Fam-Trastuzumab Deruxtecan-Nxki

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for: HER2-Positive Early Breast Cancer as 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 followed by a taxane, trastuzumab, and pertuzumab (THP). ( 1.1 ) as 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. ( 1.1 ) HER2-Positive Metastatic Breast Cancer in combination with pertuzumab as 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. ( 1.2 ) as monotherapy 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. ( 1.2 ) HER2-Low and HER2-Ultralow Metastatic Breast Cancer as monotherapy 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. ( 1.3 ) as monotherapy for the treatment of adult patients with unresectable or metastatic 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. ( 1.3 ) HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer as monotherapy 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* ( 1.4 ) HER2-Positive Locally Advanced or Metastatic Gastric Cancer as monotherapy for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. ( 1.5 ) HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors as monotherapy 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* ( 1.6 ) * These indications are 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. ( 14.3 , 14.5 )

1.1 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 [see Dosage and Administration (2.1) ]. 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.

1.2 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 [see Dosage and Administration (2.1) ]. 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.

1.3 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 [see Dosage and Administration (2.1) ] . 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 [see Dosage and Administration (2.1) ] .

1.4 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 [see Clinical Studies (14.4) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.5 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.

1.6 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. This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14.6) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine. ( 2.2 , 2.4 ) For intravenous infusion only . Do not administer as an intravenous push or bolus. DO NOT use Sodium Chloride Injection, USP. ( 2.4 ) Premedicate for prevention of chemotherapy-induced nausea and vomiting. ( 2.2 ) HER2-Positive Early Breast Cancer Neoadjuvant: ENHERTU 5.4 mg/kg every 3 weeks for 4 cycles, followed by THP regimen for 4 cycles. ( 2.2 , 2.3 ) Post Neoadjuvant: ENHERTU 5.4 mg/kg every 3 weeks for 14 cycles unless disease recurrence or unacceptable toxicity. ( 2.2 , 2.3 ) HER2-Positive, HER2-Low, or HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and HER2-Positive (IHC 3+) Solid Tumors: ENHERTU 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. ( 2.2 , 2.3 ) HER2-Positive First-line Metastatic Breast Cancer: ENHERTU 5.4 mg/kg every 3 weeks in combination with pertuzumab until disease progression or unacceptable toxicity. Cycle 1, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 840 mg. ( 2.2 , 2.3 ) Subsequent cycles, Day 1: ENHERTU 5.4 mg/kg followed by pertuzumab 420 mg. ( 2.2 , 2.3 ) HER2-Positive Gastric Cancer: 6.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. ( 2.2 , 2.3 ) Management of adverse reactions (ILD, neutropenia, thrombocytopenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of ENHERTU. ( 2.3 )

2.1 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 [see Clinical Studies (14.1) ]. HER2-Positive Metastatic Breast Cancer Select patients for treatment of unresectable or metastatic HER2-positive breast cancer with ENHERTU in combination with pertuzumab based on confirmed HER2-positive status or HER2 gene amplification (IHC 3+ or ISH+) [see Clinical Studies (14.2) ] . HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast Cancer Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression [see Clinical Studies (14.3) ] . HER2-Mutant Unresectable or Metastatic NSCLC Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens [see Clinical Studies (14.4) ] . If no mutation is detected in a plasma specimen, test tumor tissue. HER2-Positive Locally Advanced or Metastatic Gastric Cancer Select patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+). Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU. HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens [see Clinical Studies (14.6) ] . 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.

2.2 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 [see Adverse Reactions (6.1) ] , which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting. The recommended dosages for ENHERTU as monotherapy and ENHERTU in combination with pertuzumab are presented in Table 1. Administer ENHERTU as an intravenous infusion [see Dosage and Administration (2.4) ]. Table 1: Recommended Dosage Indication Recommended ENHERTU Dosage Duration of Therapy As Monotherapy HER2-Positive Early Breast Cancer – Post Neoadjuvant Treatment ENHERTU 5.4 mg/kg every 3 weeks 14 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 monotherapy ENHERTU 5.4 mg/kg every 3 weeks Until disease progression or unacceptable toxicity HER2-Positive Locally Advanced or Metastatic Gastric Cancer as monotherapy ENHERTU 6.4 mg/kg every 3 weeks Until disease progression or unacceptable toxicity In Combination HER2-Positive Metastatic Breast Cancer in combination with pertuzumab Cycle 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 weeks Until disease progression or unacceptable toxicity In Sequence HER2-Positive Early Breast Cancer followed by THP ENHERTU 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 cycles 4 cycles of ENHERTU followed by 4 cycles of THP.

