January 15, 2021 – Fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo) for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
December 23, 2019 – Fam-trastuzumab deruxtecan-nxki (ENHERTU, Daiichi Sankyo) for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting (with Pharmacist’s Applications to Practice).
January 15, 2021
On January 15, 2021, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo) for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
Efficacy was evaluated in a multicenter, open-label, randomized trial (DESTINY-Gastric01, NCT03329690) in patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy. A total of 188 patients were randomized (2:1) to receive fam-trastuzumab deruxtecan-nxki 6.4 mg/kg intravenously every 3 weeks or physician’s choice of either irinotecan or paclitaxel monotherapy.
The main efficacy outcome measures were overall survival (OS) and objective response rate (ORR) assessed by independent central review (RECIST 1.1) in the intent-to-treat population. Additional efficacy outcome measures were progression-free survival (PFS) and duration of response (DOR).
OS was 12.5 months (95% CI: 9.6, 14.3) in the fam-trastuzumab deruxtecan-nxki arm compared with 8.4 months (95% CI: 6.9, 10.7) in the irinotecan or paclitaxel arm (HR 0.59; 95% CI: 0.39, 0.88, p=0.0097). Confirmed ORR was 40.5% (95% CI: 31.8, 49.6) in the fam-trastuzumab deruxtecan-nxki arm compared with 11.3% (95% CI: 4.7, 21.9) for those receiving irinotecan or paclitaxel. Median PFS was 5.6 months (95% CI: 4.3, 6.9) in the fam-trastuzumab deruxtecan-nxki arm compared to median PFS of 3.5 months (95% CI: 2.0, 4.3) in the irinotecan or paclitaxel arm. Median DOR was 11.3 months (95% CI: 5.6, NR) vs 3.9 months (95% CI: 3.0, 4.9), respectively.
The most common (≥ 20%) adverse reactions including laboratory abnormalities were anemia, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. The Prescribing Information includes a Boxed Warning to advise health professionals of the risks of interstitial lung disease and embryo-fetal toxicity.
The recommended fam-trastuzumab deruxtecan-nxki dose for gastric cancer is 6.4 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 6 weeks ahead of the FDA goal date.
This application was granted priority review. Fam-trastuzumab deruxtecan-nxki was granted breakthrough therapy designation and orphan drug designation in gastric cancer. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
For information on the COVID-19 pandemic, see the following resources:
- FDA: Coronavirus Disease 2019 (COVID-19)
- NCI: Coronavirus: What People With Cancer Should Know
- CDC: Coronavirus (COVID-19)
December 23, 2019
On December 23, 2019, the U.S. Food and Drug Administration granted accelerated approval to Fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Enhertu is a human epidermal growth factor receptor 2 (HER2)-directed antibody and topoisomerase inhibitor conjugate, meaning that the drug targets the changes in HER2 that help the cancer grow, divide and spread, and is linked to a topoisomerise inhibitor, which is a chemical compound that is toxic to cancer cells.
“There have been many advances in the development of drugs for HER2-positive breast cancer since the introduction of Herceptin (trastuzumab) in 1998. The approval of Enhertu represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Drug development in the area of targeted therapies builds on our scientific understanding of malignant diseases not only in breast cancer, but in multiple other diseases.”
HER2-positive breast cancer is a type of breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. Approximately one of every five breast cancers have a gene mutation in the cancer cells that makes an excess of the HER2 protein. HER2-positive breast cancers are an aggressive type of breast cancer.
Enhertu’s approval was based on the results of a clinical trial enrolling 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies in the metastatic setting. These patients were heavily pretreated in the metastatic setting, receiving between two and 17 therapies prior to receiving Enhertu. Patients in the clinical trial received Enhertu every three weeks and tumor imagining was obtained every six weeks. The overall response rate was 60.3%, which reflects the percentage of patients that had a certain amount of tumor shrinkage with a median duration of response of 14.8 months.
The prescribing information for Enhertu includes a Boxed Warning to advise health care professionals and patients about the risk of interstitial lung disease (a group of lung conditions that causes scarring of lung tissues) and embryo-fetal toxicity. Interstitial lung disease and pneumonitis (inflammation of lung tissue), including cases resulting in death, have been reported with Enhertu. Health care professionals should monitor for and promptly investigate signs and symptoms including cough, dyspnea (difficult or labored breathing), fever and other new or worsening respiratory symptoms. If these symptoms arise, Enhertu may need to be withheld, the dose reduced or permanently discontinued. Women who are pregnant should not take Enhertu because it may cause harm to a developing fetus or newborn baby, or cause delivery complications. The FDA advises health care professionals to tell females of reproductive age, and males with a female partner of reproductive potential, to use effective contraception during treatment with Enhertu.
