Unresectable or Metastatic HER2-Low Breast Cancer

Select patients for treatment of unresectable or metastatic HER2-low breast cancer with ENHERTU based on HER2 expression (IHC 1+ or IHC 2+/ISH-) [see Clinical Studies (14.2)].

Unresectable or Metastatic HER2-Mutant NSCLC

Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens [see Clinical Studies (14.3)]. If no mutation is detected in a plasma specimen, test tumor tissue.

Locally Advanced or Metastatic Gastric Cancer

Select patients with locally advanced or metastatic gastric cancer based on HER2 protein overexpression or HER2 gene amplification. Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.

Additional Patient Selection Information

Information on FDA-approved tests for the detection of HER2 protein expression, HER2 gene amplification, and activating HER2 mutations is available at: http://www.fda.gov/CompanionDiagnostics.

Premedication

ENHERTU is highly emetogenic [see Adverse Reactions (6.1)], which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

Recommended Dosage for Metastatic Breast Cancer

The recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Recommended Dosage for Unresectable or Metastatic HER2-Mutant NSCLC

The recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Recommended Dosage for Locally Advanced or Metastatic Gastric Cancer

The recommended dosage of ENHERTU is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Reconstitution

• Reconstitute immediately before dilution.
• More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].
• Reconstitute each 100 mg vial by using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection, USP into each vial to obtain a final concentration of 20 mg/mL.
• Swirl the vial gently until completely dissolved. Do not shake.
• If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze.
• The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.

Dilution

• Withdraw the calculated amount from the vial(s) using a sterile syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.
• Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. DO NOT use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).
• Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
• Cover the infusion bag to protect from light.
• If not used immediately, store at room temperature for up to 4 hours including preparation and infusion, or in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours, protected from light. Do not freeze.
• Discard any unused portion left in the vial.

Administration

• If the prepared infusion solution was stored refrigerated (2°C to 8°C [36°F to 46°F]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
• Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
• Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
• Do NOT administer as an intravenous push or bolus.
• Cover the infusion bag to protect from light during administration.
• Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
• First infusion: Administer infusion over 90 minutes.
• Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 6 months (range: 0.9 to 32).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 0.9% of patients.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.9% of patients, of which 0.4% were Grade 3.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

The pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1388 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast02, DESTINY-Breast04, and DESTINY-Lung02. Among these patients, 68% were exposed for greater than 6 months and 42% were exposed for greater than one year. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were nausea (75%), decreased white blood cell count (71%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (57%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (43%), vomiting (42%), increased blood alkaline phosphatase (39%), alopecia (39%), constipation (35%), decreased appetite (32%), hypokalemia (30%), diarrhea (28%), and musculoskeletal pain (26%).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

The data described in WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 6.4 mg/kg intravenously every 3 weeks in 125 patients in DESTINY-Gastric01.

HER2-Positive Metastatic Breast Cancer

HER2-Low Metastatic Breast Cancer

The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast04 [see Clinical Studies (14.2)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.

Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).

ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, constipation, increased blood alkaline phosphatase, decreased appetite, musculoskeletal pain, diarrhea, and hypokalemia.

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04.

Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU:

• Nervous System Disorders: dysgeusia (10%)
• Respiratory, Thoracic and Mediastinal Disorders: cough (10%)
• Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%)
• Eye Disorders: blurred vision (4.9%) [including blurred vision and visual impairment]
• Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]
• Metabolism and Nutrition Disorders: dehydration (1.9%)
• Blood and Lymphatic System Disorders: febrile neutropenia (1.1%)
• Injury, Poisoning and Procedural Complications: infusion-related reactions (0.5%) [including injection-site reaction and chills]

Unresectable or Metastatic HER2-Mutant NSCLC

DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.

The safety of ENHERTU was evaluated in 101 patients in DESTINY-Lung02 [see Clinical Studies (14.3)]. Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. Nineteen percent of patients were exposed for greater than 6 months. The median age was 59 years (range 30 to 83); 64% were female; 23% were White, 64% were Asian, and 14% were other races.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).

ENHERTU was permanently discontinued due to an adverse reaction in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, hypokalemia, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia.

Tables 11 and 12 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02.

