Enhertu Drug Information

    Generic name: FAM-TRASTUZUMAB DERUXTECAN-NXKI

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    Uses of Enhertu

    HER2-Positive Early Breast Cancer

    ENHERTU followed by a taxane, trastuzumab, and pertuzumab (THP) is indicated for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer as determined by an FDA-authorized test. ENHERTU is indicated for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.

    HER2-Positive Metastatic Breast Cancer ENHERTU, in combination with pertuzumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test. ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or, in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy.

    HER2-Low and HER2-Ultralow Metastatic Breast Cancer

    ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic Hormone receptor (HR)-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting. HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

    HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized test, and who have received a prior systemic therapy. This indication is approved under accelerated approval based on objective 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.

    HER2-Positive Locally Advanced or Metastatic Gastric Cancer

    ENHERTU, as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

    HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors ENHERTU, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

    Dosage & Administration of Enhertu

    Patient Selection HER2-Positive Early Breast Cancer

    Select patients for the treatment of HER2-positive early breast cancer with ENHERTU based on HER2-positive (IHC 3+ or ISH+) status. 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. 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.

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

    Recommended Dosage

    Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine. Slow or interrupt the infusion rate if the patient develops infusion-related symptoms. Permanently discontinue ENHERTU in case of severe infusion reactions.

    Premedication ENHERTU is highly emetogenic, 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. Table 1: Recommended Dosage s Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in Tables 2 and 3. Refer to the Prescribing Information for pertuzumab for dose modification recommendations.

    Pertuzumab is not to be administered as a single agent. 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. Table 2: Dosage Reduction Schedule Interstitial Lung Disease (ILD)/ Pneumonitis In the adjuvant setting, if drug-induced ILD is suspected, rule out radiotherapy-related pneumonitis.

    If only radiotherapy-related pneumonitis is suspected, consider interruption of ENHERTU for Grade 2 and permanently discontinue ENHERTU for Grade ≥3.

    Preparation and Administration

    In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU (fam-trastuzumab deruxtecan-nxki) and not trastuzumab or ado-trastuzumab emtansine. Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.

    ENHERTU (fam-trastuzumab deruxtecan-nxki) is a hazardous drug. Follow applicable special handling and disposal procedures. 1 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. 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, protect the vial from light. Do not freeze.

    The product does not contain a preservative. Discard unused reconstituted 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 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature between 20°C to 25°C (68°F to 77 °F) 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 (2°C to 8°C ), allow the solution to reach room temperature prior to administration.

    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.

    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.

    Table 1: Recommended Dosage
    IndicationRecommended ENHERTU DosageDuration of Therapy
    As Monotherapy
    HER2-Positive Early Breast Cancer – Post Neoadjuvant TreatmentENHERTU 5.4 mg/kg every 3 weeks14 cycles unless disease recurrence or unacceptable toxicity
    HER2-Positive, HER2-Low, or HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant Unresectable or Metastatic NSCLC, and HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors as monotherapyENHERTU 5.4 mg/kg every 3 weeksUntil disease progression or unacceptable toxicity
    HER2-Positive Locally Advanced or Metastatic Gastric Cancer as monotherapyENHERTU 6.4 mg/kg every 3 weeksUntil disease progression or unacceptable toxicity
    In Combination
    HER2-Positive Metastatic Breast Cancer in combination with pertuzumabCycle 1, Day 1: ENHERTU 5.4 mg/kg, followed by pertuzumab 840 mg Administer pertuzumab 30 minutes after ENHERTU. Subsequent cycles, Day 1: ENHERTU 5.4 mg/kg, followed by pertuzumab 420 mg every 3 weeksUntil disease progression or unacceptable toxicity
    In Sequence
    HER2-Positive Early Breast Cancer followed by THPENHERTU 5.4 mg/kg every 3 weeks for 4 cycles, followed by THP regimen THP regimen: a taxane concurrent with trastuzumab (6 mg/kg every 3 weeks) and pertuzumab (an initial dose of 840 mg followed by 420 mg every 3 weeks) for 4 cycles4 cycles of ENHERTU followed by 4 cycles of THP.
    Table 2: Dosage Reduction Schedule
    Dose Reduction ScheduleBreast Cancer, NSCLC, and IHC 3+ Solid TumorsGastric Cancer
    Recommended starting dose5.4 mg/kg6.4 mg/kg
    First dose reduction4.4 mg/kg5.4 mg/kg
    Second dose reduction3.2 mg/kg4.4 mg/kg
    Requirement for further dose reductionDiscontinue treatment.Discontinue treatment.
    Table 3: Dosage Modifications for Adverse Reactions
    Adverse ReactionSeverityTreatment Modification
    Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v.5.0).
    Interstitial Lung Disease (ILD)/ Pneumonitis In the adjuvant setting, if drug-induced ILD is suspected, rule out radiotherapy-related pneumonitis. If only radiotherapy-related pneumonitis is suspected, consider interruption of ENHERTU for Grade 2 and permanently discontinue ENHERTU for Grade ≥3. [see Warnings and Precautions (5.1) ]Asymptomatic ILD/pneumonitis (Grade 1)Interrupt ENHERTU until resolved to Grade 0, then: if resolved in 28 days or less from date of onset, maintain dose. if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 2 ). consider corticosteroid treatment as soon as ILD/pneumonitis is suspected.
    Symptomatic ILD/pneumonitis (Grade 2 or greater)Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
    Neutropenia [see Warnings and Precautions (5.2) ]Grade 3 (less than 1.0 to 0.5 × 10 9 /L)Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
    Grade 4 (less than 0.5 × 10 9 /L)Interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level (see Table 2 ).
    Febrile Neutropenia [see Warnings and Precautions (5.2) ]Absolute neutrophil count of less than 1.0 × 10 9 /L and temperature greater than 38.3°C or a sustained temperature of 38°C or greater for more than one hourInterrupt ENHERTU until resolved. Reduce dose by one level (see Table 2 ).
    Thrombocytopenia [see Adverse Reactions (6.1) ]Grade 3 (platelets less than 50 to 25 × 10 9 /L)Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
    Grade 4 (platelets less than 25 × 10 9 /L)Interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level (see Table 2 ).
    Left Ventricular Dysfunction (LVD) [see Warnings and Precautions (5.3) ]Left Ventricular Ejection Fraction (LVEF) greater than 45% and absolute decrease from baseline is 10% to 20%Continue treatment with ENHERTU.
    LVEF 40% to 45%And absolute decrease from baseline is less than 10%Continue treatment with ENHERTU. Repeat LVEF assessment within 3 weeks.
    And absolute decrease from baseline is 10% to 20%Interrupt ENHERTU. 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.
    LVEF less than 40% or absolute decrease from baseline is greater than 20%Interrupt ENHERTU. Repeat LVEF assessment within 3 weeks. If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.
    Symptomatic congestive heart failure (CHF)Permanently discontinue ENHERTU.

    Side Effects of Enhertu

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) ENHERTU as Monotherapy 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. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count ( %), increased aspartate aminotransferase (46%), increased alanine aminotransferase (43%), increased blood alkaline phosphatase ( %).

    ENHERTU in Combination with Pertuzumab The pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg in combination with pertuzumab intravenously every 3 weeks in 431 patients in DESTINY-Breast07 (n=50), and DESTINY-Breast09 (n=381). In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count ( %), increased aspartate aminotransferase (63%), decreased lymphocyte count (61%), decreased platelet count (55%), increased blood alkaline phosphatase ( %). ENHERTU followed by THP The data described in the WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks for four cycles followed by THP for four cycles in 320 patients in Study DESTINY-Breast11.

