Patients and Caregivers

KADCYLA efficacy data

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Overall survival in EMILIA
Progression-free survival in EMILIA
Overall response rate in EMILIA

After reviewing the EMILIA data, explore the supportive data that’s available at the end of this page

EMILIA trial overview1

  • Randomized, open-label trial of 991 patients with locally advanced or metastatic HER2-positive (HER2+) breast cancer
  • Designed to assess efficacy and safety of KADCYLA vs lapatinib + capecitabine
  • All treatments administered in 3-week cycles
Checklist

Learn more about how the EMILIA trial was designed.

View trial design

Primary analysis: KADCYLA provided proven benefit in OS and PFS

It extended median overall survival (OS) by nearly 6 months1

  • 30.9 months median OS with KADCYLA vs 25.1 months with lapatinib + capecitabine

CO-PRIMARY ENDPOINT: OS1

EMILIA overall survival (OS) results

Image description

More time without disease progression

  • 9.6 months median PFS with KADCYLA vs 6.4 months with lapatinib + capecitabine1

CO-PRIMARY ENDPOINT: PFS BY INDEPENDENT REVIEW COMMITTEE*1

EMILIA PFS results: HR=0.650; 95% CI: 0.549-0.771; P<0.0001

Image description

*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).

KADCYLA demonstrated prolonged survival benefit across select subgroups vs lapatinib + capecitabine1

Regardless of hormone receptor status, KADCYLA provided survival benefit over lapatinib + capecitabine1

  • Patients with hormone receptor-positive tumors who took KADCYLA had a 28% reduction in the risk of progression or death and a 38% reduction in the risk of death (n=545; HR for PFS=0.72; 95% CI: 0.58, 0.91; HR for OS=0.62; 95% CI: 0.46, 0.85)

PFS AND OS FOR SELECT PATIENT SUBGROUPS/HORMONE RECEPTOR STATUS1


Category

n

PFS by Independent Review

OS

HR estimate

95% CI

HR estimate

95% CI

All patients 

991

0.65

0.55-0.77

0.68

0.55-0.85

P<0.0001

P=0.0006

Hormone receptor status

Positive (ER+ and/or PR+)

545

0.72

0.58-0.91

0.62

0.46-0.85

Negative (ER- and PR-)

426

0.56

0.44-0.72

0.75

0.54-1.03

CI=confidence interval; ER=estrogen receptor; HR=hazard ratio; PR=progesterone receptor.

Tumor response with KADCYLA surpassed lapatinib + capecitabine

Shown to shrink tumors in more patients1,3

  • Patients treated with KADCYLA had a higher partial response (42.6% vs 30.3%) than lapatinib + capecitabine; complete response was 1% and 0.5%, respectively3

SECONDARY ENDPOINT: ORR*1,3

EMILIA secondary endpoint: Objective response rate (ORR)

Image description

*ORR defined as the proportion of patients who achieved a complete response (disappearance of all target tumors) or a partial response (≥30% decrease in the sum of the longest diameters of target tumors) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.3

Nearly doubled the median duration of response (DoR)1

  • 6.1 months improvement in median DoR was demonstrated with KADCYLA1

SECONDARY ENDPOINT: DoR1

EMILIA secondary endpoint: Duration of response (DoR)

Image description

†DoR defined as the time from initial documented tumor response (complete or partial) until documented disease progression. Only patients who achieved an initial response were evaluated for DoR.10

A retrospective exploratory analysis of patients with central nervous system (CNS) metastases at baseline

  • Of the 991 patients enrolled in EMILIA, 45/495 in the KADCYLA arm and 50/496 in the lapatinib + capecitabine arm had previously treated and stable CNS metastases at baseline11
  • Stable CNS metastases were defined in EMILIA as asymptomatic and previously treated with radiotherapy. Patients with stable CNS metastases were eligible to enroll 14 days after their last radiotherapy treatment11
  • Patients with CNS metastases that were untreated, were symptomatic, or required therapy to control symptoms ≤2 months before randomization were excluded, as were patients with CNS-only disease11

