Novel Conjugate Shows Promise in HER2-Expressing Cancers

The novel antibody-drug conjugate trastuzumab duocarmazine showed promising clinical activity and was reasonably well tolerated in an early-phase trial of patients with heavily pretreated HER2-expressing metastatic cancers, including breast cancer.

“HER2-positive metastatic breast cancer is still incurable and eventual development of resistance to [HER2-targeted] treatments is almost inevitable,” wrote study authors led by Udai Banerji, MD, of the Institute of Cancer Research and the Royal Marsden in London. “New drugs that also target cancers with low HER2 expression will address an unmet need in several tumor types.”

Trastuzumab duocarmazine combines trastuzumab with a linker drug containing duocarmycin. In preclinical research, the conjugate has shown promising antitumor activity in breast, ovarian, and other cancers with varying levels of HER2 expression.

The researchers conducted a phase I dose-escalation trial including 39 patients, and a dose-expansion phase including another 146 patients. The dose-escalation portion included patients with metastatic solid tumors with variable HER2 status who were refractory to standard therapies; the expansion phase included patients with breast (99 patients; 50 had HER2-positive disease), gastric (17 patients), urothelial (16 patients), and endometrial (14 patients) cancers. Results of the study were published in Lancet Oncology.

The patients included were heavily pretreated, with a mean of 5.2 previous lines of therapy. Most of the HER2-positive breast cancer patients had received trastuzumab emtansine (80%). The full cohort was followed for a median of 5.0 months.

The dose-escalation phase of the trial yielded a recommended phase II dose of 1.2 mg/kg. In the expansion phase, treatment-related serious adverse events (AEs) occurred in 11% of patients; these included infusion-related reactions (1%) and dyspnea (1%), among others.

The most common treatment-related AEs of any grade included fatigue (33%), conjunctivitis (31%), and dry eye (31%). Ocular AEs were reported in 71% of the cohort.

The agent showed some promising clinical activity. Of 48 assessable patients with HER2-positive breast cancer, 16 achieved a partial objective response (33%). Notably, 9 patients (28%) with HER2-low, hormone receptor (HR)-positive breast cancer and 6 patients (40%) with HER2-low HR-negative disease also achieved an objective response.

One patient with gastric cancer (6%), 4 with urothelial cancer (25%), and 5 patients with endometrial cancer (39%) also achieved a response.

“This phase I study of trastuzumab duocarmazine has shown important and relevant clinical activity and a manageable safety profile in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine–resistant and HER2-low breast cancer,” the authors concluded. Trastuzumab duocarmazine is currently being tested against physician’s choice for metastatic breast cancer in the phase III TULIP trial.

In an accompanying editorial led by Xavier Pivot, MD, PhD, of the Paul Strauss Cancer Center in Strasbourg, experts noted that a number of antibody-drug conjugates involving trastuzumab are in development, as its chemical makeup allows a cytotoxic agent to be linked without affecting its binding ability to HER2. “The encouraging results from this first-in-human study with this new drug help to support the notion that the family of antibody-drug conjugates could serve as new agents with many modalities of anticancer activity, allowing for multiple new strategies in the treatment of cancer,” they wrote.