Full prescibing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf
The most common side effects for patients taking Enhertu were nausea, fatigue, vomiting, alopecia (hair loss), constipation, decreased appetite, anemia (hemoglobin in blood is below the reference range), decreased neutrophil count (white blood cells that help lead your body’s immune system response to fight infection), diarrhea, leukopenia (other white blood cells that help the immune system), cough and decreased platelet count (component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot). Decreased neutrophil count is a potentially serious and common side effect as described in the Medication Guide. Patients treated with Enhertu may be at increased risk of developing left ventricular dysfunction, which occurs when the heart is unable to pump blood effectively to the body, as this has been seen with other HER2-directed therapies for breast cancer.
Enhertu was granted Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on a result that is reasonably likely to predict a clinical benefit to patients. Further clinical trials may be required to verify and describe Enhertu’s clinical benefit.
The FDA granted this application Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Enhertu was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need. This application was approved four months prior to the FDA goal date.
The FDA granted the approval of Enhertu to Daiichi Sankyo.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
Pharmacist’s Applications to Practice
Author: Mollie Michel, PharmD
PGY-2 Hematology/Oncology Pharmacy Resident
M Health Fairview, University of Minnesota Medical Center
Fam-trastuzumab deruxtecan-nxki for the Treatment of Adult Patients with Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Breast Cancer Who Have Received Two or More Prior Anti-HER2-Based Regimens in the Metastatic Setting
What is the potential role for fam-trastuzumab deruxtecan-nxki in the treatment of breast cancer?
- Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate that is approved in the setting of HER2-positive, metastatic, or unresectable breast cancer. The trastuzumab component of the drug binds to HER2 receptors, causing the conjugate to become internalized in the cell. Once internalized, the deruxtecan is cleaved from the trastuzumab and delivers its cytotoxic effect by inhibition of topoisomerase I. The drug-to-antibody ratio in this drug conjugate is approximately 8:1.1
- HER2 overexpression is seen in 15%–20% of metastatic breast cancers.2
- The preferred treatment option for HER2-positive metastatic breast cancer is pertuzumab, trastuzumab, and a taxane, on the basis in part of the results of the CLEOPATRA trial.3,4
- Ado-trastuzumab emtansine is another antibody-drug conjugate that targets HER2 and is a common second-line agent for patients with HER2-positive metastatic breast cancer.3
- Key differences between the agents include these: the emtansine component of ado-trastuzumab emtansine works as a microtubule inhibitor, ado-trastuzumab emtansine carries a drug-to-antibody ratio of 3.2:1, and ado-trastuzumab emtansine is approved for use in early breast cancer as well as metastatic breast cancer.2-4
- Following disease progression on ado-trastuzumab emtansine, there is no single standard-of-care regimen. The recommended regimens often include an HER2-directed agent such as trastuzumab, lapatinib, or neratinib in combination with a chemotherapy agent.3
- The approval of fam-trastuzumab deruxtecan-nxki was based on the DESTINY-Breast01 study, which was an open-label single-group multicenter phase 2 trial.1,2
- The study aimed to determine efficacy of fam-trastuzumab deruxtecan-nxki after ado-trastuzumab emtansine therapy.
- Inclusion criteria: unresectable or metastatic breast cancer, disease resistant or refractory to ado-trastuzumab emtansine, the presence of at least one measurable lesion
- Exclusion criteria: clinically significant cardiac disease, active brain metastases, Eastern Cooperative Oncology Group performance status >1, history of interstitial lung disease (ILD), unresolved toxicities from prior lines of therapy.
- Baseline characteristics:
- A total of 184 patients enrolled received the standard dose.
- Those enrolled in the study had a median number of six prior lines of therapy.
- All patients had received prior trastuzumab and ado-trastuzumab emtansine.
- All were female patients with a median age of 55 years.
- Primary endpoint was overall response.
