Medical Policy

Policy Num:      05.001.024
Policy Name:    Ado-Trastuzumab Emtansine (Trastuzumab-DM1) for Treatment of HER2-Positive Malignancies             
Policy ID:          [5.001.024]  [Ac / B / M+ / P+]  [5.01.22]

Last Review:      August  19, 2024
Next Review:      August 20, 2025

Related Policies:
05.001.012 - Trastuzumab

Ado-Trastuzumab Emtansine (Trastuzumab-DM1) for Treatment of HER2-Positive Malignancies

summary

Description

Ado-trastuzumab emtansine, 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.

Summary of Evidence

For individuals with human epidermal growth factor receptor 2 (HER2)- positive progressive/recurrent or metastatic breast cancer and one or more prior failed HER2-targeted treatment regimens, including trastuzumab and a taxane, who receive ado-trastuzumab emtansine, also known as trastuzumab-DM1 (T-DM1), the evidence includes 3 randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. Based on the 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 (PFS) and an absolute improvement of 5.8 months in OS for individuals treated with T-DM1 compared with those who received lapatinib plus capecitabine. Adverse events from T-DM1 treatment are common. A 2023 RCT (DESTINY-BREAST03) compared trastuzumab deruxtecan (T-Dxd) and T-DM1 and reported significantly improved PFS (28.8 months vs 6.8 months) and OS with T-Dxd compared to T-DM1. The results of this trial led to guideline recommendations demoting T-DM1 to third-line therapy and beyond in individuals with HER2-positive breast cancer, and moving up T-Dxd to second-line therapy or earlier. Despite the results of this trial, T-DM1 may still be beneficial as a third-line therapy and beyond option in some patients. The evidence is sufficient to determine that the technology results in an 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 OS, disease-specific survival, and treatment-related mortality and morbidity. While the phase 2 trial reported longer PFS 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 PFS advantage of T-DM1 with or without pertuzumab compared with trastuzumab plus a 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 a taxane. The evidence is insufficient to determine that the technology results in an improvement in 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 and a phase 2 RCT. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. In the phase 3 KRISTINE trial, individuals 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, the corroboration of the results of the KRISTINE trial is needed. The phase 2 PREDIX HER2 trial found no difference between T-DM1 and control in pathologic response rate, with fewer serious adverse events in the T-DM1 group. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have HER2-positive early-stage breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment who receive adjuvant T-DM1, the evidence includes a phase 3 RCT and a phase 2 RCT. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. The phase 3 KATHERINE trial randomly assigned individuals to postoperative T-DM1 or trastuzumab for the succeeding 42 weeks. A significant reduction of nearly one half in the risk of invasive disease-free survival (invasive breast cancer or death), including the risk of distant recurrence, was observed. Overall, there was an absolute improvement of 11.3 percentage points in the rate of invasive disease-free survival. The trial was underpowered to detect a significant reduction in mortality and survival benefit was not observed, while serious adverse events were more common in the T-DM1 group. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

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 OS, disease-specific survival, and treatment-related mortality and morbidity. Results have shown no survival advantage of T-DM1 over a 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 insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to assess whether the use of ado-trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive malignancies improves the net health outcome.

POLICY Statement

The use of ado-trastuzumab emtansine may be considered medically necessary in individuals with:

• Human epidermal growth factor receptor 2-positive (HER2), metastatic breast cancer who have received prior HER2-targeted therapy (e.g., trastuzumab or trastuzumab with a taxane) OR who developed disease recurrence during or within 6 months of completing adjuvant therapy.

Or

• Human epidermal growth factor receptor 2-positive, early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

The use of ado-trastuzumab emtansine is investigational in all other situations, including but not limited to previously untreated progressive or recurrent locally advanced breast cancer, 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 safety considerations:

• Ado-trastuzumab emtansine is Pregnancy Category D (associated with known gestational adverse events) and should not be used in pregnant individuals. 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 section).

• Decreases in left ventricular ejection fraction have been noted. Selection criteria for the EMILIA trial included a left ventricular ejection fraction of 50% or greater.

• The safety and efficacy of ado-trastuzumab emtansine in pediatric individuals 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

Ado-trastuzumab emtansine is administered at an intravenous dose of 3.6 mg/kg 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 (ie, 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.

Coding

See the Codes table for details.

