Description
Ado-trastuzumab emtansine (Kadcyla), also known as trastuzumab-DM1 (T-DM1), is an antibody-drug conjugate that links the human epidermal growth factor receptor 2 (HER2) antagonist activity of trastuzumab to the cytotoxic activity of emtansine (DM1). The HER2 antagonist is intended as a treatment for patients with HER2-overexpressing breast cancers, and it may have applications for other HER2-positive malignancies.

For individuals with HER2-positive progressive or recurrent or metastatic breast cancer and failed second-line treatment , including trastuzumab and a taxane who receive T-DM1, the evidence includes 2 randomized controlled trials (RCTs), 3 uncontrolled trials, and 2 meta-analyses. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Based on results of the pivotal EMILIA trial, T-DM1 was approved by the U.S. Food and Drug Administration for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab and a taxane. The EMILIA trial reported an improvement of 3.2 months in progression-free survival and an absolute improvement of 5.8 months in overall survival for patients treated with T-DM1 compared with those who received lapatinib plus capecitabine. Uncontrolled studies have corroborated the efficacy of T-DM1, with reported objective response rates that have ranged from 26% to 41% in patients in 3 phase 2 studies. Adverse events from T-DM1 treatment are common. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-positive previously untreated progressive or recurrent locally advanced breast cancer or metastatic breast cancer who receive T-DM1, the evidence includes an RCT and an uncontrolled trial. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. While the phase 2 trial reported longer progression-free survival with T-DM1 than with trastuzumab plus docetaxel, the trial was open-label and progression assessed by investigators. Results of the subsequent phase 3 MARIANNE trial failed to show any progression-free survival advantage of T-DM1 with or without pertuzumab compared with trastuzumab plus taxane. Secondary analysis of this trial provided better comparative patient-reported outcomes such as quality of life, taxane-related symptoms, and rates of nausea, diarrhea, and alopecia for patients receiving T-DM1 and trastuzumab plus taxane. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have HER2-positive previously untreated early-stage breast cancer who receive neoadjuvant T-DM1, the evidence includes a phase 3 RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. In the phase 3 KRISTINE trial, patients treated with T-DM1 plus pertuzumab had an 11% lower pathologic response than patients treated with docetaxel, carboplatin, and trastuzumab plus pertuzumab. Grade 3 and 4 adverse events were lower than with the control treatment, and also lower than expected from other studies on T-DM1. Therefore, corroboration of the results of the KRISTINE trial are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have HER2-positive locally advanced or metastatic gastric or gastroesophageal junction cancer who receive T-DM1, the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Results have shown no survival advantage of T-DM1 over physician’s choice of weekly paclitaxel or docetaxel every 3 weeks. Grade 3 and 4 adverse events were numerically lower in the T-DM1 group, while rates of serious adverse events, fatal adverse events, and treatment discontinuation due to adverse events were similar. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

Background
Disease Description
Breast cancer accounts for nearly 1 in 3 cancer diagnoses in U.S. women. Breast cancer is the most common cancer in women after nonmelanoma skin cancer and ranks second for cancer mortality after lung cancer. In 2013, an estimated 230,000 new cases of breast cancer were diagnosed in women, and approximately 40,000 women died from breast cancer.¹ Metastatic breast cancer has a poor prognosis. In a cohort of 3524 women diagnosed with breast cancer between 1992 and 2007, median (overall survival was 39.2 months among patients with de novo stage IV breast cancer and 27.2 months among patients with relapsed disease (estimates independent of human epidermal growth factor receptor 2 (HER2) status).² Factors associated with reduced survival for patients with metastatic breast cancer include age 50 years or older, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status.³ 

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

Human Epidermal Growth Factor Receptor 2
Approximately 20% to 25% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with tyrosine kinase activity. HER2, previously called HER2/neu, or ErbB-2,⁵ is part of the HER tyrosine kinase receptor family that includes 4 transmembrane receptors (HER1 [also known as epidermal growth factor receptor (EGFR)], HER2, HER3, HER4). These receptors mediate tumor cell growth, survival, and differentiation. 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, and 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) that constitutively activate tyrosine kinase signaling.⁶ 

HER2 overexpression is associated with reduced time to disease recurrence and poorer prognosis. Before the advent of HER2-targeted therapy, HER2 overexpression was associated with shorter diseasefree and overall survival than 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 

Treatment of HER2-Positive Breast Cancer
Before the Food and Drug Administration (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.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 antibody-dependent cell-mediated cytotoxicity.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 [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 with 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 (previously described).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 cardiac toxicity and embryo-fetal toxicity.

Regulatory Status
Kadcyla™ (ado-trastuzumab emtansine) is approved by FDA as a single agent, 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 6 months of completing adjuvant therapy.

Related Policies
50112 Trastuzumab

Policy
KADCYLA
The indications below including FDA-approved indications and compendial uses are considered a covered benefit provided that all the approval criteria are met and the member has no exlusions to the prescribed therapy.

