Archived Policies - Prescription Drugs
Kadcyla (ado-trastuzumab emtansine)
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, Hayes, DrugDex (IIb level of evidence 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.
Kadcyla (ado-trastuzumab emtansine) may be considered medically necessary for treatment of 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).
Approximately 20-25% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein receptor with tyrosine kinase activity. Overexpression of this receptor is associated with reduced time to disease recurrence and poorer prognosis. (59)
Breast cancer accounts for nearly 1 in 3 cancer diagnoses in women in the U.S. Among women, it is the most common cancer after non-melanoma skin cancer. Breast cancer ranks second after lung cancer for cancer mortality. The prognosis for patients with metastatic breast cancer is poor. Before the advent of HER2-targeted therapy, HER2 overexpression was associated with shorter disease-free and overall survival in both lymph node-negative and lymph node-positive patients, lack of responsiveness to tamoxifen therapy, and altered responsiveness to cytotoxic chemotherapy. (7) Testing for HER2 amplification and overexpression is recommended as a routine part of the diagnostic work-up for all primary breast cancers. The main benefit of HER2 testing is prediction of response to targeted therapy.
In addition to Kadcyla, three other anti-HER2 therapies have previously been US Food and Drug Administration (FDA)-approved currently for HER2-positive cancers. These agents arrest tumor cell growth and promote apoptosis by blocking HER2-mediated intracellular signaling pathways that mediate cell growth, differentiation, and survival:
• Trastuzumab (Herceptin®) is an intravenous monoclonal antibody to an extracellular domain of the HER2 receptor (Subdomain IV) that prevents activation of intracellular tyrosine kinase signaling cascades and also promotes antibody dependent cell mediated cytotoxicity (ADCC) (8);
• Lapatinib (Tykerb®) is an oral tyrosine kinase inhibitor that blocks the intracellular tyrosine kinase domain of HER2 and downstream cell signaling cascades (13);
• Pertuzumab (Perjeta™) is an oral monoclonal antibody to the extracellular dimerization domain of the HER2 receptor (Subdomain II) that, like trastuzumab, prevents activation of intracellular tyrosine kinase signaling cascades and also promotes antibody-dependent cell-mediated cytotoxicity (ADCC). (14)
All three drugs have demonstrated improved overall survival in HER2-positive metastatic breast cancer. (8,11,15,16) Pertuzumab is FDA-approved only for patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, a different population than that studied for ado-trastuzumab emtansine (i.e., with progression after treatment with trastuzumab and a taxane). (59)
Ado-trastuzumab emtansine is a HER2 targeted antibody and microtubule conjugate comprising trastuzumab and emtansine. The prefix “ado” was added to reduce medication errors. (24) Emtansine (previously called “DM1” for “derivative of maytansine 1”) is a sulfur-containing derivative of the potent microtubule inhibitor, maytansine. Emtansine is conjugated to trastuzumab by lysine side chains, forming a stable thioether linker. (25) Ado-trastuzumab emtansine binds HER2 with an affinity comparable to that of trastuzumab. (18) Once internalized, proteolytic degradation of the linker releases both trastuzumab and the active emtansine 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. (17) Ado-trastuzumab emtansine has been shown to preserve the antitumor activity of trastuzumab. (26) Death of HER2-expressing cells therefore results from effects of both active moieties of ado-trastuzumab emtansine. Comparable pharmacokinetic data suggest that toxicity associated with trastuzumab exposure is the same whether trastuzumab is administered as ado-trastuzumab emtansine or as trastuzumab. Both drugs carry Black Box Warnings for hepatotoxicity, cardiac toxicity and embryo-fetal toxicity. (59)
In February, 2013, the US Food and Drug Administration (FDA) granted Genentech, Inc., approval to manufacture and market Kadcyla® (ado-trastuzumab emtansine). Approved label states Kadcyla is a HER2-targeted antibody and microtubule inhibitor conjugate indicated, 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: 1) Received prior therapy for metastatic disease, or 2) Developed disease recurrence during or within six months of completing adjuvant therapy. The FDA label was updated in 2013 and July 2014, but these indications have not changed. The FDA label does include a Black Box Warning for hepatotoxicity (including liver failure and death), cardiac toxicity (including reduced let ventricular ejection fraction), and embryo-fetal toxicity. (58)
Summary of Evidence
On July 6, 2010, Genentech first submitted to the FDA a Biologics License Application (BLA) requesting accelerated approval of ado-trastuzumab emtansine (Kadcyla). The submission was based on a single-arm Phase II study, TDM4374g (29), and a proof-of-concept study, TDM4258g. (30,31) FDA’s accelerated approval regulation requires that there is an unmet need in a defined patient population for whom early safety and efficacy data of the submitted drug indicate a reasonable probability of clinical benefit based on surrogate outcomes. (32) In August 2010, FDA issued a Refuse to File letter to Genentech; a Genentech press release stated that the BLA was refused because “all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.” (33) Others reported that FDA requested “a randomized Phase III ado-trastuzumab emtansine trial with a larger number of patients.” (18) In November 2012, FDA accepted for priority review a new BLA that included the Phase III EMILIA trial. Priority Review is reserved for drugs that provide a treatment option when no adequate therapy currently exists or that offer major advances in treatment. (32) The Phase III EMILIA trial and the two Phase II studies are reviewed below.
