Clinical UM Guideline

Subject: Ado-trastuzumab emtansine (Kadcyla®)
Guideline #: CG-DRUG-96 Publish Date:    06/28/2018
Status: New Last Review Date:    05/03/2018


This document addresses ado-trastuzumab emtansine (Kadcyla, Genentech, South San Francisco, CA), an antibody-drug conjugate (ADC) that targets the human epidermal growth factor receptor 2 protein (HER2).

Note: For additional information, please refer to the following related document:

Clinical Indications

Medically Necessary:

Ado-trastuzumab emtansine is considered medically necessary as a single agent therapy for individuals with metastatic breast cancer who meet all of the criteria (A-D) below:

  1. Individuals have previously received trastuzumab and a taxane, separately or in combination; AND
  2. Individuals have either:
    1. Received prior therapy for metastatic disease; or
    2. Developed disease recurrence during or within 6 months of completing adjuvant therapy; AND
  3. Individuals whose breast tumors are HER2 positive as documented by one of the following:
    1. Immunohistochemistry (IHC) is 3+; or
    2. In situ hybridization (ISH) positive by any of the following:
      1. Single probe average HER2 copy number greater than or equal to 6.0 signals/cell; or
      2. Dual-probe HER2/CEP 17 ratio greater than or equal to 2.0; or
      3. Dual-probe HER2/CEP17 ratio less than 2.0 with an average HER2 copy number greater than or equal to 6.0 signals/cell; AND
  4. Only used in a single line of therapy.

Not Medically Necessary:

Ado-trastuzumab emtansine is considered not medically necessary for individuals who do not meet the criteria listed above.

Use of ado-trastuzumab emtansine in combination with other targeted biologic agents or chemotherapy agents is considered not medically necessary.


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




Injection, ado-trastuzumab emtansine, 1 mg [Kadcyla]



ICD-10 Diagnosis



Malignant neoplasm of breast


Secondary malignant neoplasm of breast


Encounter for antineoplastic chemotherapy


Personal history of malignant neoplasm of breast

Discussion/General Information

Breast cancer is a type of tumor comprised of malignant (cancerous) cells that start to grow in the breast and may spread (metastasize) to surrounding tissues and other areas of the body (American Cancer Society, 2016).  Breast cancer is commonly treated by various modalities which include combinations of surgery, radiation therapy, chemotherapy and hormone therapy (National Cancer Institute, 2017).  The prognosis and selection of therapies can be affected by clinical and pathologic features of the tumor.  One of these includes the human epidermal growth factor receptor 2 gene ERBB2 which is commonly referred to as HER2.  Other names for this gene include NEU, Her-2, HER-2/neu and c-erb B2.  Initially the HER2 gene was detected in frozen breast tumor samples.  Amplification of the HER2 gene was later correlated to overexpression of protein levels in samples of breast cancer.  The HER2 overexpression is present in approximately 18%-25% of all early breast cancers and is associated with aggressive disease, shortened disease-free survival (DFS) and overall survival (OS) (Wolff, 2007).

Ado-trastuzumab emtansine is an ADC consisting of trastuzumab attached by a stable linker to an extremely potent microtubule-directed chemotherapy, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-L-alanine ester of maytansinol) which is a derivative of maytansine (Barginear, 2012; Product Information Label, 2016; Verma, 2012).  Maytansinoids bind tubulin competitively with vinca alkaloids and are approximately 100 times more potent than vincristine (Barginear, 2012).  Ado-trastuzumab emtansine utilizes the HER2-targeting properties of trastuzumab to selectively deliver chemotherapy to HER2-overexpressing tumor cells.  This targeted approach minimizes toxicity by limiting exposure of DM1 to normal cells.

Ado-trastuzumab emtansine was granted priority review status by the U.S. Food & Drug Administration (FDA) in November 2012, which reduced the standard 10-month review period to 6 months.  The FDA approved the biologics license application for ado-trastuzumab emtansine on February 22, 2013.  The FDA-approved indication was single-agent treatment for individuals with HER2-positive (HER2+), metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.  Individuals should have either: (1) received prior therapy for metastatic disease; or (2) developed disease recurrence during or within 6 months of completing adjuvant therapy.  Therapy was indicated until disease progression or unacceptable drug toxicity (Product Information Label, 2016).