1. FDA-Approved Indications
   1. Metastatic Breast Cancer (MBC)
      • Kadcyla, as a single agent, is indicated for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer who previously received trastuzumab and 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. 
   2. 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. 
2. Compendial Uses
   1. Single-agent therapy for recurrent or stage IV (M1) HER2-positive breast cancer.
      • Non-small cell lung cancer with HER2 mutations

All other indications are investigational/unproven therefore NOT MEDICALLY NECESSARY and are not a covered benefit. 

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY.

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 (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 after 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 ejection fraction (LVEF) have been noted. Inclusion criteria for the EMILIA trial included LVEF of 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 Considerations¹
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., with no 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.

• For adverse events requiring dose reduction:
  • If the adverse event occurred at the 3.6 mg/kg dose, ado-trastuzumab emtansine should be reduced to 3.0 mg/kg.
  • If the adverse event occurred at the 3.0 mg/kg dose, ado-trastuzumab emtansine should be reduced to 2.4 mg/kg.
  • If the adverse event occurred at the 2.4 mg/kg dose, ado-trastuzumab emtansine should be discontinued.
  • Ado-trastuzumab emtansine dose should not be increased after dose reduction.
• Elevated serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST):
  • For elevations more than 3 times the upper limit of normal (ULN) with concomitant elevated bilirubin more than 2 times ULN, ado-trastuzumab emtansine should be permanently discontinued.
  • For elevations more than 5 to ≤ 20 times ULN, ado-trastuzumab emtansine should be temporarily discontinued until recovery to ≤ 5 times ULN and then restarted at 1 level lower dose.
  • For elevations more than 20 times ULN, ado-trastuzumab emtansine should be permanently discontinued.
• Elevated bilirubin:
  • For elevations more than 2 times ULN with concomitant elevated AST or ALT more than 3 times ULN, ado-trastuzumab emtansine should be permanently discontinued.
  • For elevations > 1.5 to ≤ 3.0 times ULN, ado-trastuzumab emtansine should be temporarily discontinued until recovery to ≤ 1.5 times ULN and then restarted at the same dose.
  • For elevations > 3.0 to ≤ 10 times ULN, ado-trastuzumab emtansine should be temporarily discontinued until recovery to ≤ 1.5 times ULN and then restarted at 1 level lower dose. 
  • For elevations more than 10 times ULN, ado-trastuzumab emtansine should be permanently discontinued.

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 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

HER2-POSITIVE PROGRESSIVE OR RECURRENTOR METASTATIC BREAST CANCER AND FAILED SECOND-LINE TREATMENT
Clinical Context and Therapy Purpose
The purpose of trastuzumab-DM1 (T-DM1) in patients who have human epidermal growth factor receptor 2 (HER2)−positive progressive or recurrent or metastatic breast cancer and failed second-line treatment is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does T-DM1 improve the net health outcome?

The following PICOTS were used to select literature to inform this review. 

Patients
The relevant population of interest is patients with HER2-positive progression or recurrent or metastatic breast cancer and failed second-line treatment.

Trastuzumab is recommended as a first-line treatment for patients with HER2-positive metastatic breast cancer either in combination with pertuzumab and a taxane (preferred), or in combination with a taxane (paclitaxel with or without carboplatin, or docetaxel), vinorelbine, or capecitabine.  

Interventions
The therapy being considered is T-DM1. T-DM1 is an antibody drug conjugate of trastuzumab and emtansine. Emtansine (previously called DM1 [derivative of maytansine 1]) is a sulfur-containing derivative of the potent microtubule inhibitor, maytansine. T-DM1 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. Death of HER2-expressing cells, therefore, results from the effects of both active moieties of T-DM1.  

Comparators
The following practices are currently being used to make decisions about T-DM1.

The continuation of HER2 blockade is recommended as a second-line treatment for patients with HER2-positive metastatic breast cancer that progresses after trastuzumab therapy (either in the adjuvant setting or during first-line treatment for metastatic disease). Other treatment options are trastuzumab plus lapatinib or capecitabine, and lapatinib plus capecitabine. For patients not previously exposed to pertuzumab, combination therapy with trastuzumab plus pertuzumab — either 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.  

Outcomes
The general outcomes of interest are mortality, the time to progression of metastatic breast cancer, and toxicity from treatment.

Timing
For metastatic breast cancer that has progressed following second-line treatment, progression-free survival (PFS) is typically less than a year and overall survival (OS) is typically up to 3 years.

Setting
The setting is outpatient care by an oncologist.

Randomized Controlled Trials
Two phase 3 trials were identified, the EMILIA trial and the TH3RESA trial (see Table 1).^12,17,18,19 Both were international, randomized, stratified, active-controlled, open-label trials. EMILIA included patients with locally advanced or metastatic disease previously treated with trastuzumab and a taxane, while the TH3RESA trial included patients with progressive metastatic or recurrent disease after 2 or more HER2 targeted treatment regimens. The comparator treatments are shown in Table 2. Primary efficacy outcomes for both trials were PFS and OS.

