Biosimilar to Trastuzumab in HER2-Overexpressing Breast, Metastatic Breast, and Metastatic Gastric Cancers

By Matthew Stenger
October 10, 2019

Early in 2019, trastuzumab-dttb was approved as a biosimilar to standard trastuzumab for treatment of HER2-expressing breast cancer in the adjuvant setting, metastatic breast cancer, and metastatic gastric cancer or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease.¹

Trastuzumab-dttb is indicated for treatment of the following cancers:

Adjuvant treatment of HER2-overexpressing node-positive or node-negative (estrogen receptor–progesterone receptor–negative or with one high risk feature) breast cancer:

• As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• As part of a treatment regimen with docetaxel and carboplatin
• As a single agent following multimodality anthracycline-based therapy

Treatment of metastatic breast cancer:

• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Treatment of metastatic gastric cancer:

• In combination with cisplatin and capecitabine or fluorouracil for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

Patients must be selected for therapy based on a U.S. Food and Drug Administration (FDA)-approved companion diagnostic for a trastuzumab product. Health-care professionals should review product labeling for detailed information on the use of trastuzumab-dttb, which should not be substituted for or with ado-trastuzumab emtansine.

Approval Process

Biosimilarity of trastuzumab-dttb has been demonstrated for the condition(s) of use (eg, indication(s), dosing regimen(s), strength(s), dosage form(s), and route(s) of administration described in its full prescribing information. The approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic, clinical immunogenicity, and other clinical data demonstrating that trastuzumab-dttb is a biosimilar to the U.S. standard trastuzumab.

Trastuzumab-dttb has been approved as a biosimilar, not as an interchangeable product. As defined by the FDA, a biosimilar “is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.”

To satisfy the criteria of having no clinically meaningful differences, a manufacturer of a biosimilar product must demonstrate the absence of such differences from the reference product in terms of safety, purity, and potency (safety and effectiveness); this is generally demonstrated through human pharmacokinetic and pharmacodynamic studies, an assessment of clinical immunogenicity, and, if needed, additional clinical studies. An interchangeable product may be substituted for a reference product without the involvement of the prescriber.

Recommended Dosing

The recommended dosage and administration of trastuzumab-dttb follows:

Adjuvant treatment of HER2-overexpressing breast cancer:

Administer according to one of the following doses and schedules for a total of 52 weeks of trastuzumab-dttb therapy:

During and following paclitaxel, docetaxel, or docetaxel and carboplatin:

• Initial dose of 4 mg/kg as intravenous (IV) infusion over 90 minutes then at 2 mg/kg as IV infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin)
• One week following the last weekly dose of trastuzumab-dttb, administer trastuzumab-dttb at 6 mg/kg as IV infusion over 30 to 90 minutes every 3 weeks.

As a single agent within 3 weeks following completion of multimodality, anthracycline-based chemotherapy regimens:

• Initial dose at 8 mg/kg as IV infusion over 90 minutes
• Subsequent doses at 6 mg/kg as IV infusion over 30 to 90 minutes every 3 weeks
• Extending adjuvant treatment beyond 1 year is not recommended.

Treatment of Metastatic Breast Cancer:

• Administer trastuzumab-dttb, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute IV infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute infusions until disease progression.

Treatment of metastatic gastric cancer:

• Administer trastuzumab-dttb at an initial dose of 8 mg/kg as a 90-minute IV infusion followed by subsequent doses of 6 mg/kg as IV infusion over 30 to 90 minutes every 3 weeks until disease progression.

Safety Profile

As with standard trastuzumab, the most common expected adverse events with trastuzumab-dttb (≥ 5%) in the adjuvant treatment of breast cancer are headache, diarrhea, nausea, and chills. The most common adverse events in metastatic breast cancer (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. The most common adverse events in metastatic gastric cancer (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.

Like standard trastuzumab, the labeling for trastuzumab-dttb contains a boxed warning for increased risks of cardiomyopathy, infusion reactions, pulmonary toxicity, and embryofetal toxicity. Like standard trastuzumab, trastuzumab-dttb carries additional warnings and precautions for exacerbation of chemotherapy-induced neutropenia. The pregnancy status of women must be verified prior to initiation of trastuzumab-dttb. 

REFERENCE

1. Ontruzant (trastuzumab-dttb) for injection prescribing information, Merck Sharp & Dohme Corp, January 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/761100s000lbl.pdf. Accessed September 20, 2019.