2.3 Dosage Modifications for Adverse Reactions 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 Dose Reduction Schedule Breast Cancer, NSCLC, and IHC 3+ Solid Tumors Gastric Cancer Recommended starting dose 5.4 mg/kg 6.4 mg/kg First dose reduction 4.4 mg/kg 5.4 mg/kg Second dose reduction 3.2 mg/kg 4.4 mg/kg Requirement for further dose reduction Discontinue treatment. Discontinue treatment. Table 3: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Treatment 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 hour Interrupt 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.

2.4 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 [see Dosage and Administration (2.2) ] . Reconstitute each 100 mg vial by using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection, USP into each vial to obtain a final concentration of 20 mg/mL. Swirl the vial gently until completely dissolved. Do not shake . If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours from the time of reconstitution, 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 [36°F to 46°F]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light. Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene. Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do NOT administer as an intravenous push or bolus. Cover the infusion bag to protect from light during administration. Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line. First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

5 WARNINGS AND PRECAUTIONS Neutropenia: Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction. ( 2.3 , 5.2 ) Left Ventricular Dysfunction (LVD): Assess left ventricular ejection fraction (LVEF) prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF). ( 2.3 , 5.3 )

5.1 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU [see Adverse Reactions (6.1) ] . 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 [see Dosage and Administration (2.3) ] . 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 [see Dosage and Administration (2.3) ] . 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, ILD occurred in 12% of patients. 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). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.5% of patients treated with ENHERTU in combination with pertuzumab. 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. Median time to first onset was 2.8 months (range: 1.2 to 21).

5.2 Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. 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 [see Dosage and Administration (2.3) ] . 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. Seventeen percent had Grade 3 or 4 decreased neutrophil count. 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. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

5.3 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) [see Dosage and Administration (2.3) ] . 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, 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, LVD was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4. ENHERTU in Combination with Pertuzumab In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), LVEF decrease was reported in 11% of patients, of which 2.1% were Grade 3 or 4. ENHERTU followed by THP In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, LVD was reported in 1.3% of patients, of which 0.3% were Grade 3. 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.