In clinical trials, ado-trastuzumab emtansine was called trastuzumab emtansine (T-DM1).  The pivotal EMILIA study was a phase III randomized, multicenter international trial that enrolled individuals with HER2-positive, unresectable, locally advanced or metastatic breast cancer that were previously treated with trastuzumab and a taxane.  Participants were randomized to T-DM1 (3.6 mg/kg intravenously every 21 days) or to the control group that received oral lapatinib (1250 mg daily) and capecitabine (1000 mg/m2 of body surface area every 12 hours) for the first 14 days of each 21-day treatment cycle.  A total of 991 individuals were enrolled between February 2009 and October 2011, with 496 participants assigned to the control group and 495 participants randomized to T-DM1.  The primary endpoints of the study were progression-free survival (PFS), overall survival (OS) and safety.  PFS was significantly improved with T-DM1 with a median survival of 9.6 months compared to 6.4 months with lapatinib and capecitabine.  The hazard ratio for progression or death from any cause was 0.65 with 95% confidence interval (CI), 0.55 to 0.77; p<0.001.  Upon the second interim analysis, T-DM1 had significantly increased median OS (30.9 months vs. 25.1 months in the control group).  The hazard ratio for death from any cause was 0.68 (95% CI, 0.55 to 0.85; p<0.001).  The estimated 1-year survival rate for T-DM1 was 85.2% versus 78.4% for the lapatinib-capecitabine group.  The 2-year survival rate was 64.7% (95% CI, 59.3 to 70.2) for T-DM1 and 51.8% (95% CI, 45.9 to 57.7) in the control group.  Serious adverse events (AE) were reported in 76 participants (15.5%) in the T-DM1 cohort with the most commonly reported grade 3 or 4 AEs of thrombocytopenia (12.9%) and elevated serum concentrations of aspartate aminotransferase (4.3%) and alanine aminotransferase (2.9%).  In the lapatinib-capecitabine group, serious AEs were reported for 88 participants (18.0%) with the most commonly reported grade 3 or 4 AEs diarrhea (20.7%) and palmar-plantar erythrodysesthesia (1.4%).  Overall, the incidence of grade 3 or 4 adverse events was higher in the lapatinib-capecitabine control group (57%) compared with the T-DM1 group (40.8%).  The overall incidence of bleeding events was higher with T-DM1 (29.8%) versus lapatinib-capecitabine (15.8%); however, both groups had low rates of grade 3 or 4 bleeding events (1.4% and 0.8%, respectively).  Left ventricular ejection fraction (LVEF) of 45% or greater was maintained in 97.1% of T-DM1 participants and 93% of lapatinib-capecitabine participants.  LVEF less than 50% and at least 15% below baseline values occurred in 8 (1.7%) participants in the T-DM1 group and 7 (1.6%) participants in the control group.  One case of grade 3 left ventricular systolic dysfunction occurred in the T-DM1 cohort and there was none in the control cohort.  The investigators noted the improved PFS and OS in individuals treated with T-DM1 were observed regardless of the line of therapy for metastatic disease (Verma, 2012).

A phase II, single-arm, open-label study TDM4258g was titled “A study of trastuzumab-MCC-DM1 administered intravenously to patients with HER2-positive metastatic breast cancer who have progressed while receiving HER2-directed therapy.”  Primary endpoints were objective response rate (ORR) by independent radiologic facility (IRF) review, safety and tolerability.  A total of 112 individuals with HER2+ breast cancer were enrolled and were treated with T-DM1 3.6 mg/kg intravenously every 3 weeks for up to 1 year, with an option of continued therapy on an extension study.  Participants were treated with a median of 7 doses (range 1-17 doses) of T-DM1 with a median duration of exposure of 4.2 months.  One year of study treatment was completed by 21 participants with 19 continuing therapy on the extension study.  By IRF, 29 participants had an objective partial tumor response for an ORR of 25.9%.  The investigator assessment noted 42 (37%) ORR, which included 4 (3.6%) complete responses.  Between the investigator assessments and the IRF assessments, there was 82% agreement.  In a post-hoc exploratory analysis, 75 participants had previously reported discontinuing trastuzumab-containing therapy as a result of progressive disease.  Twenty-one of these participants achieved objective responses for an ORR of 28.0% (95% CI, 18.2% to 38.9%).  Exploratory HER2 testing analysis was performed on 95 evaluable participants with archival primary tumor samples available for central laboratory HER2 testing.  A total of 74 participants were confirmed to have HER2+ tumors with an ORR by IRF assessment of 33.8% (95% CI, 23.2% to 44.9%).  HER2-normal tumors were confirmed in 21 participants who had an ORR of 4.8% (95% CI, <1.0% to 21.8%).  Fatigue, nausea and headache were the most common AEs of any grade.  Hypokalemia, thrombocytopenia and fatigue were the most frequent grade 3 or 4 AEs.  There were 3 deaths within 30 days of treatment with T-DM1, with disease progression noted in 2 participants and clinical deterioration of metastatic disease reported in the third participant.  LVEF declined to 40%-45% in 2 participants, and there were no grade 3 LVEF decline or symptomatic congestive heart failure reported.  The authors concluded ORR by IRF and investigator assessments were noted in participants treated with T-DM1.  Additionally, the post-hoc exploratory analysis suggested T-DM1 is active after progressive disease on prior HER2-directed therapies (Burris, 2011).

