A HER2-targeted antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki (Enhertu), showed signs of clinical activity in multiple non-breast/non-gastric cancer types, according to results from a phase I study.
In the study published in Cancer Discovery, a journal of the American Association for Cancer Research, Tsurutani, Li, and colleagues tested the safety and clinical activity of the HER2-targeted antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with several different advanced HER2-overexpressing or HER2-mutated solid tumors. T-DXd combines a cytotoxic inhibitor of DNA replication called DXd with an antibody directed to HER2.
Junji Tsurutani, MD, PhD, medical oncologist at the Advanced Cancer Translational Research Institute at Showa University in Tokyo is the lead author of the study; together with senior author; Bob Li, MD, medical oncologist at Memorial Sloan Kettering Cancer Center.
High expression levels of HER2 have been observed in many different cancer types, including breast, gastric, lung, and colorectal cancers. Several HER2-targeted therapies are approved for the treatment of HER2-overexpressing breast cancer, and one such therapy is approved for gastric cancer.
“HER2-targeted therapies have proven successful for patients with breast and gastric cancers; however, there are no approved HER2-targeted therapies available for patients with other HER2-overexpressing or HER2-mutated malignancies,” said Li. “Conventional therapies for these other HER2-overexpressing cancers tend to have limited efficacy and considerable side effects. Additional treatment options are urgently needed for these patients.”
“Therapies that target HER2 can be selectively directed to HER2-overexpressing or HER2-mutated cancer cells, which could improve efficacy and help reduce toxicities caused by off-target effects on normal cells,” said Tsurutani. Moreover, advances in diagnostic testing have improved clinicians’ ability to determine a tumour’s HER2 status and have thus expanded the population of patients who might benefit from HER2-targeted therapies, explained Tsurutani.
In another study published by Li and colleagues in Cancer Discovery, T-DXd led to a partial response in a patient with lung cancer who had relapsed after treatment with another HER2-targeted ADC, ado-trastuzumab emtansine (T-DM1). This study also demonstrated that T-DM1 treatment led to clinical responses in patients with HER2-mutant or amplified lung cancers, and that combining T-DM1 with an irreversible HER kinase inhibitor enhanced cellular uptake of the drug in cell culture. Furthermore, combination treatment with T-DM1 and an irreversible HER kinase inhibitor led to a partial response in a patient with breast cancer who had previously relapsed on T-DM1. Together, results from this second study suggest that T-DXd or a combination of T-DM1 and a HER kinase inhibitor could be explored as potential treatment options for patients with relapse on T-DM1. [APBN]