Limitations of the analysis:

  • This exploratory analysis was not powered to detect differences between subgroups; therefore, the results are descriptive. Caution should be exercised when interpreting the results11
  • The sample size for this analysis is limited (n=95)11
  • Patients in the KADCYLA arm were more likely than patients in the lapatinib + capecitabine arm to have received brain and non-brain radiation, chemotherapy, HER2-targeted therapy, or other therapy after discontinuation of study treatment11
  • Baseline characteristics were similar between arms, except there was a higher proportion of Asian patients (both race and region) in the KADCYLA arm (33% vs 16%), and differences in the types of prior radiation therapy for CNS metastases in each arm11

OS IN PATIENTS WITH CNS METASTASES AT BASELINE11

26.8 months median overall survival (OS) with KADCYLA vs 12.9 months with lapatinib + capecitabine

Image description

Overall survival (OS) forest plot in patients with central nervous system (CNS) metastases at baseline in EMILIA

This analysis was based on a data cutoff of July 2012. There were 22 patients (14 in the lapatinib + capecitabine group and 8 in the KADCYLA group) whose CNS metastases were unknown.10,11

PFS (BY IRC) IN PATIENTS WITH CNS METASTASES AT BASELINE11

5.9 months median progression-free survival (PFS) by independent review committee (IRC) with KADCYLA vs 5.7 months with lapatinib + capecitabine

Image description

Progression-free survival (PFS) by independent review committee (IRC) forest plot in patients with central nervous system (CNS) metastases at baseline in EMILIA

This analysis was based on a data cutoff of January 2012. There were 22 patients (14 in the lapatinib + capecitabine group and 8 in the KADCYLA group) whose CNS metastases were unknown.10

Side effects

View safety data from the retrospective exploratory analysis of patients with CNS metastases at baseline.

Look at the data

TH3RESA trial overview8

  • Open-label, randomized, Phase III trial in patients with HER2+ MBC who received at least 2 prior regimens of HER2-directed therapy in the advanced setting8
  • Study compared KADCYLA to treatment of physician’s choice (TPC)8
Checklist

Learn more about how the TH3RESA trial was designed.

View trial design

Limitations of the analysis and other considerations:

  • Crossover from TPC to KADCYLA was permitted during the study and might have affected outcomes8
  • Median duration of treatment before crossover was 5.22 months for the KADCYLA arm and 2.79 months for the TPC arm; the median duration of KADCYLA treatment in patients who crossed over was 4.5 months8
  • The TPC arm included some patients who received single-agent chemotherapy (n=31) or a treatment regimen that did not include trastuzumab (n=49)8
  • The study did not assess clinical outcomes in patients who had previously received pertuzumab8

PRIMARY ANALYSIS: MEDIAN PFS (BY INVESTIGATOR) IN ITT POPULATION9

TH3RESA progression-free survival (PFS) by investigator results

Image description

  • Median follow-up was 7.2 months in the KADCYLA arm and 6.5 months in the TPC arm
  • At data cutoff, 44 (22%) of 198 patients in the TPC arm crossed over to the KADCYLA arm

FINAL ANALYSIS: MEDIAN OS IN ITT POPULATION8

TH3RESA overall survival (OS) results

Image description

  • Median follow-up was 30.5 months at data cutoff
  • At data cutoff, 93 (47%) of 198 patients in the TPC arm crossed over to the KADCYLA arm
Next: KADCYLA side effects
Tab 1 Tab 2
Checklist

How KADCYLA was studied

View trial design

    • KADCYLA Prescribing Information. Genentech, Inc. 2022.

      KADCYLA Prescribing Information. Genentech, Inc. 2022.

    • Roche.com. FDA approves Roche's Kadcyla (trastuzumab emtansine), the first antibody-drug conjugate for treating HER2-positive metastatic breast cancer.

      Roche.com. FDA approves Roche's Kadcyla (trastuzumab emtansine), the first antibody-drug conjugate for treating HER2-positive metastatic breast cancer.

    • Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791 and Supplementary Appendix.

      Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791 and Supplementary Appendix.

    • Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356.

      Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356.

    • Staudecher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017;117(12):1736-1742.

      Staudecher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017;117(12):1736-1742.

    • Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-9290.

      Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-9290.

    • Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett. 2006; 232:123-138.

      Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett. 2006; 232:123-138.

    • Krop IE, Kim S-B, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754.

      Krop IE, Kim S-B, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754.

    • Krop IE, Kim S-B, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(6):689-699 and Supplementary Appendix.

      Krop IE, Kim S-B, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(6):689-699 and Supplementary Appendix.

    • Data on file. Genentech, Inc.

      Data on file. Genentech, Inc.

    • Krop IE, Lin NU, Blackwell K, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol. 2015;26(2):113-119.

      Krop IE, Lin NU, Blackwell K, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol. 2015;26(2):113-119.

    • Center for Drug Evaluation and Research. Clinical review—BLA 125427: Kadcyla (ado-trastuzumab emtansine) for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125427Orig1s000MedR.pdf. Completed: January 25, 2013. Accessed September 7, 2021.

      Center for Drug Evaluation and Research. Clinical review—BLA 125427: Kadcyla (ado-trastuzumab emtansine) for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125427Orig1s000MedR.pdf. Completed: January 25, 2013. Accessed September 7, 2021.

    Indications/Important Safety Information

    Indications

    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.

    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-approved companion diagnostic for KADCYLA.

    Important Safety Information

    BOXED WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

    • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin
    • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function
    • Embryo-Fetal Toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception

    Warnings and Precautions

    Hepatotoxicity

    Hepatotoxicity, predominantly in the form of asymptomatic 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. The two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy occurred in MBC clinical trials with KADCYLA. 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 EMILIA (for patients with metastatic breast cancer [MBC]) and KATHERINE (for patients with early breast cancer [EBC]) studies. Reduce 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.

    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, 1 of which was fatal). Two of these five cases of NRH were observed in EMILIA and two were observed in KATHERINE. Diagnosis 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 scan of the liver but with normal transaminases and no manifestations of cirrhosis. Upon NRH diagnosis, 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 group and 3.3% of patients in the lapatinib + capecitabine group. In KATHERINE, left ventricular dysfunction occurred in 0.4% of patients in the KADCYLA group and 0.6% of patients in the trastuzumab group.

    Based on limited data from a retrospective observational study, 22% (7 of 32) of patients with HER2-positive MBC with a baseline LVEF of 40-49% treated with KADCYLA developed congestive heart failure (CHF) or a >10% reduction in LVEF.

    Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every 3 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% 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% 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.

    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. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with KADCYLA and for 4 months following the last dose.

    If KADCYLA is administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA or within 7 months of the last dose of KADCYLA, immediately report exposure to Genentech at 1-888-835-2555.

    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 and comorbidities 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 (IRR) 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 IRR in patients treated with KADCYLA was 1.4%. In KATHERINE, the overall incidence of IRR 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 and permanently discontinued in the event of a life-threatening IRR. Patients should be observed closely for IRR, 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 group and 16% in the lapatinib + capecitabine group. The incidence of Grade ≥ 3 hemorrhage was 1.8% in the KADCYLA group and 0.8% in the lapatinib + capecitabine group. In KATHERINE, the overall incidence of hemorrhage was 29% in the KADCYLA group and 10% in the trastuzumab group. The incidence of Grade ≥ 3 hemorrhage was 0.4% in the KADCYLA group, with one fatal case of intracranial hemorrhage, and 0.3% in the trastuzumab group.

    Although in some of the observed cases, the patients were also receiving anticoagulation therapy or 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 was reported in clinical trials of KADCYLA. The majority of these patients had Grade 1 or 2 events (< LLN to ≥50,000/mm3) with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥75,000/mm3) 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 group and 3.3% in the lapatinib + capecitabine group. The incidence of Grade ≥ 3 thrombocytopenia was 15% in the KADCYLA group and 0.4% in the lapatinib + capecitabine group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 45% and 1.3%, respectively.