Efficacy and updated safety data from the TDM4450g trial titled “A study of the efficacy and safety of trastuzumab-MCC-DM1 vs. trastuzumab [Herceptin] and docetaxel [Taxotere] in patients with metastatic HER2-positive breast cancer who have not received prior chemotherapy for metastatic diseasewere reported by Hurvitz and colleagues (2013).  The phase II open-label trial randomized 70 participants to trastuzumab plus docetaxel (HT) and assigned 67 participants to T-DM1 as first-line treatment of HER2-positive metastatic breast cancer until disease progression or unacceptable toxicity.  Primary endpoints were PFS and safety.  With the primary efficacy analysis, T-DM1 had an improved, but not statistically significant median PFS of 14.2 months compared to 9.2 months in the HT arm (HR 0.59; 95% CI, 0.36 to 0.97; p=0.035).  There were fewer grade 3 or greater AEs in the T-DM1 group compared to the HT group (46.4% vs. 90.9%).  There were also less grade 4 AEs with T-DM1 (5.8%) versus 57.6% in the HT group.  There were no reports of symptomatic congestive heart failure.  The authors concluded based on the limitations of the study, and immature OS data, the data should be considered hypothesis generating and would need to be validated with a phase III randomized study.

The National Comprehensive Cancer Network® (NCCN®) guidelines for breast cancer (2018) recommend ado-trastuzumab emtansine as a “preferred option for treatment of patients with HER2-positive metastatic breast cancer who have previously received a trastuzumab-based regimen.”  The guidelines do not recommend the use of ado-trastuzumab emtansine in the neoadjuvant setting.

The American Society of Clinical Oncology (ASCO) Clinical Practice Guideline for systemic therapy for treatment of advanced HER2+ breast cancer (Giordano, 2014) includes a strong recommendation for ado-trastuzumab emtansine to treat advanced metastatic breast cancer as: second-line therapy; or if disease has progressed during or after second-line or greater HER2-targeted therapy and the individual as not previously received ado-trastuzumab emtansine.  For individuals that have progressive disease and had already been treated with pertuzumab and ado-trastuzumab emtansine, the guidelines include a recommendation for third-line or greater HER2-targeted therapy-based treatment (i.e., trastuzumab, lapatinib in combination with trastuzumab) or hormonal therapy (for individuals with estrogen receptor-positive or progesterone receptor-positive disease).

HER2 overexpression

One of the inclusion criteria in the pivotal breast cancer EMILIA clinical trial was HER2+ status by detecting HER2 protein overexpression or gene amplification.  HER2+ was determined by a score of 3+ on immunohistochemistry (IHC) by Dako Herceptest™ (Dako Corp., Glostrup, Denmark) or evidence of fluorescence in situ hybridization (FISH) amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit (Dako Corp., Glostrup, Denmark).  In March 2013, these two tests received FDA approval as companion diagnostics to identify individuals with HER2-positive metastatic breast cancer who may be eligible for treatment with ado-trastuzumab emtansine. 

In 2007, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) developed joint guideline recommendations for HER2 testing in breast cancer and the guideline was updated in 2013 (Wolff, 2007; 2013).  The guideline was established to promote complete and standardized reporting of malignant pathology to “Improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer” (Wolff, 2013).  The guideline recommends all individuals with newly diagnosed and recurrent invasive breast cancer should have tumors HER2 tested by laboratories that are accredited to perform HER2 testing.  The updated guideline defines the results of HER2 testing as follows:

Positive HER2:

*(Observed in a homogeneous and contiguous population and within >10% of the invasive tumor cells.  By counting at least 20 cells within the area)

Equivocal HER2:

Negative HER2 if a single test (or both tests) performed show:

For individuals with equivocal results, the guidelines (Wolff, 2013) recommend additional testing with a reflex test (on the same specimen using the alternative test) or a new test (new specimen if available, using same or alternative test).

NCCN guidelines for breast cancer (2018) have incorporated the updated ASCO/CAP recommendations for HER2 status into the treatment algorithms for HER2 targeted therapy.

Cardiac Function

Ado-trastuzumab emtansine is associated with a risk of cardiac dysfunction as noted in the black box warning in the product information label.  Reduction in LVEF to less than 40% has been observed in individuals treated with ado-trastuzumab emtansine.  Recommendations from the product information label include assessment of LVEF prior to initiation of therapy and at regular intervals (for example, every 3 months) during therapy.  Initiation of ado-trastuzumab emtansine in individuals with LVEF less than 50% has not been studied.  During routine monitoring, if the LVEF is less than 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, the product label recommends withholding ado-trastuzumab emtansine therapy and repeating LVEF assessment within approximately 3 weeks.  Permanently discontinue ado-trastuzumab emtansine therapy if the LVEF has not improved or has declined further (Product Information Label, 2016).

