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5.01.22 Ado-Trastuzumab Emtansine (Trastuzumab-DM1) for Treatment of HER-2 Positive Malignancies

Medical Policy    
Section
Prescription Drug
 
Original Policy Date
March 2013
Last Review Status/Date
Created with literature search/March 2013
Issue
3:2013
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Ado-trastuzumab emtansine (Kadcyla™), also known as trastuzumab-DM1 or T-DM1, is an antibody-drug conjugate comprising trastuzumab and emtansine (DM1). It is a HER2 antagonist that is intended as treatment for patients with breast cancers that overexpress HER2, and it may also have applications for other HER-2 positive malignancies.

Background

Description of Disease. Breast cancer accounts for nearly 1 in 3 cancer diagnoses in women in the U.S. Among women, it is the most common cancer after non-melanoma skin cancer. After lung cancer, breast cancer ranks second for cancer mortality. In 2012, an estimated 229,000 new cases of invasive breast cancer will be diagnosed among women, and approximately 40,000 women are expected to die from breast cancer. (1)

Metastatic breast cancer has a poor prognosis. In a cohort of 3,524 women with de novo Stage IV or relapsed breast cancer diagnosed between 1992 and 2007, the median overall survival was 39.2 months among patients with de novo Stage IV and 27.2 months among patients with relapsed disease (estimates independent of HER2 status).(2) Factors associated with reduced survival for patients with metastatic breast cancer include age ≥50 years, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status.(3)

Systemic treatment for metastatic breast cancer is mainly palliative. The goals of treatment are to prolong survival, alleviate symptoms, and maintain or improve quality of life. Treatment is primarily with chemotherapeutic and other anti-tumor drugs. The National Comprehensive Cancer Network (NCCN) guidelines on treatment of metastatic breast cancer include specific recommendations for first-line treatment of HER2-positive metastatic breast cancer. (1, 4) All of the recommended treatment regimens in the guidelines include trastuzumab. Recommended agents that are used singly or in combination with trastuzumab are paclitaxel, docetaxel, vinorelbine, capecitabine, and carboplatin.

HER2. HER2, previously called HER2/neu, or ErbB-2, (5) is part of the HER tyrosine kinase receptor family that includes 4 transmembrane receptors (HER1 [EGFR, epidermal growth factor receptor], HER2, HER3, and HER4). These receptors mediate tumor cell growth, survival, and differentiation. The HER receptors, when activated by extracellular ligand binding, dimerize and activate cell signaling through the phosphatidyl inositol-3 (PI3)-kinase/AKT pathway, which regulates tumor cell survival, to and through the mitogen-activated protein kinase (MAPK) pathway, which regulates cellular proliferation. HER2 has no known ligand; it forms active heterodimers (particularly HER2:HER3) and, when overexpressed, homodimers (HER2:HER2) and that initiate tyrosine kinase signaling without ligand stimulation.(6)

Approximately 20-25% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein receptor with tyrosine kinase activity. Overexpression of this receptor is associated with reduced time to disease recurrence and poorer prognosis. Prior to the advent of HER2-targeted therapy, HER2 overexpression was associated with shorter disease-free and overall survival (OS) than women with either lymph node-negative or lymph node-positive breast cancers, with lack of responsiveness to tamoxifen therapy, and with altered responsiveness to cytotoxic chemotherapy. (7)

Before FDA approval of ado-trastuzumab emtansine, 3 anti-HER2 therapies were FDA-approved for HER2-positive cancers. These agents arrest tumor cell growth and promote apoptosis by blocking HER2-mediated intracellular signaling pathways that mediate cell growth, differentiation, and survival:

