Drug Trials Snapshots: ZIIHERA
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the ZIIHERA Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
ZIIHERA (zanidatamab-hrii)
(zye-HAYR-rah)
Jazz Pharmaceuticals Ireland Limited
Approval date: November 20, 2024
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
ZIIHERA is a bispecific HER2-directed antibody that is used to treat adults with previously treated, unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+]) biliary tract cancer (BTC), as detected by an FDA-approved test.
How is this drug used?
ZIIHERA is an injection. It is given by a healthcare professional directly into the vein (intravenous infusion) once every two weeks.
Who participated in the clinical trials?
FDA granted accelerated approval to ZIIHERA based predominantly on evidence from Cohort 1 of HERIZON-BTC-01 (NCT04466891) trial, which included 80 patients with previously treated unresectable or metastatic HER2-positive (IHC 2+ or 3+) BTC (cholangiocarcinoma or gall bladder cancer). The trial was conducted at 32 sites in 9 countries including Canada, Chile, China, France, Italy, the Republic of Korea, Spain, the United Kingdom, and the United States. This trial includes 17 patients treated in the United States.
The efficacy findings (N=62) represent the indicated population who had HER2 IHC 3+ expression and the safety findings (N=80) represents all study participants in Cohort 1 of HERIZON-BTC-01.
How were the trials designed?
ZIIHERA was evaluated in the HERIZON-BTC-01 study, which enrolled 87 patients with previously treated unresectable BTC in which there were extra copies of the gene that makes the HER2 protein. These patients were divided into two groups, Cohort 1 and Cohort 2. The main group (Cohort 1) had HER2 protein levels scored as intermediate (a score of 2+) or high (a score of 3+). Within this group of 80, there were 62 patients with a high score (known as IHC 3+). The second group included 7 patients who had low or no HER2 protein. All patients received ZIIHERA; there was no comparison group in the study. The trial measured how many patients had tumors that decreased in size after starting treatment, the length of time that the patient’s tumor responded to treatment, the amount of time that patients survived without disease progression, and how long patients lived. The analyses focused on the 80 patients in Cohort 1, and in particular on the 62 patients with high HER2 scores (IHC 3+).
How were the trials designed?
The efficacy of ZIIHERA was evaluated in 62 patients with HER2-positive (IHC 3+) BTC in Cohort 1 of HERIZON-BTC-01, an open-label, multicenter, single arm trial in patients with unresectable or metastatic disease. Patients were required to have received at least one prior gemcitabine-containing systemic chemotherapy regimen in the advanced disease setting and adequate cardiac function (defined as left ventricular ejection fraction ≥50%). The trial excluded patients who had received prior HER2-targeted therapies.
Patients received ZIIHERA 20 mg/kg intravenously every two weeks. ZIIHERA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate and duration of response as determined by an independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
The median age was 64 years (range: 38 to 79 years), 47% of patients were age 65 or older; 55% were female; 61% were Asian, 31% were White, 2% were American Indian or Alaskan Native, and for 6% race was unknown or not reported; 89% were not Hispanic or Latino, 8% were Hispanic or Latino, and for 3% ethnicity was unknown or not reported. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%). Fifty-three percent of patients had gallbladder cancer, 27% had intrahepatic cholangiocarcinoma, and 19% had extrahepatic cholangiocarcinoma. All patients received at least one prior line of gemcitabine-based therapy, 31% had two prior lines of therapy, and 10% had three or more prior lines of therapy for unresectable or metastatic disease.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of ZIIHERA.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race were enrolled in the clinical trial used to evaluate the efficacy of ZIIHERA.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age were enrolled in the clinical trial used to evaluate the efficacy of ZIIHERA.
