Enhertu (fam-trastuzumab deruxtecan-nxki) injection, powder, lyophilized, for solution

HER2-Positive Metastatic Breast Cancer

Select patients for treatment of unresectable or metastatic HER2-positive breast cancer with ENHERTU in combination with pertuzumab based on confirmed HER2-positive status or HER2 gene amplification (IHC 3+ or ISH+) [see Clinical Studies (14.1)].

HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast Cancer

Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression [see Clinical Studies (14.2)].

HER2-Mutant Unresectable or Metastatic 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.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer

Select patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+). Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.

HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens [see Clinical Studies (14.5)]. An FDA-approved test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available.

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.

The recommended dosages for ENHERTU as monotherapy and ENHERTU in combination with pertuzumab are presented in Table 1. Administer ENHERTU as an intravenous infusion [see Dosage and Administration (2.4)].

Do not re-escalate the ENHERTU dose after a dose reduction is made.

If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.

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 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial 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.
• Discard any unused portion left in the vials.

Administration

• If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.
• Protect from light. Do not freeze.
• The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
• If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), 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.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive 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).

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive 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.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive 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.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (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 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY- Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for greater than 6 months and 38% were exposed for greater than 12 months. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%).

HER2-Positive 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 and HER2-Ultralow Metastatic Breast Cancer

HER2-Mutant Unresectable or Metastatic 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, decreased blood potassium, 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 16 and 17 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 drug-induced 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]

HER2-Positive 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 decreased blood potassium.

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, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.

Tables 18 and 19 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%)

HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 [see Clinical Studies (14.1 and 14.5)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8.3 months (range 0.7 to 30.2).

The median age was 60 years (range 23 to 96); 74% were female; 51% were White, 42% were Asian, 2.9% were Black or African American, 3.5% were of Hispanic or Latino ethnicity; and 40% had an ECOG performance status 0 and 41% had an ECOG performance status of 1.

Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%.

Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis.

Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.

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

Tables 20 and 21 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02.

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

• Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%)
• Nervous System Disorders: dizziness (9%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%)
• Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder]
• Eye Disorders: blurred vision (4%) [including blurred vision, visual impairment]
• Metabolism and Nutrition Disorders: dehydration (3.2%)
• Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%)
• Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)
• Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.4%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction]

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)].

Animal Data

Juvenile animal studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In a six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in incisor tooth toxicity including single cell necrosis in the base area (e.g., ameloblasts, odontoblasts) and degeneration of the enamel at ≥60 mg/kg (approximately ≥9 times the human recommended dose of 5.4 mg/kg based on AUC), abnormal formation or hypoplasia of the dentin, hemorrhage in the sub-enamel organ tissue, and focal lack of the cementum at 197 mg/kg (approximately 19 times the human recommended dose of 5.4 mg/kg based on AUC). Degeneration of the enamel organ, abnormal dentin formation, hemorrhage in the sub-enamel organ tissue, focal lack of the cementum, and root fracture were observed at 197 mg/kg following a 9-week recovery period.

ENHERTU as Monotherapy

Of the 2355 patients with HER2-positive, HER2-low, or HER2-ultralow breast cancer treated with ENHERTU 5.4 mg/kg, 23% were 65 years or older and 5% were 75 years or older. No overall differences in efficacy within clinical studies 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 or older (55%) as compared to younger patients (50%).

Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were 65 years or older and 8% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.

Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.

Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01 or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.

ENHERTU in Combination with Pertuzumab

In patients with HER2-positive unresectable or metastatic breast cancer treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), 17% were 65 years or older and 3% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.

Exposure-Response Relationships

Exposure relationship for efficacy has not been fully characterized. Higher systemic exposure to fam-trastuzumab deruxtecan-nxki was associated with a higher incidence rate of any grade ILD.

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.

Distribution

The estimated volume of distribution of the central compartment (V_c) of fam-trastuzumab deruxtecan-nxki was 2.68 L.

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 (t_1/2) of fam-trastuzumab deruxtecan-nxki is 5.4-5.7 days. The estimated systemic clearance of fam-trastuzumab deruxtecan-nxki was 0.41 L/day.

The median elimination half-life (t_1/2) of DXd is 5.4-6.1 days. The estimated 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 vs Non-Asian), including White, and Black or African American; sex; body weight (27.3-125.4 kg); tumor types; mild hepatic impairment; mild or moderate renal impairment.

The pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.

Drug Interaction Studies

DESTINY-Breast09

The efficacy of ENHERTU in combination with pertuzumab was evaluated in DESTINY-Breast09 (NCT04784715), a randomized, three-arm, multicenter, global study that enrolled 1157 adult patients with HER2-positive advanced, or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before the diagnosis of advanced or metastatic disease. A single line of prior endocrine therapy was permitted for advanced or metastatic breast cancer. HER2 expression was confirmed at a central laboratory using PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail with HER2 positivity defined as HER2 IHC 3+ or ISH positive.

Patients were excluded for a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patients with symptomatic brain metastases, or ECOG performance status >1, and patients with a history of clinically significant cardiac disease.

