Medical Policies - Prescription Drugs


Kadcyla (ado-trastuzumab emtansine)

Number:RX502.038

Effective Date:10-01-2018

Coverage:

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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

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

Patient has human epidermal growth factor receptor 2 (HER2) positive, metastatic breast cancer,

Patient has received prior treatment for metastatic disease or has developed recurrent disease within 6 months of completing adjuvant therapy, and

Patient has received prior treatment with trastuzumab and a taxane.

The use of Kadcyla (ado-trastuzumab emtansine) is considered experimental investigational and/or unproven in all other situations, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer.

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 2016, an estimated 246,660 new cases of breast cancer will be 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 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 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 of HER2-Positive Breast Cancer

Before the U. S. Food and Drug Administration (FDA) approved 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 IV 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 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. (12) Ado-trastuzumab emtansine binds HER2 with an affinity comparable to that of trastuzumab. (13) Once internalized, proteolytic degradation of the linker releases both trastuzumab and the active metabolite, maleimidomethyl cyclohexane-1-carboxylate (MCC)-emtansine. MCC-emtansine contains both positive and negative charges and therefore does not readily cross plasma membranes, maintaining intracellular concentrations. (10) Ado-trastuzumab emtansine has been shown to preserve the antitumor activity of trastuzumab (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

In February 2013, Kadcyla™ (ado-trastuzumab emtansine; Genentech) was approved by the U.S. Food and Drug Administration through the priority review program as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (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. (15)

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

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

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

Rationale:

This medical policy was originally based from a 2013 BCA TEC Special Pharmacy Report (16) and has been updated periodically with literature reviews of the MEDLINE database. The most recent update with literature review covered the period through January 2017. The rationale section of this medical policy has been significantly revised.

EFFICACY

HER2-Positive, Previously Treated Metastatic Breast Cancer

Randomized Controlled Trials

EMILIA Trial

EMILIA (N=991) was a phase 3, randomized, stratified, active-controlled, open-label trial conducted in 26 countries (27% from the United States). (12) Patients had unresectable, locally advanced, or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer previously treated with trastuzumab and a taxane. Median age was 53 years, approximately 37% of patients had 3 or more metastatic sites, and 68% had visceral disease involvement. Patients were randomized to 1 of 2 treatment groups: intravenous infusions of ado-trastuzumab emtansine 3.6 mg/kg every 21 days or self-administered oral lapatinib 1250 mg daily plus oral capecitabine 1000 mg/m2 every 12 hours for the first 14 days of each 21-day treatment cycle. Primary efficacy outcomes were progression-free survival (PFS) by independent review committee and overall survival (OS). PFS was 9.6 months in the ado-trastuzumab emtansine group and 6.4 months in the lapatinib plus capecitabine group (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55 to 0.77). At a median follow-up of approximately 19 months, an interim analysis of OS crossed the predetermined stopping boundary, and the trial was discontinued. OS was 30.9 months in the ado-trastuzumab emtansine group and 25.1 months in the lapatinib plus capecitabine group (HR=0.68; 95% CI: 0.55 to 0.85) (see Table 1).

Trastuzumab emtansine 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 trastuzumab emtansine, temporary treatment interruption, dose reduction, or discontinuation may be required.

Table 1. EMILIA Trial Results (12)

Outcomes

Ado-Trastuzumab Emtansine (n=495)

Lapatinib Plus Capecitabine (n=496)

Hazard Ratio (95% CI)

P

IRC-assessed median PFS, moa

9.6

6.4

0.65 (0.55 to 0.77) <0.001

<0.001

Investigator-assessed median PFS, mo

9.4

5.8

0.6 (0.56 to 0.77)

<0.001

Overall survivala

Median follow-up≈19 mob

Median OS, mo

30.9

25.1

0.68 (0.55 to 0.85)

<0.001c

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

85.2% (82.0 to 88.5)

78.4% (74.6 to 82.3)