PFS in the control group was 5.8 months in EMILIA and 3.3 months in TH3RESA. In both trials, PFS was 3 or more months longer in the T-DM1 group (see Table 2). Controls were allowed to cross over to T-DM1 in May 2012 in EMILIA. At a median follow-up of 19 months, an interim analysis of OS in the TH3RESA trial crossed the predetermined stopping boundary, and the trial was discontinued.

OS by intention-to-treat analysis was 5.8 months longer in the T-DM1 group in the EMILIA trial and 6.9 months in the TH3RESA trial (see Table 2). The incidence of grade 3 or 4 adverse events was lower in the T-DM1 group than in the control group in the EMILIA trial but not in the TH3RESA trial.

Table 1. Summary of Key RCT Characteristics 

Study; Trial

Countries

Sites

Dates

Participants

Interventions

Active

Comparator

Verma et al. (2012), Dieras et al. (2017)12,19; EMILIA

26

213

2009 – 2012

991 patients with unresectable, locally advanced, or metastatic (HER2)-positive breast cancer previously treated with trastuzumab and a taxane

495 T-DM1

496 oral lapatinib plus oral capecitabine

Krop et al. (2014, 2017)17,18; TH3RESA

22

146

2011 – 2015

Patients with progressive disease after ≥ 2 HER2-targeted treatment regimens for metastatic or recurrent breast cancer

404 T-DM1

198 physician’s choice (chemotherapy, hormone therapy, and/or HER2-targeted therapy)a

HER2: epidermal growth factor receptor 2; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.
^a Most patients (83%) in the physician’s choice group received HER2-targeted therapy plus chemotherapy (most commonly vinorelbine); 80% of patients in this group received trastuzumab. Median treatment duration was 2.7 months in the physician’s choice group and 4.2 months in the T-DM1 group. 

Table 2. Summary of Key RCT Results 

Study; Trial	IRC-Assessed Median PFS, mo	Investigator-Assessed Median PFS, mo	Median OS, mo	IRC-Assessed ORR (95% CI), %e	Grade 3 or 4 Adverse Events
Verma et al. (2012), Dieras et al. (2017)12,19; EMILIA
N	991			486d	978
T-DM1	9.6	9.4	30.9	43.6 (38.6 to 48.6)	233 (48%)
L+P	6.4	5.8	25.1	30.8 (26.3 to 35.7)	294 (60%)
HR (95% CI)	0.65 (0.55 to 0.77)	0.6 (0.56 to 0.77)	0.68 (0.55 to 0.85)	Diff: 12.7 (6.0 to 19.4)
p	< 0.001	< 0.001	< 0.001c	< 0.001
Krop et al. (2014, 2017)17,18; TH3RESA
N		602			587
T-DM1		6.2	22.7		161 (40%)
PC		3.3	15.8		87 (47%)
HR (95% CI)		0.53 (0.42 to 0.66)	0.68 (0.54 to 0.85)
p		p < 0.001	p < 0.001
Summary HR		0.53 to 0.6	0.68

CI: confidence interval; HR: hazard ratio; IRC: independent review committee; L+P: lapatinib plus capecitabine; OR: objective response; ORR: objective response rate; OS: overall survival; PC: physician’s choice; PFS: progression-free survival; T-DM1: ado-trastuzumab emtansine.
^a Primary efficacy end point for EMILIA.
^b Median follow-up in the T-DM1 group was 19.1 mo (range, 0 – 40 mo); in the L+P group, it was 18.6 mo (range, 0 – 41 mo).
^c Crossed the O’Brien-Fleming stopping boundary of p < 0.004.
^d Eighty percent of patients in the T-DM1 group and 78% of patients in the L+P group had measurable disease at baseline.
^e Defined as the combined incidence of complete response and partial response. 

Gaps in relevance and design and conduct are shown in Tables 3 and 4. The TH3RESA trial was not blinded while the phase 3 EMILIA trial had assessor blinding of PFS and tumor response end points. Both trials had an objective end point of OS. The TH3RESA trial used physician’s choice chemotherapy, which was not standardized. Both trials had crossovers from the control group, although both used intention-to-treat and sensitivity analyses.

Table 3. Relevance Gaps 

Study; Trial	Populationa	Interventionb	Comparatorc		Outcomesd	Follow-Upe
Verma et al. (2012), Dieras et al. (2017)12,19; EMILIA
Krop et al. (2014, 2017)17,18; TH3RESA			2. physician’s choice (chemotherapy, hormone therapy, and/or HER2-targeted therapy

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
HER2: epidermal growth factor receptor 2.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 4. Study Design and Conduct Gaps

Study; Trial	Allocationa	Blindingb		Selective Reportingd	Data Completenesse		Powerd	Statisticalf
Verma et al. (2012), Dieras et al. (2017)12,19; EMILIA		1, 2. Assessor-blinded			3. OS might have been impacted by crossovers and differences in postprogression treatments
Krop et al. (2014, 2017)17,18: TH3RESA		1 – 3. Not blinded			3. OS might have been impacted by control crossovers and postprogression treatments