    HER2-Positive Early Breast Cancer DESTINY-Breast11 The safety of ENHERTU followed by THP was evaluated in 320 patients with HER2-positive (IHC 3+ or ISH+) early breast cancer who received at least one dose of ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11. ENHERTU was administered by intravenous infusion once every three weeks for four cycles followed by THP for four cycles. The median duration of treatment was 5.6 months (range: 0.7 to 9.1) for patients who received ENHERTU followed by THP.

    Serious adverse reactions occurred in 11% of patients receiving ENHERTU followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD/pneumonitis and death not otherwise specified (one patient each). In patients treated with ENHERTU followed by THP, the permanent discontinuation of ENHERTU due to adverse reactions occurred in 1.3%, of which ILD/pneumonitis accounted for 0.6%.

    Dose interruptions of ENHERTU due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count and COVID-19. Dose reductions of ENHERTU occurred in 2.5% of patients treated with ENHERTU.

    The most common (≥20%) adverse reactions in patients treated with ENHERTU followed by THP, including laboratory abnormalities, were decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis, and decreased appetite. Tables 4 and 5 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast11. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU.

    Serious adverse reactions in ≥1% of patients who received ENHERTU were ILD/pneumonitis, radiation pneumonitis, pneumonia, and platelet count decreased. Fatal adverse reactions occurred in 0.4% of patients including ILD/pneumonitis (2 patients) and respiratory tract infection (one patient). Permanent discontinuation of ENHERTU due to an adverse reaction occurred in 18% of patients.

    The adverse reaction which resulted in permanent discontinuation of ENHERTU >2% included ILD/pneumonitis. Dose interruptions of ENHERTU due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruptions in >2% included radiation pneumonitis, neutrophil count decreased, COVID-19, white blood cell count decreased, ILD/pneumonitis, platelet count decreased, upper respiratory tract infection, fatigue, cough, and pyrexia.

    Dose reductions of ENHERTU due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in >2% of patients included nausea, fatigue, platelet count decreased, ILD/pneumonitis, and neutrophil count decreased. Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast05.

    A higher incidence of radiation pneumonitis was reported for patients who received sequential vs. concurrent ART, irrespective of treatment arm: 34% for ENHERTU vs. 37% for T-DM1, respectively, with sequential ART and 29% vs. 27%, respectively, with concurrent ART. For patients treated with ENHERTU, median time to onset of first event of radiation pneumonitis was 4.1 months (range: 1.3 – 11.6 months). HER2-Positive Metastatic Breast Cancer DESTINY-Breast09 The safety of ENHERTU 5.4 mg/kg in combination with pertuzumab was evaluated in DESTINY-Breast09, a randomized, three-arm, multicenter study including 763 patients with HER2-positive (IHC 3+ or ISH+) unresectable or metastatic breast cancer.

    Three hundred eighty-one patients received ENHERTU in combination with pertuzumab and 382 patients received THP (taxane, trastuzumab, and pertuzumab). Among patients who received ENHERTU in combination with pertuzumab, the median duration of treatment was 22 months (range: 0.3 months to 44.5 months). Serious adverse reactions occurred in 27% of patients receiving ENHERTU in combination with pertuzumab.

    Serious adverse reactions in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to adverse reactions occurred in 3.4% of patients including pneumonia (n=3), ILD (n=2), sepsis (n=2), pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (one patient each). ENHERTU was discontinued for adverse reactions in 21% of patients.

    The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis (6%). The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, neutropenia, upper respiratory tract infection, fatigue, anemia, hypokalemia, ILD/pneumonitis, thrombocytopenia, pneumonia, diarrhea, transaminase increased, leukopenia, cough, pyrexia, decreased appetite, and blood bilirubin increased. Dose reductions occurred in 46% of patients treated with ENHERTU in combination with pertuzumab.

    The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase decreased lymphocyte count, decreased platelet count, increased blood alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased blood bilirubin, and abdominal pain. Tables 8 and 9 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast09.

    Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%.

    Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03. The median duration of treatment was 11 months (range: 0.7 to 45) for patients who received ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were COVID-19, ILD, pneumonia, vomiting, fatigue, and nausea.

    Fatalities due to adverse reactions occurred in 2.5% of patients including pneumonitis (2 patients), acute myeloid leukemia, brain edema, COVID-19, hemorrhage, hepatitis B, malignant pleural effusion, pneumonia, and vasogenic cerebral edema (one patient each). ENHERTU was permanently discontinued in 20% of patients, of which ILD accounted for 9%. Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02.

    Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, decreased blood potassium, 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. Tables 14 and 15 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients in DESTINY-Breast01 and Study DS8201-A-J101. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU.

    Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease (ILD)/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count. Tables 16 and 17 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast06.

    The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received 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).

    Tables 18 and 19 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04. Table 18: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast04 Other clinically relevant adverse reactions reported in less than % Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) Table 19: Selected Laboratory Abnormalities in Patients in DESTINY-Breast04 HER2-Mutant Unresectable or Metastatic NSCLC DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg and 6.4 mg/kg ); 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.

    Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. The median duration of treatment was 8 months (range: 0.7 to 28) for patients who received ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pleural effusion, thrombocytopenia, dyspnea, nausea, pneumonia, vomiting, myocarditis, pulmonary embolism, and increased troponin I.

    Fatalities due to adverse reactions occurred in 3% of patients including ILD/pneumonitis, cerebrovascular accident, and pneumococcal sepsis (one patient each). ENHERTU was permanently discontinued due to an adverse reaction in 17% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, pneumonia, blood bilirubin increased, hypokalemia, metastases to meninges, and myocarditis.

    Adverse reactions which required dose interruption (>2%) included neutropenia, COVID-19, ILD/pneumonitis, fatigue, anemia, and pneumonia. Tables 20 and 21 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02. 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%.

    Tables 22 and 23 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01. Tables 24 and 25 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02.