  • Trastuzumab (Herceptin®) is an intravenous monoclonal antibody to an extracellular domain of the HER2 receptor (Subdomain IV) that prevents activation of intracellular tyrosine kinase signaling cascades and also promotes antibody-dependent cell mediated cytotoxicity (ADCC). (5)
  • Lapatinib (Tykerb®) is an oral tyrosine kinase inhibitor that blocks the intracellular tyrosine kinase domain of HER2 and downstream cell-signaling cascades. (8)
  • Pertuzumab (Perjeta™) is an oral monoclonal antibody to the extracellular dimerization domain of the HER2 receptor (Subdomain II) that, like trastuzumab, prevents activation of intracellular tyrosine kinase signaling cascades and also promotes ADCC. (9)

Trastuzumab is recommended for first-line treatment of patients with HER2-positive metastatic breast cancer, either in combination with pertuzumab and a taxane (preferred); in combination with a taxane (paclitaxel with or without carboplatin, or docetaxel), vinorelbine, or capecitabine; or as monotherapy. Treatment with trastuzumab plus an anthracycline (doxorubicin or daunorubicin) is not recommended because of unacceptably high rates of cardiac toxicity. Most patients who initially respond to trastuzumab will eventually progress.(10, 11) For second-line treatment of HER2-positive metastatic breast cancer that progresses after trastuzumab therapy (either in the adjuvant setting or as first-line treatment for metastatic disease), continuation of HER2 blockade is recommended. For patients not previously exposed to pertuzumab, combination therapy with trastuzumab plus pertuzumab with or without cytotoxic chemotherapy (e.g., a taxane or vinorelbine) is recommended. Other treatment options are trastuzumab plus lapatinib or capecitabine and lapatinib plus capecitabine. In patients who obtain sustained disease control, the optimal duration of HER2-targeted therapy is unknown. (4)

Ado-trastuzumab emtansine. Ado-trastuzumab emtansine is an antibody-drug conjugate comprising trastuzumab and emtansine. Emtansine (previously called “DM1” for “derivative of maytansine 1”) is a sulfur-containing derivative of the potent microtubule inhibitor, maytansine. Emtansine is conjugated to trastuzumab by lysine side chains, forming a stable thioether linker. (12) Ado-trastuzumab emtansine binds HER2 with an affinity comparable to that of trastuzumab. (13) Once internalized, proteolytic degradation of the linker releases both trastuzumab and the active metabolite, maleimidomethyl cyclohexane-1-carboxylate (MCC)-emtansine. MCC-emtansine contains both positive and negative charges and therefore does not readily cross plasma membranes, maintaining intracellular concentrations. (10) Ado-trastuzumab emtansine has been shown to preserve the antitumor activity of trastuzumab (described above). (14) Death of HER2-expressing cells therefore results from effects of both active moieties of ado-trastuzumab emtansine.

Comparable pharmacokinetic data suggest that toxicity associated with trastuzumab exposure is the same whether trastuzumab is administered as ado-trastuzumab emtansine or as trastuzumab. Both drugs carry Black Box Warnings for hepatotoxicity, cardiac toxicity and embryo-fetal toxicity.

Regulatory Status

Kadcyla™ (ado-trastuzumab emtansine) is approved by the U.S. Food and Drug Administration (FDA) 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.

 


 

Policy

The use of ado-trastuzumab emtansine may be considered medically necessary when all of the following conditions have been met:

  • Patient has HER2-positive, metastatic breast cancer
  • Patient has received prior treatment for metastatic disease, or has developed recurrent disease within 6 months of completing adjuvant therapy.
  • Patient has received prior treatment with trastuzumab and a taxane

The use of ado-trastuzumab emtansine is investigational in all other situations, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer.

 


Policy Guidelines

Safety Considerations

Although there are no absolute contraindications to ado-trastuzumab emtansine, there are a number of additional safety considerations:

  • Ado-trastuzumab emtansine is Pregnancy Category D, is associated with known gestational adverse effects, and should not be used in pregnant women. Effective contraception should be used during and for at least 6 months following treatment.
  • Increases in liver function enzymes are common. Dose modifications based on liver function tests are recommended (see Dosing Considerations below).
  • Decreases in left ventricular (LV) ejection fraction have been noted. Inclusion criteria for the EMILIA trial included a LV ejection fraction of at least 50% or greater.
  • The safety and efficacy of ado-trastuzumab emtansine in pediatric patients has not been established.
  • Other safety concerns, which generally do not warrant a change in management, include infusion reactions, pulmonary toxicity, gastrointestinal tract symptoms, and fatigue.

