Kadcyla Drug Information
Generic name: ADO-TRASTUZUMAB EMTANSINE
Uses of Kadcyla
Metastatic Breast Cancer (MBC)
KADCYLA ®, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: Received prior therapy for metastatic disease, or Developed disease recurrence during or within six months of completing adjuvant therapy. Select patients for therapy based on an FDA-authorized test for KADCYLA.
Early Breast Cancer (EBC)
KADCYLA, as a single agent, is indicated for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab -based treatment. Select patients for therapy based on an FDA-authorized test for KADCYLA.
Dosage & Administration of Kadcyla
| 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 |
Side Effects of Kadcyla
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 . 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 . 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
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
Abdominal pain 19 0.8 18 1.6 Dry Mouth 17 0 4.9 0.2
Stomatitis 14 0.2 33
General Disorders and
Administration Fatigue 36 2.5 28
Pyrexia 19 0.2 8 0.4 Asthenia 18 0.4 18 1.6 Investigations Transaminases
increased 29 8.0 14
Metabolism and Nutrition Disorders Hypokalemia 10 2.7 9 4.7 Musculoskeletal and Connective
Tissue Disorders Musculoskeletal pain 36 1.8 31
Arthralgia 19 0.6 8 0 Myalgia 14 0.6 3.7 0 Nervous System
Disorders Headache 28 0.8 15
Peripheral neuropathy 21 2.2 14 0.2 Dizziness 10 0.4 11 0.2 Psychiatric
Disorders Insomnia 12 0.4 9
Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 23 0.2 8 0 Cough 18
0.2 13
Dyspnea 12 0.8 8 0.4 Skin and Subcutaneous Tissue Disorders Rash 12
0 28
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
Increased bilirubin 17 0.6 0 57 2 0 Hematology Decreased platelet count
83 14 3 21 0.4
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 . Patients were randomized to receive KADCYLA or trastuzumab. The median duration of study treatment was 10 months for patients in the KADCYLA-treated group and 10 months for patients treated with trastuzumab.
One hundred and ninety (26%) patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 111 (15%) patients in the trastuzumab group. One hundred and thirty-three patients (18%) discontinued KADCYLA due to an adverse reaction, compared with 15 patients (2.1%) who discontinued trastuzumab due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation (in ≥ 1% of patients) were platelet count decreased, blood bilirubin increased, ejection fraction decreased, AST increased, ALT increased, and peripheral neuropathy.
Dose adjustments for KADCYLA were permitted . One hundred and six patients (14%) treated with KADCYLA had dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, blood bilirubin and fatigue. Adverse reactions that led to dose delays occurred in 106 (14%) of KADCYLA treated patients.
The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia and AST increased. Selected laboratory abnormalities are shown in Table 6. The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (> 2%) were thrombocytopenia and hypertension.
Table 5 Adverse Reactions Occurring in ≥ 10% of Patients in the KATHERINE Trial Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Abdominal pain: abdominal pain, abdominal pain upper Urinary Tract Infection: urinary tract infection, cystitis Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal 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 n=740 Trastuzumab n=720 All grades (%) Grade 3 – 4 (%) All grades (%) Grade 3 – 4 (%) SMQ=standardized MedDRA queries Blood and Lymphatic System Disorders Thrombocytopenia 29 6 2.4
Anemia 10 1.1 9 0.1 Gastrointestinal Disorders Nausea 42 0.5 13 0.3
Constipation 17 0.1 8 0 Stomatitis 15 0.1 8
Vomiting 15 0.5 5 0.3 Dry Mouth 14 0.1 1.3 0 Diarrhea
12 0.8 13
Abdominal pain 11 0.4 7 0.3 General Disorders and
Administration Fatigue 50 1.1 34
Pyrexia 10 0 4 0 Infections and Infestations Urinary tract infection 10
0.3 6
Investigations Transaminases increased 32 1.5 8 0.4 Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain 30 0.7 29
Arthralgia 26 0.1 21 0 Myalgia 15 0.4 11 0 Nervous System
Disorders Headache 28 0 17
Peripheral neuropathy 28 1.6 14 0.1 Dizziness 10 0.1 8 0.3 Psychiatric
Disorders Insomnia 14 0 12
Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 22 0 3.5 0 Cough 14
0.1 12 0 Vascular Disorders Hemorrhage 29
Included one fatal hemorrhage. 10 0.3
The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in KATHERINE: blood alkaline phosphatase increased (8%), dysgeusia (8%), dyspnea (8%), neutropenia (8%), blood bilirubin increased (7%), hypokalemia (7%), pruritus (7%), hypertension (6%), lacrimation increased (6%), chills (5%), dry eye (4.5%), dyspepsia (4.3%), peripheral edema (3.9%),vision blurred (3.9%), conjunctivitis (3.5%), left ventricular dysfunction (3.0%), drug hypersensitivity (2.7%), infusion-related reaction (1.6%), radiation pneumonitis (1.5%), pneumonitis (1.1%), rash (1.1%), asthenia (0.4%), nodular regenerative hyperplasia (0.3%). Table 6 Selected Laboratory Abnormalities (KATHERINE) Parameter KADCYLA n=740 Trastuzumab n=720 All Grade (%) Grade 3 (%) Grade 4 (%) All Grade (%) Grade 3 (%) Grade 4 (%) Chemistry Increased AST 79 0.8 0 21 0.1 0 Increased ALT 55 0.7 0 21 0.1 0 Decreased potassium 26 2 0.5 9 0.7