Other Uses

Investigators continue to study the prevalence and role of HER2 and T-DM1 in other malignancies such as gastric cancer and non-small cell lung cancer (NSCLC).  However, at this time, data from these ongoing trials have not been published demonstrating the safety and efficacy of ado-trastuzumab emtansine versus current standard therapies for malignancies other than breast cancer.  In the updated 2018 NCCN clinical practice guideline for non-small cell lung cancer the NCCN Panel now recommends use of ado-trastuzumab emtansine (category 2A) in treatment of individuals with HER2 mutations in lung cancer based on a recent unpublished data from small phase 2 basket trial (Li, 2017). The NCCN guidelines for gastric cancer (2018)) do not recommend the use of ado-trastuzumab emtansine to treat these cancer types.  There is a paucity of published data from large randomized controlled trials to demonstrate long-term efficacy and safety for these off-label uses.

The use of ado-trastuzumab emtansine is also being evaluated in clinical trials studying the efficacy of adding ado-trastuzumab emtansine to specific targeted biologic agents and other drugs.  There is a phase III MARIANNE trial that is evaluating ado-trastuzumab emtansine with or without pertuzumab compared to trastuzumab plus a taxane (docetaxel or paclitaxel) for the first-line treatment of HER2-positive locally recurrent or metastatic breast cancer.  Data had not yet been published and the estimated completion date for this study is 2016.  In addition, there are ongoing studies to evaluate the timing and place in therapy for early breast cancer as well as use in the adjuvant setting.  However, at this time, there is no published evidence of safety and efficacy to support these off-label indications.

Adverse Events and Warnings:
The Product Information Label (2016) for ado-trastuzumab emtansine includes the following Black Box Warnings and recommendations:

Additional warnings and precautions from the FDA Product Information Label (2016) include:


Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Targeted biologic agent: A newer type of drug developed specifically to target genetic changes in cells that cause cancer. It works differently than standard chemotherapy drugs, often with different side effects.


Peer Reviewed Publications:

  1. Barginear MF, John V, Budman DR. Trastuzumab-DM1: A clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med. 2012; 18:1473-1479.
  2. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011; 29(4):398-405.
  3. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013; 31(9):1157-1163.
  4. Krop IE, Kim SB, González-Martín A, et al.; TH3RESA study collaborators. 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(7):689-699.
  5. Kümler I, Tuxen MK, Nielsen DL. A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev. 2014; 40(2):259-270.
  6. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial. J Clin Oncol. 2017; 35: Abstract 8510.
  7. Miller KD, Diéras V, Harbeck N, et al. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol. 2014; 32(14):1437-1444.
  8. Verma S, Miles D, Gianni L, et al.; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367(19):1783-1791.
  9. Welslau M, Diéras V, Sohn JH, et al. Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer. 2014; 120(5):642-651.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Ado-trastuzumab emtansine. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated February 15, 2018. Available at: Accessed on March 22, 2018.
  2. Ado-trastuzumab emtansine Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised April 6, 2016. Accessed on March 22, 2018.
  3. Giordano SH, Temin S, Kirshner JJ, et al.; American Society of Clinical Oncology. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014; 32(19):2078-2099.
  4. Kadcyla [Product Information], South San Francisco, CA. Genentech, July 25, 2016. Available at: Accessed on March 22, 2018.
  5. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version) National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: Accessed on March 23, 2018.
  6. NCCN Clinical Practice Guidelines in Oncology®. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: Accessed on March 23, 2018.
    1. Breast Cancer (V.1.2018). Revised March 20, 2018.
    2. Gastric Cancer (V.1.2018). Revised March 16, 2018.
    3. Non-Small Cell Lung Cancer (V.3.2018). Revised February 21, 2018.
  7. Wolff A, Hammond MEH, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013; 31(31):3997-4013.
  8. Wolff A, Hammond MEH, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007; 25(1):118-145.
Websites for Additional Information
  1. American Cancer Society. Breast Cancer. Last revised February 2, 2016. Available at: Accessed on March 22, 2018.
  2. National Cancer Institute. Breast Cancer Treatment PDQ®. Modified: February 4, 2018. Available at: Accessed on March 22, 2018.

HER2; Her2-neu
Monoclonal antibody

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.







Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00056 Ado-trastuzumab emtansine (Kadcyla®) to new clinical utilization management guideline document with the same name.