FDA Approves Zanidatamab for Previously Treated, Unresectable or Metastatic HER2+ Biliary Tract Cancer

FDA

The FDA has granted accelerated approval to zanidatamab-hrii (Ziihera) for adult patients with previously treated, unresectable or metastatic HER2-positive (immunohistochemistry 3+) biliary tract cancer, as detected by an FDA-approved test.¹

The regulatory decision was supported by data from the phase 2b HERIZON-BTC-01 trial (NCT04466891), which showed that patients treated with the bispecific antibody (n = 62) experienced an overall response rate (ORR) of 52% (95% CI, 39%-65%) and an estimated median duration of response of 14.9 months (95% CI, 7.4-not estimable).

"Biliary tract cancer is a devastating disease with a poor prognosis and 5-year survival rates under 5% in the metastatic setting. Patients with unresectable or metastatic HER2-positive biliary tract cancer have had a high unmet need with limited treatment options and few approved therapies," Rob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, stated in a news release. "The approval of [zanidatamab], which previously received breakthrough therapy designation from the FDA for this indication, is an important advance and offers the first and only dual HER2-targeted bispecific antibody and chemotherapy-free treatment for patients living with biliary tract cancer. We look forward to advancing research of zanidatamab in biliary tract cancer and other HER2-expressing solid tumors, with the goal of improving outcomes for more people diagnosed with these difficult-to-treat HER2-positive cancers."

Updated data presented at the 2024 ASCO Annual Meeting demonstrated that in the overall evaluable population enrolled in cohort 1 (n = 80), which included patients with HER2-positive IHC 3+ disease (n = 62) and IHC 2+ disease (n = 18), the confirmed ORR was 41.3%; the disease control rate was 68.8%.² The confirmed ORRs were 51.6% and 5.6% in the IHC 3+ and IHC 2+ subgroups, respectively. At a median follow-up of 22 months (range, 16-34), the median DOR increased to 14.9 months (95% CI, 7.4-not reached).

HERIZON-BTC-01 enrolled patients at least 18 years of age with advanced or metastatic HER2-positive biliary tract cancer. Prior treatment with a gemcitabine-containing regimen was required; however, prior HER2-targeted therapies were not permitted. Other key inclusion criteria consisted of at least 1 measurable lesion per RECIST 1.1 criteria and an ECOG performance status of 0 or 1.

Patients with HER2-positive IHC 3+ or 2+ disease were enrolled in cohort 1, and those with IHC 0 or 1+ disease were included in cohort 2 (n = 7). All patients received zanidatamab at 20 mg/kg once every 2 weeks in 28-day cycles. Infusion-related reaction prophylaxis was required.

Confirmed ORR per independent central review served as the trial's primary end point. Secondary end points included DOR, DCR, progression-free survival, overall survival (OS), and safety.

Additional updated data showed that the median OS was 15.5 months (95% CI, 10.4-18.5) in the overall population in cohort 1, 18.1 months (95% CI, 12.2-23.2) in patients with HER2-positive IHC 3+ disease, and 5.2 months (95% CI, 3.1-10.2) in those with IHC 2+ disease. The 12-month OS rates were 56.2% (95% CI, 44.3%-66.5%), 65.0% (95% CI, 51.6%-75.6%), and 20.8% (95% CI, 5.1%-43.7%), respectively.

Among patients treated in cohorts 1 and 2 (n = 87), 96.6% experienced any-grade treatment-emergent adverse effects (TEAEs). Any-grade treatment-related AEs (TRAEs) occurred in 72.4% of patients at grades 1 or 2 (51.7%) or grade 3 or 4 (20.7%). No grade 5 TRAEs were reported. Serious TRAEs were observed in 9.2% of patients, and TRAEs led to treatment discontinuation in 2.3% of patients.

The most common TRAEs included diarrhea (any-grade, 36.8%; grade 3/4, 4.6%), infusion-related reaction (33.3%; 1 .1%), decreased ejection fraction (10.3%; 3.4%), nausea (9.2%; 1.1%), increased alanine aminotransferase levels (6.9%; 1.1%), increased aspartate aminotransferase levels (6.9%; 2.3%), vomiting (6.9%; 0%), fatigue (5.7%; 0%), and anemia (4.6%; 3.4%).

Under the accelerated approval pathway, the FDA may require verification and description of clinical benefit for zanidatamab in a confirmatory trial for continued approval in this indication.¹

"As a clinical investigator and medical oncologist focused on advancing the care of patients with biliary tract and liver cancers, I have experienced firsthand the significant unmet need for effective therapies for patients with these diseases," James Harding, MD, associate attending physician, Gastrointestinal Oncology and Early Drug Development Services, Memorial Sloan Kettering Cancer Center, added in a news release. "Zanidatamab has demonstrated antitumor activity and is now a new option for patients with HER2-positive biliary tract cancer. I look forward to continued and successful drug development for patients with biliary tract cancer."

References

1. 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 20, 2024. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-ziiherar
2. 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