 insertions and those are poziotinib, pyrotinib, and neratinib, but the efficacy data looks pretty inferior, at least on a cross-trial comparison compared with trastuzumab deruxtecan.