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. OS: overall survival.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).

e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Two exploratory analyses of the EMILIA trial were subsequently published. Krop et al. (2015) examined outcomes in patients with asymptomatic central nervous system (CNS) metastases.²⁰ At median follow-up of 19 months, median PFS was similar between treatment groups (5.9 months in the ado-trastuzumab emtansine group vs 5.7 months in the control group), but median OS was longer in the T-DM1 group (26.8 months vs 12.9 months, respectively). No new safety signals were identified. Welslau et al. (2014) reported greater improvements in patient-reported outcomes (time to symptom worsening and increase in diarrhea symptoms) with T-DM1 than with capecitabine plus lapatinib (control).²¹ The proportion of patients experiencing a clinically significant improvement in symptoms was similar between groups.

Uncontrolled Trials
Three single-arm, open-label, phase 2 studies (conducted in the United States) enrolled patients with HER2-positive metastatic breast cancer and measurable disease (see Table 5). In the TDM4374g study (Krop et al. [2012]), 110 patients were enrolled who had been previously treated with trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine.²² The TDM4258g study (Burris et al. [2011]) enrolled 112 patients previously treated with HER2-directed therapy (trastuzumab or lapatinib).23 Objective response rate (ORR) determined by an independent radiologic facility was the primary efficacy outcome in both studies. In TDM4374g (more pretreatment), ORR was 35%, while in TDM4258g (less pretreatment), ORR was 26% (see Table x2). The median PFS (a secondary outcome) was 6.9 months in TDM4374g and 4.6 months in TDM4258g.

In the third study (Miller et al. [2014]), 64 patients with HER2-positive, locally advanced breast cancer were treated with T-DM1 3.6 mg/kg plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks.24 The primary efficacy end point was investigator-assessed ORR. Overall, the ORR was 41%, 57% in first-line setting and 33% in the other settings, with a median PFS of 7.7 months (6.6 months in first-line, 5.5 months in the other settings).

Table 5. Phase 2 Studies: Independent Radiologic Facility Efficacy Outcomes

Outcomes

Krop (2012)22 (N = 110)

Burris (2011)23 (N = 112)

Miller (2014)24 (N = 64)

Result

95% CI

Result

95% CI

Result

95% CI

Objective response, %

34.5

26.1 to 43.9

25.9

18.4 to 34.4

41

29 to 54

Complete response, %

0

NR

0

NR

5

2 to 13

Partial response, %

34.5

NR

25.9

NR

36

25 to 48

Stable disease, %

NR

NR

49.1

NR

NR

NR

Clinical benefit rate, %a

48.2

38.8 to 57.9

NR

NR

50

37 to 63

Median dur of ORR, mo

7.2

4.6 to NE

NE

6.2 to NE

13.9

6.9 to NE

Median PFS, mo

6.9

4.2 to 8.4

4.6

3.9 to 8.6

6.6

4.2 to 9.5

CI: confidence interval; dur: duration; NE: not estimable; NR: not reported; ORR: objective response rate; PFS: progression-free survival.
^aClinical benefit rate was defined as objective response (complete or partial) plus stable disease ≥ 6 mo.  

Section Summary: HER2-Positive, Progressive or Recurrent or Metastatic Breast Cancer and Failed Second-line Treatment  
Multiple RCTs, prospective single-arm trials, and meta-analyses of these studies in the second-line setting of HER2-positive breast cancer have shown improvement in OS with T-DM1 compared with chemotherapy using lapatinib plus capecitabine. The pivotal EMILIA trial reported an improvement of 3.2 months in PFS and an absolute improvement of 5.8 months in OS for patients treated with T-DM1 compared with those who received lapatinib plus capecitabine. The pooled odds from a meta-analysis reported a 40% relative reduction in the hazard of death (HR = 0.60; 95% CI, 0.48 to 0.75). Uncontrolled studies have corroborated the efficacy of T-DM1 with ORRs ranging from 26% to 41% of patients in 3 phase 2 studies.  

HER2-POSITIVE, PREVIOUSLY UNTREATED PROGRESSIVE OR RECURRENT OR LOCALLY ADVANCED METASTATIC BREAST CANCER
Clinical Context and Therapy Purpose
The purpose of T-DM1 in patients who have HER2-positive, previously untreated progressive or recurrent or locally advanced metastatic breast cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does T-DM1 improve the net health outcome?

The following PICOTS were used to select literature to inform this review. 

Patients
The relevant population of interest is patients HER2-positive, previously untreated progressive or recurrent locally advanced metastatic breast cancer.

Trastuzumab is recommended as a first-line treatment for patients with HER2-positive metastatic breast cancer either in combination with pertuzumab and a taxane (preferred), or in combination with a taxane (paclitaxel with or without carboplatin, or docetaxel), vinorelbine, or capecitabine.  