5.4 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. Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] . 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. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU [see Use in Specific Populations (8.1 , 8.3) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) ] Neutropenia [see Warnings and Precautions (5.2) ] Left Ventricular Dysfunction [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥20%), including laboratory abnormalities, in patients with: HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and HER2-Positive (including IHC 3+) Solid Tumors are decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, alopecia, constipation, decreased blood potassium, decreased appetite, diarrhea, and musculoskeletal pain. ( 6.1 ) HER2-Positive Early Breast Cancer are 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. ( 6.1 ) HER2-Positive Metastatic Breast Cancer in Combination with Pertuzumab are 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. ( 6.1 ) HER2-Positive Gastric Cancer are decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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. Among these patients, 67% were exposed for greater than 6 months and 39% were exposed for greater than 12 months. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (43%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%). 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). Among these patients, 86% were exposed for greater than 6 months and 73% were exposed for greater than 12 months. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (86%), decreased hemoglobin (80%), decreased neutrophil count (79%), nausea (74%), increased alanine aminotransferase (65%), diarrhea (64%), increased aspartate aminotransferase (63%), decreased lymphocyte count (61%), decreased platelet count (55%), increased blood alkaline phosphatase (54%), decreased blood potassium (54%), fatigue (53%), alopecia (48%), vomiting (46%), upper respiratory tract infection (32%), constipation (31%), decreased appetite (31%), decreased weight (28%), musculoskeletal pain (23%), increased blood bilirubin (23%), and abdominal pain (22%). 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 Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) The data described in WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 6.4 mg/kg intravenously every 3 weeks in 125 patients in DESTINY-Gastric01. HER2-Positive 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 [see Clinical Studies (14.1) ] . 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. Table 4: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) Patients in DESTINY-Breast11 Adverse Reactions ENHERTU 5.4 mg/kg followed by THP N = 320 ddAC 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 Nausea 65 1.9 52 0.3 Diarrhea 59 6 54 3.2 Constipation 29 0.3 24 0 Vomiting 29 0.9 21 0.6 Stomatitis Including aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, and stomatitis. 23 0.3 36 1.0 Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 16 0 12 0 Nervous System Disorders Peripheral neuropathy Including dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 59 2.5 47 2.2 Headache Including headache, migraine, and sinus headache. 18 0 16 0 Skin and Subcutaneous Tissue Disorders Alopecia 48 0 49 0 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. 31 0.9 25 1.0 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, and malaise. 41 0.6 55 2.2 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. 30 0 28 0.3 Metabolism and Nutrition Disorders Decreased appetite 20 0 18 0.3 Respiratory, Thoracic and Mediastinal Disorders Epistaxis 15 0 10 0 Cough 10 0 14 0 Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 13 0.6 20 0.3 COVID-19 10 0.9 11 0.3 Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU followed by THP treated group were: General disorders and administration site conditions: peripheral edema (9%), pyrexia (8%), mucosal inflammation (1.9%) Nervous System Disorders: dysgeusia (9%), dizziness (4.7%) Eye Disorders: dry eye (8%), blurred vision (6%) [including vision blurred, visual impairment] Gastrointestinal disorders: dyspepsia (8%), gastritis (3.4%), abdominal distension (2.5%), flatulence (0.9%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), ILD (4.4%) [including interstitial lung disease, lung opacity, pneumonia fungal, pneumonitis]. Skin and Subcutaneous Tissue Disorders: pruritus (6%) and skin hyperpigmentation (1.6%) [including skin hyperpigmentation and skin discoloration] Injury, Poisoning, and Procedural Complications: infusion-related reactions (4.7%) Investigations : decreased weight (3.4%) Blood and Lymphatic System Disorders: febrile neutropenia (0.9%) Metabolism and Nutrition Disorders: dehydration (0.3%) Table 5: Selected Laboratory Abnormalities in Patients in DESTINY-Breast11 Laboratory Parameter ENHERTU 5.4 mg/kg followed by THP N=320 ddAC 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 hemoglobin 83 2.2 97 10 Decreased white blood cell count 67 8 87 31 Decreased neutrophil count 58 17 66 38 Decreased lymphocyte count 40 3.1 93 39 Decreased platelet count 8 0.9 28 2.9 Chemistry Increased alanine aminotransferase 79 5 77 4.2 Increased aspartate aminotransferase 74 2.5 68 1 Decreased blood potassium 29 4.1 25 4.5 Increased blood alkaline phosphatase 19 0 24 0 Decreased sodium 19 1.9 23 2.6 Increased blood creatinine 8 0.6 8 1.3 Increased blood bilirubin 7 0 4.2 0.6 DESTINY-Breast05 The safety of ENHERTU was evaluated in 806 patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant HER2-targeted therapy who then received at least one dose of ENHERTU 5.4 mg/kg [see Clinical Studies (14.1) ]. ENHERTU was administered by intravenous infusion once every three weeks for 14 cycles. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU. Serious adverse reactions occurred in 17% of patients receiving 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. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased lymphocyte count, decreased neutrophil count, nausea, decreased hemoglobin, increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, decreased platelet count, increased blood alkaline phosphatase, constipation, vomiting, decreased blood potassium, diarrhea, musculoskeletal pain, and decreased appetite. Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast05. Table 6: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast05 Adverse Reactions ENHERTU 5.4 mg/kg N= 806 Ado-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 Nausea 71 4.5 29 0.1 Constipation 32 0 16 0.1 Vomiting 31 1.1 9 0.1 Diarrhea 23 1.2 9 0.4 Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 15 0.2 9 0.1 Stomatitis Including aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and stomatitis. 10 0.2 6 0.1 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, lethargy, and malaise. 54 6 37 1.0 Pyrexia 10 0.1 12 0.2 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. 23 0.7 32 0.6 Metabolism and Nutrition Disorders Decreased appetite 20 0.9 10 0 Infections and Infestations Upper respiratory tract infection Including influenza, influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 18 0.1 17 0.5 COVID-19 17 0.5 20 0.4 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. 17 1.1 3.7 0.2 Cough 13 0 11 0 Nervous System Disorders Headache Including headache, migraine, and sinus headache. 16 0.2 21 0.1 Peripheral neuropathy Including dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 13 0.4 20 1.1 Dizziness Including dizziness, dizziness postural, vertigo, and vertigo positional. 