    In KATHERINE, the overall incidence of thrombocytopenia was 29% in the KADCYLA group and 2.4% in the trastuzumab group. The incidence of Grade ≥ 3 thrombocytopenia was 6% in the KADCYLA group and 0.3% in the trastuzumab group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 19% and 0%, respectively. The overall incidence of thrombocytopenia in the KADCYLA 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/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade ≥ 3 (<50,000/mm3), do not administer KADCYLA until platelet counts recover to Grade 1 (≥75,000/mm3). Closely monitor patients with thrombocytopenia (< 100,000/mm3) 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. In EMILIA, the overall incidence of peripheral neuropathy was 21% in the KADCYLA group and 14% in the lapatinib + capecitabine group. The incidence of Grade ≥ 3 peripheral neuropathy was 2.2% and 0.2%, respectively.

    In KATHERINE, the overall incidence of peripheral neuropathy was 32% in the KADCYLA group and 17% in the trastuzumab group. Peripheral neuropathy, including sensory and motor peripheral neuropathy, was not resolved in 30% of cases for KADCYLA treated patients at the time of the primary IDFS analysis for KATHERINE. The incidence of Grade ≥ 3 peripheral neuropathy was 1.6% in the KADCYLA group and 0.1% in the trastuzumab group.

    KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade ≤ 2. Monitor patients on an ongoing basis for signs/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. Closely monitor the infusion site for possible subcutaneous infiltration during drug administration.

    Adverse Reactions

    Early Breast Cancer

    The most common adverse reactions seen with KADCYLA in the KATHERINE 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 (frequency >2%) were thrombocytopenia and hypertension.

    Metastatic Breast Cancer

    The most common adverse reactions (≥25%) with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. In EMILIA, the most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue.

    Use in Specific Populations

    Lactation

    There is no information regarding the presence of ado-trastuzumab emtansine in human milk, the effects on the breastfed infant, or the effects on milk production. DM1, the cytotoxic component of KADCYLA, may cause serious adverse reactions in breastfed infants based on its mechanism of action. Advise women not to breastfeed during treatment and for 7 months following the last dose of KADCYLA.

    You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

    Please see full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.

    • This image shows the components of KADCYLA:

      Trastuzumab–monoclonal antibody4

      • Selectively binds to HER2

      MCC–stable linker4,6

      • Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

      DM1–cytotoxic agent4,7

      • Approximately 20 to 200 times more potent than taxanes and vinca alkaloids
      • Provides cytotoxicity previously unavailable for clinical use

    • Overview
      This image shows the trial design of KATHERINE.

      Data
      KATHERINE was a randomized, multicenter, open-label trial of 1,486 patients with HER2+ early breast cancer. Patients were required to have had residual invasive disease in the breast and/or axillary lymph nodes following neoadjuvant treatment with taxane + trastuzumab-based therapy. Patients were randomized to 3.6 mg/kg of KADCYLA or 6 mg/kg of Herceptin® (trastuzumab), with 743 patients in each arm.

    • Overview
      This image shows a Kaplan-Meier curve of invasive disease-free survival (iDFS) in KATHERINE.

      Data
      Invasive disease-free survival, the primary end point, was significantly higher among patients who received KADCYLA than among those who received trastuzumab (hazard ratio, 0.54, 95% confidence interval [CI], 0.44-0.66; P<0.0001). 7-year iDFS was 80.8% in the KADCYLA group, compared to 67.1% in the trastuzumab group, representing a 46% reduction in the risk of recurrence

    • Overview
      This image shows where KADCYLA fits in the HER2+ early breast cancer treatment plan and how many cycles of it to give.

      Details
      Following 3-6 cycles of neoadjuvant taxane + trastuzumab-based treatment, and surgery, give KADCYLA for 14 cycles, or until disease recurrence or unmanageable toxicity occurs.

    • Overview
      This image shows the infusion schedule for KADCYLA in early breast cancer.