Interventions
The therapy being considered is T-DM1. T-DM1 is an antibody drug conjugate of trastuzumab and emtansine. Emtansine (previously called DM1) is a sulfur-containing derivative of the potent microtubule inhibitor, maytansine.

Comparators
The following therapies are currently being used to make decisions about T-DM1.

The continuation of HER2 blockade is recommended as a second-line treatment for patients with HER2-positive metastatic breast cancer that progresses after trastuzumab therapy (either in the adjuvant setting or during first-line treatment for metastatic disease). Other treatment options are trastuzumab plus lapatinib, or capecitabine and lapatinib plus capecitabine.  

Outcomes
The general outcomes of interest are mortality, the time to progression of locally advanced or metastatic breast cancer, and toxicity from treatment.

Timing
For metastatic breast cancer that has progressed following first-line treatment, PFS is typically less than a year and OS is typically up to 3 years.

Setting
The setting is outpatient care by an oncologist. 

Randomized Controlled Trials
Perez et al. (2014, 2017) reported on the results of the phase 3 MARIANNE trial (see Table 6).^25,26 In the MARIANNE trial (N = 1095), T-DM1 plus pertuzumab and T-DM1 alone showed PFS noninferior but not superior to the current standard of care (i.e., trastuzumab plus taxane) and decrease in grade 3 and 4 adverse events by less than 10% (see Table 7). The decline in health-related quality of life increased from 3.6 to 7.7 and 9.0 for T-DM1 plus pertuzumab, T-DM1 alone, and trastuzumab plus taxane, respectively; HRs for the decline in health-related quality of life ranged from 0.68 to 0.70.  

Table 6. Summary of Key RCT Characteristics

Study; Trial

Countries

Sites

Dates

Participants2

Interventions1

Active

Comparator

Perez et al. (2014, 2017)25,26; MARIANNE

38

241

2012 – 2014

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

367 T-DM1 alone or 363 in combination with pertuzumab

365 trastuzumab plus taxane (docetaxel or paclitaxel)

HER2: epidermal growth factor receptor 2; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

Table 7. Summary of Key RCT Results 

Study	Median PFS, mo		ORR	Grade 3 or 4 Adverse Events		Decline in HRQOL, mo
Perez et al. (2014, 2017)25,26; MARIANNE
N	732		586
T-DM1 plus pertuzumab	15.2		64.2%	46.2%		9.0
T-DM1 alone	14.1		59.7%	45.4%		7.7
Trastuzumab plus taxane	13.7		67.9%	54.1%		3.6
HR (95% CI)	0.87 (0.69 to 1.08) 0.91 (0.73 to 1.13)					0.68 (0.55 to 0.84) 0.70 (0.57 to 0.86)
Summary	0.59 to 0.91

CI: confidence interval; HR: hazard ratio; HRQOL: health-related quality of Life; ORR: objective response rate; PFS: progression-free survival; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

The purpose of the gaps tables (see Tables 8 and 9) is to display notable gaps identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 8. Relevance Gaps 

Study; Trial	Populationa	Interventionb	Comparatorc		Outcomesd	Follow-Upe
Perez et al. (2014, 2017)25,26; MARIANNE	Prior hormonal treatment of advanced breast cancer was allowed

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms. 

Table 9. Study Design and Conduct Gaps 

Study; Trial	Allocationa	Blindingb	Selective Reportingd	Data Completenesse	Powerd	Statisticalf
Perez et al. (2014, 2017)25,26; MARIANNE		1, 2. Blinding only for pertuzumab vs placebo

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.   

Section Summary: HER2-Positive, Progressive or Recurrent Locally Advanced Metastatic Breast Cancer  
The pivotal RCT conducted among HER2-positive progressive or recurrent locally advanced breast cancer patients failed to show the superiority of regimens containing T-DM1 over the current standard of care (i.e., trastuzumab plus taxane). Median PFS durations were 15.2, 14.1, and 13.7 months with T-DM1 plus pertuzumab, T-DM1 alone, and trastuzumab plus taxane, respectively. Secondary analysis showed that median time for a clinically meaningful decrease in health-related quality of life from baseline with T-DM1 with (9.0 months) or without pertuzumab (7.7 months) was longer than with trastuzumab plus taxane (3.6 months). The incidence of grade 3 or 4 adverse events was lower in T-DM1 arms than in the trastuzumab plus taxane arm.  

HER2-POSITIVE, PREVIOUSLY UNTREATED EARLY-STAGE BREAST CANCER

Clinical Context and Therapy Purpose
The purpose of T-DM1 in patients who have HER2-positive previously untreated early-stage breast cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does T-DM1 improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients with HER2-positive previously untreated early-stage breast cancer.

Trastuzumab is recommended as a first-line treatment for patients with HER2-positive metastatic breast cancer either in combination with pertuzumab and a taxane (preferred), or in combination with a taxane (paclitaxel with or without carboplatin, or docetaxel), vinorelbine, or capecitabine.  

