Dr. Pennell on the Evolution of Targeting HER2 in Lung Cancer

Nathan A. Pennell, MD, PhD, an associate professor in the Department of Medicine and director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Institute of Cleveland Clinic, discusses the evolution of targeting HER2 in lung cancer.

HER2 is a target that has been around for a long time because it is used routinely in the treatment of patients with breast cancer, says Pennell. In lung cancer, it has been recognized that HER2 mutations in the HER2 tyrosine kinase domain have been present in the disease for a long time; roughly 2% of lung adenocarcinomas have HER2 mutations, adds Pennell.

Unfortunately, the current data on targeting HER2 have proven to be disappointing, according to Pennell. TKIs that target EGFR and HER2, such as afatinib (Gilotrif), have had trials, but have demonstrated relatively marginal efficacy and an effect that is short lived. However, that seems to have changed recently with the emergence of the antibody-drug conjugates (ADCs).

ADCs have shown demonstrated promising efficacy in phase 2 trials with HER2-mutant lung cancer. Over the past few years, some trials examining these agents in lung cancer have been presented at medical meetings. For example, findings from a phase 2 trial with ado-trastuzumab emtansine (Kadcyla; T-DM1) were reported, and this agent is already available for use in HER2-positive breast cancer. The agent was examined in a cohort of patients with HER2-mutant lung cancer and was found to elicit an impressive overall response rate of 44% with a promising duration of control, says Pennell. This agent was probably used off label for HER2-positive lung cancer after these data were presented, Pennell adds.

Then, an oral presentation was delivered during the 2020 ASCO Virtual Scientific Meeting on the phase 2 DESTINY-Lung01 trial, which evaluated the ADC fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-mutated lung cancer. The agent showed an impressive response rate of 61.9%, which is comparable with what is expected with other EGFR inhibitors in EGFR-mutant lung cancer. Trastuzumab deruxtecan also had an estimated progression-free survival of 14 months. For the first time, the field is starting to see targeted drugs for this patient population that mirror targeted drugs that have been developed for other molecular alterations in lung cancer, concludes Pennell.