Increased bilirubin 12 0 0 4 0.7 0 Hematology Decreased platelet count
51 4 2 13 0.1
Decreased hemoglobin 31 1 0 29 0.3 0 Decreased neutrophils 24 1
0 19 0.6 0.6
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of KADCYLA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions from Observational Studies CHF and > 10% reduction in LVEF in patients with HER2-positive metastatic breast cancer with a baseline LVEF of 40-49% treated with KADCYLA . Adverse Reactions from Postmarketing Spontaneous Reports Tumor lysis syndrome (TLS) Skin/tissue necrosis after extravasation
Warnings & Cautions for Kadcyla
Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the
concentrations of serum transaminases, has been observed in clinical trials with KADCYLA . 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 . Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin . 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 . 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.
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 . 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. 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 . 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 .
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.
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 . 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 . 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.
Infusion-Related Reactions, Hypersensitivity Reactions Treatment with
KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRRs) and/or hypersensitivity; treatment with KADCYLA is not recommended for these patients. Infusion-related reactions, characterized by one or more of the following symptoms − flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In EMILIA, the overall incidence of IRRs in patients treated with KADCYLA was 1.4%. In KATHERINE, the overall incidence of IRRs in patients treated with KADCYLA was 1.6% . In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. KADCYLA treatment should be interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR . Patients should be observed closely for IRR reactions, especially during the first infusion.
One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of single-agent KADCYLA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.
Hemorrhage Cases of hemorrhagic events, including central nervous system, respiratory, and gastrointestinal
hemorrhage, have been reported in clinical trials with KADCYLA. Some of these bleeding events resulted in fatal outcomes. In EMILIA, the overall incidence of hemorrhage was 32% in the KADCYLA-treated group and 16% in the lapatinib plus capecitabine-treated group. The incidence of Grade ≥ 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the lapatinib plus capecitabine-treated group.
In KATHERINE, the overall incidence of hemorrhage was 29% in the KADCYLA-treated group and 10% in the trastuzumab-treated group. The incidence of Grade ≥ 3 hemorrhage was 0.4% in the KADCYLA-treated group, with one fatal case of intracranial hemorrhage, and 0.3% in the trastuzumab-treated group . Although, in some of the observed cases the patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary.
Thrombocytopenia Thrombocytopenia, or decreased platelet count, was reported in clinical trials of
KADCYLA (145 of 1624 treated patients with Grade ≥ 3; 494 of 1624 treated patients with any Grade). The majority of these patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm 3 ) with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000/mm 3 ) by the next scheduled dose. In clinical trials of KADCYLA, the incidence and severity of thrombocytopenia were higher in Asian patients. In EMILIA, the overall incidence of thrombocytopenia was 31% in the KADCYLA-treated group and 3.3% in the lapatinib plus capecitabine-treated group . The incidence of Grade ≥ 3 thrombocytopenia was 15% in the KADCYLA-treated group and 0.4% in the lapatinib plus capecitabine-treated group.
In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 45% in the KADCYLA-treated group and 1.3% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of thrombocytopenia was 29% in the KADCYLA-treated group and 2.4% in the trastuzumab-treated group . The incidence of Grade ≥ 3 thrombocytopenia was 6% in the KADCYLA-treated group and 0.3% in the trastuzumab-treated group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 19% in the KADCYLA-treated group and 0% in the trastuzumab-treated group.
