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TARGETED TREATMENTS ARE DESPERATELY NEEDED IN HER2-POSITIVE BTC1

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POOR PROGNOSIS
5-year survival rate for patients with metastatic disease is ~3% despite current treatment options2,3
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STAGNANT OUTCOMES
Median OS for second-line treatment of BTC is only ~6 months with current standard of care4*
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INNOVATION IS NEEDED
Although up to 30% of patients with advanced BTC are HER2-positive, there has never been an FDA-approved treatment specifically indicated for and studied in HER2-positive patients with BTC—until 20245-7

Test for HER2 to identify patients who could benefit from targeted treatment8

*The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Biliary Tract Cancers recommend FOLFOX as the preferred subsequent line of therapy after first-line systemic therapy.9

 

BTC=biliary tract cancer; FDA=Food and Drug Administration; FOLFOX=leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin; HER2=human epidermal growth factor receptor 2; NCCN®=National Comprehensive Cancer Network; OS=overall survival.

 
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MOA

INDICATION

ZIIHERA (zanidatamab-hrii) 50 mg/mL for Injection for IV is indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION AND INDICATION

WARNING: EMBRYO-FETAL TOXICITY
Exposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception.

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity

ZIIHERA can cause fetal harm when administered to a pregnant woman. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose of ZIIHERA.

Left Ventricular Dysfunction

ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by >10% and decreased to <50% in 4.3% of 233 patients. Left ventricular dysfunction (LVD) leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median time to first occurrence of LVD was 5.6 months (range: 1.6 to 18.7). LVD resolved in 70% of patients.

Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of adverse reactions.

The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50%.

Infusion-Related Reactions

ZIIHERA can cause infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with ZIIHERA as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients. IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within one day.

Prior to each dose of ZIIHERA, administer premedications to prevent potential IRRs. Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use.

If an IRR occurs, slow, or stop the infusion, and administer appropriate medical management. Monitor patients until complete resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening IRRs.

Diarrhea

ZIIHERA can cause severe diarrhea.

Diarrhea was reported in 48% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Withhold or permanently discontinue ZIIHERA based on severity.

ADVERSE REACTIONS

Serious adverse reactions occurred in 53% of 80 patients with unresectable or metastatic HER2-positive BTC who received ZIIHERA. Serious adverse reactions in >2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received ZIIHERA.

The most common adverse reactions in 80 patients with unresectable or metastatic HER2-positive BTC who received ZIIHERA (≥20%) were diarrhea (50%), infusion-related reaction (35%), abdominal pain (29%), and fatigue (24%).

USE IN SPECIFIC POPULATIONS

Pediatric Use

Safety and efficacy of ZIIHERA have not been established in pediatric patients.

Geriatric Use

Of the 80 patients who received ZIIHERA for unresectable or metastatic HER2-positive BTC, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were aged 65-74 years old and 2 (3%) were aged 75 years or older.

No overall differences in safety or efficacy were observed between these patients and younger adult patients.

Please click here to see the full Prescribing Information, including BOXED Warning.

References: 1. Tam VC, Ramjeesingh R, Burkes R, Yoshida EM, Doucette S, Lim HJ. Emerging systemic therapies in advanced unresectable biliary tract cancer: review and Canadian perspective. Curr Oncol. 2022;29(10):7072-7085. doi:10.3390/curroncol29100555 2. SEER*Explorer: Gallbladder relative survival rates, 2000-2021. Accessed May 28, 2024. https://seer.cancer.gov/statistics-network/explorer/ 3. SEER*Explorer: Liver and intrahepatic bile duct relative survival rates, 2000-2021. Accessed May 28, 2024. https://seer.cancer.gov/statistics-network/explorer/ 4. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701. doi:10.1016/S1470-2045(21)00027-9 5. Harding JJ, Khalil DN, Fabris L, Abou-Alfa GK. Rational development of combination therapies for biliary tract cancers. J Hepatol. 2023;78(1):217-228. doi:10.1016/j.jhep.2022.09.004 6. Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?. Cancer Metastasis Rev. 2017;36(1):141-157. doi:10.1007/s10555-016-9645-x 7. Hiraoka N, Nitta H, Ohba A, et al. Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer. Hum Pathol. 2020;105:9-19. doi:10.1016/j.humpath.2020.08.006 8. Ayasun R, Ozer M, Sahin I. The role of HER2 status in the biliary tract cancers. Cancers (Basel). 2023;15(9):2628. doi: 10.3390/cancers15092628 9. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Biliary Tract Cancers v4.2024. © 2024 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed September 12, 2024. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.