Other clinically relevant adverse reactions reported in less than 10% of patients were:

• Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease (6%) [including interstitial lung disease that was adjudicated as ILD including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure], dyspnea (5%), and epistaxis (3%)
• Gastrointestinal Disorders: abdominal pain (9%) [including abdominal discomfort, abdominal pain, and upper abdominal pain]
• Skin and Subcutaneous Disorders: rash (3%) [including rash and maculo-papular rash]
• Infections and Infestations: upper respiratory tract infection (4%) [including upper respiratory tract infection, pharyngitis, and laryngitis]
• Nervous System Disorders: headache (4%) [including headache and migraine]

Locally Advanced or Metastatic Gastric Cancer

The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.4)]. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.

Tables 13 and 14 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.

Other clinically relevant adverse reactions reported in less than 10% of patients were:

• Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)]
• Infections and Infestations: pneumonia (6%)
• Injury, Poisoning and Procedural Complications: infusion-related reactions (1.6%)

Risk Summary

Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data). Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. 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 after the last dose of ENHERTU (see Clinical Considerations).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Data

Risk Summary

There is no data regarding the presence of fam-trastuzumab deruxtecan-nxki 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.

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.

Contraception

Infertility

Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility [see Nonclinical Toxicology (13.1)].

Cardiac Electrophysiology

The administration of multiple doses of ENHERTU 6.4 mg/kg every 3 weeks did not show a large mean effect (i.e. >20 ms) on the QTc interval in an open-label, single-arm study in 51 patients with metastatic HER2-positive cancer.

Metastatic Breast Cancer

At the recommended dosage of ENHERTU for patients with metastatic breast cancer, the estimated geometric mean (coefficient of variation [CV]%) Cmax,ss of fam-trastuzumab deruxtecan-nxki and DXd were 133 µg/mL (19%) and 4.7 ng/mL (43%), respectively, and the corresponding AUCss were 780 µg∙day/mL (27%) and 29 ng∙day/mL (42%). Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 35% at steady-state (Cycle 3).

Unresectable or Metastatic HER2-Mutant NSCLC

At the recommended dosage of ENHERTU for patients with HER2-mutant NSCLC, the estimated geometric mean (CV%) Cmax,ss of fam-trastuzumab deruxtecan-nxki and DXd were 141 µg/mL (21%) and 7.2 ng/mL (44%), respectively, and the corresponding AUCss were 775 µg∙day/mL (33%) and 40.9 ng∙day/mL (43%). Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 31% at steady-state.

Locally Advanced or Metastatic Gastric Cancer

At the recommended dosage of ENHERTU for patients with HER2-positive gastric cancer, the estimated geometric mean (CV%) Cmax,ss of fam-trastuzumab deruxtecan-nxki and DXd were 126 µg/mL (18%) and 5.2 ng/mL (42%), respectively, and the corresponding AUCss were 743 µg∙day/mL (26%) and 33 ng∙day/mL (43%). Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 39% at steady-state (Cycle 3).

Distribution

Based on population pharmacokinetic analysis, the estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki was 2.68 L.

For humans, DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6, in vitro.

Elimination

The median elimination half-life (t1/2) of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive metastatic breast cancer, HER2-mutant NSCLC, and HER2-positive gastric cancer was approximately 5.4-5.7 days. The estimated systemic clearance of fam-trastuzumab deruxtecan-nxki was 0.41 L/day.

The median apparent elimination half-life (t1/2) of DXd in patients with HER2-positive metastatic breast cancer, HER2-mutant NSCLC, and HER2-positive gastric cancer was approximately 5.4-6.1 days. The estimated apparent systemic clearance of DXd was 18.3 L/h.

Specific Populations

No clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (20-96 years), race (Asian, White, or Black), sex, body weight (27-125 kg), mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), mild or moderate renal impairment (creatinine clearance [CLcr] 30 to < 90 mL/min).

The pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr <30 mL/min) is unknown.

Drug Interaction Studies

DESTINY-Breast03

The efficacy of ENHERTU was evaluated in study DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. HER2 expression was based on archival tissue tested at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients were excluded for a history of ILD/pneumonitis requiring treatment with steroids, ILD/pneumonitis at screening, or clinically significant cardiac disease. Patients were also excluded for untreated and symptomatic brain metastases, ECOG performance status >1, or prior treatment with an anti-HER2 antibody-drug conjugate in the metastatic setting.

