Targeted therapy induces a response in HER2-amplified bile ducts

ABSTRACT: 4008

CHICAGO ― The HER2-targeted bispecific antibody zanidatamab shows a durable response in patients with treatment-resistant HER2-positive bile duct cancer (BTC), researchers from The University of Texas MD Anderson Cancer Center report to the American Society of Clinical Oncology (ASCO) Annual 2023 Meeting. Study results were also published today in Lancet oncology.

In the first cohort of the HERIZON-BTC-01 Phase II global trial, covering 80 patients with HER2-positive tumors, the objective confirmed response rate (cORR) was 41% with a mean response duration (DOR) of 12.9 months with a median follow-up of 12.4 months. Among the 33 respondents, 49% had sustained responses and 82% had responses that lasted more than 16 weeks. This is the largest study of HER2-targeted drugs in BTC.

“Chemotherapy for patients with bile duct cancer who have progressed to first-line therapy is usually associated with a 5% response rate,” said global trial lead Shubham Pant, MD, professor of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics.. “These results provide evidence that zanidatamab can achieve a lasting response and may offer new treatment opportunities for patients who previously had limited options.”

Patients with advanced BTC who progress after first-line treatment are offered standard-of-care therapy with limited clinical benefit and only modest improvement in survival. HER2-targeted therapy has improved survival in HER2-positive breast and gastric cancers, but there are currently no approved HER2-targeted therapies for BTC.

Zanidatamab was first evaluated in a Phase I trial led by Funda Meric-Bernstam, MD, chair of Investigational Cancer Therapeutics. The trial results support HER2 as an actionable target in various types of cancer, including bile duct cancer. Based on these results, MD Anderson investigators are advancing zanidatamab into this Phase II trial for patients with BTC.

Bile duct cancer, also known as cholangiocarcinoma, develops in the bile ducts, the thin series of tubes that run from the liver to the small intestine. There are three types of BTC, whose names are based on the location where the cancer forms. According to the American Cancer Society, about 8,000 people in the US are diagnosed each year with BTC. However, the true count is likely higher because these cancers are difficult to diagnose and are often misclassified, explains Pant. The five-year survival rate for metastatic BTC is less than 5%, highlighting the urgent need for new treatments.

This open-label single-arm trial evaluated the anti-tumor activity of zanidatamab in patients with advanced HER2-amplified BTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. Trials were conducted in 67 locations; Patients were divided into two cohorts based on HER2 expression (positive or low/negative) by tumor immunohistochemistry. The primary end point was the corr in the HER2-positive cohort.

The study enrolled 80 patients in the HER2-positive cohort and seven patients in the HER2-low/negative cohort. All patients had received a previous line of gemcitabine-containing therapy. The mean age was 64 years and the patients were 65.5% Asian, 28.7% white and 5.7% other. Of the trial participants, 52% had gallbladder cancer, 30% had intrahepatic cholangiocarcinoma, and 18% had extrahepatic cholangiocarcinoma.

No response to zanidatamab was observed in the HER2-low/negative group. In both cohorts, grade 3 treatment-related adverse events occurred in 18% of patients. Two patients (2.3%) discontinued zanidatamab because of side effects. No side effects related to grade 4 or 5 treatment were reported.

“Given these data, we strongly believe that there should be ongoing efforts to explore zanidatamab as a viable treatment option for HER2-positive bile duct cancer,” said Pant. “We are encouraged by the potential impact of zanidatamab in improving patient outcomes.”

Pant and his team are still evaluating progression-free survival and overall survival in these patients. In addition, clinical trials are underway to further investigate the therapeutic potential of zanidatamab as monotherapy in combination with first-line chemotherapy for HER2-positive BTC.

This study was funded by Zymeworks BC Inc. and BeiGene Ltd. Pant has worked in a consulting/advisory role for and received research support from Zymeworks. The full list of co-authors and their disclosures can be found here.

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