Dosing Considerations (15)

Ado-trastuzumab emtansine is administered at a dose of 3.6 mg/kg intravenously every 3 weeks.

The first infusion is administered over 90 minutes with slowing or interruptions for fever, chills, or other infusion-associated symptoms, followed by 90 minutes of observation and vital sign monitoring.

If the first infusion is well tolerated (i.e., without any signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation

 


Benefit Application

 

BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all FDA-approved drugs may not be considered investigational, and thus these drugs may be assessed only on the basis of their medical necessity.

 


 

Rationale

This policy was developed from a TEC Special Pharmacy (SP) Report completed in 2013. (15) For this SP report, a literature search was performed through December 2012 for clinical studies of ado-trastuzumab emtansine. The evidence that was identified for this policy review consists of one RCT that was performed in support of application for FDA-approval, and two uncontrolled studies.

Efficacy

Randomized, controlled trial. The Phase III EMILIA trial (N=991) was a randomized, stratified, active-controlled, open-label trial conducted in 26 countries (27% U.S.). (16) Patients had unresectable, locally advanced or metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane. Median age was 53 years, approximately 37% of patients had 3 or more metastatic sites, and 68% had visceral disease involvement. Patients were stratified (by world region, number of prior chemotherapy regimens for advanced disease, and visceral disease involvement) and randomized to one of 2 treatment groups: intravenous infusions of ado-trastuzumab emtansine 3.6 mg/kg every 21 days or self-administered oral lapatinib 1,250 mg daily plus oral capecitabine 1,000 mg/m2 every 12 hours for the first 14 days of each 21-day treatment cycle.

The Phase III EMILIA trial was rated good quality, with no areas of major bias identified. Potential bias introduced by the open-label trial design was minimized by assessor blinding of PFS and tumor response endpoints and by the use of an easily measured endpoint, overall survival (OS).

Primary efficacy outcomes were PFS by independent review committee and overall survival (OS). PFS was 9.6 months in the ado-trastuzumab emtansine group and 6.4 months in the lapatinib+capecitabine group (hazard ratio [HR]: 0.65 [95% CI: 0.55, 0.77]). Statistically nonsignificant differences in PFS were found in patients without visceral involvement, in patients from Asia and other parts of the world (stratified subgroups), in patients 65 to 74 years of age and in patients without measurable disease at baseline (prespecified subgroups). At a median follow-up of approximately19 months, an interim analysis of OS crossed the pre-determined stopping boundary, and the trial was discontinued. OS was 30.9 months in the ado-trastuzumab emtansine group and 25.1 in the lapatinib+capecitabine group (HR: 0.68 [95% CI: 0.55, 0.85]). (Table 1)

Uncontrolled trials. Two single-arm, open-label, Phase II studies conducted in the U.S. enrolled patients with HER2-positive metastatic breast cancer and measurable disease. In TDM4374g (N=110), patients were previously treated with trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine. (17) Ninety-eight percent of patients were female, median age was 53 years, 74% of patients had 3 or more metastatic sites, and patients had received a median of 7 systemic treatments for metastatic disease. In TDM4258g (n=112), patients were previously treated with HER2-directed therapy (trastuzumab or lapatinib). (18) Median age was 55 years, 75% of patients had 3 or more metastatic sites, and patients had received a median of 5 systemic treatments for metastatic disease. All patients in both studies received ado-trastuzumab emtansine 3.6 mg/kg IV (intravenous) every 3 weeks with dose modifications for adverse events.

