Trastuzumab Deruxtecan Targets HER2+ Cancers

The antibody–drug conjugate (ADC) trastuzumab deruxtecan (DS-8201a; Daiichi Sankyo) may be an effective treatment for patients with HER2-positive cancers whose disease has progressed despite receiving other therapies. In a phase I trial—the results of which were presented at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, IL, on June 1—patients treated with the drug had high overall response rates (ORR) and rates of tumor shrinkage, but also experienced significant side effects.

Trastuzumab deruxtecan consists of trastuzumab, a HER2-targeting monoclonal antibody, connected via a cleavable linker to deruxtecan, a cytotoxic payload composed of an exatecan derivative that inhibits topoisomerase I.

In the ongoing trial, Hiroji Iwata, MD, PhD, of the Aichi Cancer Center Hospital in Nagoya, Japan, who presented the results, reported that 111 patients with HER2-positive breast cancer and 34 patients with HER2-low breast cancer had an ORR of 54.5% and 50%, respectively. Median progression-free survival (PFS) was not reached in the HER2-positive group and was 12.9 months in the HER2-low group. In 44 patients with HER2-positive gastric cancer and 51 patients with other HER2-positive cancers, the ORR was 43.2% and 38.7%, and median PFS was 5.6 months and 12.1 months, respectively. Tumor shrinkage occurred in 86.3% of all patients.

Overall, 97.5% of patients experienced treatment-related adverse events, most of which were gastrointestinal or hematologic, and 41.9% had side effects deemed grade 3 or higher. During the trial, 9.5% of patients stopped treatment due to side effects, and 10 patients, or 4.1%, died.

“The clinical efficacy is very impressive, but the safety data needs to be carefully looked at,” said Ron Bose, MD, PhD, of the Washington University School of Medicine in St. Louis, MO, and who was not involved in the trial. “I'm concerned about the fatalities that they saw, and I think investigating ways to reduce those fatalities and mitigate the side effects needs to be done.”

Bose added that patients with metastatic HER2-positive breast cancer typically receive trastuzumab plus pertuzumab (Perjeta; Genentech) with a taxane first, then ado-trastuzumab emtansine (Kadcyla; Genentech), another trastuzumab ADC, as a second-line treatment. However, some patients still experience disease progression, so “there is definitely clinical need for new drugs for refractory HER2-positive breast cancer.”

Dennis Slamon, MD, PhD, of the University of California, Los Angeles, who was not connected to the trial, praised trastuzumab deruxtecan for a “high-potency payload” that led to a response even in patients with HER2-low breast cancer. He pointed out, however, that “the ability to potentially effectively treat low HER2–expressing cancers is indeed a two-edged sword,” because healthy cells also express HER2.

Adam Bass, MD, of Dana-Farber Cancer Institute in Boston, MA, who also wasn't involved in the trial, noted that second-line therapies that have succeeded in breast cancer, including ado-trastuzumab emtansine, have proved ineffective in gastric cancer, leaving patients with few treatment options.

“Any toxicity has to somewhat temper enthusiasm, but I think especially in gastric and gastroesophageal cancer, where we haven't had as much success as in breast cancer, seeing efficacy is encouraging,” he said. “These patients tend not to do very well with single-agent targeted therapy, so I think when you see something that has some encouraging signal, you definitely want to pursue it further.” –Catherine Caruso