Estimated 2-year OS (95% CI), %

64.7% (59.3 to 70.2)

51.8% (45.9 to 57.7)

Ado-Trastuzumab Emtansine

(n=397)d

Lapatinib Plus Capecitabine (n=389)d

Difference (95% CI)

p

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

43.6% (38.6 to 48.6)

30.8% (26.3 to 35.7)

12.7% (6.0 to 19.4)

<0.001

Partial response

42.6%

30.3

Complete response

1.0%

0.5%

Median duration of OR (95% CI), mo

12.6 (8.4 to 20.8)

6.5 (5.5 to 7.2)

CI: confidence interval; IRC: independent review committee; ORR: objective response rate; OS: overall survival; PFS: progression-free survival.

a Primary efficacy end point.

bMedian follow-up in the ado-trastuzumab emtansine group was 19.1 mo (range, 0-40 mo) and in the lapatinib plus capecitabine group, 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 ado-trastuzumab emtansine group and 78% of patients in the lapatinib plus capecitabine group had measurable disease at baseline.

e Defined as the combined incidence of complete response and partial response.

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. (17) Patients with untreated and/or symptomatic CNS metastases or with CNS-only disease were excluded from the EMILIA trial. For the post hoc analyses, patients with treated, asymptomatic CNS metastases at baseline (n=45 in the ado-trastuzumab emtansine group; n=50 in the control group) were reviewed. 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; HR=1.00; 95% CI, 0.54 to 1.84; stratified [by world region, prior chemotherapy regimen for advanced or metastatic disease, and presence of visceral metastases], p=1.00), but median OS was longer in the ado-trastuzumab emtansine group (26.8 months vs 12.9 months, respectively; HR=0.38 [95% CI, 0.18 to 0.80]; p=0.008). 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 ado-trastuzumab emtansine than with capecitabine-lapatinib (control). (18) The proportion of patients experiencing a clinically significant improvement in symptoms was similar between groups.

TH3RESA Trial

In 2014, Krop et al. published results of the TH3RESA trial in patients with progressive disease after 2 or more HER2-targeted treatment regimens for recurrent or metastatic breast cancer. (19) TH3RESA was an international, phase 3, open-label randomized controlled trial (RCT) that compared ado-trastuzumab emtansine with treatment of physician’s choice (chemotherapy, hormone therapy, and/or HER2-targeted therapy). Eligible patients had been treated with both trastuzumab and lapatinib in the advanced setting and a taxane in any setting. Patients were randomized 2:1 to trastuzumab emtansine (n=404) or physician’s choice treatment (n=198), stratified by world region (U.S. vs Western Europe vs other), number of previous regimens for advanced disease (2-3 vs >3), and presence of visceral disease (any vs none). Coprimary end points were investigator-assessed PFS and OS. Analysis was intention to treat. 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 versus 4.2 months in the ado-trastuzumab emtansine group. At follow-up of approximately 7 months, median PFS was almost twice as long in the ado-trastuzumab group (6.2 months) as in the physician’s choice group (3.3 months; stratified HR=0.53; 95% CI, 0.42 to 0.66; p<0.001). This finding was replicated in subgroup analyses of patients who did (n=149) or did not (n=49) receive trastuzumab in the physician’s choice group, and in several other subgroup analyses. For U.S. patients (99 in the ado-trastuzumab group, 48 in the physician’s choice group), median PFS did not differ statistically between groups (HR=0.71; 95% CI, 0.44 to 1.14). In interim OS analysis, 15% of patients in the ado-trastuzumab emtansine group and 22% in the physician’s choice group died, a statistically nonsignificant result due to statistical correction (O’Brien-Fleming stopping boundary). Incidence of grade 3 or greater adverse events was lower in the ado-trastuzumab emtansine group than in the physician’s choice group (32% vs 43%, respectively). Of several hematologic adverse events (neutropenia, febrile neutropenia, anemia, leukopenia, thrombocytopenia), only thrombocytopenia occurred more commonly in the ado-trastuzumab emtansine group (15% vs 3%). Nine (2%) patients who received ado-trastuzumab emtansine had grade 3 or worse hemorrhage compared with 1 (<1%) patient who received physician’s choice treatment.