Interventions
The therapy being considered is T-DM1. T-DM1 is an antibody drug conjugate of trastuzumab and emtansine. Emtansine (previously called DM1) is a sulfur-containing derivative of the potent microtubule inhibitor, maytansine.

Comparators
The following therapies are currently being used to make decisions about T-DM1.

Outcomes
The general outcomes of interest are recurrence, residual disease, and toxicity from treatment.

Timing
For breast cancer that has progressed following first-line treatment, PFS may be monitored for 5 years. 

Setting
The setting is outpatient care by an oncologist.

Randomized Controlled Trials
The KRISTINE trial (Hurvitz et al. [2018]) was an international multicenter open-label phase 3 study that compared neoadjuvant treatment using T-DM1 plus pertuzumab with therapy using docetaxel, carboplatin, and trastuzumab plus pertuzumab (see Table 10). The T-DM1 plus pertuzumab group had a lower pathologic response to treatment (44%) compared with standard therapy (56%; p = 0.016) (see Table 11). T-DM1 was associated with a grade 3 and 4 adverse event rate of 13% compared with 64% who received docetaxel, carboplatin, and trastuzumab plus pertuzumab.

Table 10. Summary of Key RCT Characteristics

Study; Trial

Countries

Sites

Dates

Participants

Interventions

Active

Comparator

Hurvitz et al. (2018)27; KRISTINE

Asia, E.U., U.S., Canada

68

2014 – 2015

Patients with previously untreated HER2-positive stage II-III breast cancer

223 neoadjuvant treated with T-DM1 plus pertuzumab

221 neoadjuvant treated with docetaxel, carboplatin, and trastuzumab plus pertuzumab

HER2: epidermal growth factor receptor 2; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.   

Table 11. Summary of Key RCT Results 

Study; Trial	Pathologic Complete Response	Any Adverse Event	Grade 3 and 4 Adverse Events	Time to Deterioration in HRQOL (95% CI), mo
Hurvitz et al. (2018)27; KRISTINE
N	444	442	442	444
T-DM1 plus pertuzumab, n (%)	99 (44.4)	197 (88)	29 (13)	4.6 (4.1 to 8.0)
Standard therapy, n (%)	123 (55.7)	216 (99)	141 (64)	3.0 (2.8 to 3.4)
Diff (95% CI)	-11.3 (-20.5 to -2.0)
p	0.016

 CI: confidence interval; Diff: difference; HRQOL: health-related quality of life; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

The purpose of the gaps tables (see Tables 12 and 13) is to display notable gaps identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. While pathologic complete response may predict long-term response, its significance in this population is uncertain. The KRISTINE trial is ongoing.

Table 12. Relevance Gaps

Study; Trial	Populationa	Interventionb		Comparatorc	Outcomesd		Follow-Upe
Hurvitz et al. (2018)27; KRISTINE					2. Pathologic response		2. Insufficient to determine PFS

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
PFS: progression-free survival.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms. 

Table 13. Study Design and Conduct Gaps 

Study; Trial	Allocationa	Blindingb	Selective Reportingd	Data Completenesse	Powerd	Statisticalf
Hurvitz et al. (2018)27; KRISTINE		1 – 3 Open-label

 The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: HER2-Positive Previously Untreated Early-Stage Breast Cancer  
The evidence on T-DM1 for neoadjuvant treatment of early-stage breast cancer includes an international phase 3 trial (KRISTINE) that compared T-DM1 plus pertuzumab with docetaxel, carboplatin, and trastuzumab plus pertuzumab. T-DM1 plus pertuzumab resulted in a lower pathologic response to treatment compared with the control therapy. T-DM1 plus pertuzumab was associated a grade 3 and 4 adverse event rates of 13% in this study compared with an adverse event rate of 64% in the group treated with docetaxel, carboplatin, and trastuzumab plus pertuzumab; this difference was not statistically significant. The grade 3 and 4 adverse event rate associated with T-DM1 treatment in the KRISTINE trial is considerably lower than the grade 3 and 4 adverse event rates with T-DM1 in other breast cancer trials, which have ranged from 40% to 48%. Pathologic response was used as a surrogate outcome measure; disease-free survival and OS will be reported in a future study. Corroboration of the findings of the KRISTINE trial are need to determine whether neoadjuvant T-DM1 can be considered to be an alternative therapy in patients who are unable to tolerate treatment with docetaxel, carboplatin, and trastuzumab plus pertuzumab.

HER2-POSITIVE, LOCALLY ADVANCED OR METASTATIC GASTRIC OR GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA

Clinical Context and Therapy Purpose
The purpose of T-DM1 in patients who have HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does T-DM1 improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients who have HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. The goals of therapy are palliation of symptoms and prolongation of survival.

Interventions
The therapy being considered is T-DM1. T-DM1 is a replacement option for current therapy. 