11 0.4 7 0.1 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 1.2 0 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. 10 0.4 14 0.1 Investigations Decreased weight 12 0.2 7 0.1 Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were: Gastrointestinal disorders: dyspepsia (8%), gastritis (2.5%), abdominal distension (1.7%), flatulence (1.5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (4.5%), epistaxis (3.8%) Skin and Subcutaneous Tissue Disorders: pruritus (4.2%), skin hyperpigmentation (3.5%) [including pigmentation disorder, skin discoloration, skin hyperpigmentation] Nervous System Disorders: dysgeusia (3.7%) Eye Disorders: dry eye (2.7%), vision blurred (2.7%) [including vision blurred, visual impairment] Metabolism and Nutrition Disorders: dehydration (1%) Injury, Poisoning, and Procedural Complications: infusion related reaction (0.7%) [including hypersensitivity, infusion related reaction] Blood and Lymphatic System Disorders: febrile neutropenia (0.5%) Table 7: Selected Laboratory Abnormalities in Patients in DESTINY-Breast05 Laboratory Parameter ENHERTU 5.4 mg/kg N=806 Ado-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 count 80 17 46 2.3 Decreased lymphocyte count 72 35 54 17 Decreased neutrophil count 72 23 38 4.9 Decreased hemoglobin 61 2.9 36 2 Decreased platelet count 46 8 93 33 Chemistry Increased aspartate aminotransferase 60 1 91 4.3 Increased alanine aminotransferase 53 1 80 4.2 Increased blood alkaline phosphatase 39 0 53 0.1 Decreased blood potassium 27 1.7 44 2.1 Increased blood creatinine 13 0.2 9 0.1 Increased blood bilirubin 9 0 20 0 Radiotherapy-Related Pneumonitis and Skin Injury in the Post Neoadjuvant Early Breast Cancer Setting Among patients receiving sequential or concurrent adjuvant radiotherapy in DESTINY-Breast05, radiation pneumonitis occurred in 31% of patients receiving ENHERTU 5.4 mg/kg (N=757) and 31% of patients receiving ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg (N=750), as reported by the investigator. All cases of patients receiving ENHERTU and adjuvant radiotherapy (ART) were either Grade 1 (27%) or Grade 2 (4.9%). Similarly, all cases of patients receiving T-DM1 and ART were either Grade 1 (24%) or Grade 2 (7%). 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). Among patients receiving ART and ENHERTU, radiation skin injury occurred in 20% of all patients, of which 1.6% were Grade 3 and none were Grade 4. Among patients receiving ART and T-DM1, radiation skin injury occurred in 18% of all patients, of which 0.4% were Grade 3 and none were Grade 4. 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 [see Clinical Studies (14.2) ] . Three hundred eighty-one patients received ENHERTU in combination with pertuzumab and 382 patients received THP (taxane [docetaxel or paclitaxel], 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%). Dose interruptions due to adverse reactions occurred in 69% of patients. 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 . 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 Reactions ENHERTU 5.4 mg/kg + Pertuzumab N= 381 THP THP=taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab N=382 All Grades % Grade 3-4 % All Grades % Grades 3-4 % Gastrointestinal Disorders Nausea 75 5 34 0.3 Diarrhea 64 8 62 6 Vomiting 46 2.4 18 0.5 Constipation 33 0.3 12 0 Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 23 0.3 13 0 Stomatitis Including aphthous ulcer, mouth ulceration, oral mucosal eruption, and stomatitis. 16 1.3 17 1.3 Dyspepsia 12 0 6 0 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, lethargy, and malaise. 53 8 42 2.1 Pyrexia 16 0 18 1.0 Skin and Subcutaneous Tissue Disorders Alopecia 48 0 53 0.5 Rash Including rash, rash macular, rash maculo-papular, rash pruritic, and rash pustular. 17 0.3 22 0.3 Pruritus 11 0 11 0.3 Infections and Infestations Upper respiratory tract infection Including Influenza, Influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 33 1.6 30 0.5 COVID-19 28 0.3 22 0.3 Metabolism and Nutrition Disorders Decreased appetite 32 2.4 18 0.8 Hypoalbuminemia 11 0.3 8 0.3 Investigations Decreased weight 30 3.1 11 0.8 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. 24 1 33 0.3 Nervous System Disorders Headache Including headache and migraine. 19 0.3 14 0 Dysgeusia 13 0 9 0 Dizziness 12 0.3 10 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 17 0.3 13 0 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 ENHERTU 12 0 1 0 Eye Disorders Dry eye 11 0 6 0 Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU in combination with pertuzumab were: Blood and Lymphatic System Disorders: febrile neutropenia (2.9%) Eye Disorders: blurred vision (4.2%) Gastrointestinal Disorders: abdominal distension (6%), gastritis (3.9%), flatulence (2.4%) General Disorders and Administration Site Conditions: mucosal inflammation (9%) Injury, poisoning, and procedural complications: infusion related reactions (2.6%) [including hypersensitivity and infusion-related reactions] Metabolism and Nutrition Disorders: dehydration (2.9%) Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%) Skin and Subcutaneous Tissue Disorders: dry skin (7%), skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder] Table 9: Selected Laboratory Abnormalities in Patients in DESTINY-Breast09 Laboratory Parameter ENHERTU 5.4 mg/kg + Pertuzumab N= 381 THP 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 count 87 11 82 31 Decreased hemoglobin 80 12 86 6 Decreased neutrophil count 78 29 66 40 Decreased lymphocyte count 62 14 58 11 Decreased platelet count 56 8 20 1.9 Chemistry Increased alanine aminotransferase 66 3.2 45 1.9 Increased aspartate aminotransferase 62 2.1 41 1.9 Increased blood alkaline phosphatase 55 0.3 36 0.3 Decreased blood potassium 54 20 29 6 Increased blood bilirubin 23 0.3 10 0.3 Increased blood creatinine 9 1.8 7 0.3 DESTINY-Breast03 The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast03 [see Clinical Studies (14.2) ] . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU and 7 months (range: 0.7 to 25) for patients who received ado-trastuzumab emtansine. Serious adverse reactions occurred in 19% of patients receiving ENHERTU. 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%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased neutrophil count, increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocyte count, increased alanine aminotransferase, decreased platelet count, fatigue, vomiting, increased blood alkaline phosphatase, alopecia, decreased blood potassium, constipation, musculoskeletal pain, diarrhea, decreased appetite, headache, respiratory infection, abdominal pain, increased blood bilirubin, and stomatitis. Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03. Table 10: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03 Adverse Reactions ENHERTU 5.4 mg/kg N=257 Ado-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 Nausea 76 7 30 0.4 Vomiting 49 1.6 10 0.8 Constipation 34 0 20 0 Diarrhea 29 1.2 7 0.4 Abdominal pain Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain. 21 0.8 8 0.4 Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption. 20 0.8 5 0 Dyspepsia 11 0 6 0 General Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, malaise, and lethargy. 49 6 35 0.8 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. 37 0.4 3.1 0 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. 31 1.2 25 0.4 Metabolism and Nutrition Disorders Decreased appetite 29 …

