Trastuzumab Deruxtecan Shows Promise in HER2 Targeted Therapy

The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) showed promising activity in multiple non-breast/non-gastric cancer types with heavily pretreated HER2-expressing or HER2-mutant solid tumors, according to a recent study published in Cancer Discovery.¹

More specifically, the T-DXd combination showed even greater antitumor activity in patients with HER2-mutant non-small cell lung cancer (NSCLC).

"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," Bob Li, MD, senior author on the study said in a press release. ² "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."

The phase I study enrolled 60 patients with HER2-expressing non-breast/non-gastric and/or HER2-mutant solid tumors (colorectal cancer, n = 20; NSCLC, n = 18; and other, n = 22). Of the 60 enrollees, 59 patients received ≥1 dose of 6.4 mg/kg of the T-DXd combination. The researchers tested the safety and efficacy of T-DXd in patients with different advanced HER2-tumors.

“In this first-in-human clinical study investigating T-DXd for treatment of patients with advanced solid tumors, the 6.4 mg/kg dose demonstrated encouraging preliminary antitumor activity with an acceptable safety profile in patients with heavily pretreated, HER2-expressing and/or HER2-mutant solid tumors,” wrote the researchers.

Moving forward, the researchers stress that there is a newfound need to develop new treatment options for patients with HER2 tumors outside of HER2-breast and gastric cancer because of the limited efficacy of conventional therapies. More, further studies are requested by the researchers to examine the efficacy of treatment in a HER2-overexpressing population of patients with colorectal cancer is warranted because of the small sample size included in this study.

Limitations of the study were important to note, starting with the fact that the study implemented a nonrandomized, small sample to conduct research. This means the results should be limited to exploratory, with further studies exploring the research deeper. More, the biomarker selection was heterogenous, resulting in a lack of data for the full spectrum of concomitant mutations and their response to T-DXd.

The T-DXd combination incorporates a cytotoxic inhibitor of DNA replication called DXd and combines it with an antibody directed to HER2. This antibody binds to HER2-expressing cancer cells, while DXd is then released into the target cell, where its “inhibitory effect on DNA replication leads to cell death.”

“T-DXd demonstrated promising antitumor activity with an acceptable safety profile in patients with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially in HER2-mutant NSCLC,” wrote the researchers. “If the results of this trial are replicated in subsequent trials, T-DXd may represent a promising option for patients with a variety of HER2-expressing or HER2-mutant cancers, for which there are no approved HER2-targeted therapies.”

References:

1. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discovery. DOI: 10.1158/2159-8290.CD-19-1014.

2. HER2-targeted therapy trastuzumab deruxtecan shows early promise in patients with non-breast and non-gastric cancers [news release]. Published March 25, 2020. https://medicalxpress.com/news/2020-03-her2-targeted-therapy-trastuzumab-deruxtecan-early.html. Accessed March 25, 2020.