A phase I trial reported positive results for an antibody–drug conjugate that targets HER2-positive tumors. Trastuzumab duocarmazine, which kills tumor cells by causing DNA damage, induced partial responses in 33% of patients whose tumors were resistant to the approved antibody–drug conjugate trastuzumab emtansine. The drug caused fatigue, neutropenia, pneumonitis, and eye-related side effects.

A novel antibody–drug conjugate (ADC) triggers responses in patients with HER2-expressing breast cancer and other solid tumors, a phase I clinical trial indicates (Lancet Oncol 2019;20:1124–35). The drug could become a new treatment for patients with breast cancer who are resistant to the ADC trastuzumab emtansine (Kadcyla, T-DM1; Genentech) or who have low HER2 expression.

T-DM1, a second-line treatment for patients with HER2-positive breast cancer, kills cells by inhibiting microtubule polymerization. However, patients usually develop resistance, prompting researchers to develop new ADCs. The ADC tested in the current trial, trastuzumab duocarmazine, also targets HER2-expressing cells, but its payload triggers DNA damage.

The dose-escalation portion of the trial included 39 patients with advanced or metastatic solid tumors, each of whom received 0.3 to 2.4 mg/kg of trastuzumab duocarmazine. One third of the patients reported grade 3 or 4 side effects, including fatigue and neutropenia. Many also experienced eye problems, with 31% developing conjunctivitis, for example. Four cases of pneumonitis—one fatal—occurred, all in patients who received doses of 1.5 mg/kg or higher, so researchers set the dose at 1.2 mg/kg in the dose-expansion stage of the trial.

For that portion of the study, the researchers enrolled 146 patients with metastatic HER2-expressing tumors. Fifty patients had HER2-positive breast cancer, 32 had HER2-low hormone receptor (HR)–positive breast cancer, and 17 had HER2-low HR-negative breast cancer. The remaining 47 patients had gastric, urothelial, or endometrial tumors.

Eye-related side effects were again prevalent: 71% of patients were affected by problems such as conjunctivitis, keratitis, and dry eye. These adverse effects have been seen with other ADCs—although they haven't been described with T-DM1—but the mechanism remains unclear, says co-author Philippe Aftimos, MD, of the Jules Bordet Institute and the Free University of Brussels in Belgium.

The ADC produced partial responses in 33% of the patients with HER2-positive metastatic breast cancer; 28% with HER2-low, HR-positive metastatic breast cancer; and 40% with HER2-low, HR-negative metastatic breast cancer. The median progression-free survival for these three groups was 7.6 months, 4.1 months, and 4.9 months, respectively. The researchers also saw signs of drug activity in the patients with other cancer types: Partial responses occurred in 25% of patients with urothelial cancer and 39% of those with endometrial cancer.

The results suggest that patients with HER2-positive breast cancer resistant to T-DM1 “can still respond to other ADCs with different payloads,” says co-author Udai Banerji, MD, PhD, of the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, UK. Because trastuzumab duocarmazine works through a different mechanism, it may kill cells that are resistant to T-DM1, he says.

Patients with breast cancer and low HER2 expression, for whom there are no approved anti-HER2 therapies, could also benefit from trastuzumab duocarmazine, says Aftimos. “We have proof that targeting HER2 in HER2-low breast cancer is an effective strategy.” Although trastuzumab alone does not benefit these patients, the ADC may work through a bystander effect, allowing it to kill adjacent tumor cells even if they don't overexpress HER2, he says.

The trial was too small to confirm that “this drug works at a substantial level in patients who have progressed on T-DM1,” cautions Ian Krop, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who wasn't connected to the study. But if larger studies prove definitive, he says, the ADC will be a useful addition to breast cancer treatment. “It's not a home run, but a substantial number of patients seem to benefit.” –Mitch Leslie

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