Lactation: Advise not to breastfeed. (8.2) Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of ENHERTU. ( 8.3 )

8.1 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 [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] . Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU ( see Clinical Considerations ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations 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. Data Human Data There are no available data on the use of ENHERTU in pregnant women. 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.

8.2 Lactation Risk Summary There is no data regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception Females ENHERTU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility [see Nonclinical Toxicology (13.1) ] .

8.4 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.

8.5 Geriatric Use ENHERTU as Monotherapy Of the 2233 patients treated with ENHERTU 5.4 mg/kg, 28% were 65 years or older and 6% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (56%) as compared to younger patients (49%). Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. ENHERTU in Combination with Pertuzumab In patients with HER2-positive unresectable or metastatic breast cancer treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), 17% were 65 years or older and 3% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. ENHERTU followed by THP Of the 320 patients with HER2-positive early breast cancer treated with ENHERTU 5.4 mg/kg followed by THP, 12% were 65 years or older and 1.6% were 75 years or older. No overall difference in efficacy was observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (38%) as compared to younger patients (30%).

8.6 Renal Impairment No dose adjustment of ENHERTU is recommended in patients with mild (creatinine clearance [CLcr] 60 to <90 mL/min) or moderate (CLcr 30 to <60 mL/min) renal impairment [see Clinical Pharmacology (12.3) ] . A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment [see Warnings and Precautions (5.1) ]. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment No dose adjustment of ENHERTU is recommended in patients with mild (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. In patients with moderate hepatic impairment, due to potentially increased exposure, monitor for increased adverse reactions related to the topoisomerase inhibitor, DXd [see Dosage and Administration (2.3) ]. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology (12.3) ].