The overall incidence of thrombocytopenia in the KADCYLA-treated group for Asian patients was 50%. Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose . KADCYLA has not been studied in patients with platelet counts < 100,000/mm 3 prior to initiation of treatment. In the event of decreased platelet count to Grade ≥ 3 (< 50,000/mm 3 ) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm 3 ) . Closely monitor patients with thrombocytopenia (< 100,000/mm 3 ) and patients on anti-coagulant treatment during treatment with KADCYLA.
Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported
in clinical trials of KADCYLA (26 of 1624 treated patients with Grade ≥ 3; 435 of 1624 treated patients with any Grade). In EMILIA, the overall incidence of peripheral neuropathy was 21% in the KADCYLA-treated group and 14% in the lapatinib plus capecitabine-treated group . The incidence of Grade ≥ 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of peripheral neuropathy was 32% in the KADCYLA-treated group and 17% in the trastuzumab-treated group. Peripheral neuropathy, including sensory and motor peripheral neuropathy, for KADCYLA treated patients 30% of cases were not resolved at the time of the primary IDFS analysis for KATHERINE. The incidence of Grade ≥ 3 peripheral neuropathy was 1.6% in the KADCYLA-treated group and 0.1% in the trastuzumab-treated group.
KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade ≤ 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity .
Extravasation
In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown.
The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.
Drug Interactions with Kadcyla
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.
Pregnancy Safety for Kadcyla
Pregnancy If KADCYLA is administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA or within 7 months following the last dose of KADCYLA, health care providers and patients should immediately report KADCYLA exposure to Genentech at 1-888-835-2555. Risk Summary KADCYLA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KADCYLA in pregnant women. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death were observed in the postmarketing setting in patients treated with trastuzumab, the antibody component of KADCYLA . Based on its mechanism of action, the DM1 component of KADCYLA can also cause embryo-fetal harm when administered to a pregnant woman.
Apprise the patient of the potential risks to a fetus. There are clinical considerations if KADCYLA is used in a pregnant woman, or if a patient becomes pregnant within 7 months following the last dose of KADCYLA. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received KADCYLA 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 KADCYLA in pregnant women.
In the post-marketing setting, cases of oligohydramnios, and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed after treatment with trastuzumab during pregnancy. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped.
In one case, trastuzumab therapy resumed after amniotic index improved, and oligohydramnios recurred. Animal Data There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function.
DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.
Pediatric Use of Kadcyla
Pediatric Use Safety and effectiveness of KADCYLA have not been established in pediatric patients.
Overdosage Information for Kadcyla
There is no known antidote for overdose of KADCYLA. In clinical trials, overdose of KADCYLA has been reported at approximately two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal case, the patient incorrectly received KADCYLA at 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to KADCYLA were not established.
Clinical Studies of Kadcyla
Metastatic Breast Cancer
The efficacy of KADCYLA was evaluated in a randomized, multicenter, open-label trial (EMILIA) (NCT00829166) of 991 patients with HER2-positive, unresectable locally advanced or metastatic breast cancer. Prior taxane and trastuzumab-based therapy was required before trial enrollment. Patients with only prior adjuvant therapy were required to have disease recurrence during or within six months of completing adjuvant therapy.
Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 determined at a central laboratory. Patients were randomly allocated (1:1) to receive lapatinib plus capecitabine or KADCYLA. Randomization was stratified by world region (United States, Western Europe, other), number of prior chemotherapy regimens for unresectable locally advanced or metastatic disease (0–1, > 1) and visceral versus non-visceral disease as determined by the investigators. KADCYLA was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle.
Lapatinib was administered at 1250 mg/day orally once per day of a 21-day cycle and capecitabine was administered at 1000 mg/m 2 orally twice daily on Days 1−14 of a 21-day cycle. Patients were treated with KADCYLA or lapatinib plus capecitabine until progression of disease, withdrawal of consent, or unacceptable toxicity. At the time of the primary analysis, median time on study drug was 5.7 months (range: 0–28.4) for KADCYLA, 4.9 months (range: 0–30.8) for lapatinib, and 4.8 months (range: 0–30.4) for capecitabine.
The co-primary efficacy outcomes of the study were progression-free survival (PFS) based on tumor response assessments by an independent review committee (IRC), and overall survival (OS). PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause (whichever occurred earlier). Overall survival was defined as the time from the date of randomization to the date of death from any cause. Additional outcomes included PFS (based on investigator tumor response assessments), objective response rate (ORR), duration of response and time to symptom progression. Patient demographics and baseline tumor characteristics were balanced between treatment arms.