    Table 4: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) Patients in DESTINY-Breast11
    Adverse ReactionsENHERTU 5.4 mg/kg followed by THP N = 320ddAC followed by THP N = 312
    All Grades %Grade 3 or 4 %All Grades %Grade 3 or 4 %
    THP= paclitaxel, trastuzumab, and pertuzumab; ddAC=dose dense doxorubicin and cyclophosphamide; Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea651.9520.3
    Diarrhea596543.2
    Constipation290.3240
    Vomiting290.9210.6
    Stomatitis Including aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, and stomatitis.230.3361.0
    Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain.160120
    Nervous System Disorders
    Peripheral neuropathy Including dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.592.5472.2
    Headache Including headache, migraine, and sinus headache.180160
    Skin and Subcutaneous Tissue Disorders
    Alopecia480490
    Rash Including dermatitis, dermatitis acneiform, dermatitis bullous, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and urticarial dermatitis.310.9251.0
    General Disorders and Administration Site Conditions
    Fatigue Including asthenia, fatigue, and malaise.410.6552.2
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including arthralgia, back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity.300280.3
    Metabolism and Nutrition Disorders
    Decreased appetite200180.3
    Respiratory, Thoracic and Mediastinal Disorders
    Epistaxis150100
    Cough100140
    Infections and Infestations
    Upper respiratory tract infection Including influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection.130.6200.3
    COVID-19100.9110.3
    Table 5: Selected Laboratory Abnormalities in Patients in DESTINY-Breast11
    Laboratory ParameterENHERTU 5.4 mg/kg followed by THP N=320ddAC followed by THP N = 312
    All Grades %Grades 3-4 %All Grades %Grades 3-4 %
    THP= paclitaxel, trastuzumab, and pertuzumab; ddAC= dose dense doxorubicin and cyclophosphamide Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased hemoglobin832.29710
    Decreased white blood cell count6788731
    Decreased neutrophil count58176638
    Decreased lymphocyte count403.19339
    Decreased platelet count80.9282.9
    Chemistry
    Increased alanine aminotransferase795774.2
    Increased aspartate aminotransferase742.5681
    Decreased blood potassium294.1254.5
    Increased blood alkaline phosphatase190240
    Decreased sodium191.9232.6
    Increased blood creatinine80.681.3
    Increased blood bilirubin704.20.6
    Table 6: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast05
    Adverse ReactionsENHERTU 5.4 mg/kg N= 806Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kg N=801
    All Grades %Grade 3 or 4 %All Grades %Grades 3 or 4 %
    Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea714.5290.1
    Constipation320160.1
    Vomiting311.190.1
    Diarrhea231.290.4
    Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain.150.290.1
    Stomatitis Including aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and stomatitis.100.260.1
    General Disorders and Administration Site Conditions
    Fatigue Including asthenia, fatigue, lethargy, and malaise.546371.0
    Pyrexia100.1120.2
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including arthralgia, back pain, bone pain, limb discomfort, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity.230.7320.6
    Metabolism and Nutrition Disorders
    Decreased appetite200.9100
    Infections and Infestations
    Upper respiratory tract infection Including influenza, influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection.180.1170.5
    COVID-19170.5200.4
    Respiratory, Thoracic and Mediastinal Disorders
    Interstitial lung disease Including COVID-19 pneumonia, interstitial lung disease, lung opacity, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia, and pneumonitis which was adjudicated as ILD (irrespective of causality). Adjudicated drug-related ILD for ENHERTU was 10% for all Grades and 0.9% for Grades 3 or 4 and for T-DM1, 1.6% for all Grades and 0% for Grades 3 or 4.171.13.70.2
    Cough130110
    Nervous System Disorders
    Headache Including headache, migraine, and sinus headache.160.2210.1
    Peripheral neuropathy Including dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.130.4201.1
    Dizziness Including dizziness, dizziness postural, vertigo, and vertigo positional.110.470.1
    Skin and Subcutaneous Tissue Disorders
    Alopecia1601.20
    Rash Including dermatitis, dermatitis acneiform, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and Stevens-Johnson syndrome.100.4140.1
    Investigations
    Decreased weight120.270.1
    Table 7: Selected Laboratory Abnormalities in Patients in DESTINY-Breast05
    Laboratory ParameterENHERTU 5.4 mg/kg N=806Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kg N = 801
    All Grades %Grades 3-4 %All Grades %Grades 3-4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count8017462.3
    Decreased lymphocyte count72355417
    Decreased neutrophil count7223384.9
    Decreased hemoglobin612.9362
    Decreased platelet count4689333
    Chemistry
    Increased aspartate aminotransferase601914.3
    Increased alanine aminotransferase531804.2
    Increased blood alkaline phosphatase390530.1
    Decreased blood potassium271.7442.1
    Increased blood creatinine130.290.1
    Increased blood bilirubin90200
    Table 8: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in Combination with Pertuzumab in DESTINY-Breast09
    Adverse ReactionsENHERTU 5.4 mg/kg + Pertuzumab N= 381THP THP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab N=382
    All Grades %Grade 3-4 %All Grades %Grades 3-4 %
    Gastrointestinal Disorders
    Nausea755340.3
    Diarrhea648626
    Vomiting462.4180.5
    Constipation330.3120
    Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain.230.3130
    Stomatitis Including aphthous ulcer, mouth ulceration, oral mucosal eruption, and stomatitis.161.3171.3
    Dyspepsia12060
    General Disorders and Administration Site Conditions
    Fatigue Including asthenia, fatigue, lethargy, and malaise.538422.1
    Pyrexia160181.0
    Skin and Subcutaneous Tissue Disorders
    Alopecia480530.5
    Rash Including rash, rash macular, rash maculo-papular, rash pruritic, and rash pustular.170.3220.3
    Pruritus110110.3
    Infections and Infestations
    Upper respiratory tract infection Including Influenza, Influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection.331.6300.5
    COVID-19280.3220.3
    Metabolism and Nutrition Disorders
    Decreased appetite322.4180.8
    Hypoalbuminemia110.380.3
    Investigations
    Decreased weight303.1110.8
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity.241330.3
    Nervous System Disorders
    Headache Including headache and migraine.190.3140
    Dysgeusia13090
    Dizziness120.3100
    Respiratory, Thoracic, and Mediastinal Disorders
    Cough170.3130
    Interstitial lung disease Interstitial lung disease includes chronic obstructive pulmonary disease (n=1), interstitial lung disease (n=23), pneumonia (n=3), and pneumonitis (n=22). These events were adjudicated as ILD and related to use of ENHERTU12010
    Eye Disorders
    Dry eye11060
    Table 9: Selected Laboratory Abnormalities in Patients in DESTINY-Breast09
    Laboratory ParameterENHERTU 5.4 mg/kg + Pertuzumab N= 381THP THP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab] N=382
    All Grades %Grade 3-4 %All Grades %Grades 3-4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count87118231
    Decreased hemoglobin8012866
    Decreased neutrophil count78296640
    Decreased lymphocyte count62145811
    Decreased platelet count568201.9
    Chemistry
    Increased alanine aminotransferase663.2451.9
    Increased aspartate aminotransferase622.1411.9
    Increased blood alkaline phosphatase550.3360.3
    Decreased blood potassium5420296
    Increased blood bilirubin230.3100.3
    Increased blood creatinine91.870.3
    Table 10: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03
    Adverse ReactionsENHERTU 5.4 mg/kg N=257Ado-trastuzumab emtansine 3.6 mg/kg N=261
    All Grades %Grades 3-4 %All Grades %Grades 3-4 %
    Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea767300.4
    Vomiting491.6100.8
