HER2-Targeted Therapy Shows Promise across Tumor Types

The antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; Enhertu; Daiichi Sankyo/AstraZeneca) has shown promising activity across multiple types of HER2-expressing advanced solid tumors, including traditionally hard-to-treat malignancies, according to data presented at the 2023 American Society of Clinical Oncology Annual Meeting in Chicago, IL, June 2–6. The findings may eventually lead to approval of a tumor-agnostic anti-HER2 therapy.

“These results represent a shift in how we think about cancer care,” said Bradley McGregor, MD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the study. “Seeing that we can deliver chemotherapy through an ADC and have efficacy, with no new safety signals, across a variety of tumor types is very, very encouraging.”

The phase II, open-label DESTINY-PanTumor02 study enrolled 267 patients with HER2-expressing locally advanced or metastatic cancers, including biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic, as well as rare tumors, whose disease had progressed following prior treatment or who had few treatment options. After a median of 9.7 months, treatment with T-DXd resulted in an overall objective response rate (ORR) of 37.1% and a median duration of response (mDOR) of 11.8 months—with 46.1% having stable disease at data cutoff.

The drug was most effective in patients with the highest levels of HER2 expression as assessed by immunohistochemistry—namely a score of IHC 3+. Among those patients, the ORR was 61.3% and the mDOR was 22.1 months. Additionally, patients with endometrial, cervical, and ovarian cancers had higher ORRs, ranging from 45% to 57.5%, compared with other tumor types, which ranged from 4% to 39%. Treatment in the pancreatic cancer group, which had the lowest response rate, was stopped early; only two patients in the group were considered IHC 3+.

While T-DXd is already the standard of care for HER2-expressing breast cancer, HER2⁺ gastric cancer, and lung cancers with HER2 mutations, this is the first study to assess its effectiveness in a broader set of tumor types with low to high levels of HER2 expression.

“Patients that had a response had a deep response that was quite durable, and many patients had prolonged disease stabilization,” said the study's lead author, Funda Meric-Bernstam, MD, of The University of Texas MD Anderson Cancer Center in Houston. “Many tumor types had a more than 50% objective response rate for the IHC 3+ population.”

Patients with IHC 2+ HER2 expression had a lower but still encouraging mDOR of 9.8 months. If approved, the drug could potentially be appropriate for an even broader group of patients, said McGregor.

“These are early results with short follow-up, and further analysis is really important to understand exactly how they fit into our clinical treatment paradigms,” he said. “But if eventually we have a drug that is approved and that can make a difference, it might make sense to test more cancer patients for HER2 expression.”

The study is ongoing, with overall and progression-free survival to be assessed after additional follow-up, said Meric-Bernstam. Investigators also plan to conduct genomic analyses and examine other variables that may contribute to varied response rates across tumor types. For example, activating mutations may contribute to low response rates in pancreatic cancer, she said, as has been seen in studies of anti-HER2 therapies for colorectal and other cancers with activating KRAS mutations.

Investigators will also look at possible cross-resistance in patients who were treated with a tyrosine kinase inhibitor, as well as the effect of denser stromal tissue surrounding pancreatic tumors compared with other types of tumors. –Janet Colwell