Systematic Reviews

Two meta-analyses by Ma et al. (20) and Shen et al., (21) both published in 2016, have supported findings that treatment with single-agent ado-trastuzumab emtansine is superior to capecitabine plus lapatinib or physician choice in patients with metastatic breast cancer who have been previously treated with trastuzumab and a taxane, separately or in combination. In the Ma analysis, instead of pooling OS or PFS data, the reviewers pooled the percentage of patients with event (death or PFS) at discreet time interval (2, 4, 6, 8, 10, 12 months) for the phase 3 and 2 trials. In the Shen analysis, risk of bias or quality assessment of studies included in the meta-analysis was not conducted. In the efficacy analysis, the pooled odds ratio that included 2 trials for OS was 0.60 (95% CI, 0.48 to 0.75) and the pooled odds ratio for PFS that included 3 trials was 0.60 (95% CI, 0.53 to 0.69). For the safety analysis, increased transaminases (OR=4.040; 95% CI 1.429 to 11.427), thrombocytopenia (OR=8.500; 95% CI, 3.964 to 18.226), and fatigue (OR=1.288; 95% CI 1.041 to 1.593) occurred more frequently in patients who received ado-trastuzumab emtansine compared to controls.

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. In TDM4374g (N=110), patients were previously treated with trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine. (12) Ninety-eight percent of patients were female, median age was 53 years, 74% of patients had 3 or more metastatic sites, and patients had received a median of 7 systemic treatments for metastatic disease. In TDM4258g (N=112), patients previously treated with HER2-directed therapy (trastuzumab or lapatinib) were enrolled. (22) Median age was 55 years, 75% of patients had 3 or more metastatic sites, and patients had received a median of 5 systemic treatments for metastatic disease. All patients in both studies received ado-trastuzumab emtansine 3.6 mg/kg intravenously (IV) every 3 weeks with dose modifications for adverse events. Objective response rate (ORR; defined as complete plus partial responses) determined by an independent radiologic facility was the primary efficacy outcome in both studies. In TDM4374g (more pretreatment), ORR was 35% (95% CI, 26% to 44%). In TDM4258g (less pretreatment), ORR was 26% (95% CI, 18% to 34%). There were no complete responses. Median PFS, a secondary outcome, was 6.9 months (95% CI, 4.2 to 8.4 months) in TDM4374g and 4.6 months (95% CI, 3.9 to 8.6 months) in TDM4258g (see Table 2).

In the third study, 64 patients with HER2-positive, locally advanced breast cancer were treated with ado-trastuzumab emtansine 3.6 mg/kg plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. (23) The primary efficacy end point was investigator-assessed ORR. Of the 64 patients, 43 were in the second-line or greater setting; 21 were in the first-line setting. Overall ORR was 41%, 57% in first-line setting and 33% in the other settings, with median PFS was 7.7 months (6.6 months in first-line, 5.5 months in the other settings).

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

Outcomes

Krop (2012)12

(N=110)

Burris (2011)22

(N=112)

Miller (2014)23

(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.

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

HER2-Positive, Progressive or Recurrent or Metastatic Breast Cancer

Hurvitz et al. (2013) conducted a phase 2, open-label, RCT (TDM4450g) of ado-trastuzumab emtansine as first-line treatment of HER2-positive metastatic or recurrent locally advanced breast cancer. (24) With a median follow-up of 14 months, median PFS was 14.2 months in the ado-trastuzumab emtansine group and 9.2 months in the trastuzumab plus docetaxel group (HR=0.59; 95% CI, 0.36 to 0.97; p=0.04). Respective ORRs were 64% and 58% (p=0.46). Survival results were confounded because 50% of patients in the control group crossed over to ado-trastuzumab emtansine after progression. At 23-month median follow-up, preliminary analysis showed no statistical difference between groups (13 deaths in each group; HR=1.06; 95% CI, 0.48 to 2.35; p=0.89). Fewer grade 3 or higher adverse events (46% 91%), adverse events leading to treatment discontinuation (7% vs 41%), and serious adverse events (20% vs 26%) occurred in the ado-trastuzumab emtansine group than in the comparator group.