    Constipation340200
    Diarrhea291.270.4
    Abdominal pain Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain.210.880.4
    Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption.200.850
    Dyspepsia11060
    General Disorders and Administration Site Conditions
    Fatigue Including fatigue, asthenia, malaise, and lethargy.496350.8
    Skin and Subcutaneous Tissue Disorders
    Alopecia This Grade 3 event was reported by the investigator. Per NCI CTCAE v.5.0, the highest NCI CTCAE grade for alopecia is Grade 2.370.43.10
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort.311.2250.4
    Metabolism and Nutrition Disorders
    Decreased appetite291.6170.4
    Investigations
    Decreased weight171.260.4
    Respiratory, Thoracic, and Mediastinal Disorders
    Respiratory infection Including respiratory tract infection, lower and upper respiratory tract infection, pneumonia, influenza, influenza-like illness, viral upper respiratory infection, bronchitis, and respiratory syncytial virus infection.220.8121.1
    Epistaxis110160.4
    Cough110.4100
    Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For ado-trastuzumab emtansine: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism.110.81.90
    Nervous System Disorders
    Headache Including headache and migraine.220.4160
    Peripheral neuropathy Including peripheral neuropathy, peripheral sensory neuropathy, and paresthesia.130.4140.4
    Dizziness130.480
    Table 11: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03
    Laboratory ParameterENHERTU 5.4 mg/kg N=257Ado-trastuzumab emtansine 3.6 mg/kg N=261
    All Grades %Grades 3-4 %All Grades %Grades 3-4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count748240.8
    Decreased neutrophil count7018302.3
    Decreased hemoglobin647386
    Decreased lymphocyte count5514233.9
    Decreased platelet count5277924
    Chemistry
    Increased aspartate aminotransferase670.8835
    Increased alanine aminotransferase531.6676
    Increased blood alkaline phosphatase490.8460.8
    Decreased blood potassium354.7391.5
    Increased blood bilirubin200140
    Increased blood creatinine160.880.4
    Table 12: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast02
    Adverse ReactionsENHERTU 5.4 mg/kg N=404Treatment of Physician's Choice N=195
    All Grades %Grades 3-4 %All Grades %Grades 3-4 %
    Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea737372.6
    Vomiting383.7131
    Constipation350.3110.5
    Diarrhea272.7547
    Abdominal pain Including abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain, and gastrointestinal pain221202.1
    Dyspepsia12090
    Stomatitis Including aphthous ulcer, mouth ulceration, and stomatitis121211
    General Disorders and Administration Site Conditions
    Fatigue Including asthenia, fatigue, lethargy, and malaise629371
    Skin and Subcutaneous Tissue Disorders
    Alopecia370.34.10
    Metabolism and Nutrition Disorders
    Decreased appetite311.7180.5
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, bone pain, limb discomfort, musculoskeletal chest pain, musculoskeletal pain, muscle spasms, myalgia, neck pain, and pain in extremity250.7180.5
    Nervous System Disorders
    Headache Including headache and migraine200.360
    Investigations
    Decreased weight180.33.60
    Respiratory, Thoracic, and Mediastinal Disorders
    Cough130100
    Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, idiopathic interstitial pneumonia, lung disorder, pulmonary toxicity, and pneumonia.100.70.50.5
    Table 13: Selected Laboratory Abnormalities in Patients in DESTINY-Breast02
    Laboratory ParameterENHERTU 5.4 mg/kg N=404Treatment of Physician's Choice N=195
    All Grades %Grades 3-4 %All Grades %Grades 3-4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count7012423.2
    Decreased hemoglobin679543.2
    Decreased neutrophil count6416344.7
    Decreased lymphocyte count5817384.7
    Decreased platelet count482.7311.6
    Chemistry
    Increased alanine aminotransferase431321.6
    Increased aspartate aminotransferase370.7292.1
    Increased blood alkaline phosphatase370170
    Decreased blood potassium303.7298
    Increased blood bilirubin230.3442.1
    Increased blood creatinine70.3130
    Table 14: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101
    Adverse ReactionsENHERTU 5.4 mg/kg N=234
    All Grades %Grades 3 or 4 %
    Events were graded using NCI CTCAE version 4.03.
    Gastrointestinal Disorders
    Nausea797
    Vomiting473.8
    Constipation350.9
    Diarrhea291.7
    Abdominal pain Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain191.3
    Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosa blistering. One Grade 1 event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01).140.9
    Dyspepsia120
    General Disorders and Administration Site Conditions
    Fatigue Including fatigue and asthenia596
    Skin and Subcutaneous Tissue Disorders
    Alopecia460.4 This Grade 3 event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2.
    Rash Including rash, pustular rash, and maculo-papular rash100
    Metabolism and Nutrition Disorders
    Decreased appetite321.3
    Respiratory, Thoracic, and Mediastinal Disorders
    Cough200
    Dyspnea131.3
    Epistaxis130
    Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis.92.6 All events had fatal outcomes (n=6).
    Nervous System Disorders
    Headache Including headache, sinus headache, and migraine190
    Dizziness100
    Infections and Infestations
    Upper respiratory tract infection Including influenza, influenza-like illness, and upper respiratory tract infection150
    Eye Disorders
    Dry eye110.4 This Grade 4 event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for dry eye is Grade 3.
    Table 15: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTU in DESTINY-Breast01 and Study DS8201-A-J101
    Laboratory ParameterENHERTU 5.4 mg/kg N=234
    All Grades %Grades 3 or 4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.
    Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count707
    Decreased hemoglobin707
    Decreased neutrophil count6216
    Decreased platelet count373.4
    Chemistry
    Increased aspartate aminotransferase410.9
    Increased alanine aminotransferase380.4
    Decreased blood potassium263
    Table 16: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast06
    Adverse ReactionsENHERTU 5.4 mg/kgChemotherapy
    N=434N=417
    All Grades %Grades 3 or 4 %All Grades %Grades 3 or 4 %
    Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea702.1300.5
    Diarrhea342.3272.6
    Vomiting341.4120.2
    Constipation320.7150.5
    Abdominal pain Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain.200.5140.2
    Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption.150110.5
    Dyspepsia1204.80
    General Disorders and Administration Site Conditions
    Fatigue Including fatigue, asthenia, malaise, and lethargy.534.4402.4
    Pyrexia120.270
    Skin and Subcutaneous Tissue Disorders
    Alopecia480210.5
    Rash Including dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.120.2438
    Metabolism and Nutrition Disorders
    Decreased appetite261.4120.5
    Infections and Infestations
    COVID-19 Including COVID-19, COVID-19 pneumonia.260.9131
    Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis.19090
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort.240.5231.9
    Nervous System Disorders
    Headache Including migraine, headache, and sinus headache.180.5100
    Dysgeusia120.260
    Respiratory, Thoracic, and Mediastinal Disorders
    Cough16090
    Interstitial lung disease Including bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity.110.70.20
    Epistaxis1003.60.2
    Table 17: Selected Laboratory Abnormalities in Patients in DESTINY-Breast06
    Laboratory ParameterENHERTU 5.4 mg/kgChemotherapy
    N=434N=417
    All Grades %Grades 3 or 4 %All Grades %Grades 3 or 4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.
    Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count86137111
    Decreased neutrophil count75275320
    Decreased hemoglobin699585
    Decreased lymphocyte count6619468
    Decreased platelet count486251
    Chemistry
    Increased alanine aminotransferase443.2300.7
    Increased blood alkaline phosphatase430.2220.2