- Confirmed overall response rate of 60.3% (95% confidence interval [CI]: 52.9–67.4)
- Secondary endpoints
- Duration of response: 14.8 months (95% CI: 13.8–16.9)
- Progression-free survival: 16.4 months (95% CI: 12.7 to not reached)
- Disease control rate: 97.3% (95% CI: 93.8–99.1%)
- Clinical benefit rate: 76.1% (95% CI: 69.3–82.1%)
- Most common adverse events (≥20%, all grades): nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia
- Most common adverse events grades 3 or higher: neutropenia (16%), nausea (7%), leukopenia (6%), vomiting (3.8%), thrombocytopenia (3.4%), ILD (2.6%)
- National Comprehensive Cancer Network (NCCN) recommends fam-trastuzumab deruxtecan-nxki as a category 2A treatment option for patients with HER2-positive metastatic breast cancer after two prior lines of anti-HER2 therapies.3
What role can the pharmacist play in the management of patients on fam-trastuzumab deruxtecan- nxki?1
- 5.4 mg/kg intravenous (IV) every 3 weeks until disease progression or unacceptable toxicities
- Infusion rates
- First infusion should be administered over 90 minutes.
- If first infusion was tolerated, subsequent infusions can be administered over 30 minutes.
- No dose adjustments required for renal or hepatic impairment
- Moderate emetic risk; follow NCCN antiemesis guidelines for recommendations of antiemetics5
- There are no known drug-drug or drug-food interactions.1
- The deruxtecan portion does get metabolized by CYP3A4; however, pharmacokinetic studies found no clinically meaningful drug-drug interactions with either CYP3A inhibitors or CYP3A inducers.
- Pharmacists can ensure that appropriate laboratory and organ function monitoring is complete prior to and during therapy.2
- Patients should have an echocardiogram prior to initiation of therapy and repeated every four cycles.
- Comprehensive metabolic panel and complete blood count with platelet differential were taken weekly for cycle 1, then on day 1 of subsequent cycles.
- Female patients of reproductive age should receive a pregnancy test prior to initiation of therapy.
- Management of adverse effects may require interruptions in treatment or dose reductions, and the manufacturer provides specific instructions for ILD, neutropenia, febrile neutropenia, and left ventricular dysfunction. Recommended dose reductions include these:
- First dose reduction: 4.4 mg/kg
- Second dose reduction: 3.2 mg/kg
- Requirement for further dose reduction: permanently discontinue treatment
- Patients should be educated on the signs and symptoms of ILD and advised to report any new symptoms to their healthcare provider right away.
- Can cause embryo-fetal toxicity, and contraception should be used by both men and women receiving the drug.
- Women of reproductive potential: use effective contraception during treatment and for 7 months following discontinuation of treatment.
- Men with women partners of reproductive potential: use effective contraception during treatment and for 4 months following discontinuation of treatment.
- Fam-trastuzumab deruxtecan-nxki is not interchangeable with ado-trastuzumab emtansine, conventional trastuzumab (or trastuzumab biosimilars), or trastuzumab/hyaluronidase.1
- Should only be administered as an IV infusion and requires administration through a 0.2 or 0.22 micron in-line filter
- Supplied as a 100-mg vial for reconstitution
- Reconstitute with 5 mL of sterile water for injection.
- Do not use normal saline.
- Do not shake, only gently swirl.
- Solution should be further diluted in 100 mL of dextrose 5% solution.
- Do not dilute in normal saline.
- Infusion bag should be protected from light.
- Reconstitute with 5 mL of sterile water for injection.
- Vials should be stored in their original container in the refrigerator. Protect from light, and do not freeze.
- Once reconstituted, the vials can be stored in the refrigerator for 24 hours. Protect from light, and do not freeze.
- The final diluted product can be stored at room temperature for 4 hours or in a refrigerator for up to 24 hours. Protect from light, and do not freeze.
- This is a cytotoxic drug, so applicable special handling and disposal procedures should be followed.
- A patient assistance program called ENHERTU4U is available.6
- Enhertu (fam-trastuzumab drextecan-nxki) [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; December 2019.
- Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020; 383:610-621.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 4.2020 (May 8, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed June 9, 2020.
- Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015; 372:724-734.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2020 (April 23, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed June 9, 2020.
- Daiichi Sankyo, Inc. and AstraZeneca. Enhertu Patient Assistance Program. Available at https://www.enhertu4u.com/patient.html