Zanidatamab Demonstrates Activity in Pretreated HER2+ Biliary Tract Cancer

By targeting both extracellular domain 2 (ECD2) and 4 (ECD4) with the novel bispecific antibody zanidatamab investigators are hopeful that they will be able to offer patients an agent with a unique mechanism of action capable of improving upon the poor outcomes associated with second-line FOLFOX in patients with HER2-positive biliary tract cancer (BTC), according to Shubham Pant, MD, MBBS.

“Zanidatamab is a HER2-directed bispecific [antibody that] binds to two different domains on the HER2 protein,” Pant explained. “It’s similar to where trastuzumab [Herceptin] and pertuzumab [Perjeta] bind––ECD2 and ECD4––but it’s in one compound. Mechanistically [this leads to] potentially better drug delivery.”

At the July 28, 2023, data cutoff, and a median follow-up of 21.9 months (range, 16-34), findings from a long-term analysis of the phase 2b HERIZON-BTC-01 trial (NCT04466891) demonstrated that patients with HER2-positive BTC who received zanidatamab (n = 80) achieved a median overall survival (OS) of 15.5 months (95% CI, 10.4-18.5); the 6- and 12-month OS rates were 80.3% (95% CI, 69.4%-87.6%) and 56.2% (95% CI, 44.3%-66.5%), respectively. Additionally, the confirmed objective response rate (ORR) was 41.3% (95% CI, 30.4%-52.8%), including a 2.5% complete response rate, and the median duration of response (DOR) was 14.9 months (95% CI, 7.4-not reached).¹

In an interview with OncLive, Pant, professor, Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in Houston, Texas, discussed the significance of the updated findings from HERIZON-BTC-01, which he presented in a poster during the 2024 ASCO Annual Meeting.

OncLive: What were the key findings from the primary analysis of HERIZON-BTC-01 that were previously presented?

Pant: [This] was a global trial in patients with BTC. [During the 2023 ASCO Annual Meeting], we presented [results from] the cohort of patients with advanced BTC who had an immunohistochemistry [IHC] of 2-plus or 3-plus, who were in situ hybridization-positive and HER2-positive. [The study enrolled] 80 patients.

Zanidatamab was [administered] once intravenously every 2 weeks, and we [evaluated] ORR and progression-free survival. At the time when we reported the results this past year, the ORR was 41.3%. FOLFOX, which is an unselected second-line [therapy] for BTC, [confers an ORR of approximately] 5% and [with zanidatamab we saw] a 41.3% response rate. The DOR was [approximately] 12.9 months. The patients who [achieved] a response responded [for a] longer [period].

This year we [presented] an updated follow-up analysis. The ORR was unchanged at 41.3%, but the DOR increased to 14.9 months, so the responding patients stayed on the therapy for a longer [period]. We also reported the median OS, which was 15.5 months.

This is a population [with advanced disease], so these are good results. We also [examined] the long-term adverse effects [and these] remained about the same, with no new safety signals. The results that we reported last year held up, and we saw an improvement in DOR.

Were there any findings regarding patient-reported outcomes that were of note?

There was an improvement in the patient-reported outcomes and quality of life [outcomes]. In responding patients, we [observed an] improvement in all those outcomes. These were presented this year at the 2024 Gastrointestinal Cancers Symposium.

How could zanidatamab potentially address unmet needs for patients with HER2-positive BTC?

It’s an important trial because it is the first of its kind only in HER2-positive BTC. There is an unmet need [because] second-line FOLFOX has an [approximate] 5% response rate. We need new therapeutics for these patients.

It’s interesting to see that HER2 is an oncogenic driver in this disease. That means if [a patient] is HER2-positive and you target it, you can potentially get these higher response rates. Now we are at the next point in the clinical development [of zanidatamab] where we are going to [conduct] a phase 3 trial in frontline patients. [In this randomized trial], we are going to [compare] zanidatamab with the standard of care in the first-line setting of HER2-positive BTC.

Reference

1. Pant S, Fan J, Oh DY, et al. Zanidatamab in previously-treated HER2-positive (HER2+) biliary tract cancer (BTC): overall survival (OS) and longer follow-up from the phase 2b HERIZON-BTC-01 study. J Clin Oncol. 2024;42(suppl 16):4091. doi:10.1200/JCO.2024.42.16_suppl.4091