New clinical trials to target HER2 positive solid cancers

HER2-positive cancers overexpress the human epidermal growth factor receptor 2. When expressed at abnormally high levels, HER2 leads to uncontrolled cell growth and a more aggressive behavior than their HER2-negative counterparts. Despite this, outcomes for some HER2-positive cancers, like breast cancer, are generally quite good if treated with HER2-directed therapies. For example, HER2-positive breast cancers have a 5-year survival rate of 91% for all stages. These impressive outcomes can be attributed to the arsenal of new HER2-targeted therapeutics researchers have developed in recent years. Depending on the HER2-positive cancer, patients may receive combinations of monoclonal antibodies that target HER2, tyrosine kinase inhibitors, or other chemotherapy. In some cases, patients receive antibody-drug conjugates that consist of antibodies fused to a chemotherapy drug to selectively kill cancer cells. Combining targeted therapies like antibody-drug conjugates and tyrosine kinase inhibitors is a way to potentially overcome treatment resistance and improve patient outcomes.

One benefit of tyrosine kinase inhibitors is that they are small molecules and thus able to be given as oral therapy. However, a drawback of these agents is that they lack specificity for their target, meaning that they tend to not only inhibit the activity of the target, but also can block kinases outside of their intended target. Traditional HER2-directed tyrosine kinase inhibitors can also inhibit HER1, or epidermal growth factor receptor, which is associated with adverse events like diarrhea and rashes. To avoid these off-target effects, researchers have been testing a new drug called zongertinib in combination with the HER2-targeted antibody trastuzumab, as well as antibody-drug conjugates. Zongertinib is unique because it is highly specific for HER2, relatively sparing the other tyrosine kinases that play other roles in the cell. Zongertinib is also irreversible, meaning that it forms a chemical bond to HER2 to inhibit signaling. An international group of researchers, led by Dr. Sara Hurvitz from the Clinical Research Division, hopes that this new combination of drugs can alleviate some of the adverse off-target effects patients experience during treatment. Other clinical trials have shown that antibody drug conjugates combined with a reversible HER2 inhibitor, like tucatinib, improves progression free survival for patients with breast cancer patient, but no studies have been done to study the impact of an irreversible HER2 inhibitor and antibody drug conjugate on cancer progression.

To evaluate the safety and efficacy of this therapeutic combination, the team designed a Phase Ib/II clinical trial for patients with HER2-positive metastatic breast cancer or gastric adenocarcinomas. In general, Phase I trials are designed to identified toxicities and find drug doses that minimize them, while Phase II trials determine whether the drug has the desired therapeutic effect.  An ongoing Phase Ia clinical trial for zongertinib has demonstrated that the drug is safe to use and effective at targeting their tumors. Still, questions regarding proper dosing and anticancer activity remain. Phase Ib will establish these key metrics. The team plans to enroll participants into several groups that will receive varying doses of zongertinib in combination with the approved antibody-drug conjugates T-DM1 and T-DXd or standard chemotherapy (trastuzumab and capecitabine). This phase of the trial aims to evaluate the safe dose of zongertinib in combination with these other therapies to evaluate further in a larger group of patients. Over the course of this phase, researchers will measure how quickly the drug breaks down in patients’ bodies at different doses. Following this phase, researchers will select two of the tested doses for optimization during Phase II.

During Phase II, researchers will enroll more participants into the same groups outlined above. Half of the patients in each group will receive one of the selected zongertinib doses (dose level A), and one group will receive the other dose level (dose level B). Unlike Phase Ib, Phase II will include a group treated with zongertinib only to assess how well the drug performs on its own. Before enrolling a full cohort of participants, the researchers will randomize at least six patients into the two dose groups and monitor how they respond to treatment for three weeks. If the small group of patients respond well, more participants will be enrolled into the trial, with a final goal of treating roughly 60 patients in each drug combination group. Over the course of the trial, researchers will monitor tumor size using CT and/or PET scans. They will also monitor safety of the drugs by evaluating parameters like heart and liver function. This phase of the trial will assess the percentage of participants who have their tumors shrink or completely disappear in response to the treatment.

Overall, this trial will evaluate the safety and efficacy of zongertinib in combination with other approved regimens and on its own. The team hopes that new drug options will limit off-target effects of current HER2 inhibitors and further improve survival outcomes for patients.

This work was supported by funding from Boehringer Ingelheim.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Sara Hurvitz contributed to this work.

Hurvitz S, Simonelli M, Yarza R, Berz D, Kitano S, Del Conte G, Eyzaguirre DA, Doger de Speville Uribe BG, Maier D, Erzen D, Yazgili SA, Curigliano G, Deng T, Yan M, Zhang Q, Wang X, Nakayama I, Shitara K. 2025. Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers. Future Oncol. 21(26):3385-3393. doi: 10.1080/14796694.2025.2569553.