Enhertu

1 INDICATIONS AND USAGE ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated: 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-approved test. ( 1.1 ) 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. ( 1.1 ) 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-approved test, that has progressed on one or more endocrine therapies in the metastatic setting. ( 1.2 ) 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-approved test, who have received a prior chemotherapy in the metastatic setting; or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. ( 1.2 ) 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-approved test, and who have received a prior systemic therapy* ( 1.3 ) 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. ( 1.4 ) 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* ( 1.5 ) * 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 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-approved 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. 1.2 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-approved 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-approved 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) ] . 1.3 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-approved 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 (14.3) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.4 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. 1.5 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 (14.5) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

2 DOSAGE AND ADMINISTRATION 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, 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 Metastatic Breast Cancer Select patients for treatment of unresectable or metastatic HER2-positive breast cancer with ENHERTU in combination with pertuzumab based on confirmed HER2-positive status or HER2 gene amplification (IHC 3+ or ISH+) [see Clinical Studies (14.1) ] . HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast Cancer Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression [see Clinical Studies (14.2) ] . HER2-Mutant Unresectable or Metastatic NSCLC Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens [see Clinical Studies (14.3) ] . If no mutation is detected in a plasma specimen, test tumor tissue. HER2-Positive Locally Advanced or Metastatic Gastric Cancer Select patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+). Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU. HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens [see Clinical Studies (14.5) ] . An FDA-approved test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available. Additional Patient Selection Information Information on FDA-approved tests for the detection of HER2 protein expression, HER2 gene amplification, and activating HER2 mutations is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage and Schedules 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 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 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 HER2-Positive Locally Advanced or Metastatic Gastric Cancer as monotherapy ENHERTU 6.4 mg/kg every 3 weeks Until disease progression or unacceptable toxicity 2.3 Dosage Modifications 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 [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 1 ). 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 1 ). 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 1 ). 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 1 ). Left Ventricular Dysfunction [see Warnings and Precautions (5.3) ] 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 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light. Do not freeze . The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated. Dilution Withdraw the calculated amount from the vial(s) using a sterile syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored. Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP . DO NOT use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene). Gently invert the infusion bag to thoroughly mix the solution. Do not shake . Cover the infusion bag to protect from light. Discard any unused portion left in the vials. Administration If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time. Protect from light. Do not freeze . The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours. If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light. Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene. Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do NOT administer as an intravenous push or bolus. Cover the infusion bag to protect from light during administration. Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line. First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

4 CONTRAINDICATIONS None . None. ( 4 )

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: 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 monotherapy or ENHERTU in combination with pertuzumab [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 Metastatic 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. 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 monotherapy or ENHERTU in combination with pertuzumab. 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 Metastatic 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 1.2% 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. 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 ejection fraction (LVEF) decrease 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 LVEF decrease 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 Metastatic 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, LVEF decrease 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. 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) ] .