Figure 3. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were enrolled in the clinical trial used to evaluate the efficacy of ZIIHERA.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics in the Efficacy and Safety Populations
Demographic | Efficacy Population N=62 | Safety Population N=80 |
|---|---|---|
| Age at informed consent, years | ||
| Mean (SD) | 62.6 (9.31) | 62.5 (9.56) |
| Median | 64.0 | 64.0 |
| Min, max | 38, 79 | 32, 79 |
| Age category, years, n (%) | ||
| <65 | 33 (53.2) | 41 (51.3) |
| ≥65 | 29 (46.8) | 39 (48.8) |
| Sex, n (%) | ||
| Female | 34 (54.8) | 45 (56.3) |
| Male | 28 (45.2) | 35 (43.8) |
| Ethnicity, n (%) | ||
| Hispanic or Latino | 5 (8.1) | 5 (6.3) |
| Not Hispanic or Latino | 55 (88.7) | 72 (90.0) |
| Not reported | 2 (3.2) | 2 (2.5) |
| Unknown | 0 | 1 (1.3) |
| Racea, n (%) | ||
| American Indian or Alaska Native | 1 (1.6) | 1 (1.3) |
| Asian | 38 (61.3) | 52 (65.0) |
| White | 19 (30.6) | 23 (28.8) |
| Not reportableb | 2 (3.2) | 2 (2.5) |
| Unknown | 2 (3.2) | 2 (2.5) |
| Racea, n (%) | ||
| Asian | 38 (61.3) | 52 (65.0) |
| Not Asian | 24 (38.7) | 28 (35.0) |
| Geographic region, n (%) | ||
| North America | 15 (24.2) | 18 (22.5) |
| Asia | 36 (58.1) | 50 (62.5) |
| Other | 11 (17.7) | 12 (15.0) |
Source: Adapted from FDA Review
a Patients may select more than one race category.
b Not Reportable: Collection and/or reporting of this information is prohibited by local and/or regional laws or regulations.
Abbreviations: SD, standard deviation
What are the benefits of this drug?
In the HERIZON-BTC-01 study 52% of patients with HER2-positive IHC3+ BTC had their tumors respond to treatment. The median duration of response was 14.9 months.
What are the benefits of this drug (results of trials used to assess efficacy)?
Efficacy results from the clinical trial are summarized in Table 2. The primary benefits were in the large proportion of patients who responded to treatment and how long the response endured.
Table 2. Efficacy Results, Efficacy Population
Efficacy Parametera | ZIIHERA N=62 |
|---|---|
| Objective response rate, % (95% CI) | 52 (39, 65) |
| Complete response, n (%) | 2 (3.2) |
| Partial response, n (%) | 30 (48) |
| Duration of response | N=32 |
| Medianb, months (95% CI) | 14.9 (7.4, NE) |
| Duration ≥6 months, n (%)c | 19 (59) |
| Duration ≥12 months, n (%)c | 14 (44) |
Source: ZIIHERA Prescribing Information
a Assessed by independent central review
b Based on Kaplan-Meier estimate
c Based on observed duration of response
Abbreviations: CI, confidence interval; NE, not estimable
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: ZIIHERA worked similarly males and females.
- Race: ZIIHERA worked similarly in all races.
- Age: ZIIHERA worked similarly in patients younger and older than 65 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Observations of efficacy based on population subgroups are provided in Table 3.
Table 3. Objective Response Rate by Subgroup, Efficacy Population
Subgroup | ZIIHERA N=62 n/Ns (%) |
|---|---|
| Sex | |
| Female | 20/34 (58.8) |
| Male | 12/28 (42.9) |
| Race | |
| Asian | 22/38 (57.9) |
| Not Asian | 10/24 (41.7) |
| Age, years | |
| <65 | 17/33 (51.5) |
| ≥65 | 15/29 (51.7) |
Source: Adapted from FDA Review
Abbreviations: n, number of patients meeting criteria; N, number of patients in treatment arm; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
What are the possible side effects?
ZIIHERA may cause serious side effects including diarrhea, decrease in heart function, reactions during infusion, and harm to unborn baby.
The most commonly observed side effects (reported by greater than 20% of patients) include: diarrhea, reactions during infusion, abdominal pain, and fatigue.
Permanent discontinuation due to a side effect occurred in 2.5% of patients who received ZIIHERA.
What are the possible side effects (results of trials used to assess safety)?
Table 4 summarizes side effects reported by greater than 15% of patients with unresectable or metastatic HER2-positive BTC receiving ZIIHERA.
