FDA Approves Enhertu

FDA Approves Enhertu (fam-trastuzumab deruxtecan-nxki) for HER2-Positive Unresectable or Metastatic Breast Cancer Following Two or More Prior Anti-HER2 Based Regimens

20 December 2019 -- AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) today announced that the US Food and Drug Administration (FDA) has approved Enhertu® (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under Accelerated Approval based on tumor 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.

Enhertu is a HER2-directed antibody-drug conjugate (ADC) and the FDA approval is based on the results of the registrational Phase II trial DESTINY-Breast01 of Enhertu (5.4 mg/kg) monotherapy in 184 female patients with HER2-positive metastatic breast cancer. All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab.

The Phase II trial results showed a confirmed objective response rate of 60.3% (n=111; 95% CI: 52.9-67.4), including a 4.3% complete response rate (n=8) and a 56.0% partial response rate (n=103). A median duration of response of 14.8 months (95% CI: 13.8-16.9) was demonstrated as of August 1, 2019. In addition, a median progression-free survival of 16.4 months (95% CI: 12.7-not estimable), based upon a median duration of follow-up of 11.1 months, was recently presented at the San Antonio Breast Cancer Symposium and published online in The New England Journal of Medicine.

José Baselga, Executive Vice President, Oncology R&D, said: “Enhertu has shown impressive results in women with HER2-positive metastatic breast cancer, with the majority of women benefiting from treatment and the median duration of the response exceeding 14 months. With this first approval, we are proud to bring Enhertu to patients with high unmet need and we look forward to further exploring its potential in additional settings.”

Antoine Yver, Executive Vice President and Global Head, Oncology R&D, Daiichi Sankyo, said: “The approval of Enhertu underscores that this specifically engineered HER2-directed antibody-drug conjugate is delivering on its intent to establish an important new treatment for patients with HER2-positive metastatic breast cancer. Since the beginning of our clinical trial program four years ago, we have focused on the opportunity to transform the treatment landscape for patients with HER2-positive metastatic breast cancer, and we are extremely proud of how quickly we delivered Enhertu to patients in the US, as Enhertu represents one of the fastest-developed biologics in oncology.”

Enhertu is approved with a Boxed WARNING for Interstitial Lung Disease (ILD)/pneumonitis and Embryo-Fetal Toxicity. The safety of Enhertu has been evaluated in a pooled analysis from both the Phase II trial DESTINY-Breast01 and the earlier Phase I trial among a total of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu (5.4mg/kg). ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients—two deaths previously reported in the Phase I trial and four deaths previously reported in the Phase II trial DESTINY-Breast01. Patients and physicians should be aware of ILD/pneumonitis and patients should be actively monitored for potential signs and symptoms. If ILD/pneumonitis is identified, it should be managed as per the FDA approved US Prescribing information. Management may require dose modification or treatment discontinuation and steroid treatment.

Enhertu can cause fetal harm when administered to a pregnant woman. The most common adverse reactions (frequency ≥20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough and thrombocytopenia.

Enhertu will be available by prescription in the US within the coming weeks. AstraZeneca and Daiichi Sankyo are committed to ensuring that patients in the US who are prescribed Enhertu can access the medication and receive necessary financial support. Provider and patient support, reimbursement and distribution for Enhertu in the US will be accessible by visiting www.Enhertu4U.com or calling 1-833-Enhertu (1-833-364-3788).

Please visit www.Enhertu.com for full Prescribing Information, including Boxed WARNING, and Medication Guide.

Financial considerations

Following US approval, an amount of $125m is due from AstraZeneca to Daiichi Sankyo as the first milestone payment in HER2-positive breast cancer. Upon approval, this will be capitalized together with the upfront payment already made earlier in the year 2019.

Future sales of Enhertu in the US will be recognized by Daiichi Sankyo. AstraZeneca will report its share of gross profit margin from the sales in the US as collaboration revenue in the Company’s financial statements. For further details on the financial arrangements, please consult the announcement of the collaboration agreement from March 2019.