6 ADVERSE REACTIONS 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 metastatic 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 metastatic breast cancer in treatment with ENHERTU 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 Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) The pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY- Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for greater than 6 months and 38% were exposed for greater than 12 months. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%). 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%). HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) The data described in WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 6.4 mg/kg intravenously every 3 weeks in 125 patients in DESTINY-Gastric01. HER2-Positive Metastatic Breast Cancer 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 (14.1) ] . 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 (6.6%). 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 4 and 5 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast09 . Table 4: 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, gastrointestinal pain. 23 0.3 13 0 Stomatitis including aphthous ulcer, mouth ulceration, oral mucosal eruption, stomatitis 16 1.3 17 1.3 Dyspepsia 12 0 6 0 General Disorders and Administration Site Conditions Fatigue including asthenia, fatigue, lethargy, 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, 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, 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, pain in extremity. 24 1 33 0.3 Nervous System Disorders Headache including headache, 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 (grouped term) includes PTs of chronic obstructive pulmonary disease (n=1), interstitial lung disease (n=23), pneumonia (n=3), pneumonitis (n=22). These events were adjudicated as ILD and related to use of T-DXd 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%) Injury, poisoning, and procedural complications: infusion related reaction (1.8%) [including hypersensitivity and infusion-related reactions Investigations: increased blood bilirubin (9%), increased blood creatinine (3.1%) Metabolism and Nutrition Disorders: dehydration (2.9%) Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%) Skin and Subcutaneous Tissue Disorders: skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder] Table 5: 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 (14.1) ] . 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 6 and 7 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03. Table 6: 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 1.6 17 0.4 Investigations Decreased weight 17 1.2 6 0.4 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 22 0.8 12 1.1 Epistaxis 11 0 16 0.4 Cough 11 0.4 10 0 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. 11 0.8 1.9 0 Nervous System Disorders Headache Including headache and migraine 22 0.4 16 0 Peripheral neuropathy Including peripheral neuropathy, peripheral sensory neuropathy, and paresthesia 13 0.4 14 0.4 Dizziness 13 0.4 8 0 Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder] Nervous System Disorders: dysgeusia (6%) Metabolism and Nutrition Disorders: dehydration (4.3%) Eye Disorders: blurred vision (3.5%) Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) [see Warnings and Precautions (5.3) ] Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) [including hypersensitivity and infusion-related reactions] Blood and Lymphatic System Disorders: febrile neutropenia (0.8%) Table 7: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03 Laboratory Parameter 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 % 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 74 8 24 0.8 Decreased neutrophil count 70 18 30 2.3 Decreased hemoglobin 64 7 38 6 Decreased lymphocyte count 55 14 23 3.9 Decreased platelet count 52 7 79 24 Chemistry Increased aspartate aminotransferase 67 0.8 83 5 Increased alanine aminotransferase 53 1.6 67 6 Increased blood alkaline phosphatase 49 0.8 46 0.8 Decreased blood potassium 35 4.7 39 1.5 Increased blood bilirubin 20 0 14 0 Increased blood creatinine 16 0.8 8 0.4 DESTINY-Breast02 The safety of ENHERTU was evaluated in 404 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast02 [see Clinical Studies (14.1) ] . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.7 to 45) for patients who received ENHERTU. Serious adverse reactions occurred in 26% of patients receiving 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%. Dose interruptions due to adverse reactions occurred in 45% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, COVID-19, anemia, fatigue, leukopenia, upper respiratory tract infection, and thrombocytopenia. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, neutropenia, and vomiting. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased alanine aminotransferase, vomiting, increased aspartate aminotransferase, alopecia, increased blood alkaline phosphatase, constipation, decreased appetite, decreased blood potassium, diarrhea, musculoskeletal pain, increased blood bilirubin, abdominal pain, and headache. Tables 8 and 9 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02. Table 8: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast02 Adverse Reactions ENHERTU 5.4 mg/kg N=404 Treatment 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 Nausea 73 7 37 2.6 Vomiting 38 3.7 13 1 Constipation 35 0.3 11 0.5 Diarrhea 27 2.7 54 7 Abdominal pain Including abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain, and gastrointestinal pain 22 1 20 2.1 Dyspepsia 12 0 9 0 Stomatitis Including aphthous ulcer, mouth ulceration, and stomatitis 12 1 21 1 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, lethargy, and malaise 62 9 37 1 Skin and Subcutaneous Tissue Disorders Alopecia 37 0.3 4.1 0 Metabolism and Nutrition Disorders Decreased appetite 31 1.7 18 0.5 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 extremity 25 0.7 18 0.5 Nervous System Disorders Headache Including headache and migraine 20 0.3 6 0 Investigations Decreased weight 18 0.3 3.6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 10 0 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. 