    Increased aspartate aminotransferase412.6271.2
    Decreased blood potassium358152.9
    Increased blood bilirubin161.9231.5
    Increased blood creatinine101.981
    Table 18: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast04
    Adverse ReactionsENHERTU 5.4 mg/kgChemotherapy
    N=371N=172
    All Grades %Grades 3 or 4 %All Grades %Grades 3 or 4 %
    Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea764.6300
    Vomiting401.6130
    Constipation340.8220
    Diarrhea271.3221.7
    Abdominal pain Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain180.5130
    Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation130.3120.6
    General Disorders and Administration Site Conditions
    Fatigue Including fatigue, asthenia, and malaise549484.7
    Pyrexia120.3130
    Skin and Subcutaneous Tissue Disorders
    Alopecia400330
    Rash Including rash, pustular rash, pruritic rash, maculo-papular rash, palmar-plantar erythrodysesthesia syndrome, papular rash, macular rash, eczema, erythema multiforme, dermatitis, urticarial dermatitis, drug eruption, and dermatitis bullous130234.7
    Metabolism and Nutrition Disorders
    Decreased appetite322.4191.2
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, arthralgia, noncardiac chest pain, musculoskeletal stiffness, arthritis, spinal pain, and neck pain321.3310.6
    Investigations
    Decreased weight160.380
    Vascular Disorders
    Hemorrhage Including esophageal varices, hemorrhage, hemorrhoidal hemorrhage, epistaxis, hematuria, conjunctival hemorrhage, vaginal hemorrhage, gingival bleeding, genital hemorrhage, eye hemorrhage, hemoptysis, hemorrhagic cystitis, pharyngeal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, and esophageal hemorrhage1603.50
    Nervous System Disorders
    Headache Including headache and migraine150.360
    Peripheral neuropathy Including peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia130295
    Dizziness Including dizziness, postural dizziness, and vertigo110.560
    Infections and Infestations
    Upper respiratory tract infection Including upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis140.350
    Respiratory, Thoracic and Mediastinal Disorders
    Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis.121.30.60
    Dyspnea101.391.2
    Table 19: Selected Laboratory Abnormalities in Patients in DESTINY-Breast04
    Laboratory ParameterENHERTU 5.4 mg/kgChemotherapy
    N=371N=172
    All Grades %Grades 3 or 4 %All Grades %Grades 3 or 4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities.
    Hematology
    Decreased white blood cell count7097825
    Decreased hemoglobin648536
    Decreased neutrophil count64147338
    Decreased lymphocyte count55184011
    Decreased platelet count446210.6
    Chemistry
    Increased aspartate aminotransferase382.2384.1
    Increased alanine aminotransferase360.8384.1
    Increased blood alkaline phosphatase340.3240
    Decreased blood potassium253.3171.2
    Increased blood bilirubin162.7150.6
    Increased blood creatinine151.190.6
    Table 20: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02
    Adverse ReactionsENHERTU 5.4 mg/kg N=101
    All Grades %Grades 3 or 4 %
    Events were graded using NCI CTCAE version 5.0.
    Gastrointestinal Disorders
    Nausea674
    Constipation381
    Vomiting Including vomiting and retching323
    Diarrhea241
    Stomatitis Including mucosal inflammation, stomatitis, and mouth ulceration170
    Abdominal pain Including abdominal discomfort, abdominal pain, and upper abdominal pain100
    General Disorders and Administration Site Conditions
    Fatigue Including asthenia, fatigue, and malaise488
    Metabolism and Nutrition Disorders
    Decreased appetite412
    Skin and Subcutaneous Tissue Disorders
    Alopecia220
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, bone pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity211
    Respiratory, Thoracic, and Mediastinal Disorders
    Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure151
    Infections and Infestations
    Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis120
    Table 21: Select Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02
    Laboratory ParameterENHERTU 5.4 mg/kg N=101 Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.
    All Grades Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. %Grades 3 or 4 %
    Hematology The denominator used to calculate the rate varied from 100 to 101 based on the number of patients with a baseline value and at least one post-treatment value.
    Decreased hemoglobin6812
    Decreased white blood cell count667
    Decreased neutrophil count5919
    Decreased lymphocyte count5626
    Decreased platelet count495
    Chemistry
    Increased aspartate aminotransferase511
    Decreased albumin500
    Increased alanine aminotransferase412
    Increased alkaline phosphatase370
    Decreased blood potassium295
    Table 23: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01
    Laboratory ParameterENHERTU 6.4 mg/kg N=125Irinotecan or Paclitaxel N=62
    All Grades %Grades 3 or 4 %All Grades %Grades 3 or 4 %
    Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.
    Hematology
    Decreased hemoglobin75385523
    Decreased white blood cell count74295313
    Decreased neutrophil count72514523
    Decreased lymphocyte count70285312
    Decreased platelet count6812125
    Chemistry
    Increased aspartate aminotransferase589328
    Increased blood alkaline phosphatase5483410
    Increased alanine aminotransferase479171.7
    Decreased blood potassium304.8188
    Increased blood bilirubin24753.4
    Table 24: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
    Adverse ReactionsENHERTU 5.4 mg/kg N= 347
    All Grades %Grade 3 or 4 %
    Gastrointestinal Disorders
    Nausea697
    Vomiting353.5
    Diarrhea314.3
    Constipation280.6
    Stomatitis Including stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis.200.9
    Abdominal pain Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain.182
    Dyspepsia120.3
    General Disorders and Administration Site Conditions
    Fatigue Including fatigue, asthenia, malaise, lethargy.5910
    Pyrexia110
    Edema Including peripheral edema, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema110.6
    Metabolism and Nutrition Disorders
    Decreased appetite342.6
    Skin and Subcutaneous Tissue Disorders
    Alopecia340.3
    Rash Including rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic rash dermatitis acneiform, dermatitis, eczema, palmar-plantar erythrodysesthesia syndrome.130.6
    Infections and Infestations
    Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis.200
    Pneumonia62.3
    Musculoskeletal and Connective Tissue Disorders
    Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, limb discomfort.190.3
    Respiratory, Thoracic and Mediastinal Disorders
    Cough Including cough, productive cough, upper-airway cough syndrome180
    Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, ILD, organizing pneumonia, respiratory failure, acute respiratory failure, alveolitis, lung opacity, lymphangitis, pneumonia, bacterial pneumonia, pulmonary fibrosis, and radiation pneumonitis. Grade 5 adjudicated drug-induced ILD events were pneumonitis, respiratory failure, acute respiratory failure, lymphangitis, pulmonary fibrosis.160.6
    Dyspnea Including dyspnea, exertional dyspnea121.7
    Nervous System Disorders
    Headache Including migraine, headache, sinus headache.150
    Investigations
    Decreased weight100.3
    Table 25: Selected Laboratory Abnormalities in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
    Laboratory ParameterENHERTU 5.4 mg/kg N= 347 Percentages were calculated using the number of patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.
    All Grades %Grades 3 or 4 %
    Hematology
    Decreased white blood cell count7511
    Decreased hemoglobin6710
    Decreased neutrophil count6621
    Decreased lymphocyte count5821
    Decreased platelet count517
    Chemistry
    Increased aspartate aminotransferase451.5
    Increased alanine aminotransferase441.5
    Increased blood alkaline phosphatase361.2
    Decreased blood potassium296
    Decreased sodium222.9
    Increased blood bilirubin150.6
    Increased blood creatinine140.6