Patients were randomized 1:1:1 to receive either, ENHERTU 5.4 mg/kg plus pertuzumab (N=383), THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab) (N=387), or an investigational therapy (N=387) by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Patients with hormone receptor (HR) positive disease (N=416) were allowed to receive concurrent endocrine therapy after 6 cycles of ENHERTU or after discontinuation of the taxane in the THP arm; this occurred in 13.5% of patients in the ENHERTU in the combination with pertuzumab arm and in 38.3% of patients in the THP arm. Randomization was stratified by prior treatment status (de novo vs recurrent), hormone receptor status, and PIK3CA mutation status.

The major efficacy outcome was progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on Response Evaluation Criteria in Solid Tumors v1.1. Additional efficacy outcome measures were overall survival (OS) and confirmed objective response rate (ORR) assessed by BICR.

The median age was 54 years (range: 20-88); 82% were <65 years; 100% were female; 50% of the patients were Asian, 37% were White, 2% were American Indian or Alaska Native, and 3% were Black or African American; 14% were Hispanic or Latino; 8% other or race unknown; 52% had de novo disease and 48% had recurrent disease; 53% were HR-positive and 47% HR-negative; and 31% of patients had a PIK3CA mutation.

The trial demonstrated a statistically significant improvement in PFS for patients randomized to ENHERTU in combination with pertuzumab compared to THP. Efficacy results are summarized in Table 22 and Figure 1. At the time of the PFS analysis, OS data was not mature with 126 (16%) of patients who died across both study arms in the overall population.

Figure 1: Kaplan-Meier Plot of Progression-Free Survival per BICR

Figure 1

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 23 and Figures 2 and 3.

Figure 2: Kaplan-Meier Plot of Progression-Free Survival per BICR (Intent-to-Treat Analysis Set)
Figure 2

Figure 3: Kaplan-Meier Plot of Overall Survival
Figure 3

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 24 and Figures 4 and 5.

Figure 4: Kaplan-Meier Plot of Progression-free Survival Per BICR
Figure 4

Figure 5: Kaplan-Meier Plot of Overall Survival
Figure 5

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 25.

DESTINY-Breast06

The efficacy of ENHERTU was evaluated in study DESTINY-Breast06 (NCT04494425), a randomized (1:1), multicenter, open-label study that randomized 866 adult patients with advanced or metastatic HR+ breast cancer with HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) expression as determined by Ventana's PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay and evaluated at a central laboratory. HER2-ultralow is defined as membrane staining that is seen in >0 and ≤10% of tumor cells. Patients were eligible if they had disease progression on (a) at least 2 lines of endocrine therapy in the metastatic setting or (b) one line of endocrine therapy in the metastatic setting and demonstrated progression within 24 months of the start of adjuvant endocrine therapy, or within 6 months of starting first line endocrine therapy in combination with a CDK 4/6 inhibitor in the metastatic setting. Patients with prior chemotherapy in the neoadjuvant or adjuvant setting were eligible if they had a disease-free interval greater than 12 months. The study excluded patients with prior chemotherapy for advanced or metastatic disease, patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, uncontrolled or significant cardiovascular disease, untreated and symptomatic brain metastases, or ECOG performance status >1.

Patients were randomized to receive either ENHERTU 5.4 mg/kg (N=436) by intravenous infusion every three weeks or physician's choice of single agent chemotherapy (N=430, capecitabine 60%, nab-paclitaxel 24%, or paclitaxel 16%). Randomization was stratified by prior CDK4/6 inhibitor use (yes or no), prior taxane use in the non-metastatic setting (yes or no), and HER2 IHC status of tumor samples (IHC 2+/ISH- vs IHC 1+ vs IHC 0 with membrane staining). Treatment with ENHERTU was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.

The major efficacy outcome measure was PFS in patients with HER2-low breast cancer assessed by BICR based on RECIST v1.1. Additional efficacy outcome measures were PFS assessed by BICR based on RECIST v1.1 in the overall population, OS in HER2-low patients, and OS in the overall population.

The median age was 57 years (range: 28 to 87); 31% were age 65 or older; 99.9% were female; 53% were White, 35% were Asian, 0.8% were Black or African American, 0.1% were American Indian or Alaska Native, and 7% were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of 0 (59%) or 1 (39%) at baseline; 18% were IHC 0 with membrane staining, 55% were IHC 1+, 27% were IHC 2+/ISH-; 67% had liver metastases, 32% had lung metastases, 8% had brain metastases, and 3% had bone-only metastases. Patients had a median of 2 prior lines of endocrine therapy in the metastatic setting (range: 1 to 5) with 17% having 1 and 68% having 2. Eighty-nine percent of patients had prior endocrine therapy in combination with CDK4/6i treatment in the metastatic setting, 41% had prior taxane use in the non-metastatic setting.

Efficacy results are summarized in Table 26 and Figure 6. At the time of the PFS final analysis, overall survival (OS) data was immature, and a total of 335 (39%) of patients had died across both study arms in the overall population.