Objective response rate (ORR, defined as complete responses plus partial responses) by independent radiologic facility (IRF) was the primary efficacy outcome in both studies. In TDM4374g (more pre-treatment), ORR was 35% (95% confidence interval [CI]: 26, 44). In TDM4258g (less pre-treatment), ORR was 26% (95% CI: 18, 34). There were no complete responses. Median progression-free survival (PFS), a secondary outcome, was 6.9 months (95% CI: 4.2, 8.4) in TDM4374g and 4.6 months (95% CI: 3.9, 8.6) in TDM4258g. (Table 2)

Adverse Events

Adverse events were commonly reported in patients receiving ado-trastuzumab emtansine. In the ado-trastuzumab emtansine group of the EMILIA trial, 96% of patients experienced an adverse event. In the 2 Phase II studies, the most common adverse events were fatigue (63%), nausea (44%), thrombocytopenia (38%), and headache (31%). The most common Grade 3 or 4 adverse event in all 3 studies was thrombocytopenia. This and other adverse events are reviewed below. (Table 3)

Thrombocytopenia

In the EMILIA trial, any Grade and Grade 3 or 4 thrombocytopenia occurred in 28% and 13% of patients in the ado-trastuzumab emtansine group, respectively, and in 2.5% and 0.2% of patients in the lapatinib+capecitabine group, respectively.

The association between thrombocytopenia and severe hemorrhagic events is unclear. In the 2 Phase II studies, 3 patients (1.3%) experienced Grade 3 epistaxis. Two of these patients had concurrent Grade 2 or 3 thrombocytopenia. Eight patients in these studies (3.6%) received a platelet transfusion. The incidence of bleeding events in the EMILIA trial was higher in the ado-trastuzumab emtansine group than in the lapatinib+capecitabine group (any Grade: 29.8% and 15.8%, respectively; Grade 3 or 4: 1.4% and 0.8%, respectively).

Elevated Liver Enzymes

In the EMILIA trial, elevated serum transaminases of any Grade occurred in approximately 20% of patients in the ado-trastuzumab emtansine group and 9% of patients in the lapatinib+capecitabine group. With ado-trastuzumab emtansine dose modification, most patients (80%) with Grade 3 or 4 elevated serum transaminases continued treatment. Increases were commonly observed by Day 8 of each treatment cycle and generally returned to baseline before the next cycle. Aspartate aminotransferase (AST) elevations occurred more commonly than alanine aminotransferase (ALT) elevations. The incidence of Grade 1 or 2 serum transaminase elevations, but not the proportion of Grade 3 or 4 events, increased with successive cycles.

Heart Failure

A left ventricular ejection fraction (LVEF) of 50% or more was an entry criterion for the EMILIA trial and the Phase II studies. In a Phase II safety population of 273 patients (including TDM4258g and TDM4374g), 8 patients (3%) developed an asymptomatic decrease from baseline LVEF of 10 percentage points or more to an absolute LVEF less than 50%. In the EMILIA trial, 1.7% (8 patients) in the ado-trastuzumab emtansine group and 1.6% (7 patients) in the lapatinib+capecitabine group had an LVEF less than 50% and a decrease from baseline of 15 percentage points. At the time of final data cut-off, Grade 3 left ventricular systolic dysfunction developed in only one ado-trastuzumab emtansine -treated patient.

Infusion Reactions

In the Phase II TDM4258g study, infusion-related reactions occurred in 13.6% of patients; all were Grade 1 or 2.

Off-Label Use

Conference abstracts have presented results of several Phase I and Phase II studies of ado-trastuzumab emtansine for off-label uses. The main categories for off-label uses are for breast cancer at earlier stages or in various combination therapies for breast cancer, and for use in non-breast cancers.

Earlier Stages of Breast Cancer. The MARIANNE trial, currently in progress, is a Phase III, 3-arm trial comparing ado-trastuzumab emtansine, ado-trastuzumab emtansine plus pertuzumab, and trastuzumab plus a taxane for first-line treatment of metastatic breast cancer. GDC-0941 is an oral inhibitor of a downstream intracellular pathway regulated by HER2. Constitutive activation of this pathway is thought to contribute to trastuzumab insensitivity in HER2-positive breast cancer. A Phase Ib dose escalation study of this combination in patients with HER2-positive breast cancer who progressed on prior trastuzumab therapy is currently in progress.

