Novel Agent Active Across Heavily Pretreated HER2+ Tumors

Murali Beeram, MD

The novel bispecific antibody ZW25 induced a disease control rate (DCR) of 82% in heavily pretreated patients across several HER2-positive tumor types, according to phase I study results presented at the 2018 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium.

The DCR rate comprised a 41% (n = 7) partial response rate and a 41% (n = 7) stable disease rate. Three (18%) patients had progressive disease.

“As a clinician, I am excited by the single agent antitumor activity and tolerability we are seeing with ZW25, particularly in these patents with advanced HER2 expressing cancers that have progressed after multiple prior therapies, including HER2 targeted agents,” said study investigator Murali Beeram, MD, who presented the results at the meeting.

“In fact, trastuzumab is the only HER2 targeted therapy approved for gastric cancer and there are no approved HER2-targeted therapies for other types of cancer that are driven by the HER2 receptor. ZW25 has been well tolerated to date, which should allow it to be used in combination with other agents for potentially even better responses,” added Beeram, a clinical investigator at the START Center for Cancer Care in San Antonio.

Beeram shared data on 24 patients with HER2-expressing cancers who had received the recommended phase II dose of ZW25. Seventeen of these patients were evaluable for response, including 8 with gastroesophageal cancers, 4 with colorectal cancer, and 1 each with gall bladder cancer, cholangiocarcinoma, cervical cancer, cancer of the fallopian tube, and salivary gland cancer. The heavily pretreated patient population had received a median of 3 prior cancer treatments. Antitumor activity was evaluated every 8 weeks by RECIST criteria.

Among all 24 patients, the median progression-free survival was 6.21 months (95% CI, 1.94-9.33). The response rate was 50% in the gastroesophageal subgroup, who had received a median of 4 prior treatments. Among the 9 other evaluable patients, the response rate was 33%.

ZW25 was well tolerated. Treatment-related adverse events (AEs) were all grade 1 or 2 except for 1 case of grade 3 fatigue. AEs occurring in ≥25% of patients included diarrhea, infusion reaction, and nausea. There were no observed treatment-related serious AEs or grade 4/5 AEs.

According to manufacturer Zymeworks Inc, “ZW25 is a bispecific antibody that can simultaneously bind two nonoverlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function and has led to encouraging antitumor activity in patients.”

At the EORTC-NCI-AACR Symposium, meeting co-chair Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles, who was not an author on the study, commented, “Although these are early results on a small number of patients, they suggest that this new HER2 targeted antibody can have an effect on difficult-to-treat cancers that have either failed to respond to previous therapies or have recurred. We look forward to further results from this study, as well as the further studies that are planned.”

Beeram, M. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in HER2-expressing gastroesophageal and other cancers. Presented at: 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 13-16, 2018; Dublin, Ireland. Abstract 6.