    Warnings & Cautions for Enhertu

    Interstitial Lung Disease/Pneumonitis

    Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. 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 (Grade 1) ILD, consider corticosteroid treatment (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). Withhold ENHERTU until recovery.

    In cases of symptomatic ILD (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Permanently discontinue ENHERTU in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD. Median time to first onset was 5.5 months (range: 0.9 to 31.5).

    Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU. ENHERTU in Combination with Pertuzumab In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), ILD occurred in 12% of patients. Median time to first onset was 8.0 months (range: 0.6 to 33.8).

    ENHERTU followed by THP In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, ILD occurred in 4.4% of patients. Median time to first onset was 2.7 months (range: 1.1 to 6.0). Fatal outcomes due to ILD and/or pneumonitis occurred in one patient (0.3%) treated with ENHERTU followed by THP.

    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. 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.

    HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) ENHERTU as Monotherapy In patients treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen 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 1% of patients. ENHERTU in Combination with Pertuzumab In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), decreased neutrophil count occurred in 79% of patients. Median time to first onset was 22 days (range: 5 to 994).

    Twenty-nine percent had Grades 3 or 4 decreased neutrophil count. Febrile neutropenia was reported in 2.6% of patients. ENHERTU followed by THP In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, a decrease in neutrophil count was reported in 58% of patients.

    Median time to first onset of decreased neutrophil count was 42 days (range: 11 to 165). Febrile neutropenia was reported in 0.9% of patients. 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.

    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.

    Left Ventricular Dysfunction

    Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular dysfunction (LVD) has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated.