BENEFIT APPLICATION

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved drugs may not be considered investigational, and thus these drugs may be assessed only on the basis of their medical necessity.

BACKGROUND

Metastatic Breast Cancer

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 2022, National Cancer Institute estimates project that 287,850 new cases of female breast cancer will be diagnosed and approximately 43,250of those diagnosed will die from breast cancer.^1,Although White women are more likely than Black women to receive a breast cancer diagnosis, Black women have an increased risk of breast cancer mortality compared with White women. Both Asian/Pacific Islander women and Hispanic women have a lower risk of breast cancer diagnosis or mortality relative to White and Black women.

Metastatic breast cancer has a poor prognosis. In a cohort of 3524 women diagnosed with breast cancer between 1992 and 2007, Dawood et al (2010) reported a median overall survival of 39.2 months among individuals with de novo stage IV breast cancer and 27.2 months among individuals with relapsed disease (estimates independent of human epidermal growth factor receptor 2 [HER2] status).^2, Factors associated with reduced survival for individuals 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,

Human Epidermal Growth Factor Receptor 2

Approximately 15% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with tyrosine kinase activity.^4, 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), HER2, HER3, and 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 phosphatidylinositol-3 -kinase/AKT pathway, which regulates tumor cell survival, and the mitogen-activated protein kinase 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 HER2-targeted therapy, HER2 overexpression was associated with shorter disease-free 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

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 treatment guidelines for metastatic breast cancer include specific recommendations for first-line treatment of HER2-positive metastatic breast cancer.^8, All recommended treatment regimens include trastuzumab. Recommended agents used singly or in combination with trastuzumab are paclitaxel, docetaxel, vinorelbine, capecitabine, and carboplatin.

Treatment of HER2-Positive Breast Cancer

Before the U.S. Food and Drug Administration (FDA) approved ado-trastuzumab emtansine (T-DM1), it approved 3 anti-HER2 therapies for HER2-positive cancers. These agents arrest tumor cell growth and promote apoptosis by blocking HER2-mediated intracellular signaling pathways that affect 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 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.^9,
• Pertuzumab (Perjeta™) is an intravenous 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 promotes antibody-dependent cell-mediated cytotoxicity.^10,

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. Monotherapy is also an option for first-line treatment. 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 eventually progress.^11,12, 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). For patients not previously exposed to pertuzumab, combination therapy with trastuzumab plus pertuzumab-either with or without cytotoxic chemotherapy (eg, 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.^8,

Ado-Trastuzumab Emtansine

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. Emtansine is conjugated to trastuzumab by lysine side chains, forming a stable thioether linker.^13, T-DM1 binds HER2 with an affinity comparable to that of trastuzumab.^14, Once internalized, proteolytic degradation of the linker releases both trastuzumab and the active metabolite. The active metabolite, maleimidomethyl cyclohexane-1-carboxylate-emtansine, contains both positive and negative charges and therefore does not readily cross plasma membranes, maintaining intracellular concentrations.^11,T-DM1 has been shown to preserve the antitumor activity of trastuzumab (previously described).^15, Death of HER2-expressing cells, therefore, results from the effects of both active moieties of T-DM1.

Comparable pharmacokinetic data have suggested that toxicity associated with trastuzumab exposure is the same whether trastuzumab is administered as T-DM1 or as trastuzumab. Both drugs carry black box warnings for cardiac toxicity and embryo-fetal toxicity.

Regulatory Status

In February 2013, Kadcyla® (ado-trastuzumab emtansine; Genentech) was approved by the FDA through the priority review program 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.

On May 3, 2019, the FDA expanded the indication to include adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

Kadcyla® is not approved by the FDA for the treatment of patients with:

• HER2-positive previously untreated metastatic breast cancer, or

• HER2-positive locally advanced or metastatic gastric or gastroesophageal junction cancer.

T-DM1 has a black box for hepatotoxicity, cardiotoxicity, and embryo-fetal toxicity. In the event of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy with T-DM1, temporary treatment interruption, dose reduction, or discontinuation may be required.

