FDA Approves Companion Diagnostic for Zanidatamab in HER2+ Biliary Tract Cancer

The FDA has approved the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody test for use as a companion diagnostic to assess HER2-positive status in patients with biliary tract cancer and identify those eligible for treatment with zanidatamab-hrii (Ziihera).¹

On November 20, 2024, the FDA granted accelerated approval to the bispecific antibody zanidatamab for the treatment of adult patients with previously treated, unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) biliary tract cancer, as detected by an FDA-approved test.²

“This test is a step forward in furthering access to personalized medicine,” Jill German, head of the Pathology Lab at Roche Diagnostics, stated in a news release.¹ “The prognosis for patients diagnosed with biliary tract cancer is poor, as very few treatment options exist. Now, these patients have access to the first standardized test that could make them eligible for targeted therapy, potentially improving clinical outcomes.”

The FDA approval of zanidatamab was backed by findings from the phase 2b HERIZON-BTC-01 trial (NCT04466891), which enrolled 87 patients with HER2-amplified, locally advanced unresectable or metastatic biliary tract cancer, including gallbladder cancer and intra-/extra-hepatic cholangiocarcinoma, who had received prior gemcitabine-containing therapy.² Patients were excluded if they had received prior HER2-targeted therapy. All patients needed to have centrally confirmed HER2 status on tissue samples.

Patients received intravenous zanidatamab at 20 mg/kg every 2 weeks. Confirmed overall response rate (cORR) by independent central review served as the primary end point. Key secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival (OS), and safety.³

The data that supported the approval showed that patients with HER2 IHC 3+ biliary tract cancer who received the bispecific antibody (n = 62) achieved an ORR of 52% (95% CI, 39%-65%) and an estimated median DOR of 14.9 months (95% CI, 7.4-not evaluable).^2,3

Long-term follow-up data presented at the 2024 ASCO Annual Meeting showed that at a median follow-up of 22 months (range, 16-34) and a data cutoff date of July 28, 2023, the cORR and DCR were maintained from the primary analysis in patients with HER2-positive disease, at 41.3% and 68.8%, respectively.³ One additional patient had achieved a complete response. A preplanned subgroup analysis of cORR by HER2 expression demonstrated cORRs in both the IHC 3+ and IHC 2+ cohorts at 51.6% and 5.6%, respectively.

The median DOR increased to 14.9 months (95% CI, 7.4-not reached) from the primary analysis. The median OS was 15.5 months (95% CI, 10.4-18.5). The median OS in the IHC 3+ and IHC 2+ cohorts was 18.1 months (95% CI, 12.2-23.2) and 5.2 months (3.1-10.2), respectively. The 12-month OS rate was 56.2% (95% CI, 44.3%-66.5%) in the HER2-positive population; this rate was 65.0% (95% CI, 51.6%-75.6%) and 20.8% (95% CI, 5.1%-43.7%) in the IHC 3+ and IHC 2+ cohorts, respectively.

Safety was evaluated in 87 patients in HERIZON-BTC-01. A total of 96.6% of patients had any treatment-emergent adverse effects (AEs); 72.4% of patients had any treatment-related AEs (TRAEs; grade 1/2, 51.7%; grade 3/4, 20.7%). Overall, the most common any-grade TRAEs observed in patients treated with zanidatamab were diarrhea (36.8%), infusion-related reactions (33.3%), decreased injection fraction levels (10.3%), and nausea (9.2%).

Serious TRAEs occurred in 9.2% of patients who received zanidatamab. In total, 2.3% of patients who received zanidatamab permanently discontinued treatment with the agent due to an AE. However, at the long-term follow-up analysis, no patients had discontinued treatment due to a TRAE since the prior analysis. TRAEs leading to dose reductions included grade 3 diarrhea (n = 1), grade 1 diarrhea/grade 1 nausea (n = 1), and grade 2 weight decrease (n = 1).

One patient had a fatal AE of hepatic failure.² However, no deaths on the trial were attributed to zanidatamab.³

The ongoing, confirmatory phase 3 HERIZON-BTC-302 trial (NCT06282575) is evaluating frontline zanidatamab plus standard-of-care (SOC) therapy vs SOC therapy alone in patients with HER2-positive biliary tract cancer.¹

References

1. Roche receives FDA approval for first companion diagnostic to identify patients with biliary tract cancer eligible for HER2-targeted treatment with ZIIHERA. News release. Roche. November 25, 2024. Accessed November 25, 2024. https://www.prnewswire.com/news-releases/roche-receives-fda-approval-for-first-companion-diagnostic-to-identify-patients-with-biliary-tract-cancer-eligible-for-her2-targeted-treatment-with-ziihera-302314548.html
2. Jazz Pharmaceuticals announces U.S. FDA approval of Ziihera® (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). News release. Jazz Pharmaceuticals. November 20, 2024. Accessed November 25, 2024. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-ziiherar
3. Pant S, Fan J, Oh D-Y, 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