    Manage LVD through treatment interruption. Permanently discontinue ENHERTU if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF).

    Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment. 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.

    Embryo-Fetal Toxicity Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman. 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. 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 7 months after the last dose of ENHERTU.

    Pregnancy Safety for Enhertu

    Pregnancy 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. 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 respectively.

    Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received ENHERTU during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. In postmarketing reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported.

    These case reports described oligohydramnios in pregnant women who received a HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped. Animal Data There were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.

    Pediatric Use of Enhertu

    Pediatric Use Safety and effectiveness of ENHERTU have not been established in pediatric patients. 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.

    Clinical Studies of Enhertu

    HER2-Positive Early Breast Cancer DESTINY-Breast11

    The efficacy of ENHERTU followed by THP was evaluated in DESTINY-Breast11 (NCT05113251), a randomized, three-arm, open-label, multicenter, global study that enrolled 927 adult patients with HER2-positive, high-risk, early-stage breast cancer. The study included previously untreated adult patients with HER2-positive (IHC 3+ or ISH+), as determined by a central laboratory using PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and VENTANA HER2 Dual ISH DNA Probe Cocktail assay, locally advanced high-risk (lymph node positive or with a primary tumor stage T3-4) or inflammatory early breast cancer. Patients were excluded for a history of ILD/pneumonitis requiring treatment with steroids, ILD/pneumonitis at screening, or ECOG performance status >1.

    An additional investigational therapy. Randomization was stratified by hormone receptor (HR) status (ER and/or PgR positive vs ER and PR negative) by local assessment and HER2-positive status (IHC 3+ vs other, where 'other' is defined as ISH+ in the absence of IHC 3+ status) by central assessment. Treatment was continued until completion of planned therapy, unacceptable toxicity, or disease progression.

    The major efficacy outcome was centrally assessed pathological complete response (pCR) rate, defined as the absence of invasive cancer in the breast and axillary lymph nodes (ypT0/Tis ypN0) following surgery. The study demonstrated a statistically significant improvement in pCR rate for patients randomized to ENHERTU followed by THP compared to ddAC followed by THP. Efficacy results are summarized in Table 26.

    Table 26: Efficacy Results in DESTINY-Breast11 DESTINY-Breast05 The efficacy of ENHERTU was evaluated in DESTINY-Breast05 (NCT04622319), a randomized, two-arm, open-label, multicenter, global study that enrolled 1635 adult patients with HER2-positive breast cancer with residual invasive disease after neoadjuvant therapy. HER2 expression was confirmed at a central laboratory using PATHWAY/VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail assay with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients received concurrent or sequential adjuvant radiotherapy as per investigator discretion and hormonal therapy as per local guidelines.

    In addition to all patients receiving computed tomography (CT) scans of the chest at screening, patients receiving radiotherapy also received regular CT scans of the chest during treatment period, and after end of treatment. Patients were randomized 1:1 to receive either ENHERTU 5.4mg/kg (N=818) by intravenous infusion every three weeks or trastuzumab emtansine (T-DM1) (N=817) 3.6 mg/kg by intravenous infusion every three weeks for a maximum of 14 cycles, or until disease recurrence or unacceptable toxicity. Randomization was stratified by operative status at disease presentation (operable, inoperable), post neoadjuvant pathological nodal status (positive, negative), tumor hormone receptor status (positive, negative), and HER2-targeted neoadjuvant therapy (single, dual).

    The major efficacy outcome measure was invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer or death from any cause. Additional efficacy outcome measures included disease-free survival (DFS) and overall survival (OS). Tumor characteristics were: 71% had HR+ status and 29% had HR- status; 52% had inoperable tumors at disease presentation (T4, N0-3, M0 or T1-3, N2-3, M0); 81% had post neoadjuvant pathological nodal status (ypN1-3).

    Characteristics of adjuvant radiotherapy were: 37% of patients received sequential adjuvant radiotherapy, 56% of patients received concurrent adjuvant RT. Efficacy results are summarized in Table 27 and Figure 1. At the time of the IDFS analysis, a total of 47 (2.9%) patients had died across both study arms.

    Table Figure 1: Kaplan-Meier plot of invasive disease-free survival (IDFS) Figure 1

    HER2-Positive Metastatic Breast Cancer 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. Patients were randomized 1:1:1 to receive either, ENHERTU 5.4 mg/kg plus pertuzumab (N=383), THP (taxane, 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 (RECIST) v1.1.

    Additional efficacy outcome measures were overall survival (OS) and confirmed objective response rate (ORR) assessed by BICR. The study 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 28 and Figure 2.

    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. Table 28: Efficacy Results in DESTINY-Breast09 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. 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 RECIST v.1.1 and overall survival (OS). Confirmed objective response rate (ORR) was an additional outcome measure.

    Patients had an ECOG performance status of 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 29 and Figures 3 and 4. Table 29: Efficacy Results in DESTINY-Breast03 (Intent-to-Treat Analysis Set) Figure 4: 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. 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.

    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 30 and Figures 5 and 6. Table 30: Efficacy Results in DESTINY-Breast02 8.3 Figure 5: Kaplan-Meier Plot of Progression-free Survival Per BICR Figure 6: 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. 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).

    All 184 patients were female, and the majority were White (55%) or Asian (38%). Ninety-two percent had visceral disease, 29% had bone metastases, and 13% had brain metastases. Fifty-three percent were HR+.

    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 31.

    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.

    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. 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 32 and Figure 7.

    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. Confirmed ORR (BICR) was in patients randomized to ENHERTU and chemotherapy and with measurable disease at baseline, respectively. Figure 7: Kaplan-Meier Plot of Progression Free Survival (Overall Population) 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-).

    Efficacy results are summarized in Table 33 and Figures 8 and 9. Patients were prospectively selected for treatment with ENHERTU based on the presence of activating HER2 (ERBB2) mutations by local testing using tissue. Samples from DESTINY-Lung01 were retrospectively tested using Oncomine™ Dx Target Test (Life Technologies Corporation, Tissue-test) and Guardant360 ® CDx test (Guardant Health Inc., Plasma test).

    Demographic and baseline disease characteristics were similar for patients in DESTINY-Lung01 and DESTINY-Lung02, except for race (34% Asian vs 64% Asian, respectively). Response rates were consistent across dose levels. Increased rates of ILD/pneumonitis were observed at the higher dose.

    The approved recommended dose of 5.4 mg/kg intravenously every 3 weeks in the DESTINY-Lung02 study is described below. The efficacy of ENHERTU was evaluated in DESTINY-Lung02, a multicenter, multicohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic HER2-mutant non-squamous NSCLC with disease progression after one prior systemic therapy.

    Patients with a history of steroid dependent ILD/pneumonitis, clinically significant cardiac disease, clinically active brain metastases, and ECOG performance status >1 were excluded. The major efficacy outcomes were confirmed ORR as assessed by BICR using RECIST v1.1 and DOR. The final analysis occurred after all responders had been followed for at least 6 months from the date of initial response or until disease progression or death, whichever came first.

    Fifty-four percent of patients were never-smokers and 46% were former smokers; 98% of patients had adenocarcinoma histology. Efficacy results are provided in Table 34. Table 34: Efficacy Results for DESTINY-Lung02

    HER2-Positive Locally Advanced or Metastatic Gastric Cancer

    The efficacy of ENHERTU was evaluated in study DESTINY-Gastric01 (NCT03329690), a multicenter, open-label, randomized trial conducted in Japan and South Korea that enrolled 188 adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH 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. HER2 expression was determined by a central lab on tissue obtained either before or after prior trastuzumab treatment. Patients were excluded for a history of treated or current ILD, a history of clinically significant cardiac disease, active brain metastases, or ECOG performance status >1.

