Kadcyla (ado-trastuzumab emtansine)

Metastatic Breast Cancer (MBC)

Kadcyla (ado-trastuzumab emtansine), 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-approved companion diagnostic 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-approved companion diagnostic for Kadcyla.

Hepatotoxicity

• Inform patients of the possibility of severe liver injury and advise patients to immediately seek medical attention if they experience symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus, anorexia, etc..

Left Ventricular Dysfunction

• Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness.

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 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]. 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 Trial1

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)

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 Trial¹

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)

Immunogenicity

As with all therapeutic proteins, there is the potential for an immune response to Kadcyla. A total of 1243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to Kadcyla. Following Kadcyla dosing, 5.1% (63/1243) of patients tested positive for anti-Kadcyla antibodies at one or more post-dose time points. In clinical studies, 6.4% (24/376) of patients tested positive for anti-Kadcyla antibodies. In Emilia, 5.2% (24/466) of patients tested positive for anti-Kadcyla antibodies, of which 13 were also positive for neutralizing antibodies. In Katherine, 3.7% (15/401) of patients tested positive for anti-Kadcyla antibodies, of which 5 were also positive for neutralizing antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact of anti-Kadcyla antibodies on the pharmacokinetics, safety, and efficacy of Kadcyla. The presence of Kadcyla in patient serum at the time of ADA sampling may interfere with the ability of this assay to detect anti-Kadcyla antibodies. As a result, data may not accurately reflect the true incidence of anti-Kadcyla antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to Kadcyla with the incidence of antibodies to other products may be misleading. Clinical significance of anti-Kadcyla antibodies is not yet known.

Patient Selection

Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens. Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-approved tests specific for breast cancers by laboratories with demonstrated proficiency. Information on the FDA-approved 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.

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 (21day 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.
• 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.
• 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.

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.
• 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.

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential that Kadcyla exposure during pregnancy or within 7 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
• Advise women who are exposed to Kadcyla during pregnancy or who become pregnant within 7 months following the last dose of Kadcyla that there is a pregnancy pharmacovigilance program that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Genentech.
• Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Kadcyla.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of Kadcyla.

Lactation

• Advise women not to breastfeed during treatment and for 7 months after the last dose of Kadcyla.