In the phase 3 MARIANNE (NCT01120184) trial, patients with centrally assessed HER2-positive progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer with a 6-month or more interval since treatment in the neoadjuvant setting with taxanes or vinca alkaloids were randomized 1:1:1 to trastuzumab emtansine plus pertuzumab (n=363), trastuzumab emtansine alone (n=367), or trastuzumab plus taxane (docetaxel or paclitaxel) (n=365). (25) Results published in 2015 in abstract form showed that neither trastuzumab emtansine arm (with or without pertuzumab) was associated with improved PFS compared with the trastuzumab plus taxane arm. Median PFS rates in the 3 treatment arms were 15.2, 14.1, and 13.7 months, respectively. Compared to trastuzumab plus taxane arm, the hazard ratio in trastuzumab emtansine with and without pertuzumab was 0.87 (95% CI, 0.69 to 1.08) and 0.91 (95% CI, 0.73 to 1.13), respectively. Secondary analysis of patient-reported outcomes such as quality of life, taxane-related symptoms, and rates of nausea, diarrhea, and alopecia was published in 2016. (26) Results showed that patients in the ado-trastuzumab emtansine arms reported a lower incidence of and a longer time to clinically important difference in neurotoxicity, as well as less alopecia versus patients receiving trastuzumab plus a taxane.

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

The open-label, GATSBY trial randomized 415 patients with HER2-positive unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer to receive trastuzumab emtansine (3.6 mg/kg every 3 weeks or 2.4 mg/kg every week) or physicians’ choice of paclitaxel 80 mg/m2 every week or docetaxel 75 mg/m2 every 3 weeks. (27) Patients had to have progressed during or after first-line fluoropyrimidine plus platinum therapy with or without HER2-targeted therapy. As of June 2015, median OS was 7.9 months for the weekly trastuzumab emtansine group and 8.6 months for the taxane group (HR=1.15; 95% CI, 0.87 to 1.51). Median PFS was 2.7 months and 2.9 months, respectively. Grade 3 and 4 adverse events were numerically lower in the T-DM1 group (59.8% vs 70.3%), while rates of serious adverse events, fatal adverse events, and treatment discontinuation due to adverse events were similar. Thus, trastuzumab emtansine did not show an efficacy benefit over taxane for HER2-positive local advanced or metastatic gastric or gastroesophageal junction cancer.

Summary of Evidence

For individuals who have human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who failed treatment for metastatic disease, including trastuzumab and a taxane, who receive ado-trastuzumab emtansine, 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, ado-trastuzumab emtansine 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 overall survival for patients treated with ado-trastuzumab emtansine compared with those who received lapatinib plus capecitabine. Uncontrolled studies have corroborated the efficacy of ado-trastuzumab emtansine with objective response rates reported as ranging from 26% to 41% of patients in 3 phase 2 studies. Adverse events from ado-trastuzumab emtansine 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 progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer who receive ado-trastuzumab emtansine, the evidence includes 1 RCT and 1 uncontrolled trial. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. While the phase 2 trial reported longer PFS with ado-trastuzumab emtansine 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 trastuzumab emtansine with or without pertuzumab compared to trastuzumab plus taxane. Secondary analysis of this trial provided better patient-reported outcomes such as quality of life, taxane-related symptoms, and rates of nausea, diarrhea, and alopecia in patients receiving trastuzumab emtansine compared to 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 locally advanced or metastatic gastric or gastroesophageal junction cancer who receive ado-trastuzumab emtansine, the evidence includes 1 RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Results have shown no survival advantage of trastuzumab emtansine 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 (59.8% vs 70.3%), 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 clinical practice guidelines from the National Comprehensive Cancer Network (NCCN; v.2.2016) recommend ado-trastuzumab emtansine as a preferred option for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer previously treated with trastuzumab (4) (category 2A recommendation, based on lower level evidence with uniform panel consensus). As of September 2016, ado-trastuzumab emtansine has not been considered in the NCCN guidelines on treatment of gastric cancer (v.3.2016). (28)

