Zanidatamab update adds support for HER2-positive biliary tract cancer therapy

medwireNews: The final analysis of the HERIZON-BTC-01 trial points to a durable clinical benefit for zanidatamab in patients with treatment-refractory, HER2-positive biliary tract cancer (BTC), the investigators report.

The phase 2b study of the dual HER2-targeted bispecific antibody included 80 patients (56% women, median age 64 years) with previously treated, unresectable or metastatic disease, despite receiving gemcitabine chemotherapy, and an immunohistochemistry (IHC) score for HER2 overexpression of 2+ or 3+. Participants received zanidatamab 20 mg/kg every 2 weeks in 28-day cycles until discontinuation criteria were met, and 44.0% switched to another treatment after ending zanidatamab therapy.

At a median follow-up of 33.4 months, the primary endpoint of confirmed objective response rate (cORR) was 41.3%, with a median response duration of 14.9 months. There were three complete and 30 partial responses, while 22 patients had stable disease and 24 progressive disease, giving a disease control rate of 69%. The median progression-free survival and overall survival (OS) durations were 5.5 and 15.5 months, respectively.

James Harding (Memorial Sloan Kettering Cance Center, New York, USA) and co-authors of the research letter to JAMA Oncology say that two patients who were initially reported as having a partial response achieved a complete response by the final analysis, “supporting continued benefit with zanidatamab.”

Of note, the 62 participants with IHC 3+ had better outcomes than the 18 patients with IHC 2+ for both cORR (51.6 vs 5.6%) and median OS duration (18.1 vs 5.2 months).

“Relative to IHC 3+ tumors, the more modest activity in IHC 2+/amplified tumors observed here supports reflex IHC testing and identifies a cohort for deeper investigation,” the investigators comment.

Furthermore, there was a correlation between zanidatamab response and improvement from baseline on the Brief Pain Inventory-Short Form worst score, suggesting “potential positive impact on quality of life,” the researchers say.

Specifically, participants who experienced a complete or partial response had respective decreases of 4.0 points and 1.0 point (on a scale of 0–10 points, where 10 points equals worst pain imaginable), whereas those with progressive disease had an increase of 2.4 points.

There were “[n]o new safety concerns” with zanidatamab therapy or treatment-related deaths, the investigators note. Diarrhea, decreased ejection fraction, and anemia were the only grade 3 treatment-related adverse events occurring in more than two patients (5.0, 3.8, and 3.8%, respectively), and 3.0% of patients discontinued treatment due to side effects.

“These findings support the clinically meaningful benefit of zanidatamab for patients with treatment-refractory HER2-positive BTC,” write Harding et al.

“The ongoing phase 3 HERIZON-BTC-302 trial (NCT06282575) is evaluating zanidatamab with standard-of care first-line treatment in patients with HER2-positive (IHC 3+ or IHC 2+/amplified) BTC,” they add.

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JAMA Oncol 2025; doi:10.1001.jamaoncol.2025.4736