All patients had metastatic disease at study entry. The median age was approximately 53 years (range 24-84 years), 74% were White, 18% were Asian and 5% were Black. All but 5 patients were women.
Twenty-seven percent of patients were enrolled in United States, 32% in Europe and 16% in Asia. Tumor prognostic characteristics including hormone receptor status (positive: 55%, negative: 43%), presence of visceral disease (68%) and non-visceral disease only (33%) and the number of metastatic sites (< 3: 61%, ≥ 3: 37%) were similar in the study arms. The majority of patients (88%) had received prior systemic treatment in the metastatic setting.
Twelve percent of patients had prior treatment only in the neoadjuvant or adjuvant setting and had disease relapse within 6 months of treatment. All but one patient received trastuzumab prior to study entry; approximately 85% of patients received prior trastuzumab in the metastatic setting. Over 99% percent of patients had received a taxane, and 61% of patients had received an anthracycline prior to study entry.
Overall, patients received a median of 3 systemic agents in the metastatic setting. Among patients with hormone receptor-positive tumors, 44.4% received prior adjuvant hormonal therapy and 44.8% received hormonal therapy for locally advanced/metastatic disease. The randomized trial demonstrated a statistically significant improvement in IRC-assessed PFS in the KADCYLA-treated group compared with the lapatinib plus capecitabine-treated group, and an increase in median PFS of 3.2 months (median PFS of 9.6 months in the KADCYLA-treated group vs. 6.4 months in the lapatinib plus capecitabine group). See Table 7 and Figure 1. The results for investigator-assessed PFS were similar to those observed for IRC-assessed PFS. At the time of PFS analysis, 223 patients had died.
More deaths occurred in the lapatinib plus capecitabine arm (26%) compared with the KADCYLA arm (19%), however the results of this interim OS analysis did not meet the pre-specified stopping boundary for statistical significance. At the time of the second interim OS analysis, 331 events had occurred. The co-primary endpoint of OS was met; OS was significantly improved in patients receiving KADCYLA (HR = 0.68, 95% CI: 0.55, 0.85, p = 0.0006). This result crossed the pre-specified efficacy stopping boundary (HR = 0.73 or p = 0.0037). The median duration of survival was 30.9 months in the KADCYLA arm vs. 25.1 months in the lapatinib plus capecitabine arm.
See Table 7 and Figure 2. A treatment benefit with KADCYLA in terms of PFS and OS was observed in patient subgroups based on stratification factors, key baseline demographic and disease characteristics, and prior treatments. In the subgroup of patients with hormone receptor-negative disease (n=426), the hazard ratios for PFS and OS were 0.56 (95% CI: 0.44, 0.72) and 0.75 (95% CI: 0.54, 1.03), respectively. In the subgroup of patients with hormone receptor-positive disease (n=545), the hazard ratios for PFS and OS were 0.72 (95% CI: 0.58, 0.91) and 0.62 (95% CI: 0.46, 0.85), respectively.
In the subgroup of patients with non-measurable disease (n=205), based on IRC assessments, the hazard ratios for PFS and OS were 0.91 (95% CI: 0.59, 1.42) and 0.96 (95% CI: 0.54, 1.68), respectively; in patients with measurable disease the hazard ratios were 0.62 (95% CI: 0.52, 0.75) and 0.65 (95% CI: 0.51, 0.82), respectively. The PFS and OS hazard ratios in patients who were younger than 65 years old (n=853) were 0.62 (95% CI: 0.52, 0.74) and 0.66 (95% CI: 0.52, 0.83), respectively. In patients ≥ 65 years old (n=138), the hazard ratios for PFS and OS were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively.