Comparators
The following therapy is currently being used to make decisions about HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

Trastuzumab is a humanized monoclonal antibody that targets the HER2 receptor. Trastuzumab inhibits downstream signal activation and induces cellular toxicity. Trastuzumab is administered with 1 or more chemotherapeutic agents that may include cisplatin or paclitaxel. 

Outcomes
The general outcomes of interest are the response to treatment, measured by PFS and OS, and toxicity from treatment.

Timing
For HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, the median OS is less than a year. 

Setting
The setting is outpatient care by an oncologist.

Randomized Controlled Trials
GATSBY trial (Thuss-Patience et al. [2017], NCT01641939) evaluated the efficacy and tolerability of T-DM1 in the second-line setting of HER2-positive advanced gastric cancer (see Table 14).²⁸ The primary end point of OS was assessed in the intention-to-treat population. T-DM1 did not show an efficacy benefit over taxane for HER2-positive local advanced or metastatic gastric or gastroesophageal junction cancer (see Table 15).  

Table 14. Summary of Key RCT Characteristics 

Study; Trial	Countries	Sites	Dates		Participants	Interventions
					Active	Comparator
Thuss-Patience et al. (2017)28; GATSBY	28	107	Patients with HER2-positive unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer		228 T-DM1	117 taxane (paclitaxel or docetaxel)

HER2: epidermal growth factor receptor 2; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

Table 15. Summary of Key RCT Results 

Study; Trial	Median OS (95% CI), mo		Grade 3 and 4 Adverse Events
Thuss-Patience et al. (2017)28; GATSBY
N	335		335
T-DM1	7.9 (6.7 to 9.5)		59.8%
Taxane	8.6 (7.1 to 11.2)		70.3%
HR (95% CI)	1.15 (0.87 to 1.51)
p	0.86

CI: confidence interval; HR: hazard ratio; OS: overall survival RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

The purpose of the gaps tables (see Tables 16 and 17) is to display notable gaps identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 16. Relevance Gaps 

Study; Trial	Populationa	Interventionb	Comparatorc		Outcomesd	Follow-Upe
Thuss-Patience et al. (2017)28; GATSBY	3. Histologic subtype unknown for 38% of population

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. 
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.  

Table 17. Study Design and Conduct Gaps 

Study; Trial	Allocationa	Blindingb	Selective Reportingd		Data Completenesse	Powerd	Statisticalf
Thuss-Patience et al. (2017)28; GATSBY		1 – 3. Not blinded

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: HER2-Positive Locally Advanced or Metastatic Gastric or Gastroesophageal Junction  
The pivotal RCT conducted among patients with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction cancer failed to show the superiority of T-DM1 over physicians’ choice of chemotherapy. Median OS durations were 7.9 months for T-DM1 and 8.6 months for taxane (p = 0.86).

SUMMARY OF EVIDENCE
For individuals with HER2-positive progressive or recurrent or metastatic breast cancer and failed second-line treatment , including trastuzumab and a taxane who receive T-DM1, the evidence includes 2 randomized controlled trials (RCTs), 3 uncontrolled trials, and 2 meta-analyses. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Based on results of the pivotal EMILIA trial, T-DM1 was approved by the U.S. Food and Drug Administration for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab and a taxane. The EMILIA trial reported an improvement of 3.2 months in progression-free survival and an absolute improvement of 5.8 months in overall survival for patients treated with T-DM1 compared with those who received lapatinib plus capecitabine. Uncontrolled studies have corroborated the efficacy of T-DM1, with reported objective response rates that have ranged from 26% to 41% in patients in 3 phase 2 studies. Adverse events from T-DM1 treatment are common. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-positive previously untreated progressive or recurrent locally advanced breast cancer or metastatic breast cancer who receive T-DM1, the evidence includes an RCT and an uncontrolled trial. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. While the phase 2 trial reported longer progression-free survival with T-DM1 than with trastuzumab plus docetaxel, the trial was open-label and progression assessed by investigators. Results of the subsequent phase 3 MARIANNE trial failed to show any progression-free survival advantage of T-DM1 with or without pertuzumab compared with trastuzumab plus taxane. Secondary analysis of this trial provided better comparative patient-reported outcomes such as quality of life, taxane-related symptoms, and rates of nausea, diarrhea, and alopecia for patients receiving T-DM1 and trastuzumab plus taxane. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have HER2-positive previously untreated early-stage breast cancer who receive neoadjuvant T-DM1, the evidence includes a phase 3 RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. In the phase 3 KRISTINE trial, patients treated with T-DM1 plus pertuzumab had an 11% lower pathologic response than patients treated with docetaxel, carboplatin, and trastuzumab plus pertuzumab. Grade 3 and 4 adverse events were lower than with the control treatment, and also lower than expected from other studies on T-DM1. Therefore, corroboration of the results of the KRISTINE trial are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have HER2-positive locally advanced or metastatic gastric or gastroesophageal junction cancer who receive T-DM1, the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Results have shown no survival advantage of T-DM1 over physician’s choice of weekly paclitaxel or docetaxel every 3 weeks. Grade 3 and 4 adverse events were numerically lower in the T-DM1 group, while rates of serious adverse events, fatal adverse events, and treatment discontinuation due to adverse events were similar. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.   