IMPORTANT SAFETY INFORMATION

Indication

Enhertu is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor 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.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with Enhertu. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue Enhertu in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

Exposure to Enhertu during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with Enhertu. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with Enhertu, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with Enhertu. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt Enhertu until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue Enhertu. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with Enhertu. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received Enhertu, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of Enhertu and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, Enhertu may require dose interruption or reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt Enhertu until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt Enhertu until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt Enhertu until resolved. Reduce dose by one level.

Left Ventricular Dysfunction

Patients treated with Enhertu may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including Enhertu. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received Enhertu, two cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment with Enhertu has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue Enhertu if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with Enhertu. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with Enhertu and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt Enhertu and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue Enhertu. If LVEF recovers to within 10% from baseline, resume treatment with Enhertu at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt Enhertu and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue Enhertu. Permanently discontinue Enhertu in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity

Enhertu can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of Enhertu. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of Enhertu. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Enhertu and for at least 4 months after the last dose of Enhertu.

Adverse Reactions

The safety of Enhertu was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. Enhertu was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving Enhertu. Serious adverse reactions in >1% of patients who received Enhertu were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

Enhertu was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with Enhertu. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with Enhertu. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

Use in Specific Populations

Pregnancy : Enhertu can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if Enhertu is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of Enhertu.

: Enhertu can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if Enhertu is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of Enhertu. Lactation : There are no data regarding the presence of Enhertu in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Enhertu and for 7 months after the last dose.

: There are no data regarding the presence of Enhertu in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Enhertu and for 7 months after the last dose. Females and Males of Reproductive Potential : Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of Enhertu. Contraception: Females: Enhertu can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Enhertu and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Enhertu and for at least 4 months following the last dose. Infertility: Enhertu may impair male reproductive function and fertility.

: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of Enhertu. Contraception: Females: Enhertu can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Enhertu and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Enhertu and for at least 4 months following the last dose. Infertility: Enhertu may impair male reproductive function and fertility. Pediatric Use : Safety and effectiveness of Enhertu have not been established in pediatric patients.

: Safety and effectiveness of Enhertu have not been established in pediatric patients. Geriatric Use : Of the 234 patients with HER2-positive breast cancer treated with Enhertu 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%).

: Of the 234 patients with HER2-positive breast cancer treated with Enhertu 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%). Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide.

About HER2-Positive Breast Cancer

Approximately one in five breast cancers are HER2-positive. Despite recent improvements and approvals of new medicines, there remains significant clinical needs for patients with HER2-positive metastatic breast cancer. This disease remains incurable with patients eventually progressing after available treatment.

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis in patients with breast cancer. To be considered HER2-positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+ and/or FISH amplification is considered positive.

About DESTINY-Breast01

DESTINY-Breast01 is a registrational Phase II, single-arm open-label, global, multicenter, two-part trial evaluating the safety and efficacy of Enhertu in 184 female patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with ado-trastuzumab emtansine. The primary endpoint of the trial is objective response rate, as determined by independent central review. Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival, overall survival and safety. Enrollment into DESTINY-Breast01 was completed in September 2018 with 184 patients at more than 100 sites globally.

About the Clinical Development Program

A comprehensive development program for fam-trastuzumab deruxtecan-nxki is underway globally with five pivotal trials in HER2-expressing metastatic breast and gastric cancers, including a trial in patients with metastatic breast cancer and low levels of HER2 expression (HER2-low). Phase II trials are underway for HER2-expressing advanced colorectal cancer, as well as metastatic non-squamous HER2-overexpressing or HER2-mutated non-small cell lung cancer. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

About Enhertu

Enhertu® (fam-trastuzumab deruxtecan-nxki) is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise and the most advanced program in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

About the Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize fam-trastuzumab deruxtecan-nxki as a potential new medicine worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply.

Enhertu received Priority Review, Breakthrough Therapy Designation, and Fast Track Designation from the FDA for the treatment of select patients with HER2-positive metastatic breast cancer.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

Source: AstraZeneca

Posted: December 2019

Enhertu (fam-trastuzumab deruxtecan-nxki) FDA Approval History