    Randomization was stratified by HER2 status (IHC 3+ or IHC 2+/ISH+), ECOG performance status (0 or 1), and region (Japan or South Korea). Tumor imaging assessments were performed at screening and every 6 weeks from the first treatment dose. The major efficacy outcomes were ORR assessed by ICR according to RECIST v1.1 and OS in the intent-to-treat population.

    Additional efficacy outcomes were PFS and DOR. All patients received a trastuzumab product. A total of 30% of patients were identified as HER2-positive using tissue obtained following prior treatment with a trastuzumab product.

    Efficacy results are summarized in Table 35, and the Kaplan-Meier curve for OS is shown in Figure 10. Table 35: Efficacy Results in DESTINY-Gastric01

    HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors The efficacy of ENHERTU was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. Patients received ENHERTU 5.4 mg/kg by intravenous infusion every three weeks. All outcomes were assessed by independent central review (ICR) based on RECIST v1.1.

    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 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. 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. Efficacy results are summarized in Table 36 and Table 37.

    Table 26: Efficacy Results in DESTINY-Breast11
    Efficacy ParameterENHERTU 5.4 mg/kg followed by THP (N=321)ddAC followed by THP (N=320)
    Pathological Complete Response (pCR)
    CI = confidence interval, THP = paclitaxel, trastuzumab, and pertuzumab, ddAC = dose dense doxorubicin and cyclophosphamide
    Number of patients with pCR, n216180
    pCR rate, % (95% CI)67.3 (61.9, 72.4)56.3 (50.6, 61.8)
    Treatment difference estimate, % (95% CI) Based on Miettinen and Nurminen method stratified by HER2 status and HR status11.2 (3.9, 18.3)
    p-value The 2-sided stratified Miettinen and Nurminen test p-value is compared with the allocated alpha of 0.030.003
    Table 27: Efficacy Results in DESTINY-Breast05
    Efficacy ParameterENHERTU (5.4 mg/kg) N=818Ado-Trastuzumab emtansine (3.6 mg/kg) N=817
    Invasive Disease-Free Survival (IDFS)
    CI = confidence interval;
    Number of events (%)51 (6)102 (12)
    3-year event free rate, % (95% CI)92.4 (89.7, 94.4)83.7 (80.2, 86.7)
    Hazard ratio (95% CI)0.47 (0.34, 0.66)
    p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.0183 for this interim analysis (with 74% of the planned number of events for final analysis).p<0.0001
    Disease-Free Survival (DFS)
    Number of events (%)52 (6)103 (13)
    3-year event free rate, % (95% CI)92.3 (89.5, 94.3)83.5 (79.9, 86.4)
    Hazard ratio (95% CI)0.47 (0.34, 0.66)
    p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.0144 for this interim analysis (with 70% of the planned number of events for final analysis).p<0.0001
    Table 28: Efficacy Results in DESTINY-Breast09
    Efficacy ParameterENHERTU 5.4 mg/kg + Pertuzumab N = 383THP THP = taxane (docetaxel or paclitaxel), trastuzumab, and pertuzumab N = 387
    CI = confidence interval; NE = not estimable, N = number
    Progression-Free Survival (PFS) per BICR
    Number of events (%)118 (31)172 (44)
    Median, months (95% CI)40.7 (36.5, NE)26.9 (21.8, NE)
    Hazard ratio (95% CI)0.56 (0.44, 0.71)
    p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.00043 for this interim analysis (with 73% of the planned number of events for final analysis).< 0.0001
    Confirmed Objective Response Rate (ORR) per BICR
    Patients with Measurable Disease at Baseline, N374371
    ORR (95% CI) 95% CI was based on Clopper-Pearson method.87 (83, 90)81 (77, 85)
    Complete Response, %158
    Partial Response, %7273
    Table 29: Efficacy Results in DESTINY-Breast03
    Efficacy ParameterENHERTU 5.4 mg/kgAdo-trastuzumab emtansine 3.6 mg/kg
    CI = confidence interval; NR = not reached; NE = not estimable
    Progression-Free Survival (PFS) per BICR
    N261263
    Number of events (%)87 (33.3)158 (60.1)
    Median, months (95% CI)NR (18.5, NE)6.8 (5.6, 8.2)
    Hazard ratio (95% CI)0.28 (0.22, 0.37)
    p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.0002 for this interim analysis (with 73% of the planned number of events for final analysis).p< 0.0001
    Overall Survival (OS)
    N261263
    Number of events (%)72 (27.6)97 (36.9)
    Median, months (95% CI)NR (40.5, NE)NR (34.0, NE)
    Hazard ratio (95% CI)0.64 (0.47, 0.87)
    p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.013 for this interim analysis (with 68% of the planned number of events for final analysis).p=0.0037
    Confirmed Objective Response Rate (ORR) per BICR Analysis was performed based on the patients with measurable disease assessed by BICR at baseline.
    N248241
    n (%)205 (82.7)87 (36.1)
    95% CI(77.4, 87.2)(30.0, 42.5)
    Complete Response n (%)39 (15.7)20 (8.3)
    Partial Response n (%)166 (66.9)67 (27.8)
    Table 30: Efficacy Results in DESTINY-Breast02
    Efficacy ParameterENHERTU N=406Treatment of Physician's Choice N=202
    CI = confidence interval; NE=not estimable
    PFS per BICR
    Number of events (%)200 (49.3)125 (61.9)
    Median, months (95% CI)17.8 (14.3, 20.8)6.9 (5.5, 8.4)
    Hazard ratio (95% CI)0.36 (0.28, 0.45)
    p-valuep<0.0001
    Overall Survival (OS)
    Number of events (%)143 (35.2)86 (42.6)
    Median, months (95% CI)39.2 (32.7, NE)26.5 (21.0, NE)
    Hazard ratio (95% CI)0.66 (0.50, 0.86)
    p-value The stratified log-rank test p-value is compared with the allocated alpha of 0.004 for this interim analysis (with 53% of the planned number of events for final analysis)p=0.0021
    Confirmed Objective Response Rate (ORR) per BICR
    n (%)283 (69.7)59 (29.2)
    95% CI(65.0, 74.1)(23.0, 36.0)
    Complete Response n (%)57 (14.0)10 (5.0)
    Partial Response n (%)226 (55.7)49 (24.3)
    Duration of Response per BICR
    Median, months (95% CI)19.6 (15.9, NE)8.3 (5.8, 9.5)
    Table 31: Efficacy Results by Independent Central Review in DESTINY-Breast01
    Efficacy ParameterDESTINY-Breast01 N=184
    ORR 95% CI calculated using Clopper-Pearson method.
    Confirmed Objective Response Rate (95% CI)60.3% (52.9, 67.4)
    Complete Response4.3%
    Partial Response56.0%
    Duration of Response DOR is based on median duration of follow-up of 11.1 months. Median, months (95% CI) Median DOR based on Kaplan-Meier estimate; 95% CI calculated using Brookmeyer-Crowley method.14.8 (13.8, 16.9)
    Table 32: Efficacy Results in DESTINY-Breast06
    Efficacy ParameterHER2-lowOverall Population (HER2-low and HER2-ultralow)
    ENHERTU (N=359)Chemotherapy (N=354)ENHERTU (N=436)Chemotherapy (N=430)
    CI = confidence interval
    Progression Free Survival (PFS) per BICR
    Number of events (%)225 (62.7)232 (65.5)269 (61.7)271 (63.0)
    Median, months (95% CI)13.2 (11.4, 15.2)8.1 (7.0, 9.0)13.2 (12.0, 15.2)8.1 (7.0, 9.0)
    Hazard ratio (95% CI)0.62 (0.52, 0.75) Based on stratified analysis with stratification factors prior CDK4/6 inhibitor use (yes vs no) and HER2 IHC status of tumor samples (IHC 1+ vs IHC 2+/ISH-).0.64 (0.54, 0.76) Based on unstratified analysis.
    p-value<0.0001<0.0001
    Confirmed Objective Response Rate (ORR) per BICR Analysis was performed based on the patients with measurable disease assessed by BICR at baseline.
    N326324393389
    n (%)202 (62.0)114 (35.2)246 (62.6)134 (34.4)
    95% CI56.5, 67.330.0, 40.757.6, 67.429.7, 39.4
    Complete Response n (%)9 (2.8)010 (2.5)0
    Partial Response n (%)193 (59.2)114 (35.2)236 (60.1)134 (34.4)
    Duration of Response (DOR) per BICR
    Median, months (95% CI)14.1 (11.9, 15.9)8.6 (6.7, 11.3)14.3 (12.5, 15.9)8.6 (6.9, 11.5)
    Table 33: Efficacy Results in DESTINY-Breast04
    Efficacy ParameterHR+ CohortOverall Population (HR+ and HR- Cohorts)
    ENHERTU (N=331)Chemotherapy (N=163)ENHERTU (N=373)Chemotherapy (N=184)
    CI = confidence interval
    Overall Survival
    Number of events (%)126 (38.1)73 (44.8)149 (39.9)90 (48.9)
    Median, months (95% CI)23.9 (20.8, 24.8)17.5 (15.2, 22.4)23.4 (20.0, 24.8)16.8 (14.5, 20.0)
    Hazard ratio (95% CI)0.64 (0.48, 0.86)0.64 (0.49, 0.84)
    p-value0.00280.001
    Progression-Free Survival per BICR
    Number of events (%)211 (63.7)110 (67.5)243 (65.1)127 (69.0)
    Median, months (95% CI)10.1 (9.5, 11.5)5.4 (4.4, 7.1)9.9 (9.0, 11.3)5.1 (4.2, 6.8)
    Hazard ratio (95% CI)0.51 (0.40, 0.64)0.50 (0.40, 0.63)
    p-value<0.0001<0.0001
    Confirmed Objective Response Rate per BICR
    n (%)175 (52.9)27 (16.6)195 (52.3)30 (16.3)
    95% CI47.3, 58.411.2, 23.247.1, 57.411.3, 22.5
    Complete Response n (%)12 (3.6)1 (0.6)13 (3.5)2 (1.1)
    Partial Response n (%)164 (49.5)26 (16.0)183 (49.1)28 (15.2)
    Duration of Response per BICR
    Median, months (95% CI)10.7 (8.5, 13.7)6.8 (6.5, 9.9)10.7 (8.5, 13.2)6.8 (6.0, 9.9)
    Table 34: Efficacy Results for DESTINY-Lung02
    Efficacy ParameterDESTINY-Lung02 N=102
    ORR 95% CI calculated using Clopper-Pearson method NE=not estimable
    Confirmed Objective Response Rate (95% CI)50.0% (39.9, 60.1)
    Complete Response2.9%
    Partial Response47.1%
    Duration of Response Median, months (95% CI) Median DOR based on Kaplan-Meier estimate; 95% CI calculated using Brookmeyer-Crowley method12.6 (6.4, NE)
    Table 35: Efficacy Results in DESTINY-Gastric01
    Efficacy ParameterENHERTU N=126Irinotecan or Paclitaxel N=62
    CI = confidence interval; NR = not reached
    Overall Survival (OS) OS was evaluated following a statistically significant outcome of ORR.
    Median, months (95% CI) Median based on Kaplan-Meier estimate; 95% CI for median calculated using Brookmeyer-Crowley method12.5 (9.6, 14.3)8.4 (6.9,10.7)
    Hazard ratio (95% CI) Based on the stratified Cox proportional hazards regression model (stratified by region)0.59 (0.39, 0.88)
    p-value Based on the stratified log-rank test (stratified by region)0.0097
    Progression-Free Survival (PFS) Assessed by independent central review
    Median, months (95% CI)5.6 (4.3, 6.9)3.5 (2.0, 4.3)
    Hazard ratio (95% CI)0.47 (0.31, 0.71)
    Confirmed Objective Response Rate (ORR)
    n (%)51 (40.5)7 (11.3)
    95% CI 95% exact binomial confidence interval(31.8, 49.6)(4.7, 21.9)
    p-value Based on the stratified Cochran-Mantel-Haenszel test (stratified by region)<0.0001
    Complete Response n (%)10 (7.9)0 (0.0)
    Partial Response n (%)41 (32.5)7 (11.3)
    Duration of Response (DOR)
    Median, months (95% CI)11.3 (5.6, NR)3.9 (3.0, 4.9)
    Table 36: Efficacy Results in HER2-Positive (IHC 3+) Patients in DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
    Efficacy ParameterDESTINY-PanTumor02 N=111DESTINY-Lung01 N=17DESTINY-CRC02 N=64
    CI=Confidence interval
    Confirmed ORR (95% CI) Assessed by independent central review CI is derived based on the Clopper-Pearson method51.4% (41.7, 61.0)52.9% (27.8, 77.0)46.9% (34.3, 59.8)
    Complete Response Rate2.7%5.9%0%
    Partial Response Rate48.6%47.1%46.9%
    Duration of Response
    Median Calculated using the Kaplan-Meier technique, months (range)19.4 (1.3, 27.9 Denotes ongoing response )6.9 (4.0, 11.7 )5.5 (1.3+, 9.7 )
    Table 37: Efficacy Results in HER2-positive (IHC 3+) Patients by Tumor Type in DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
    Tumor TypePatientsConfirmed ORR Assessed by independent central reviewDOR Range
    N% (95% CI) CI is derived based on the Clopper-Pearson method(months)
    CI=Confidence interval, NA=Not applicable, PD=Progressive disease, PR=Partial response, SD=Stable disease
    Colorectal Cancer6446.9 (34.3, 59.8)(1.3 Denotes ongoing response, 9.7 )
    Bladder Cancer2737.0 (19.4, 57.6)(2.8, 19.7 )
    Biliary Tract Cancer2245.5 (24.4, 67.8)(2.1, 22.0 )
    NSCLC1752.9 (27.8, 77.0)(4.0, 11.7 )
    Endometrial Cancer1656.3 (29.9, 80.2)(5.8, 23.7 )
    Ovarian Cancer1566.7 (38.4, 88.2)(1.3, 27.9 )
    Cervical Cancer1070.0 (34.8, 93.3)(7.2, 25.0 )
    Salivary Gland Cancer966.7 (29.9,92.5)(5.6, 20.1)
    Pancreatic Cancer50 (0, 52.2)NA
    Oropharyngeal Neoplasm1PR15.3
    Vulvar Cancer1PR2.6
    Extramammary Paget's Disease1PR19.4
    Lacrimal Gland Cancer1PR19.8
    Lip and/or Oral Cavity Cancer1SDNA
    Esophageal Adenocarcinoma1PR2.8
    Esophageal Squamous Cell Carcinoma1PDNA

    Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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