RATIONALE

This evidence review was created in March 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 4, 2024

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and 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 technology, 2 domains are examined: the relevance, and 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

HER2-Positive Progressive/Recurrent or Metastatic Breast Cancer and One or More Prior Failed HER2-Targeted Treatment Regimens

Clinical Context and Therapy Purpose

The purpose of trastuzumab-DM1 (T-DM1) in individuals who have human epidermal growth factor receptor 2 (HER2)-positive progressive/recurrent or metastatic breast cancer and one or more prior failed HER2-targeted treatment regimens 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 the use of T-DM1 improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with HER2-positive progression/recurrent or metastatic breast cancer and one or more prior failed HER2-targeted treatment regimens.

Trastuzumab is recommended as a first-line treatment for individuals 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.^14, 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: standard treatment.

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 individuals not previously exposed to pertuzumab, combination therapy with trastuzumab plus pertuzumab-either with or without cytotoxic chemotherapy (eg, 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.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Two, phase 3 trials of T-DM1 versus control were identified, the EMILIA trial and the TH3RESA trial ( Table 1).^13,16,17,18, Both were international, randomized, stratified, active-controlled, open-label trials. There were some differences between the included populations and control interventions in the trials. EMILIA included individuals with locally advanced or metastatic disease previously treated with trastuzumab and a taxane, while the TH3RESA trial included individuals with progressive metastatic or recurrent disease after 2 or more HER2-targeted treatment regimens. Thus, in EMILIA, T-DM1 was used in a ≥ second-line setting, while in TH3RESA it was used in a ≥ third-line setting. The control intervention in EMILIA was oral lapatinib plus oral capecitabine, and in TH3RESA the control was chosen at the discretion of the treating physician. Primary efficacy outcomes for both trials were progression-free survival (PFS) and overall survival (OS).

PFS in the control group was 5.8 months in EMILIA and 3.3 months in TH3RESA. In EMILIA, PFS was 3.6 months longer in the T-DM1 group, and in TH3RESA, PFS in the T-DM1 group was 3.0 months longer ( 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

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

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; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.a Primary efficacy endpoint for EMILIA and TH3RESA.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<.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.

Limitations 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 endpoints. Both trials had an objective endpoint of OS. The TH3RESA trial used the physician's choice of chemotherapy, which was not standardized. Both trials had crossovers from the control group, although both used intention-to-treat and sensitivity analyses.

Table 3. Study Relevance Limitations

The study limitations 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 Limitations

The study limitations 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 individuals with asymptomatic central nervous system metastases.^19, At a 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 an increase in diarrhea symptoms) with T-DM1 than with capecitabine plus lapatinib (control).^20, The proportion of individuals experiencing a clinically significant improvement in symptoms was similar between groups.

Section Summary: HER2-Positive, Progressive or Recurrent or Metastatic Breast Cancer and Failed Second-line Treatment

Two RCTs (EMILIA and TH3RESA) of ≥ second-line T-DM1 in individuals with HER2-positive breast cancer reported improvement in OS and PFS compared with standard treatment controls. When compared with controls, OS was 5.8 months longer in the T-DM1 group in the EMILIA trial and 6.9 months longer in the TH3RESA trial, while PFS in the T-DM1 group was 3.6 months longer in EMILIA and 3.0 months longer in TH3RESA.

Summary of Evidence

For individuals with HER2-positive progressive/recurrent or metastatic breast cancer and one or more prior failed HER2-targeted treatment regimens, including trastuzumab and a taxane, who receive T-DM1, the evidence includes 2 randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. Based on the 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 OS for individuals treated with T-DM1 compared with those who received lapatinib plus capecitabine. Adverse events from T-DM1 treatment are common. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

HER2-Positive, Previously Untreated Progressive/Recurrent Locally Advanced or Metastatic Breast Cancer

Clinical Context and Therapy Purpose

The purpose of T-DM1 in individuals who have HER2-positive, previously untreated progressive/recurrent locally advanced or 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 the use of T-DM1 improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations

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

Trastuzumab is recommended as a first-line treatment for individuals 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: standard treatment.

The continuation of HER2 blockade is recommended as a second-line treatment for individuals 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.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Perez et al (2014, 2017) reported on the results of the phase 3 MARIANNE trial (Table 5).^22,23, In the MARIANNE trial (N=1095), T-DM1 plus pertuzumab and T-DM1 alone showed PFS was noninferior but not superior to the current standard of care (ie, trastuzumab plus taxane) with a decrease in grade 3 and 4 adverse events (Table 6). The decline in health-related QOL increased from 3.6 to 7.7 and 9.0 for T-DM1 plus pertuzumab, T-DM1 alone, and trastuzumab plus taxane, respectively; hazard ratios (HRs) for the decline in health-related QOL ranged from 0.68 to 0.70.