Phase III EMILIA Trial
Efficacy and safety of ado-trastuzumab emtansine were assessed in the randomized, active controlled, open-label, Phase III EMILIA trial. (25) EMILIA was conducted in 26 countries (27% US) and enrolled 991 patients (986 women and 5 men) with unresectable locally advanced or metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane. HER2 positivity was centrally confirmed using IHC (3+) and FISH (amplification ratio ≥2.0) assays. Eighty-six percent of patients were younger than 65 years, and 3% were 75 years of age or older. The majority of patients were white (75%). Only 5% were black. Patients were stratified by world region (Western Europe, US, or other), number of prior chemotherapy regimens for advanced disease (none or one, or more than one), and visceral disease involvement (yes or no), and randomized to one of two 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. The first ado-trastuzumab emtansine infusion was 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 well tolerated (i.e., without any signs or symptoms of infusion reaction), subsequent infusions were administered over 30 minutes followed by 30 minutes of observation. Dose interruptions, reductions, and discontinuations of all study drugs were predefined for adverse events. Median doses received were 3.5 mg/kg (range 2.7 to 4.0) for ado-trastuzumab emtansine, 1250 mg (range 250 to 1332) for lapatinib, and 1730 mg/m2 (range 782 to 2338) for capecitabine total daily dose.
Some (34) have criticized the choice of comparator in the EMILIA trial because of recent data indicating that 1) lapatinib plus trastuzumab is more effective than lapatinib alone in patients who progress on trastuzumab-containing therapy (35); and 2) modest benefit may be achieved in this population by continuing trastuzumab. (36) However, these treatment approaches had not been accepted into common practice at the inception of the EMILIA trial. (37-39) Then-current guidelines from the National Comprehensive Cancer Network (NCCN) recommended all three options – lapatinib plus capecitabine (the EMILIA trial control), trastuzumab plus lapatinib, or trastuzumab plus other chemotherapy – in patients with recurrent or metastatic, trastuzumab exposed, HER2-positive breast cancer. (37) Thus, the choice of comparator is considered adequate. Trials comparing the combination of lapatinib plus trastuzumab to lapatinib plus capecitabine were not identified.
Primary efficacy outcomes were progression-free survival (PFS) as determined by independent review committee (IRC) and overall survival (OS). PFS was analyzed when 508 IRC-assessed events (progression or death from any cause) occurred. This provided 90% power to detect a 33% improvement in median PFS (hazard ratio [HR] of 0.75) assuming a median PFS of 6.2 months in the lapatinib plus capecitabine group. Median PFS by IRC was 3.2 months longer in the ado-trastuzumab emtansine group than in the lapatinib plus capecitabine group, a statistically significant difference. Statistically nonsignificant differences in PFS were found (in stratified analyses) in patients without visceral involvement at baseline and in patients from Asia and other parts of the world, and (in prespecified subgroup analyses) in patients age 65 to 74 years (compared to patients younger than 65 years) and in those with nonmeasurable disease at baseline. In post hoc subgroup analysis, PFS was statistically greater in ado-trastuzumab emtansine-treated patients regardless of line of therapy for metastatic disease (first, second, or third or more). Finally, a sensitivity analysis for PFS was conducted. Data for patients who received nonprotocol breast-cancer treatment before documented progression were censored at the last tumor assessment before initiation of the nonprotocol treatment. Nonprotocol treatments comprised: 1) any therapies intended for the treatment of breast cancer, including cytotoxic chemotherapy (other than that specified by the trial protocol), immunotherapy, hormonal therapy, and biologic agents; and 2) radiotherapy other than palliative radiotherapy to treat painful bone metastases. In this analysis, PFS was 2.8 months longer in the ado-trastuzumab emtansine group, a statistically significant difference.