National Institute for Health and Clinical Excellence

In December 2015, the National Institute for Health and Clinical Excellence (NICE) issued a guidance on trastuzumab emtansine for treating HER2-positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. (29) The guidance does not recommend trastuzumab emtansine for this indication. The guidance cites concerns about the generalizability of the EMILIA trial results, including:

Patients in EMILIA had Eastern Cooperative Oncology Group (ECOG) scores of 0 and 1 while patients in clinical practice would more likely have ECOG scores of 2.

Patients in England have been receiving trastuzumab plus docetaxel plus pertuzumab as first-line treatment, but only 9.5% of patients enrolled in EMILIA had received pertuzumab as part of their first-line treatment regimen.

EMILIA results showed improved survival in the trastuzumab emtansine group regardless of line of therapy, the recommendation is for the drug as a second-line therapy.

American Society of Clinical Oncology

In 2014, the American Society of Clinical Oncology published evidence-based guidelines on systemic therapy for patients with advanced HER2-positive breast cancer. (30) Ado-trastuzumab emtansine was recommended as second-line treatment for patients whose cancer progresses during or after first-line HER2-targeted therapy (e.g., with trastuzumab, pertuzumab, and a taxane). Ado-trastuzumab emtansine was also recommended in subsequent lines unless previously tried (strength of both recommendations: strong, based on high-quality evidence).

National Health Service In 2012, the U.K.’s National Institute for Health Research Horizon Scanning Centre identified T-DM1 in combination with pertuzumab (Perjeta) for first-line treatment of HER2-positive metastatic breast cancer as an emerging health therapeutic agent that may “significantly impact patients or the provision of health services.” (31)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

Breast cancer

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

May 2017

NCT02131064a

A Study Comparing Kadcyla Plus Perjeta Treatment to Chemotherapy Combined With Herceptin Plus Perjeta in Patients With HER2-Positive Breast Cancer

444

Jan 2018

NCT01702571

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

2200

July 2018

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

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)

1484

Mar 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

2500

May 2023

Gastric cancer

NCT01702558a

A Combination Study of Trastuzumab Emtansine and Capecitabine in Patients With Breast Cancer or Gastric Cancer

235

July 2017

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9354

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. SEER Stat Fact Sheet: Breast Cancer. Available at: http://seer.cancer.gov. Accessed September 22, 2016.

2. Dawood S, Broglio K, Ensor J, et al. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol. Nov 2010; 21(11):2169-2174. PMID 20427349

3. Chang J, Clark GM, Allred DC, et al. Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer. Feb 1 2003; 97(3):545-553. PMID 12548595

4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, version 2.2016. Available at: https://www.nccn.org. Accessed September 22, 2016.

5. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med. Jul 5 2007; 357(1):39-51. PMID 17611206

6. Baselga J. Treatment of HER2-overexpressing breast cancer. Ann Oncol. Oct 2010; 21 Suppl 7:vii36-40. PMID 20943641

7. Press MF, Sauter G, Bernstein L, et al. Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res. Sep 15 2005; 11(18):6598-6607. PMID 16166438

8. GlaxoSmithKline. Tykerb (lapatinib) tablets prescribing information, October 2013. Available at: https://www.gsksource.com. Accessed January 19, 2015.