Patients were randomized 1:1 to receive either ENHERTU 5.4 mg/kg (N=261) or ado-trastuzumab emtansine 3.6 mg/kg (N=263) by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and visceral versus non-visceral disease. Tumor imaging was obtained every 6 weeks and CT/MRI of the brain was mandatory for all patients at baseline. The major efficacy outcomes were progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 and overall survival (OS). Confirmed objective response rate (ORR) was an additional outcome measure.

The median age was 54 years (range: 20-83); 80% were <65 years; 99.6% were female; 60% were Asian, 27% were White, and 3.6% were Black; 11% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of 0 (63%) or 1 (37%) at baseline. Seventy-three percent had visceral disease, 16% had brain metastases at baseline, 52% were hormone receptor positive (HR+), and 48% of patients had received one line of prior systemic therapy in the metastatic setting. The percentage of patients who had not received prior treatment for metastatic disease was 10%.

Efficacy results are summarized in Table 15 and Figures 1 and 2.

Figure 1: Kaplan-Meier Plot of Progression-Free Survival per BICR (Intent-to-Treat Analysis Set)

Figure 2: Kaplan-Meier Plot of Overall Survival

DESTINY-Breast02

The efficacy of ENHERTU was evaluated in study DESTINY-Breast02 (NCT03523585), a multicenter, open-label, randomized study that enrolled 608 patients with HER2-positive, unresectable and/or metastatic breast cancer who were previously treated with ado-trastuzumab emtansine. HER2 expression was based on archival tissue tested at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients were randomized 2:1 to receive either ENHERTU 5.4 mg/kg (N=406) by intravenous infusion every 3 weeks or treatment of physician's choice (TPC) (N=202, trastuzumab plus capecitabine or lapatinib plus capecitabine) until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and visceral versus non-visceral disease. The major efficacy outcomes were PFS as assessed by BICR based on RECIST v1.1 and OS.

The median age was 54 years (range: 22 to 88); 80% were <65 years; 99% were female; 63% were White, 29% were Asian, and 3% were Black or African American; 11% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of 0 (57%) or 1 (42%) at baseline. Seventy-eight percent had visceral disease, 18% had brain metastases at baseline, 59% were hormone receptor positive (HR+), and 5% of patients had received one line of prior systemic therapy in the metastatic setting.

Efficacy results are summarized in Table 16 and Figures 3 and 4.

Figure 3: Kaplan-Meier Plot of Progression-free Survival Per BICR

Figure 4: Kaplan-Meier Plot of Overall Survival

DESTINY-Breast01

The efficacy of ENHERTU was evaluated in study DESTINY-Breast01 (NCT03248492), a multicenter, single-arm, trial that enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. Patients were excluded for a history of treated ILD or current ILD at screening. Patients were also excluded for history of clinically significant cardiac disease, active brain metastases, and ECOG performance status >1. HER2 expression was based on archival tissue tested at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive.

Patients received ENHERTU 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Tumor imaging was obtained every 6 weeks and CT/MRI of the brain was mandatory for patients with brain metastases at baseline. The major efficacy outcomes were confirmed objective response rate (ORR) assessed by independent central review (ICR) using RECIST v1.1 and duration of response (DOR).

The median age was 55 years (range: 28-96); 76% of patients were <65 years. All 184 patients were female, and the majority were White (55%) or Asian (38%). Patients had an ECOG performance status of 0 (55%) or 1 (44%) at baseline. Ninety-two percent had visceral disease, 29% had bone metastases, and 13% had brain metastases. Fifty-three percent were HR+. Sum of diameters of target lesions were <5 cm in 42%, and ≥5 cm in 50% (not evaluable by central review in 8% of patients).

The median number of prior cancer regimens in the locally advanced/metastatic setting was 5 (range: 2-17).

All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab.

Efficacy results are summarized in Table 17.

Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of reconstitution. Do not freeze. Do not shake the reconstituted or diluted solution [see Dosage and Administration (2.4)].