Table 7 Summary of Efficacy from EMILIA KADCYLA N=495 Lapatinib+Capecitabine N=496 PFS: progression-free survival; OR: objective response Progression-Free Survival (independent review) Number (%) of patients with event 265 (53.5%) 304 (61.3%) Median duration of PFS (months) 9.6
Hazard Ratio (stratified Stratified by world region (United States, Western Europe, other)
number of prior chemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs. > 1), and visceral vs. non-visceral disease. ) 0.650 95% CI for Hazard Ratio p-value (Log-Rank test, stratified ) < 0.0001 Overall Survival The second interim analysis for OS was conducted when 331 events were observed and the results are presented in this table. Number (%) of patients who died 149 (30.1%) 182 (36.7%) Median duration of survival (months) 30.9
Hazard Ratio (stratified ) 0.682 95% CI for Hazard Ratio p-value (Log-Rank
test ) 0.0006 Objective Response Rate (independent review) Patients with measurable disease 397 389 Number of patients with OR (%) 173 (43.6%) 120 (30.8%) Difference (95% CI) 12.7% Duration of Objective Response (months) Number of patients with OR 173 120 Median duration (95% CI) 12.6
Figure 1 Kaplan-Meier Curve of
IRC-Assessed Progression-Free Survival for EMILIA Figure 2 Kaplan-Meier Curve of Overall Survival for EMILIA Figure 1 Figure 2
Early Breast Cancer
KATHERINE (NCT01772472) was a randomized, multicenter, open-label trial of 1486 patients with HER2-positive, early breast cancer. Patients were required to have had neoadjuvant taxane and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph nodes. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment as per local guidelines.
Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory using Ventana's PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 Dual ISH DNA Probe Cocktail assays. Patients were randomized (1:1) to receive KADCYLA or trastuzumab. Randomization was stratified by clinical stage at presentation, hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plus additional HER2-directed agent), and pathological nodal status evaluation after preoperative therapy.
KADCYLA was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg on Day 1 of a 21-day cycle. Patients were treated with KADCYLA or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of consent, or unacceptable toxicity.
At the time of the major efficacy outcome analysis, median treatment duration was 10 months for both KADCYLA- and trastuzumab-treated patients. Patients who discontinued KADCYLA for reasons other than disease recurrence could complete the remainder of the planned HER2-directed therapy with trastuzumab if appropriate based on toxicity considerations and investigator discretion. The major efficacy outcome of the study was invasive disease-free survival (IDFS). IDFS was defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.
Additional efficacy outcomes included IDFS including second primary non-breast cancer, disease free survival (DFS), and overall survival (OS). Patient demographics and baseline tumor characteristics were generally balanced between treatment arms. The median age was approximately 49 years (range 23-80 years), 73% were White, 9% were Asian, 6% were American Indian or Alaska Native and 3% were Black or African American. Most patients (99.7%) were women.
Enrollment by region was as follows: 23% in North America, 54% in Europe and 23% throughout the rest of the world. Tumor prognostic characteristics including hormone receptor status (positive: 72%, negative: 28%), clinical stage at presentation (inoperable: 25%, operable: 75%) and pathological nodal status after preoperative therapy (node positive: 46%, node negative or not evaluated: 54%) were similar across study arms. The majority of patients (77%) had received an anthracycline-containing neoadjuvant chemotherapy regimen.
Twenty percent of patients received another HER2-targeted agent in addition to trastuzumab as a component of neoadjuvant therapy; 94% of these patients received pertuzumab. A statistically significant improvement in IDFS and OS was observed in patients who received KADCYLA compared with trastuzumab. The efficacy results from KATHERINE are summarized in Table 8, Figure 3, and Figure 4. Table 8 Efficacy Results from KATHERINE KADCYLA N=743 Trastuzumab N=743 HR: Hazard Ratio; CI: Confidence Intervals, Invasive Disease-Free Survival (IDFS) Hierarchical testing applied for IDFS and OS, Data from the pre-specified interim analysis of IDFS (67% of the number of events for the planned final analysis) with the p-value compared with the allocated alpha of 0.012 Number (%) of patients with event 91 (12.2%) 165 (22.2%) HR Unstratified analysis 0.50 p-value (Log-Rank test, unstratified) < 0.0001 3-year event-free rate 3-year event-free rate derived from Kaplan-Meier estimates, % 88.3
Overall Survival (OS), Data from the pre-specified second interim analysis of OS
(82% of the number of events for the planned final analysis) with the p-value compared with the allocated alpha of 0.0263 based on the actual number of OS events at the time of the analysis Number (%) of patients with event 89 (12.0%) 126 (17.0%) HR 0.66 p-value (Log-Rank test, unstratified) 0.0027 IDFS including second primary non-breast cancer Number (%) of patients with event 95 (12.8%) 167 (22.5%) HR 0.51 3-year event-free rate, % 87.7
Disease-Free Survival (DFS) Number (%) of patients with event 98 (13.2%) 167
(22.5%) HR 0.53 3-year event-free rate, % 87.4
Figure 3 Kaplan-Meier Curve of Invasive Disease-Free Survival in
KATHERINE Figure 4 Kaplan-Meier Curve of Overall Survival in KATHERINE Figure 3 Figure 4
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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