Table 5. Summary of Key RCT Characteristics

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

Table 6. Summary of Key RCT Results

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.a versus trastuzumab plus taxaneb versus T-DM1

Tables 7 and 8 display notable limitations 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 the evidence supporting the position statement.

Table 7. Study Relevance Limitations

The study limitations 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 8. Study Design and Conduct Limitations

The study limitations 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/Recurrent Locally Advanced or Metastatic Breast Cancer

The pivotal RCT conducted among HER2-positive progressive or recurrent locally advanced breast cancer individuals failed to show the superiority of regimens containing T-DM1 over the current standard of care (ie, 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 QOL from baseline with T-DM1 (9.0 months) or without pertuzumab (7.7 months) was longer than with trastuzumab plus taxane (3.6 months). The likelihood of grade 3 or 4 adverse events was lower in T-DM1 arms than in the trastuzumab plus taxane arm.

Summary of Evidence

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 OS, 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 a 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 a taxane..The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

HER2-Positive, Previously Untreated Early-Stage Breast Cancer

Clinical Context and Therapy Purpose

The purpose of T-DM1 in individuals 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 following PICO was used to select literature to inform this review.

Populations

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

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 HER2-positive previously untreated early-stage breast cancer: standard treatment.

Outcomes

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

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

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 (Table 9).^24, The T-DM1 plus pertuzumab group had a lower pathologic response to treatment (44%) compared with standard therapy (56%; p=.016) (Table 10). 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.

Hatscheck et al (2021) reported the results from the phase 2 PREDIX HER2 trial, conducted at 9 centers in Sweden, comparing neoadjuvant T-DM1 monotherapy with docetaxel, trastuzumab, and pertuzumab (Table 10) in individuals with primarily stage II or III breast cancer.^25, The study reported interim results at a mean follow-up of 40.4 months (through December 2020), with ongoing follow-up planned through 2029. Results of the study are summarized in Table 10. Among the 88 individuals with pathologic complete response (pCR), 21 were subsequently diagnosed with residual ductal carcinoma in situ. Additionally, the study found no difference between groups in event-free survival (Χ²=0.85, 95% confidence interval [CI], 0.60 to 4.13; p=.36). The study also reported that changes in health-related quality of life (HRQoL) fluctuated over the course of one year with no clear, sustained differences between groups, and that by 1-year follow-up, HRQoL scores were similar to those at baseline for both groups.

Table 9. Summary of Key RCT Characteristics

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

Table 10. Summary of Key RCT Results

CI: confidence interval; Diff: difference; HRQOL: health-related quality of life; NR: not reported; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

Tables 11 and 12 display notable limitations 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 the evidence supporting the position statement. While the pathologic complete response may predict long-term response, its significance in this population is uncertain. Both trials are ongoing.

Table 11. Study Relevance Limitations

PFS: progression-free survival.The study limitations 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 12. Study Design and Conduct Limitations

The study limitations 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 and a phase 2 trial (PREDIX HER2) comparing T-DM1 monotherapy with docetaxel and trastuzumab plus pertuzumab. In the KRISTINE trial, 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%. In PREDIX HER2, there were no clear differences between neoadjuvant T-DM1 monotherapy and control therapy in pathologic response, while incidence of serious adverse events was lower with T-DM1.In both trials, the pathologic response was used as a surrogate outcome measure; disease-free survival and OS will be reported in future reports. Corroboration of the findings of the KRISTINE trial and complete follow-up from the PREDIX HER2 trial is needed 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.

Summary of Evidence

For individuals who have HER2-positive previously untreated early-stage breast cancer who receive neoadjuvant T-DM1, the evidence includes a phase 3 RCT and a phase 2 RCT. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. In the phase 3 KRISTINE trial, individuals 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, the corroboration of the results of the KRISTINE trial is needed. The phase 2 PREDIX HER2 trial found no difference between T-DM1 and control in pathologic response rate, with fewer serious adverse events in the T-DM1 group. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

HER2-Positive, Breast Cancer (Adjuvant T-DM1)

Clinical Context and Therapy Purpose

The purpose of T-DM1 in individuals who have breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with HER2-positive breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. Individuals who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2–targeted therapy have a worse prognosis than those who have no residual cancer.