Additional indications being studied include initial treatment of metastatic breast cancer, in combination with pertuzumab and/or paclitaxel for previously treated metastatic disease, or in patients previously treated with systemic chemotherapy.

Other cancer types. In preclinical studies of gastric cancer, ado-trastuzumab emtansine has shown efficacy. An ongoing Phase I study is assessing the combination of ado-trastuzumab emtansine plus capecitabine in patients with metastatic HER2-positive gastric cancer. A Phase III trial (N=412) comparing two different doses of ado-trastuzumab emtansine (3.6 mg/kg every three weeks or 2.4 mg/kg weekly) to standard taxane therapy in patients with HER2- positive advanced gastric cancer who experienced disease progression during or after first-line therapy is currently in progress.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

None

Ongoing clinical trials

A search of online site ClinicalTrials.gov returned numerous trials of ado-trastuzumab emtansine for various stages of breast cancer, in different combinations with other agents, and a smaller number of trials on treatment of gastric cancer. A summary of the ongoing studies is given in Table 4.

Summary

Trastuzumab emtansine (ado-trastuzumab emtansine) is an antibody-drug conjugate that links the HER2 antagonist activity of trastuzumab to the cytotoxic activity of emtansine (DM1). Based on results of the pivotal EMILIA trial, ado-trastuzumab emtansine is FDA-approved for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab and a taxane. The EMILIA trial reported an improvement in progression-free survival of 3.2 months and an absolute improvement in overall survival of 5.8 months for patients treated with ado-trastuzumab emtansine compared with lapatinib plus capecitabine. Uncontrolled studies corroborate the efficacy of ado-trastuzumab emtansine with objective response rates reported for 26% and 35% of patients in two Phase II studies. Adverse events from ado-trastuzumab emtansine treatment are common. Thrombocytopenia is the most common dose-limiting side effect, with 13% of ado-trastuzumab emtansine -treated patients in EMILIA experiencing grade 3 or 4 thrombocytopenia. Increases in liver enzymes are also common. Decreases in left ventricular ejection fraction (LVEF) have been observed; ado-trastuzumab emtansine has not been studied in patients with a LVEF of less than 50% before initiation of treatment.

As a result of the available evidence and the FDA-approval indications, ado-trastuzumab emtansine may be considered medically necessary for patients with metastatic breast cancer who have been previously treated with a trastuzumab and a taxane and either received prior therapy for metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy.

Practice Guidelines and Position Statements

Trastuzumab emtansine is not currently included in any identified guidelines.

  • In June 2012, the U.K.’s National Institute for Health Research (NIHR) Horizon Scanning Centre identified T-DM1 in combination with pertuzumab (Perjeta®) for first-line treatment of HER2-positive metastatic breast cancer as an emerging health technology that may “significantly impact patients or the provision of health services.”(19)
  • In September 2012, the U.K.’s National Institute for Health and Clinical Excellence (NICE) published the draft scope for a proposed Health Technology Appraisal entitled, “Trastuzumab emtansine for the treatment of locally advanced or metastatic HER2-positive breast cancer after treatment with trastuzumab and a taxane.”(20) A completion date for the appraisal was not provided.