      Details
      The initial infusion of KADCYLA in EBC takes 90 minutes plus an observation time of at least 90 minutes to monitor for infusion-related reactions. If prior infusions were well tolerated, subsequent infusions take 30 minutes plus an observation time of at least 30 minutes.

      Treat for a total of 14 cycles (every 3 weeks) unless there is disease recurrence or unmanageable toxicity.

    • Overview
      This image shows the dose reduction schedule for adverse reactions to KADCYLA.

      Details
      The starting dose for KADCYLA is 3.6 mg/kg. The first dose reduction for KADCYLA is 3 mg/kg. The second dose reduction for KADCYLA is 2.4 mg/kg. After that, discontinue KADCYLA.

    • Overview
      This image shows a Kaplan-Meier curve of overall survival (OS) in KATHERINE.

      Data
      Overall survival, the second interim endpoint, was significantly higher among patients who received KADCYLA than among those who received trastuzumab (hazard ratio, 0.66 (95% CI: 0.51-0.87; P=0.0027). 7-year OS was 89.1% in the KADCYLA group, compared to 84.4% in the trastuzumab group, representing a 34% reduction in the risk of death.

    • This image shows subgroup analysis of invasive disease-free survival, presented as a forest plot.

    • This image shows the 3-year subgroup analysis of invasive disease-free survival, presented as a forest plot.

    • This image shows the 7-year subgroup analysis of invasive disease-free survival, presented as a forest plot.

    • This image shows the components of KADCYLA:

      Trastuzumab-monoclonal antibody1

      • Selectively binds to HER2

      MCC-stable linker1,3

      • Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

      DM1 cytotoxic agent1,4

      • Approximately 20 to 200 times more potent than taxanes and vinca alkaloids
      • Provides cytotoxicity previously unavailable for clinical use

    • Overview
      This image shows the trial design of EMILIA.

      Details
      EMILIA was a randomized, open-label, international trial involving 991 patients with HER2+, unresectable, locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane (separately or in combination). Inclusion criteria included progression during or after the most recent treatment for locally advanced or metastatic disease or within 6 months after treatment for early-stage disease. Four hundred ninety-five patients were randomized to 21-day cycles of 3.6 mg/kg IV of KADCYLA on day 1. Four hundred ninety-six patients were randomized to 1,250 mg of lapatinib by mouth once daily, and 1,000 mg/m² of capecitabine by mouth twice daily on days 1-14. Treatment continued until disease progression or unacceptable toxicity.

    • Overview
      This image shows the trial design of TH3RESA.

      Details
      TH3RESA was a phase 3, randomized, multicenter, open-label trial of 602 patients with HER2+ advanced breast cancer (ABC). Patients were required to have had disease progression after treatment with ≥2 prior HER2-directed therapies for ABC and prior treatment with trastuzumab, lapatinib, and a taxane. Patients were randomized to 3.6 mg/kg IV of KADCYLA or treatment of physician’s choice (TPC)* per local practice, with 404 patients in the KADCYLA arm and 198 patients in the TPC arm. Patients in the TPC arm who had disease progression had the option to cross over to the KADCYLA arm, and 93 patients did so.

    • Overview
      This image shows overall survival (OS) results for EMILIA.

      Data
      KADCYLA significantly increased median OS (30.9 months, vs 25.1 months with lapatinib + capecitabine—a nearly 6-month improvement in median OS; hazard ratio for death from any cause, 0.68; 95% confidence interval, 0.55 to 0.85; P=0.0006).

    • Overview
      This image shows progression-free survival (PFS) results for EMILIA.

      Data
      Treatment with KADCYLA significantly improved PFS as assessed by independent review (median survival, 9.6 months, vs 6.4 months with lapatinib + capecitabine—a 50% improvement in median PFS; stratified hazard ratio for progression or death from any cause, 0.65; 95% confidence interval, 0.55 to 0.77; P<0.0001).

    • Overview
      This image shows objective response rate (ORR) results for EMILIA.

      Data
      Patients treated with KADCYLA had a higher ORR (43.6%, vs 30.8% with lapatinib + capecitabine—a 12.7% improvement in ORR; 95% confidence interval, 6.0-19.4%).