The primary analysis of OS was planned when 632 deaths occurred. This provided 80% power to detect a 25% improvement in OS (HR of 0.80) assuming a median OS of 17.2 months in the lapatinib-plus-capecitabine group. Additionally, interim OS analyses occurred at the time of the primary PFS analysis and when 50% of the targeted events (i.e., 316 deaths) occurred. Stopping boundaries (O’Brien-Fleming) were determined for all OS analyses with preservation of the Type I error rate by use of an alpha spending function (Lan-DeMets). At the first interim analysis with a median duration of follow-up of approximately 13 months, the stopping boundary was not crossed. At the second interim analysis with a median follow-up of 19.1 months in the ado-trastuzumab emtansine group and 18.6 months in the lapatinib-plus-capecitabine group, the stopping boundary was crossed and the trial was discontinued.
Phase II Studies
TDM4374g and TDM 4258g were single-arm, open-label studies conducted in the US in patients with HER2-positive metastatic breast cancer. Both studies enrolled patients with measurable disease only. HER2 status at study entry was determined by local laboratory criteria, but HER2 positivity was confirmed centrally by IHC (3+) and FISH (amplification ratio ≥2.0) using archival tissue from the time of diagnosis. In TDM4374g, patients were required to have received prior treatment with trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine. In TDM4258g, patients were required to have received and progressed on prior treatment with HER2-directed therapy (trastuzumab or lapatinib). All patients received adotrastuzumab emtansine 3.6 mg/kg IV every 3 weeks with dose modifications for adverse events. In TDM4372g, the median number of doses received was 7.0 (range 1 to 30) with a median duration of exposure of 19.3 weeks (range 0.1 to 88.0). In TDM4258g, the median number of doses received was 7 (range 1 to 17) with a median duration of exposure of 4.2 months; 21 patients (19%) completed one year of study treatment.
Primary efficacy outcomes in both studies were objective response rate (ORR) and safety. ORR was defined as defined as complete or partial response on two consecutive tumor assessments at least 4 weeks apart by an independent radiologic facility (IRF). Tumor assessments were conducted every other cycle (every 6 weeks) by investigator and retrospectively by the IRF. In TDM4374g, retrospective review was conducted by double reader as needed; in TDM4258g, retrospective review was by single reader. Secondary outcomes included duration of response and PFS.
The incidence of objective response was 34% in TDM4374g (more previous treatment) and 26% in TDM4258g (less previous treatment). There were no complete responses. The median duration of response was 7.2 months in TDM4374g and was not reached in TDM4258g. PFS was 6.9 months and 4.6 months in the two studies, respectively. In exploratory analyses, efficacy outcomes were correlated with biomarkers assessed retrospectively. In study TDM4374g, no clear relationship between centrally-confirmed HER2 positivity, HER2 mRNA copy number, or PIK3CA (phosphatidyl inositol-3-kinase catalytic subunit) mutation status was found. In TDM4258g, both ORR and PFS were greater among patients with centrally-confirmed HER2 positivity than those with normal HER2. PFS also was longer in patients with higher HER2 mRNA copy number. These exploratory results were based on small subgroups, and confidence intervals were largely overlapping. Validation in prospective studies is needed.
Off Label Indications
No published trials of ado-trastuzumab emtansine for indications other than recurrent, locally advanced or metastatic HER2-positive breast cancer in patients previously treated with trastuzumab and a taxane were identified. Several conference abstracts have presented studies of ado-trastuzumab emtansine in earlier stages of breast cancer or in combination therapies for breast cancer. These include:
• A Phase II trial of ado-trastuzumab emtansine versus trastuzumab plus docetaxel in patients with previously untreated metastatic HER2-positive breast cancer (TDM4450g46): Both PFS (investigator assessed) and ORR were greater in the ado-trastuzumab emtansine group than in the control group. There were fewer Grade 3 or more adverse events in the adotrastuzumab emtansine group (46% v. 89%).