Medicare National Coverage

None

Table 1. EMILIA: Results(12) 

 

Ado-trastuzumab emtansine n=495

Lapatinib+ capecitabine n=496

HR (95% CI)

P valuea

IRC-assessed median PFS, monthsb

9.6

6.4

0.65 (0.55, 0.77)

<0.001

Stratified by world region

Western Europe (n=317)

--

--

0.56 (0.41, 0.74)

--

U.S. (n=270)

--

--

0.70 (0.51, 0.98)

--

Asia (n=158)

--

--

0.74 (0.50, 1.08)

--

Other (n=246)

--

--

0.73 (0.51, 1.03)

--

Stratified by number of prior chemotherapy regimens for advanced disease

0-1 (n=609)

--

--

0.68 (0.55, 0.85)

--

≥1 (n=382)

--

--

0.63 (0.49, 0.82)

--

Stratified by visceral involvement

Yes (n=669)

--

--

0.55 (0.45, 0.67)

--

No (n=322)

--

--

0.96 (0.71, 1.30)

--

Investigator-assessed median PFS, months

9.4

5.8

0.66 (0.56, 0.77)

<0.001

Sensitivity analysis median PFS,c months

9.5

6.7

0.68 (0.57, 0.81)

<0.001

OSb

Median follow-up ~13 months

Median OS, months

--

--

0.62 (0.48, 0.81)

0.0005d

Estimated 1-year OS, % (95% CI)

85.2 (82.0, 88.5)

78.4 (74.6, 82.3)

--

--

Median months to symptom progressiong

7.1

4.6

0.80 (0.67, 0.95)

0.012

 

T-DM1 n=397h

Lapatinib+ capecitabine n=389h

Difference (95% CI)

P valuei

IRC-assessed ORR,j % (95% CI)

43.6 (38.6, 48.6)

30.8 (26.3, 35.7)

12.7 (6.0, 19.4)

<0.001

Partial response, %

42.6

30.3

--

--

Complete response, %

1.0

0.5

--

--

Median duration of OR, months (95% CI)

12.6 (8.4, 20.8)

6.5 (5.5, 7.2)

--

--

CI, confidence interval; HR, hazard ratio; HR, hazard ratio; IRC, independent review committee; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

a Stratified log-rank test.

b Primary efficacy endpoint

c Data for patients who received nonprotocol breast-cancer treatment before documented progression was censored at the last tumor assessment before initiation of the nonprotocol treatment. Nonprotocol treatments comprised (1) any therapies intended for the treatment of breast cancer, including cytotoxic chemotherapy (other than that specified by the trial protocol), immunotherapy, hormonal therapy, and biologic agents; and (2) radiotherapy other than palliative radiotherapy to treat painful bone metastases.

d Did not cross the O’Brien-Fleming stopping boundary of p<0.0003

e Median follow-up in the ado-trastuzumab emtansine group was 19.1 months (range: 0 to 40) and in the lapatinib+capecitabine group, 18.6 months (range: 0 to 41).

f Crossed the O’Brien-Fleming stopping boundary of p<0.0037

g Defined as the time from randomization to the first decrease of ≥5 points from baseline Functional Assessment of Cancer Therapy–Breast, Trial Outcome Index (FACT-B TOI) in women with ≥1 post-baseline score (n not reported).

h80% of patients in the ado-trastuzumab emtansine group and 78% of patients in the lapatinib+capecitabine group had measurable disease at baseline.

i Stratified Mantel–Haenszel chi-square test

j Defined as the combined incidence of complete response and partial response

Table 2. Phase II Studies: IRF Efficacy Outcomes

Outcome

TDM 4374g

Krop 2012(17)

N=110

TDM 4258g

Burris 2011(18)

N=112

Result

95% CI

Result

95% CI

Objective response, %

34.5

26.1, 43.9

25.9

18.4, 34.4

Complete response, %

0

NR

0

NR

Partial response, %

34.5

NR

25.9

NR

Stable disease, %

NR

NR

49.1

NR

Clinical benefit rate,a %

48.2

38.8, 57.9

NR

NR

Median duration of objective response, months

7.2

4.6, NE

Not reached

6.2, NE

Median PFS, months

6.9

4.2, 8.4

4.6

3.9, 8.6

CR, complete response; IRF, independent radiologic facility; NE, not estimable; NR, not reported; PFS, progression-free survival; PR, partial response; SD, stable disease

a Clinical benefit rate was defined as objective response (complete or partial) plus stable disease ≥6 months.