    • Overview
      This image shows duration of response (DoR) results for EMILIA.

      Data
      Treatment with KADCYLA significantly improved DoR (median DoR, 12.6 months, vs 6.5 months with lapatinib + capecitabine—nearly doubling DoR; 95% confidence interval, 8.4-20.8).

    • Overview
      This image shows overall survival (OS) in patients with central nervous system (CNS) metastases at baseline in EMILIA.

      Data
      The estimated median OS was 26.8 months with KADCYLA vs 12.9 months with lapatinib + capecitabine.

    • Overview
      This image shows progression-free survival (PFS) by independent review committee (IRC) in patients with central nervous system (CNS) metastases at baseline in EMILIA.

      Data
      The estimated median PFS was 5.9 months with KADCYLA vs 5.7 months with lapatinib + capecitabine.

    • Overview
      This image shows progression-free survival (PFS) by investigator results for TH3RESA.

      Data
      Median PFS with KADCYLA was 6.2 months, vs 3.3 months with treatment of physician’s choice (TPC). Stratified HR=0.528; 95% confidence interval, 0.422 to 0.661; P<0.0001.

    • Overview
      This image shows overall survival (OS) results for TH3RESA in the ITT population.

      Data
      Median OS with KADCYLA was 22.7 months, vs 15.8 months with treatment of physician’s choice (TPC). Stratified HR=0.68; 95% confidence interval, 0.54 to 0.85; P=0.0007.

    • Overview
      This image shows the most common severe (Grade ≥3) adverse reactions in EMILIA.

      Data
      Numerical values presented on the image:

      Grade ≥3 nausea seen in 0.8% of KADCYLA patients, compared to 2.5% of lapatinib + capecitabine patients

      Grade ≥3 fatigue seen in 2.5% of KADCYLA patients, compared to 3.5% of lapatinib + capecitabine patients

      Grade ≥3 thrombocytopenia seen in 15% of KADCYLA patients, compared to 0.4% of lapatinib + capecitabine patients

      Grade ≥3 increased transaminases seen in 8.0% of KADCYLA patients, compared to 2.5% of lapatinib + capecitabine patients

      Grade ≥3 diarrhea seen in 1.6% of KADCYLA patients, compared to 21% of lapatinib + capecitabine patients

      Grade ≥3 peripheral neuropathy seen in 2.2% of KADCYLA patients, compared to 0.2% of lapatinib + capecitabine patients

      Grade ≥3 vomiting seen in 0.8% of KADCYLA patients, compared to 4.5% of lapatinib + capecitabine patients

      Grade ≥3 anemia seen in 4.1% of KADCYLA patients, compared to 2.5% of lapatinib + capecitabine patients

      Grade ≥3 stomatitis seen in 0.2% of KADCYLA patients, compared to 2.5% of lapatinib + capecitabine patients

      Grade ≥3 hypokalemia seen in 2.7% of KADCYLA patients, compared to 4.7% of lapatinib + capecitabine patients

      Grade ≥3 neutropenia seen in 2.0% of KADCYLA patients, compared to 4.3% of lapatinib + capecitabine patients

    • This image shows recommended dosing for KADCYLA: 3.6 mg/kg every 3 weeks.

    • Overview
      This image shows the infusion schedule for KADCYLA in metastatic breast cancer.

      Details
      The initial infusion of KADCYLA in EBC takes 90 minutes plus an observation time of at least 90 minutes to monitor for infusion-related reactions. If prior infusions were well tolerated, subsequent infusions take 30 minutes plus an observation time of at least 30 minutes.

      Treat until disease progression or unmanageable toxicity.

    • Overview
      This image shows the dose reduction schedule for adverse reactions to KADCYLA.

      Details
      The starting dose for KADCYLA is 3.6 mg/kg. The first dose reduction for KADCYLA is 3 mg/kg. The second dose reduction for KADCYLA is 2.4 mg/kg. After that, discontinue KADCYLA.