12.1 Mechanism of Action Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate. The antibody is a humanized anti-HER2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor attached to the antibody by a cleavable linker. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death.

12.2 Pharmacodynamics Exposure-Response Relationships Exposure-response relationship for efficacy has not been fully characterized. Higher systemic exposure to fam-trastuzumab deruxtecan-nxki was associated with a higher incidence rate of any grade ILD. Cardiac Electrophysiology At the dosage of ENHERTU 6.4 mg/kg every 3 weeks, a mean increase in the QTc interval >20 ms was not observed.

12.3 Pharmacokinetics The pharmacokinetics of fam-trastuzumab deruxtecan-nxki and its payload DXd were evaluated in patients with cancer and are presented as mean (% coefficient of variation), unless otherwise specified. At a dose of 5.4 mg/kg, the maximum concentration (C max ss ) of fam-trastuzumab deruxtecan-nxki is 132 µg/mL (20%) and of DXd is 4.7 ng/mL (48%) and the AUC ss of fam-trastuzumab deruxtecan-nxki is 772 µg∙day/mL (27%) and of DXd is 29 ng∙day/mL (48%). At a dose of 6.4 mg/kg, the C max,ss of fam-trastuzumab deruxtecan-nxki is 126 µg/mL (18%) and of DXd is 5.2 ng/mL (42%) and the AUC ss of fam-trastuzumab deruxtecan-nxki is 743 µg∙day/mL (26%) and of DXd is 33 ng∙day/mL (43%), respectively. Following a single dose, C max and AUC of fam-trastuzumab deruxtecan-nxki and DXd increase in a dose proportional manner over a dose range of 3.2 mg/kg to 8 mg/kg (approximately 0.5 to 1.25 times the highest approved dose). Accumulation of fam-trastuzumab deruxtecan-nxki is approximately 1.4-fold at steady-state (Cycle 3). Distribution The estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki is 2.7 L (% CV 16%). DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6 in vitro. Elimination The median elimination half-life of fam-trastuzumab deruxtecan-nxki is 5.4 to 5.7 days. The estimated systemic clearance of fam-trastuzumab deruxtecan-nxki is 0.4 L/day (24%). The median elimination half-life of DXd is 5.4-6.1 days. The estimated systemic clearance of DXd is 18 L/h (28%). Metabolism The monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways. DXd is primarily metabolized by CYP3A4. Specific Populations No clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (20-96 years); race (Asian [48%] vs Non-Asian [52%]), including White (43%), and Black or African American (1.9%); sex; body weight (27-138 kg); tumor types; mild hepatic impairment; and mild or moderate renal impairment. The pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd in patients with moderate to severe hepatic impairment or severe renal impairment is unknown. Drug Interaction Studies Clinical Studies No clinically significant differences in pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed when used concomitantly with itraconazole (strong CYP3A inhibitor) or ritonavir (strong CYP3A inhibitor and OATP inhibitor). In Vitro Studies CYP450 Enzymes : DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A nor induce CYP1A2, CYP2B6, or CYP3A. UGT Enzymes: DXd is not a substrate of UGT. Transporter Systems : DXd is not an inhibitor of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP. DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP.

12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of fam-trastuzumab deruxtecan-nxki or of other fam-trastuzumab deruxtecan products. Among patients who received ENHERTU as a single agent over a 6 to 9 month treatment period in 13 clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 2.2% (49/2,231) of patients who received ENHERTU 5.4 mg/kg every three weeks and in 2.6% (21/793) of patients who received ENHERTU 6.4 mg/kg every three weeks . Among patients who received ENHERTU (5.4 mg/kg every three weeks) in combination with pertuzumab for a median of 16 months in 2 clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 7.7% (33/426) of patients. These anti-drug antibodies have no clinically significant effect on the pharmacokinetics or safety of fam-trastuzumab deruxtecan-nxki. Because of the low occurrence of anti-drug antibodies, the effect of antibodies on the effectiveness of fam-trastuzumab deruxtecan-nxki products is unknown. Among patients with anti-drug antibodies, neutralizing antibodies against fam-trastuzumab deruxtecan-nxki were detected in 6% (4/70) of patients who received ENHERTU as a single agent (5.4 mg/kg or 6.4 mg/kg every 3 weeks) and in 18% (6/33) of patients who received ENHERTU (5.4 mg/kg every 3 weeks) in combination with pertuzumab.