Table 4. Adverse Reactions (≥15%) in Patients With Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA, Safety Population
Adverse Reaction* | ZIIHERA, N=80 | |
|---|---|---|
| All Grades % | Grades 3 or 4 % | |
| Gastrointestinal disorders | ||
| Diarrheaa | 50 | 10 |
| Abdominal painb | 29 | 1 |
| Nausea | 18 | 1 |
| Vomiting | 15 | 1 |
| Injury, poisoning and procedural complications | ||
| Infusion-related reaction | 35 | 1 |
| General disorders and administration site conditions | ||
| Fatiguec | 24 | 4 |
| Skin and subcutaneous tissue disorders | ||
| Rashd | 19 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 16 | 0 |
Source: ZIIHERA Prescribing Information
* Graded per CTCAE version 5.
a Diarrhea includes diarrhea and enteritis
b Abdominal pain includes abdominal pain and abdominal pain upper
c Fatigue includes asthenia and fatigue
d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, rash, rash maculopapular, and rash pustular
Abbreviations: BTC, biliary tract cancer; CTCAE, Common Terminology Criteria for Adverse Events
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects was similar in males and females.
- Race: The occurrence of side effects was similar in Asian and White patients.
- Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 5. Side Effects (≥20%) by Sex, Safety Population
| Preferred Term | ZIIHERA Female N=45 | ZIIHERA Male N=35 |
|---|---|---|
| Any AE | 43 (95.6) | 35 (100) |
| Diarrhea | 23 (51.1) | 17 (48.6) |
| Infusion related reaction | 18 (40.0) | 10 (28.6) |
| Alanine aminotransferase increased | 7 (15.6) | 9 (25.7) |
| Abdominal pain | 8 (17.8) | 8 (22.9) |
| Anemia | 11 (24.4) | 8 (22.9) |
| Decreased appetite | 5 (11.1) | 8 (22.9) |
| Aspartate aminotransferase increased | 8 (17.8) | 8 (22.9) |
| Fatigue | 4 (8.9) | 7 (20.0) |
| Nausea | 9 (20.0) | 5 (14.3) |
| Vomiting | 9 (20.0) | 3 (8.6) |
Source: Adapted from FDA Review
Abbreviations: AE, adverse event
Table 6. Side Effects (≥20%) by Race, Safety Population*
Preferred Term | ZIIHERA Asian N=52 | ZIIHERA White N=23 |
|---|---|---|
| Any AE | 50 (96.2) | 23 (100) |
| Diarrhea | 20 (38.5) | 16 (69.6) |
| Nausea | 5 (9.6) | 7 (30.4) |
| Fatigue | 3 (5.8) | 6 (26.1) |
| Infusion related reaction | 21 (40.4) | 6 (26.1) |
| Decreased appetite | 6 (11.5) | 5 (21.7) |
| Vomiting | 5 (9.6) | 5 (21.7) |
| Anemia | 14 (26.9) | 4 (17.4) |
| Alanine aminotransferase increased | 12 (23.1) | 2 (8.7) |
| Aspartate aminotransferase increased | 12 (23.1) | 2 (8.7) |
Source: Adapted from FDA Review
* Five patients are not included in the table: one patient was reported as American Indian or Alaskan Native; four patients had race status as not reportable or unknown.
Abbreviations: AE, adverse event
Table 7. Side Effects (≥20%) by Age, Safety Population
Preferred Term | ZIIHERA <65 Years N=41 | ZIIHERA ≥65 Years N=39 |
|---|---|---|
| Any AE | 40 (97.6) | 38 (97.4) |
| Diarrhea | 23 (56.1) | 17 (43.6) |
| Infusion related reaction | 15 (36.6) | 13 (33.3) |
| Decreased appetite | 5 (12.2) | 8 (20.5) |
| Ejection fraction decreased | 3 (7.3) | 8 (20.5) |
| Fatigue | 3 (7.3) | 8 (20.5) |
| Hypokalemia | 3 (7.3) | 8 (20.5) |
| Anemia | 12 (29.3) | 7 (17.9) |
| Abdominal pain | 10 (24.4) | 6 (15.4) |
| Alanine aminotransferase increased | 10 (24.4) | 6 (15.4) |
| Aspartate aminotransferase increased | 10 (24.4) | 6 (15.4) |
Source: Adapted from FDA Review
Abbreviations: AE, adverse event
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.