10 0.7 0.5 0.5 Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) and epistaxis (8%) Skin and Subcutaneous Tissue Disorders: rash (8%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritus (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder] Nervous System Disorders: dizziness (8%) and dysgeusia (8%) Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Warnings and Precautions (5.3) ] Eye Disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (3%) Metabolism and Nutrition Disorders: dehydration (2.7%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.2%) Blood and Lymphatic System Disorders: febrile neutropenia (0.3%) Table 9: Selected Laboratory Abnormalities in Patients in DESTINY-Breast02 Laboratory Parameter ENHERTU 5.4 mg/kg N=404 Treatment 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 count 70 12 42 3.2 Decreased hemoglobin 67 9 54 3.2 Decreased neutrophil count 64 16 34 4.7 Decreased lymphocyte count 58 17 38 4.7 Decreased platelet count 48 2.7 31 1.6 Chemistry Increased alanine aminotransferase 43 1 32 1.6 Increased aspartate aminotransferase 37 0.7 29 2.1 Increased blood alkaline phosphatase 37 0 17 0 Decreased blood potassium 30 3.7 29 8 Increased blood bilirubin 23 0.3 44 2.1 Increased blood creatinine 7 0.3 13 0 DESTINY-Breast01 and Study DS8201-A-J101 The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) [see Clinical Studies (14.1) ] . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31). In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%) or 1 (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases. Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, 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. ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, vomiting, alopecia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelet count, constipation, decreased appetite, diarrhea, decreased blood potassium, and cough. Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients in DESTINY-Breast01 and Study DS8201-A-J101. Table 10: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101 Adverse Reactions ENHERTU 5.4 mg/kg N=234 All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 4.03. Gastrointestinal Disorders Nausea 79 7 Vomiting 47 3.8 Constipation 35 0.9 Diarrhea 29 1.7 Abdominal pain Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 19 1.3 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). 14 0.9 Dyspepsia 12 0 General Disorders and Administration Site Conditions Fatigue Including fatigue and asthenia 59 6 Skin and Subcutaneous Tissue Disorders Alopecia 46 0.4 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 rash 10 0 Metabolism and Nutrition Disorders Decreased appetite 32 1.3 Respiratory, Thoracic, and Mediastinal Disorders Cough 20 0 Dyspnea 13 1.3 Epistaxis 13 0 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. 9 2.6 All events had fatal outcomes (n=6). Nervous System Disorders Headache Including headache, sinus headache, and migraine 19 0 Dizziness 10 0 Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, and upper respiratory tract infection 15 0 Eye Disorders Dry eye 11 0.4 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. Other clinically relevant adverse reactions reported in less than 10% of patients were: Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%) Blood and Lymphatic System Disorders: febrile neutropenia (1.7%) Table 11: 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 Parameter ENHERTU 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 count 70 7 Decreased hemoglobin 70 7 Decreased neutrophil count 62 16 Decreased platelet count 37 3.4 Chemistry Increased aspartate aminotransferase 41 0.9 Increased alanine aminotransferase 38 0.4 Decreased blood potassium 26 3 HER2-Low and HER2-Ultralow Metastatic Breast Cancer DESTINY-Breast06 The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast06 [see Clinical Studies (14.2) ] . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU. Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease (ILD)/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each). ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19, and musculoskeletal pain. Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast06. Table 12: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast06 Adverse Reactions ENHERTU 5.4 mg/kg Chemotherapy N=434 N=417 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 70 2.1 30 0.5 Diarrhea 34 2.3 27 2.6 Vomiting 34 1.4 12 0.2 Constipation 32 0.7 15 0.5 Abdominal pain Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain 20 0.5 14 0.2 Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption 15 0 11 0.5 Dyspepsia 12 0 4.8 0 General Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, malaise, and lethargy 53 4.4 40 2.4 Pyrexia 12 0.2 7 0 Skin and Subcutaneous Tissue Disorders Alopecia 48 0 21 0.5 Rash Including dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular 12 0.2 43 8 Metabolism and Nutrition Disorders Decreased appetite 26 1.4 12 0.5 Infections and Infestations COVID-19 Including COVID-19, COVID-19 pneumonia 26 0.9 13 1 Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis 19 0 9 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 24 0.5 23 1.9 Nervous System Disorders Headache Including migraine, headache, and sinus headache 18 0.5 10 0 Dysgeusia 12 0.2 6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 16 0 9 0 Interstitial lung disease Including bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity 11 0.7 0.2 0 Epistaxis 10 0 3.6 0.2 Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were: Nervous System Disorders: dizziness (9%) Investigations: decreased weight (7%) Eye Disorders: dry eye (7%), and blurred vision (5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (6%) Gastrointestinal Disorders: abdominal distension (4.8%), flatulence (2.3%), and gastritis (0.7%) Skin and Subcutaneous Tissue Disorders: pruritus (3.9%), and skin hyperpigmentation (0.9%) Metabolism