Trastuzumab

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION Do not substitute KADCYLA for or with trastuzumab. HER2 Testing: Perform using FDA-authorized tests by laboratories with demonstrated proficiency. ( 2.1 ) For intravenous infusion only . Do not administer as an intravenous push or bolus. Do not use Dextrose (5%) solution. ( 2.4 ) The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity, or a total of 14 cycles for patients with EBC. Do not administer KADCYLA at doses greater than 3.6 mg/kg. ( 2.2 ) Management of adverse reactions (infusion-related reactions, hepatotoxicity, left ventricular cardiac dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy) may require temporary interruption, dose reduction, or treatment discontinuation of KADCYLA. ( 2.3 ) 2.1 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) , Clinical Studies (14) ]. Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-authorized tests specific for breast cancers by laboratories with demonstrated proficiency. Information on the FDA-authorized tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.2 Recommended Doses and Schedules Do not substitute trastuzumab for or with KADCYLA. The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle). Do not administer KADCYLA at doses greater than 3.6 mg/kg . Closely monitor the infusion site for possible subcutaneous infiltration during drug administration [see Warnings and Precautions (5.9) ] . First infusion: Administer infusion over 90 minutes. Observe patients during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions [see Warnings and Precautions (5.5) ] . Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated. Observe patients during the infusion and for at least 30 minutes after infusion. Metastatic Breast Cancer (MBC) Patients with MBC should receive treatment until disease progression or unmanageable toxicity. Early Breast Cancer (EBC) Patients with EBC should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity. 2.3 Dose Modifications Do not re-escalate the KADCYLA 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. Slow or interrupt the infusion rate of KADCYLA if the patient develops an infusion-related reaction. Permanently discontinue KADCYLA for life-threatening infusion-related reactions [see Warnings and Precautions (5.5) ] . Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction or treatment discontinuation of KADCYLA as per guidelines provided in Tables 1 and 2 . Table 1 Recommended Dose Reduction Schedule for Adverse Reactions Dose Reduction Schedule Dose Level Starting dose 3.6 mg/kg First dose reduction 3 mg/kg Second dose reduction 2.4 mg/kg Requirement for further dose reduction Discontinue treatment Table 2 Dose Modification Guidelines for KADCYLA ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, DILI = Drug Induced Liver Injury; LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal Dose Modifications for Patients with MBC Adverse reaction Severity Treatment modification Increased Transaminase (AST/ALT) Grade 2 (> 2.5 to ≤ 5× the ULN) Treat at the same dose level. Grade 3 (> 5 to ≤ 20× the ULN) Do not administer KADCYLA until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level Grade 4 (> 20× the ULN) Discontinue KADCYLA Hyperbilirubinemia Grade 2 (> 1.5 to ≤ 3× the ULN) Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level. Grade 3 (> 3 to ≤ 10× the ULN) Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level. Grade 4 (> 10× the ULN) Discontinue KADCYLA Drug Induced Liver Injury (DILI) Serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN Permanently discontinue KADCYLA in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication Nodular Regenerative Hyperplasia (NRH) All Grades Permanently discontinue KADCYLA Thrombocytopenia Grade 3 (25,000 to < 50,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then treat at the same dose level Grade 4 (< 25,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then reduce one dose level Left Ventricular Dysfunction Symptomatic CHF Discontinue KADCYLA LVEF < 40% Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 40% is confirmed, discontinue KADCYLA LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA LVEF 40% to ≤ 45% and decrease is < 10% points from baseline Continue treatment with KADCYLA . Repeat LVEF assessment within 3 weeks. LVEF > 45% Continue treatment with KADCYLA . Pulmonary Toxicity Interstitial lung disease (ILD) or pneumonitis Permanently discontinue KADCYLA Peripheral Neuropathy Grade 3-4 Do not administer KADCYLA until resolution Grade ≤ 2 Dose Modification Guidelines for EBC Adverse reaction Severity Treatment modification Increased Alanine Transaminase (ALT) Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment) Do not administer KADCYLA until ALT recovers to Grade ≤ 1, and then reduce one dose level Grade 4 (> 20 × ULN at any time) Discontinue KADCYLA Increased Aspartate Transaminase (AST) Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment) Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then treat at the same dose level Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment) Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then reduce one dose level Grade 4 (> 20 × ULN at any time) Discontinue KADCYLA Hyperbilirubinemia TBILI > 1.0 to ≤ 2.0 × the ULN on day of scheduled treatment Do not administer KADCYLA until total bilirubin recovers to ≤ 1.0 × ULN, and then reduce one dose level TBILI > 2 × ULN at any time Discontinue KADCYLA Nodular Regenerative Hyperplasia (NRH) All Grades Permanently discontinue KADCYLA Thrombocytopenia Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level. Grade 4 at any time < 25,000/mm 3 Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then reduce one dose level. Left Ventricular Dysfunction LVEF < 45% Do not administer KADCYLA Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue KADCYLA. LVEF 45% to