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 HER2-positive early-stage breast cancer with residual invasive disease after neoadjuvant treatment: standard treatment.

Individuals without pathological complete response after preoperative treatment are at increased risk of recurrence. Therefore, these patients are currently recommended to receive the same adjuvant therapies as would be used for any patient with HER2-positive breast cancer, regardless of surgical findings. For example, individuals with HER2-positive breast cancer are recommended to complete a total of 1 year of trastuzumab treatment. They may also receive postsurgical radiation as part of breast conservation or for the presence of other high-risk features. In addition, those with hormone receptor-positive disease are recommended to receive hormonal therapy after surgery. T-DM1 is a replacement option for current therapy.

Outcomes

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

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

The KATHERINE trial (vonMinckwitz et al [2018]) was an international, multicenter, open-label, phase 3 study that compared adjuvant T-DM1 with trastuzumab in patients with residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab.^26, The primary endpoint was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause) (Tables 13 and 14). Results of the pre-specified interim analysis reported invasive disease or death had occurred in 91 individuals in the T-DM1 group (12.2%) and 165 individuals in the trastuzumab group (22.2%). Thus, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. Consistent benefit of T-DM1 was observed in invasive disease-free survival (iDFS) across multiple stratification cohorts including patients with hormone-receptor-positive or hormone-receptor-negative disease, individuals with positive or negative pathological nodal status after neoadjuvant therapy, and individuals with either no residual invasive primary disease or residual primary disease of 1 cm or less in the breast. More adverse events were associated with T-DM1 than with trastuzumab alone and a greater proportion of patients in the T-DM1 discontinuing treatment due to an adverse event compared to trastuzumab group (18% vs. 2.1%). Conte et al (2020) reported results of patient-reported outcomes from the phase 3 KATHERINE trial and found that HRQoL was generally similar between treatment arms (adjuvant T-DM1 vs. trastuzumab) and generally maintained in both arms over the course of treatment.^27, No clinically meaningful changes (≥10 points) from baseline in mean European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 and breast cancer module scores occurred in either arm. All 14 cycles of assigned therapy were completed in 71.4% of patients who received T-DM1 and 81.0% of patients who received trastuzumab.

Table 13. Summary of Key RCT Characteristics

ECOG; European Cooperative Oncology Group; HER2: epidermal growth factor receptor 2; IV; Intravenous; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.

Table 14. Summary of Key RCT Results

AE: adverse events; CI: confidence interval; HR: hazard ratio; iDFS; invasive disease-free survival; NCI-CTCAE; National Cancer Institute Common Terminology Criteria for Adverse Events; RCT: randomized controlled trial; T-DM1: ado-trastuzumab emtansine.a The most common adverse event leading to discontinuation of the trial drug in the T-DM1 group were a decreased platelet count in 31 of 740 patients (4.2%), an increased blood bilirubin level in 19 patients (2.6%), an increased aspartate aminotransferase level in 12 patients (1.6%), an increased alanine aminotransferase level in 11 patients (1.5%), peripheral sensory neuropathy in 11 patients (1.5%), and a decreased ejection fraction in 9 patients (1.2%). The most common adverse events leading to discontinuation of the trial drug in the trastuzumab group was a decreased ejection fraction in 10 of 720 patients (1.4%).

Tables 15 and 16 display notable limitations 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 the evidence supporting the position statement. Additional follow-up will be necessary to determine whether there is an effect of adjuvant T-DM1 on OS.

Table 15. Study Relevance Limitations

The study limitations 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 16. Study Design and Conduct Limitations

The study limitations 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, Breast Cancer (Adjuvant T-DM1)

The evidence on T-DM1 for adjuvant treatment of HER2-positive early-stage breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment includes an international phase 3 trial (KATHERINE) that randomly assigned individuals to postoperative T-DM1 or trastuzumab for the succeeding 42 weeks. A significant reduction of nearly one half in the risk of iDFS (invasive breast cancer or death), including the risk of distant recurrence, was observed. Overall, there was an absolute improvement of 11.3 percentage points in the rate of iDFS. The trial was underpowered to detect a significant reduction in mortality and survival benefit was not observed. The HR for death was 0.70 (95% CI: 0.47 to 1.05). More serious adverse events occurred in individuals who received T-DM1 than in those who received trastuzumab (12.7% vs. 8.1%), and more patients discontinued T-DM1 than trastuzumab (18.0% vs. 2.1%) before the completion of the anticipated 14 postsurgical cycles.