and Nutrition Disorders: dehydration (1.6%) Blood and lymphatic system disorders: febrile neutropenia (1.2%) Injury, Poisoning, and Procedural Complications: infusion related reaction (1.2%) Table 13: Selected Laboratory Abnormalities in Patients in DESTINY-Breast06 Laboratory Parameter ENHERTU 5.4 mg/kg Chemotherapy N=434 N=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 count 86 13 71 11 Decreased neutrophil count 75 27 53 20 Decreased hemoglobin 69 9 58 5 Decreased lymphocyte count 66 19 46 8 Decreased platelet count 48 6 25 1 Chemistry Increased alanine aminotransferase 44 3.2 30 0.7 Increased blood alkaline phosphatase 43 0.2 22 0.2 Increased aspartate aminotransferase 41 2.6 27 1.2 Decreased blood potassium 35 8 15 2.9 Increased blood bilirubin 16 1.9 23 1.5 Increased blood creatinine 10 1.9 8 1 DESTINY-Breast04 The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast04 [see Clinical Studies (14.2) ] . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, constipation, increased blood alkaline phosphatase, decreased appetite, musculoskeletal pain, diarrhea, and decreased blood potassium. Tables 14 and 15 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04. Table 14: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast04 Adverse Reactions ENHERTU 5.4 mg/kg Chemotherapy N=371 N=172 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 76 4.6 30 0 Vomiting 40 1.6 13 0 Constipation 34 0.8 22 0 Diarrhea 27 1.3 22 1.7 Abdominal pain Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain 18 0.5 13 0 Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation 13 0.3 12 0.6 General Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, and malaise 54 9 48 4.7 Pyrexia 12 0.3 13 0 Skin and Subcutaneous Tissue Disorders Alopecia 40 0 33 0 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 bullous 13 0 23 4.7 Metabolism and Nutrition Disorders Decreased appetite 32 2.4 19 1.2 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 pain 32 1.3 31 0.6 Investigations Decreased weight 16 0.3 8 0 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 hemorrhage 16 0 3.5 0 Nervous System Disorders Headache Including headache and migraine 15 0.3 6 0 Peripheral neuropathy Including peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia 13 0 29 5 Dizziness Including dizziness, postural dizziness, and vertigo 11 0.5 6 0 Infections and Infestations Upper respiratory tract infection Including upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis 14 0.3 5 0 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. 12 1.3 0.6 0 Dyspnea 10 1.3 9 1.2 Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU: Nervous System Disorders: dysgeusia (10%) Respiratory, Thoracic and Mediastinal Disorders: cough (10%) Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%) Eye Disorders: blurred vision (4.9%) [including blurred vision and visual impairment] Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder] Metabolism and Nutrition Disorders: dehydration (1.9%) Blood and Lymphatic System Disorders: febrile neutropenia (1.1%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) [including injection-site reaction and chills] Table 15: Selected Laboratory Abnormalities in Patients in DESTINY-Breast04 Laboratory Parameter ENHERTU 5.4 mg/kg Chemotherapy N=371 N=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 count 70 9 78 25 Decreased hemoglobin 64 8 53 6 Decreased neutrophil count 64 14 73 38 Decreased lymphocyte count 55 18 40 11 Decreased platelet count 44 6 21 0.6 Chemistry Increased aspartate aminotransferase 38 2.2 38 4.1 Increased alanine aminotransferase 36 0.8 38 4.1 Increased blood alkaline phosphatase 34 0.3 24 0 Decreased blood potassium 25 3.3 17 1.2 Increased blood bilirubin 16 2.7 15 0.6 Increased blood creatinine 15 1.1 9 0.6 HER2-Mutant Unresectable or Metastatic NSCLC DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis. The safety of ENHERTU was evaluated in 101 patients in DESTINY-Lung02 [see Clinical Studies (14.3) ] . Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. Nineteen percent of patients were exposed for greater than 6 months. The median age was 59 years (range 30 to 83); 64% were female; 23% were White, 64% were Asian, and 14% were other races. Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%). ENHERTU was permanently discontinued due to an adverse reaction in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia. Tables 16 and 17 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02. Table 16: 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 Reactions ENHERTU 5.4 mg/kg N=101 All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 61 3 Constipation 31 1 Vomiting Including vomiting and retching 26 2 Diarrhea 19 1 Stomatitis Including mucosal inflammation and stomatitis 12 0 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, and malaise 32 4 Metabolism and Nutrition Disorders Decreased appetite 30 1 Skin and Subcutaneous Tissue Disorders Alopecia 21 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity 15 1 Other clinically relevant adverse reactions reported in less than 10% of patients were: Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease (6%) [including interstitial lung disease that was adjudicated as drug-induced ILD including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure], dyspnea (5%), and epistaxis (3%) Gastrointestinal Disorders: abdominal pain (9%) [including abdominal discomfort, abdominal pain, and upper abdominal pain] Skin and Subcutaneous Disorders: rash (3%) [including rash and maculo-papular rash] Infections and Infestations: upper respiratory tract infection (4%) [including upper respiratory tract infection, pharyngitis, and laryngitis] Nervous System Disorders: headache (4%) [including headache and migraine] Table 17: Select Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02 Laboratory Parameter ENHERTU 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 98 to 99 based on the number of patients with a baseline value and at least one post-treatment value. Decreased white blood cell count 60 4 Decreased hemoglobin 58 10 Decreased neutrophil count 52 12 Decreased lymphocyte count 43 16 Decreased platelet count 40 4 Chemistry Decreased albumin 39 0 Increased aspartate aminotransferase 35 1 Increased alanine aminotransferase 34 2 Increased alkaline phosphatase 22 0 Decreased blood potassium 17 2 HER2-Positive Locally Advanced or Metastatic Gastric Cancer The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.4) ] . Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m 2 biweekly or paclitaxel (N=7) 80 mg/m 2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group. Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%). ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. Tables 18 and 19 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01. Table 18: Adverse Reactions in ≥10% All Grades or ≥2% Grades 3 or 4 of Patients Receiving ENHERTU in DESTINY-Gastric01 ENHERTU 6.4 mg/kg N=125 Irinotecan or Paclitaxel N=62 Adverse Reactions All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 4.03. Gastrointestinal Disorders Nausea 63 4.8 47 1.6 Diarrhea 32 2.4 32 1.6 Vomiting 26 0 8 0 Constipation 24 0 23 0 Abdominal pain Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 14 0.8 15 3.2 Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering 11 1.6 4.8 0 Metabolism and Nutrition Disorders Decreased appetite 60 17 45 13 Dehydration 6 2.4 3.2 1.6 Blood and Lymphatic System Disorders Febrile neutropenia 4.8 4.8 3.2 3.2 General Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, and malaise 55 9 44 4.8 Pyrexia 24 0 16 0 Peripheral edema 10 0 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 22 0 15 0 Respiratory, Thoracic and Mediastinal Disorders 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. 10 2.4 0 0 Hepatobiliary Disorders Abnormal hepatic function 8 3.2 1.6 1.6 Other clinically relevant adverse reactions reported in less than 10% of patients were: Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3) ] Infections and Infestations: pneumonia (6%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%) Table 19: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01 Laboratory Parameter ENHERTU 6.4 mg/kg N=125 Irinotecan 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 hemoglobin 75 38 55 23 Decreased white blood cell count 74 29 53 13 Decreased neutrophil count 72 51 45 23 Decreased lymphocyte count 70 28 53 12 Decreased platelet count 68 12 12 5 Chemistry Increased aspartate aminotransferase 58 9 32 8 Increased blood alkaline phosphatase 54 8 34 10 Increased alanine aminotransferase 47 9 17 1.7 Decreased blood potassium 30 4.8 18 8 Increased blood bilirubin 24 7 5 3.4 HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 [see Clinical Studies (14.1 and 14.5) ] . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8.3 months (range 0.7 to 30.2). The median age was 60 years (range 23 to 96); 74% were female; 51% were White, 42% were Asian, 2.9% were Black or African American, 3.5% were of Hispanic or Latino ethnicity; and 40% had an ECOG performance status 0 and 41% had an ECOG performance status of 1. Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock. ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. Tables 20 and 21 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02. Table 20: 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 Reactions ENHERTU 5.4 mg/kg N= 347 All Grades % Grade 3 or 4 % Gastrointestinal Disorders Nausea 69 7 Vomiting 35 3.5 Diarrhea 31 4.3 Constipation 28 0.6 Stomatitis Including stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis. 20 0.9 Abdominal pain Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain. 18 2 Dyspepsia 12 0.3 General Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, malaise, lethargy. 59 10 Pyrexia 11 0 Edema Including peripheral edema, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema 11 0.6 Metabolism and Nutrition Disorders Decreased appetite 34 2.6 Skin and Subcutaneous Tissue Disorders Alopecia 34 0.3 Rash Including rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic rash dermatitis acneiform, dermatitis, eczema, palmar-plantar erythrodysesthesia syndrome. 13 0.6 Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis. 20 0 Pneumonia 6 2.3 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. 19 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough Including cough, productive cough, upper-airway cough syndrome 18 0 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. 16 0.6 Dyspnea Including dyspnea, exertional dyspnea 12 1.7 Nervous System Disorders Headache Including migraine, headache, sinus headache. 15 0 Investigations Decreased weight 10 0.3 Other clinically relevant adverse reactions reported in less than 10% of patients were: Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%) Nervous System Disorders: dizziness (9%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%) Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder] Eye Disorders : blurred vision (4%) [including blurred vision, visual impairment] Metabolism and Nutrition Disorders : dehydration (3.2%) Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%) Blood and Lymphatic System Disorders: febrile neutropenia (1.7%) Injury, Poisoning, and Procedural Complications : infusion-related reactions (1.4%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction] Table 21: Selected Laboratory Abnormalities in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 Laboratory Parameter ENHERTU 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 count 75 11 Decreased hemoglobin 67 10 Decreased neutrophil count 66 21 Decreased lymphocyte count 58 21 Decreased platelet count 51 7 Chemistry Increased aspartate aminotransferase 45 1.5 Increased alanine aminotransferase 44 1.5 Increased blood alkaline phosphatase 36 1.2 Decreased blood potassium 29 6 Decreased sodium 22 2.9 Increased blood bilirubin 15 0.6 Increased blood creatinine 14 0.6

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.