Table 3. Ado-Trastuzumab Emtansine Studies: Adverse Event Summarya

 

Adverse Event, %

EMILIA

Verma 2012(12)

TDM4374g

Krop 2012(17)

N=110

TDM4258g

Burris 2011(18)

N=112

Ado-trastuzumab emtansine

N=490

Lapatinib plus Capecitabine

N=488

Any Grade

Grade 3 or 4

Any Grade

Grade 3 or 4

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Diarrhea

23.3

1.6

79.7

20.7

12.7

0

25.9

0

Palmar–plantar erythrodysesthesia

1.2

0

58.0

16.4

NR

NR

NR

NR

Vomiting

19.0

0.8

29.3

4.5

16.4

0

24.1

0.9

Neutropenia

5.9

2.0

8.6

4.3

NR

NR

NR

NR

Hypokalemia

8.6

2.2

8.6

4.1

20.9

0.9

24.1

8.9

Fatigue

35.1

2.4

27.9

3.5

61.8

4.5

65.2

4.5

Nausea

39.2

0.8

44.7

2.5

37.3

0.9

50.9

0.9

Mucosal inflammation

6.7

0.2

19.1

2.3

NR

NR

NR

NR

Anemia

10.4

2.7

8.0

1.6

20.0

1.8

20.5

2.7

Elevated ALT

16.9

2.9

8.8

1.4

13.6

2.7

NR

NR

Elevated AST

22.4

4.3

9.4

0.8

26.4

2.7

NR

NR

Thrombocytopenia

28.0

12.9

2.5

0.2

38.2

9.1

NR

8.0

ALT, alanine aminotransferase; AST, aspartate aminotransferase; NR, not reported

a Adverse events with an incidence of Grade 3 or 4 events of 2% or higher in either group of the EMILIA trial are shown.

Table 4. Active Trials of Ado-Trastuzumab Emtansine Listed atClinicalTrials.gov

Trial Name

Phase (N)

Population

Breast Cancer

[NCT01120184] A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE)

III (1095)

Adults with HER2-positive progressive or recurrent locally advanced breast cancer or with previously untreated metastatic breast cancer

[NCT01419197] A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-Positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-Directed Therapy (TH3RESA)

III (600)

Adults with HER2-positive metastatic breast cancer who have received at least two prior regimens of HER2-directed therapy

[NCT01702571] A Study of Trastuzumab Emtansine in Patients With HER2 Positive Breast Cancer Who Have Received Prior Anti-HER2 And Chemotherapy-based Treatment

III (1000)

Adults with HER2-positive locally advanced or metastatic breast cancer who have received prior anti-HER2 and chemotherapy-based treatment

[NCT01772472] A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE)

III (1484)

Adults with HER2-positive breast cancer who have residual tumor present in breast or axillary lymph nodes following preoperative therapy

[NCT01745965] A Prospective, Randomized Multicenter, Open-label Comparison of Preoperative Trastuzumab Emtansine (T-DM1) With or Without Standard Endocrine Therapy vs. Trastuzumab With Standard Endocrine Therapy Given for Twelve Weeks in Patients With Operable HER2+/HR+ Breast Cancer Within the ADAPT Protocol

II (380)

Women age 18-75 years with operable HER2+/HR+ breast cancer within the ADAPT protocol

[NCT00934856] A Study of Trastuzumab Emtansine (T-DM1) in Combination With Docetaxel, and Potentially Pertuzumab, in Patients With Advanced Breast Cancer

I (96)

Adults with untreated, locally advanced breast cancer or metastatic HER2-positive breast cancer

Gastric Cancer

[NCT01641939] A Study of Trastuzumab Emtansine Versus Taxane in Patients With Advanced Gastric Cancer

III (N=412)

Adults with HER2-positive advanced gastric cancer who experienced disease progression during or after first-line therapy

[NCT01702558] A Combination Study of Trastuzumab Emtansine And Capecitabine in Patients With Breast Cancer Or Gastric Cancer