9. Genentech, Inc. PerjetaTM (pertuzumab) injection for intravenous use prescribing information, September 2013. Available at: http://www.perjeta.com/. Accessed January 19, 2015.

10. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. Oct 15 2011; 17(20):6437-6447. PMID 22003071

11. Burris HA, 3rd, Tibbitts J, Holden SN, et al. Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer. Clin Breast Cancer. Oct 2011; 11(5):275-282. PMID 21729661

12. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. Nov 8 2012; 367(19):1783-1791. PMID 23020162

13. Burris HA. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Expert Opin Biol Ther. Jun 2011; 11(6):807-819. PMID 21506905

14. Girish S, Gupta M, Wang B, et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol. May 2012; 69(5):1229-1240. PMID 22271209

15. KADCYLA® (ado-trastuzumab emtansine) for injection, for intravenous use. Available at: http://www.gene.com. Accessed Sep, 2016.

16. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Trastuzumab emtansine (T-DM1). TEC Specialty Pharmacy Reports. 2013; #03-2013.

17. 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

18. 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

19. 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

20. Ma B, Ma Q, Wang H, et al. Clinical efficacy and safety of T-DM1 for patients with HER2-positive breast cancer. Onco Targets Ther. 2016; 9:959-976. PMID 27013890

21. Shen K, Ma X, Zhu C, et al. Safety and efficacy of trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer: a meta-analysis. Sci Rep. 2016; 6:23262. PMID 26979925

22. 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

23. 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

24. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. Mar 20 2013; 31(9):1157-1163. PMID 23382472

25. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. J Clin Oncol 33, 2015 (suppl; abstr 507). PMID

26. Patient-reported outcomes (PROs) from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab (P) vs trastuzumab + taxane (HT) for HER2-positive advanced breast cancer. J Clin Oncol 34, 2016 (suppl; abstr 593). PMID

27. A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC). J Clin Oncol 34, 2016 (suppl 4S; abstr 5). PMID

28. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 3.2016. Available at: https://www.nccn.org. Accessed September 22, 2016.

29. National Institute for Health and Clinical Excellence (NICE). Trastuzumab emtansine for treating HER2-positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. Available at: https://www.nice.org. Accessed September 22, 2016.

30. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. Jul 1 2014; 32(19):2078-2099. PMID 24799465

31. U.K. National Institute for Health Research (NIHR). Trastuzumab emtansine in combination with pertuzumab for HER2-positive metastatic breast cancer - first line, June 2012. 2012; Available at: http://www.hsc.nihr.ac.uk/topics/trastuzumab-emtansine-in-combination-with-pertuzum/. Accessed January 19, 2015.

32. Ado-Trastuzumab Emtansine (Trastuzumab-DM1) for Treatment of HER2-Positive Malignancies. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (October 2016) 5.01.22.

Policy History:

DateReason
10/1/2018 Reviewed. No changes.
4/1/2017 Document updated with literature review. Coverage unchanged.
3/15/2016 Reviewed. No changes.
7/15/2015 New medical document. Kadcyla (ado-trastuzumab emtansine) may be considered medically necessary in adults with HER2-positive metastatic breast cancer who have received previous treatment with trastuzumab and a taxane either separately or in combination, and either: 1) Received prior therapy for metastatic disease, or 2) Developed recurrent disease during, or within 6 months of completing, adjuvant therapy. Kadcyla (ado-trastuzumab emtansine) is considered experimental, investigational and/or unproven for all other indications, including but not limited to colorectal cancer, gastric cancer, or hepatobiliary cancers (cholangiocarcinoma and gall bladder cancer).

Archived Document(s):

Title:Effective Date:End Date:
Kadcyla (ado-trastuzumab emtansine)04-01-201709-30-2018
Kadcyla (ado-trastuzumab emtansine)03-15-201603-31-2017
Kadcyla (ado-trastuzumab emtansine)07-15-201503-14-2016
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