• A Phase Ib/II single-arm study of ado-trastuzumab emtansine in combination with pertuzumab in patients with previously treated locally advanced or metastatic HER2-positive breast cancer or newly diagnosed metastatic disease (TDM4373g47): ORRs were 39% in the recurrent disease group and 57% in the newly diagnosed group. The most common Grade 3 or more adverse event was thrombocytopenia (12%).
• A Phase Ib dose escalation study of ado-trastuzumab emtansine in combination with paclitaxel in patients with HER2-positive metastatic breast cancer who previously received HER2-targeted therapy (TDM4652g48): Maximum tolerated doses of ado-trastuzumab emtansine 2.0 mg/kg every three weeks with paclitaxel 80 mg/m2 weekly were established.
• A Phase II study of ado-trastuzumab emtansine in patients with HER2-positive breast cancer previously treated with anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting and LVEF of 55% or more (TDM4874g49): In an interim analysis of 60 patients, no Grade 2 or more left ventricular systolic dysfunction, heart failure, or LVEF less than 50% were reported.
Constitutive activation of the phosphatidyl inositol-3-kinase (PI3K) pathway, one of the intracellular signaling pathways activated by HER2 dimerization, is thought to contribute to trastuzumab insensitivity in HER2-positive breast cancer. (17,29) GDC-0941 is an oral direct PI3K inhibitor currently in development for the treatment of solid tumors (lung, breast) and non- Hodgkin lymphoma. (50) One Phase Ib dose-escalation study examined the combination of adotrastuzumab emtansine and GDC-0941 in patients with HER2-positive breast cancer who progressed on prior trastuzumab therapy (GDC4627g51). The dose-limiting toxicity in two cohorts was Grade 4 thrombocytopenia. In preliminary analysis, no dose-limiting toxicity was observed at ado-trastuzumab emtansine 3.0 mg/kg every three weeks and GDC-0941 100 mg daily for two weeks of every three-week cycle.
In preclinical studies of gastric cancer, ado-trastuzumab emtansine demonstrated greater efficacy than trastuzumab in several in vitro cell lines. (52) In a mouse model, ado-trastuzumab emtansine in combination with pertuzumab demonstrated greater efficacy than ado-trastuzumab emtansine alone. (53) Clinical trials are in progress.
The National Comprehensive Cancer Network (NCCN) Compendia recommendations are the same as the FDA labeled indications. (59)
Several studies of ado-trastuzumab emtansine are currently in progress. Because the HER2 inhibitors, pertuzumab and trastuzumab, target two different extracellular domains of the HER2 receptor and are thought to synergistically increase efficacy in HER2-positive cancers, there is considerable interest in results from the MARIANNE trial (NCT01120184). (54) MARIANNE is a Phase III, three-arm trial comparing ado-trastuzumab emtansine, adotrastuzumab emtansine plus pertuzumab, and trastuzumab plus a taxane for first-line treatment of metastatic breast cancer. The primary endpoint is PFS, and secondary endpoints include overall survival and quality of life. A Phase I study examines ado-trastuzumab emtansine triple therapy with docetaxel and pertuzumab (NCT00934856). Phase III trials of varying doses of adotrastuzumab emtansine in patients with earlier (NCT01772472) and later (NCT01419197) stage breast cancer also are in progress. Other studies found at clinicaltrials.gov for breast cancer include NCT01702571 (March 2017), NCT01745965 (October 2019), NCT00934856 (December 2013). (60)
A Phase III trial in patients with advanced gastric cancer compares ado-trastuzumab emtansine 3.6 mg/kg every three weeks to ado-trastuzumab emtansine 2.4 mg/kg weekly and to standard taxane therapy (NCT01641939, September 2015). A Phase I study assesses combination ado-trastuzumab emtansine plus capecitabine therapy in patients with gastric cancer or breast cancer (NCT01702558, May 2016.). (60)
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|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).|