In an exploratory analysis of the HER2-ultralow subgroup (n=153), median PFS was 15.1 months (95% CI: 10.0, 17.3) in patients randomized to ENHERTU and 8.3 months (95% CI: 5.8, 15.2) in patients randomized to chemotherapy with a hazard ratio of 0.76 (95% CI: 0.49, 1.17). Confirmed ORR (BICR) was 65.7% (95% CI: 53.1, 76.8) and 30.8% (95% CI: 19.9, 43.4) in patients randomized to ENHERTU and chemotherapy and with measurable disease at baseline, respectively. Median DOR was 14.3 months (95% CI: 11.8, not estimable) and 14.1 months (95% CI: 5.9, not estimable) in patients randomized to ENHERTU and chemotherapy, respectively.

Figure 6: Kaplan-Meier Plot of Progression Free Survival (Overall Population)
Figure 6

DESTINY-Breast04

The efficacy of ENHERTU was evaluated in study DESTINY-Breast04 (NCT03734029), a randomized, multicenter, open-label study that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The study included 2 cohorts: 494 hormone receptor-positive (HR+) patients and 63 hormone receptor-negative (HR-) patients. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-, as determined at a central laboratory using Ventana's PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay. Patients must have received chemotherapy in the metastatic setting or have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Patients who were HR+ must have received at least one endocrine therapy or be ineligible for endocrine therapy. Patients were randomized 2:1 to receive either ENHERTU 5.4 mg/kg (N=373) by intravenous infusion every 3 weeks or physician's choice of chemotherapy (N=184, eribulin, capecitabine, gemcitabine, nab paclitaxel, or paclitaxel). Randomization was stratified by HER2 IHC status of tumor samples (IHC 1+ or IHC 2+/ISH-), number of prior lines of chemotherapy in the metastatic setting (1 or 2), and HR status/prior CDK4/6i treatment (HR+ with prior CDK4/6 inhibitor treatment, HR+ without prior CDK4/6 inhibitor treatment, or HR-). Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The study excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for untreated or symptomatic brain metastases or ECOG performance status >1.

The major efficacy outcome measure was PFS in patients with HR+ breast cancer assessed by BICR based on RECIST v1.1. Additional efficacy outcome measures were PFS assessed by BICR based on RECIST v1.1 in the overall population (all randomized HR+ and HR- patients), OS in HR+ patients, and OS in the overall population.

The median age was 57 years (range: 28 to 81); 24% were age 65 or older; 99.6% were female; 48% were White, 40% were Asian, and 2% were Black or African American; 3.8% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of 0 (55%) or 1 (45%) at baseline; 58% were IHC 1+, 42% were IHC 2+/ISH-; 70% had liver metastases, 33% had lung metastases, and 6% had brain metastases. In the metastatic setting, patients had a median of 3 prior lines of systemic therapy (range: 1 to 9) with 58% having 1 and 41% having 2 prior chemotherapy regimens; 3.9% were early progressors (progression in the neo/adjuvant setting). In HR+ patients, the median number of prior lines of endocrine therapy was 2 (range: 0 to 9) and 70% had prior CDK4/6i treatment.

Efficacy results are summarized in Table 27 and Figures 7 and 8.

Figure 7: Kaplan-Meier Plot of Overall Survival (Overall Population)
Figure 7

Figure 8: Kaplan-Meier Plot of Progression-Free Survival (Overall Population)
Figure 8

DESTINY-PanTumor02

DESTINY-PanTumor02 (NCT04482309) was a multicenter, multicohort, open-label trial that included 111 adult patients with locally advanced, unresectable, or metastatic HER2-positive (IHC 3+ by either local or central assessment) solid tumors that progressed following at least one prior systemic regimen in the advanced/metastatic setting or that had no satisfactory alternative treatment option.

The median age was 64 years (range 23 to 85); 59% were female; 58% were White, 34% were Asian, and 4% were Black or African American; 3% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of either 0 (49%) or 1 (51%) at baseline. The median number of prior regimens in any treatment setting was 2.

DESTINY-Lung01

DESTINY-Lung01 (NCT03505710) was a multicenter, open-label, 2-cohort trial that included 17 patients with previously treated, unresectable, or metastatic, centrally confirmed HER2-positive (IHC 3+) NSCLC. Patients must have relapsed from or be refractory to standard treatment or have no available standard treatment.

The median age was 59 years (range 31 to 74); 59% were male; 65% were White, 18% were Asian, and 12% were Black or African American. Patients had an ECOG performance status of either 0 (12%) or 1 (88%) at baseline. The median number of prior regimens in any treatment setting was 3.

DESTINY-CRC02

DESTINY-CRC02 (NCT04744831) was a multicenter, randomized, 2-arm trial that included 64 patients with previously treated, unresectable or metastatic centrally confirmed HER2-positive (IHC 3+) colorectal cancer (CRC). Unless contraindicated, patients must have received fluoropyrimidine, oxaliplatin and irinotecan. If clinically indicated, patients must have received anti-EGFR treatment, anti-VEGF treatment and anti-PDL1 therapy.

The median age was 58 years (range 25 to 78); 53% were male; 55% were Asian and 41% were White; 1.6% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of either 0 (58%) or 1 (42%) at baseline. The median number of prior regimens in any treatment setting was 4.

Efficacy results are summarized in Table 30 and Table 31.