Summary of Evidence

For individuals who have HER2-positive early-stage breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment who receive adjuvant T-DM1, the evidence includes a phase 3 RCT and a phase 2 RCT. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. The phase 3 KATHERINE trial randomly assigned individuals to postoperative T-DM1 or trastuzumab for the succeeding 42 weeks. A significant reduction of nearly one half in the risk of invasive disease-free survival (invasive breast cancer or death), including the risk of distant recurrence, was observed. Overall, there was an absolute improvement of 11.3 percentage points in the rate of invasive disease-free survival. The trial was underpowered to detect a significant reduction in mortality and survival benefit was not observed, while serious adverse events were more common in the T-DM1 group. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

HER2-Positive, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Clinical Context and Therapy Purpose

The purpose of T-DM1 in individuals 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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals 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.

Comparators

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

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.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

The 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 (Table 17).^28, The primary endpoint 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 (Table 18).

Table 17. Summary of Key RCT Characteristics

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

Table 18. Summary of Key RCT Results

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

Tables 19 and 20 display notable limitations 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 the evidence supporting the position statement.

Table 19. Study Relevance Limitations

The study limitations 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 20. Study Design and Conduct Limitations

The study limitations 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 individuals 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=.86).

Summary of Evidence

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 OS, disease-specific survival, and treatment-related mortality and morbidity. Results have shown no survival advantage of T-DM1 over a 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 insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

In 2018, the American Society of Clinical Oncology (ASCO) updated its evidence-based guidelines on systemic therapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer.^29, Ado-trastuzumab emtansine (T-DM1) was recommended as a second-line treatment for patients whose cancer had progressed during or after first-line HER2-targeted therapy (eg, with trastuzumab, pertuzumab, and a taxane). A 2022 guideline update now recommends trastuzumab deruxtecan (T-Dxd) as the preferred second-line treatment for patients whose cancer has progressed during or after first-line HER2-targeted therapy (eg, with trastuzumab, pertuzumab, and a taxane).^30, The updated guidelines offer the following recommendation for T-DM1: "If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment and the patient has already received pertuzumab and T-Dxd (if a patient has not received pertuzumab, clinicians may offer pertuzumab), clinicians should recommend third-line or greater HER2-targeted therapy based treatment. Overall, there is a lack of head-to-head trials; therefore, there is insufficient evidence to recommend one regimen over another. The patient and the clinician should discuss differences in treatment schedules, routes, and toxicities during the decision-making process...[1 available option is]: If a patient has not received trastuzumab emtansine (T-DM1) in second-line, should offer a T-DM1 regimen (Type: Evidence based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong)."

In February 2021, ASCO published key recommendations on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer.^31, Specifically, patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity.

In May 2021, ASCO published guideline recommendations concerning optimal neoadjuvant therapy for breast cancer.^32, The Expert Panel did not recommend use of the neoadjuvant T-DM1 plus pertuzumab in patients with node-positive or high-risk node-negative, HER2-positive disease due to the lower pathologic complete response rate.

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network (NCCN) guidelines for breast cancer (v.2.2024 ) cite T-DM1 as an option for third-line and beyond for treatment of patients with recurrent, unresectable (local or regional), or stage IV (M1) disease. The guideline states that the optimal sequence for third-line therapy and beyond is not known.^8,T-DM1 monotherapy is also listed as an option for HER2-positive preoperative/adjuvant therapy regimens in the category "useful in certain circumstances".

T-DM1 has not been considered in the NCCN (v.2.2024 ) guidelines on the treatment of gastric cancer.^33,

National Institute for Health and Care Excellence

In 2017, NICE issued guidance on trastuzumab emtansine for treating HER2-positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane.^34,"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."

In June 2020, NICE issued technology appraisal guidance recommending trastuzumab emtansine as an option for the adjuvant treatment of HER2-positive early breast cancer in adults who have residual invasive disease in the breast or lymph nodes after neoadjuvant taxane-based and HER2-targeted therapy. The next review of this guidance will take place in 2023.^35,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 21.

Table 21. Summary of Key Trials

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

REFERENCES

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