II (130)

Adults with HER2-positive metastatic breast cancer or locally advanced or metastatic gastric cancer

References: 

 

  1. Carlson RW, Allred DC, Anderson BO et al. Metastatic Breast Cancer, Version 1.2012: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw 2012; 10(7):821-29.
  2. Dawood S, Broglio K, Ensor J et al. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol 2010; 21(11):2169-74.
  3. Chang J, Clark GM, Allred DC et al. Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 2003; 97(3):545-53.
  4. National Comprehensive Care Network. Breast Cancer. NCCN Clinical Practice Guidelines in Oncology 2012; version 1.2012. Available online at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Last accessed June, 2012.
  5. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357(1):39-51.
  6. Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010; 10(6):489-91.
  7. Press MF, Sauter G, Bernstein L et al. Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 2005; 11(18):6598-607.
  8. GlaxoSmithKline. Tykerb (lapatinib) tablets prescribing information, December 2012. 2012. Available online at: http://us.gsk.com/html/medicines/index.html.
  9. Perjeta ™ (pertuzumab) injection for intravenous use prescribing information, June 2012. Genentech, Inc. http://www.perjeta.com/. Accessed February 2013.
  10. LoRusso PM, Weiss D, Guardino E et al. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res 2011; 17(20):6437-47.
  11. Burris HA, 3rd, Tibbitts J, Holden SN et al. Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer. Clin Breast Cancer 2011; 11(5):275-82.
  12. Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367(19):1783-91.
  13. Burris HA. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Expert Opin Biol Ther 2011; 11(6):807-19.
  14. Girish S, Gupta M, Wang B et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 2012; 69(5):1229-40.
  15. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Trastuzumab emtansine (T-DM1). TEC Specialty Pharmacy Reports 2013; #03-2013.
  16. Verma S, Dieras V, Gianni L et al. EMILIA: A phase III, randomized, multicenter study of trastuzumab-DM1 (T-DM1) compared with lapatinib (L) plus capecitabine (X) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC) and previously treated with a trastuzumab-based regimen. J Clin Oncol 2011; 29(15).
  17. Krop IE, LoRusso P, Miller KD et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30(26):3234-41.
  18. 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.
  19. UK National Institure for Health Research (NIHR). Trastuzumab emtansine in combination with pertuzumab for HER2-positive metastatic breast cancer - first line, June 2012. 2012. Available online at: http://www.hsc.nihr.ac.uk/topics/trastuzumab-emtansine-in-combination-with-pertuzum/.
  20. UK National Institure for Health and Clinical Excellence (NICE). Proposed technology appraisals: trastuzumab-emtansine for the treatment of refractory HER2 positive breast cancer [ID603]. 2013. Available online at: http://www.nice.org.uk/ourguidance/niceguidancebytype/technologyappraisals/proposedappraisals/nowave.jsp#Trastuzumab.

Codes

Number

Description

CPT 

  No specific codes

HCPCS 

C9131 Injection, ado-trastuzumab emtansine, 1 mg (effective 7/1/13)
ICD-9-CM Daignosis 174.0-174.9 Malignant neoplasm of the female breast code range
  175.0-175.9 Malignant neoplasm of the male breast code range
ICD-10-CM (effective 10/1/14  C50.011-C50.929 Malignant neoplasm of breast code range 
   D05.00-D05.92 Carcinoma in situ of breast code range
  Z17.0 Estrogen receptor positive status [ER+]
ICD-10-PCS (effective 10/1/14)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for drugs

 


Index

Ado-trastuzumab emtansine


Policy History

 

Date Action Reason
03/14/13 New policy added to pharmacy section New policy created with literature review through December 2012. Policy statement created that ado-trastuzumab emtansine is medically necessary for patients with locally advanced or metastatic breast cancer who have been previously treated with a HER2 antagonist and a taxane; investigational for all other indications.
06/13/13 Replace policy – coding update only Added HCPCS code C9131