WARNINGS AND PRECAUTIONS Pulmonary Toxicity: Permanently discontinue KADCYLA in patients diagnosed with interstitial lung disease or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, permanently discontinue KADCYLA for Grade ≥ 3 or for Grade 2 not responding to standard treatment. ( 2.2 , 5.4 ) Infusion-Related Reactions, Hypersensitivity Reactions: Monitor for signs and symptoms during and after infusion. If significant infusion-related reactions or hypersensitivity reactions occur, slow or interrupt the infusion and administer appropriate medical therapies. Permanently discontinue KADCYLA for life threatening infusion-related reaction. ( 2.1 , 2.2 , 5.5 ) Hemorrhage: Fatal cases of hemorrhage occurred in clinical trials among patients with no known identified risk factors, as well as among patients with thrombocytopenia and those receiving anti-coagulation and antiplatelet therapy. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary . ( 5.6 ) Thrombocytopenia: Monitor platelet counts prior to each KADCYLA dose. Institute dose modifications as appropriate. ( 2.2 , 5.7 ) Neurotoxicity: Monitor for signs or symptoms. Withhold dosing temporarily for patients experiencing Grade 3 or 4 peripheral neuropathy. ( 2.2 , 5.8 , 13.2 ) 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1) ] . Serious hepatotoxicity, including 3 fatal cases, has been observed in clinical trials (n=1624) with KADCYLA as single-agent. All fatal cases occurred in MBC clinical trials with KADCYLA, which included severe drug-induced liver injury and associated hepatic encephalopathy. Some of the patients experiencing hepatotoxicity had comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active liver disease (such as, hepatitis B virus or hepatitis C virus) were excluded from the EMILIA and KATHERINE studies [see Clinical Studies (14.1) ] . Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2) ] . Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 × ULN or bilirubin > 1.5 × ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (5 cases out of 1624 treated patients, one of which was fatal). Two of these five cases of NRH were observed in EMILIA and two were observed in KATHERINE [see Adverse Reactions (6.1) ] . NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. Serious cases of heart failure, with no fatal cases, have been observed in clinical trials with KADCYLA. In EMILIA, left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group. In KATHERINE, left ventricular dysfunction occurred in 0.4% of patients in the KADCYLA-treated group and 0.6% of patients in the trastuzumab-treated group [see Adverse Reactions (6.1) ] . Based on limited data from a retrospective observational study, 22% (7 of 32) of patients with HER2-positive metastatic breast cancer (MBC) with a baseline LVEF of 40-49% treated with KADCYLA developed a congestive heart failure (CHF) or a > 10% reduction in LVEF [see Adverse Reactions (6.2) ]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution's normal limits. KADCYLA has not been studied in an adequately controlled study in patients with LVEF < 50%. For patients with MBC, if, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further. For patients with EBC, if, at routine monitoring, LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2) ] . Patients with a history of symptomatic CHF, serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from the EMILIA and KATHERINE studies [see Clinical Studies (14.1) ] . 5.3 Embryo-Fetal Toxicity KADCYLA can cause fetal harm when administered to a pregnant woman. Cases of oligohydramnios, and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed in the post-marketing setting in patients treated with trastuzumab, the antibody component of KADCYLA. DM1, the cytotoxic component of KADCYLA, can cause embryo-fetal toxicity based on its mechanism of action. Verify the pregnancy status of females of reproductive potential prior to the initiation of KADCYLA. Advise pregnant women and females of reproductive potential that exposure to KADCYLA during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA [see Use in Specific Populations (8.1 , 8.3) ]. 5.4 Pulmonary Toxicity Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. In patients with MBC, pneumonitis was reported at an incidence of 0.8% (7 out of 884 treated patients), with one case of Grade 3 pneumonitis. The overall incidence of pneumonitis was 1.2% in EMILIA. In KATHERINE, pneumonitis was reported at an incidence of 1.1% (8 out of 740 patients treated with KADCYLA), with one case of Grade 3 pneumonitis. Radiation pneumonitis was reported at an incidence of 1.8% (11 out of 623 patients treated with adjuvant radiotherapy and KADCYLA), with 2 cases of Grade 3 radiation pneumonitis [see Adverse Reactions (6.1) ] . Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, KADCYLA should be permanently discontinued for Grade ≥ 3 or for Grade 2 not responding to standard treatment [see Dose Modifications (2.3) ] . Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary toxicity. 5.5 Infusion-Related Reactions, Hypersensitivity React

CONTRAINDICATIONS None . None. ( 4 )

DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have been conducted. In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with KADCYLA should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying KADCYLA treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse reactions.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Hepatotoxicity [See Warnings and Precautions (5.1) ] Left Ventricular Dysfunction [See Warnings and Precautions (5.2) ] Embryo-Fetal Toxicity [See Warnings and Precautions (5.3) ] Pulmonary Toxicity [See Warnings and Precautions (5.4) ] Infusion-Related Reactions, Hypersensitivity Reactions [See Warnings and Precautions (5.5) ] Hemorrhage [See Warnings and Precautions (5.6) ] Thrombocytopenia [See Warnings and Precautions (5.7) ] Neurotoxicity [See Warnings and Precautions (5.8) ] Metastatic Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. ( 6.1 ) Early Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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. The data in the WARNINGS AND PRECAUTIONS reflect exposure to KADCYLA as a single agent at 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) in 1624 patients including 884 patients with HER2-positive metastatic breast cancer and 740 patients with HER2-positive early breast cancer (KATHERINE trial). Metastatic Breast Cancer In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (≥ 25%) adverse reactions were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. The adverse reactions described in Table 3 were identified in patients with HER2-positive metastatic breast cancer treated in the EMILIA trial [see Clinical Studies (14.1) ] . Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively. In the EMILIA trial, 43% of patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 59% of patients in the lapatinib plus capecitabine-treated group. Dose adjustments for KADCYLA were permitted [see Dosage and Administration (2.2) ] . Thirty-two patients (7%) discontinued KADCYLA due to an adverse reaction, compared with 41 patients (8%) who discontinued lapatinib, and 51 patients (10%) who discontinued capecitabine due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation were thrombocytopenia and increased transaminases. Eighty patients (16%) treated with KADCYLA had adverse reactions leading to dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse reactions that led to dose delays occurred in 116 (24%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia. Table 3 reports the adverse reactions that occurred in patients in the KADCYLA-treated group (n=490) of the EMILIA trial. Selected laboratory abnormalities are shown in Table 4 . The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients on the KADCYLA Treatment Arm in the EMILIA Trial Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Abdominal pain: abdominal pain, abdominal pain upper Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Hypokalemia: hypokalemia, blood potassium decreased Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow). Adverse Reactions KADCYLA (3.6 mg/kg) n=490 Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) n=488 All Grades (%) Grade 3 – 4 (%) All Grades (%) Grade 3 – 4 (%) SMQ=standardized MedDRA queries Blood and Lymphatic System Disorders Thrombocytopenia 31 15 3.3 0.4 Anemia 14 4.1 11 2.5 Gastrointestinal Disorders Nausea 40 0.8 45 2.5 Constipation 27 0.4 11 0 Diarrhea 24 1.6 80 21 Vomiting 19 0.8 30 4.5 Abdominal pain 19 0.8 18 1.6 Dry Mouth 17 0 4.9 0.2 Stomatitis 14 0.2 33 2.5 General Disorders and Administration Fatigue 36 2.5 28 3.5 Pyrexia 19 0.2 8 0.4 Asthenia 18 0.4 18 1.6 Investigations Transaminases increased 29 8.0 14 2.5 Metabolism and Nutrition Disorders Hypokalemia 10 2.7 9 4.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 36 1.8 31 1.4 Arthralgia 19 0.6 8 0 Myalgia 14 0.6 3.7 0 Nervous System Disorders Headache 28 0.8 15 0.8 Peripheral neuropathy 21 2.2 14 0.2 Dizziness 10 0.4 11 0.2 Psychiatric Disorders Insomnia 12 0.4 9 0.2 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 23 0.2 8 0 Cough 18 0.2 13 0.2 Dyspnea 12 0.8 8 0.4 Skin and Subcutaneous Tissue Disorders Rash 12 0 28 1.8 Vascular Disorders Hemorrhage 32 1.8 16 0.8 The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in EMILIA: dyspepsia (9%), urinary tract infection (9%), chills (8%), dysgeusia (8%), neutropenia (7%), peripheral edema (7%), pruritus (6%), hypertension (5%), blood alkaline phosphatase increased (4.7%), vision blurred (4.5%), conjunctivitis (3.9%), dry eye (3.9%), lacrimation increased (3.3%), drug hypersensitivity (2.2%), left ventricular dysfunction (1.8%), infusion-related reaction (1.4%), pneumonitis (1.2%), nodular regenerative hyperplasia (0.4%), portal hypertension (0.4%). Table 4 Selected Laboratory Abnormalities (EMILIA) Parameter KADCYLA (3.6 mg/kg) Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Chemistry Increased AST 98 7 0.5 65 3 0 Increased ALT 82 5 0.2 54 3 0 Decreased potassium 33 3 0 31 6 0.8 Increased bilirubin 17 0.6 0 57 2 0 Hematology Decreased platelet count 83 14 3 21 0.4 0.6 Decreased hemoglobin 60 4 1 64 3 0.2 Decreased neutrophils 39 3 0.6 38 6 2 Early Breast Cancer KADCYLA has been evaluated as a single-agent in 740 patients with HER2-positive early breast cancer. The adverse reactions described in Table 5 were identified in patients with HER2-positive early breast cancer treated in the KATHERINE trial [see Clinical Studies (14.2) ] . Patients were randomized to receive KADCYLA or trastuzumab. The median durat

Mechanism of Action Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate. The antibody is the humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a microtubule inhibitor. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death. In addition, in vitro studies have shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2.