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
Based on results of the EMILIA trial, current National Comprehensive Cancer Network guidelines (v.1.2018) recommend ado-trastuzumab emtansine (T-DM1) as a preferred option for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer previously treated with trastuzumab (category 2A recommendation, based on lower level evidence with uniform panel consensus).⁷ 

As of June 2018, T-DM1 has not been considered in the National Comprehensive Cancer Network guidelines on treatment of gastric cancer (v.2.2018).²⁹  

National Institute for Health and Care Excellence
In 2017, the National Institute for Health and Care Excellence issued guidance on trastuzumab emtansine for treating HER2-positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane.³⁰ "Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for treating human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane, separately or in combination."  

American Society of Clinical Oncology
In 2018, the American Society of Clinical Oncology updated its evidence-based guidelines on systemic therapy for patients with advanced HER2-positive breast cancer.³¹ T-DM1was recommended as a second-line treatment for patients whose cancer has progressed during or after first-line HER2-targeted therapy (e.g., with trastuzumab, pertuzumab, and a taxane). T-DM1 was also recommended in subsequent lines unless previously tried (strength of both recommendations: strong, based on high-quality evidence).  

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 18.  

Table 18. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
Breast cancer
NCT01702571	A Study of Trastuzumab Emtansine in Patients With HER2-Positive Breast Cancer Who Have Received Prior Anti-HER2 And Chemotherapy-based Treatment	2003	Sept. 2019
NCT01745965a	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	380	Oct. 2020
NCT01853748	A Randomized Phase II Study of Trastuzumab Emtansine (T-DM1) vs. Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT Trial)	500	Dec. 2021
NCT01772472a	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)	1487	April 2023
NCT01966471a	A Study of Kadcyla (Trastuzumab Emtansine) Plus Perjeta (Pertuzumab) Following Anthracyclines in Comparison With Herceptin (Trastuzumab) Plus Perjeta and a Taxane Following Anthracyclines as Adjuvant Therapy in Patients With Operable HER2-positive Primary Breast Cancer	1846	Jan. 2024

 NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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16. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Trastuzumab emtansine (T-DM1). TEC Specialty Pharmacy Reports. 2013;#03-2013. PMID
17. Krop IE, Kim SB, Gonzalez-Martin 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. Jun 2014;15(7):689-699. PMID 24793816
18. Krop IE, Kim SB, Martin AG, 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. Jun 2017;18(6):743-754. PMID 28526538
19. Dieras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. Jun 2017;18(6):732-742. PMID 28526536
20. 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. Jan 2015;26(1):113-119. PMID 25355722
21. Welslau M, Dieras 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. Mar 1 2014;120(5):642-651. PMID 24222194
22. 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. Sep 10 2012;30(26):3234-3241. PMID 22649126
23. 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. Feb 1 2011;29(4):398-405. PMID 21172893
24. Miller KD, Dieras 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. May 10 2014;32(14):1437-1444. PMID 24733796
25. Perez EA, Hurvitz SA, Amler LC, et al. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res. May 23 2014;16(3):R50. PMID 24887458
26. Perez EA, Barrios C, Eiermann W, et al. Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol. Jan 10 2017;35(2):141-148. PMID 28056202
27. Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. Jan 2018;19(1):115-126. PMID 29175149
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Coding Section

Codes	Number	Description
CPT		No specific codes
HCPCS	J9354	Injection, ado-trastuzumab emtansine, 1 mg
ICD-9 Diagnosis	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 10/01/15)	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 10/01/15)		Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for drugs.
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology^© American Medical Association. All Rights Reserved" 

History From 2014 Forward     

02/01/2023	Interim review to remove errant code J9358 from the policy.
09/15/2022	Annual review, no change to policy intent.
09/20/2021	Annual review, no change to policy intent.
10/29/2020	Interim review to add the statement: BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.
09/16/2020	Annual review, no change to policy intent.
08/17/2020	Changing review month.
06/17/2020	Updated coding. Added Code J9358 to be effective 7/1/2020. No other changes.
07/24/2019	Annual review, updating policy verbiage to only address use of Kadcyla, refer to CAM 50112 for trastuzumab/ trastuzumab-dkst (Herceptin/Ogivri).
08/15/2018	Annual review, no change to policy intent. Updating description, rationale and references.
08/23/2017	Annual review, updating policy to include coverage for gastric and gastroesophogeal junction adenocarcinoma. Medical necessity criteria expanded for clarity. Also updating rationale and references.
08/09/2016	Annual review, no change to policy intent. Updating background, description and rationale.
08/20/2015	Annual review, no change to policy intent. Updating background, description, guidelines, rationale and references. Adding coding.
08/04/2014	Annual review. Updated background, description, guidelines, rationale and references. Added related policy. No change to policy intent.