Trastuzumab and Other HER2 Inhibitors
Trastuzumab or lapatinib may be considered medically necessary for the treatment of patients with breast cancer whose tumors overexpress the HER2 protein (HER2-positive breast cancer.) This includes use as adjuvant therapy, neoadjuvant therapy, and treatment of metastatic disease.
Pertuzumab (Perjeta™) may be considered medically necessary for the treatment of previously untreated HER2-positive breast cancer or recurrent breast cancer after adjuvant therapy, when used in combination with trastuzumab and docetaxel. This includes use as adjuvant therapy, neoadjuvant therapy, and treatment of metastatic disease.
Ado-trastuzumab emtansine (Kadcyla™) may be considered medically necessary when all of the following conditions have been met:
All other uses of ado-trastuzumab emtansine are considered investigational, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer.
Conditions Other Than HER2-positive Breast Cancer
Trastuzumab may be considered medically necessary, when used in combination with systemic chemotherapy, for treatment of patients with advanced (locally advanced or metastatic) gastric cancer or gastroesophageal junction adenocarcinoma whose tumors overexpress the HER2 protein (HER2-positive cancer).
Except as noted above, Trastuzumab and lapatinib are considered investigational for the treatment of conditions other than HER2-positive breast cancer including, but not limited to, HER2-negative breast cancer, osteosarcoma, nonsmall-cell lung, ovarian, prostate, head and neck, esophageal, gastric, pancreatic, colorectal, endometrial, or urothelial cancers.
All other uses of pertuzumab and ado-trastuzumab emtansine are considered investigational.
Appropriate patient selection for Trastuzumab therapy is predicated on detection of HER2 overexpression. HER2 overexpression should be assessed only by facilities with demonstrated proficiency in the specific assay being used. Unreliable results may result from improper assay performance. Several assays are commercially available to aid selection of patients for Trastuzumab therapy. These include the HercepTest™ and Pathway® HER2/neu, which are immunohistochemical assays (IHC), and PathVysion® and HER2 FISH pharmDx™, which are fluorescence in situ hybridization assays (FISH).
As discussed in the Rationale section, randomized clinical trials have consistently reported a beneficial effect of adjuvant trastuzumab in conjunction with adjuvant chemotherapy in patients with completely resected HER2-positive breast cancer. However, these trials have not resolved the following issues:
Duration of Therapy
While data support the use of adjuvant trastuzumab for a year, evidence is inadequate to determine if a second year of Trastuzumab therapy increases benefit. This comparison is a focus of the HERA trial, but data from its third arm, given 2 years of trastuzumab, are not yet available.
Starting Trastuzumab Long After Completing Adjuvant Chemotherapy
Trastuzumab was rapidly integrated into the adjuvant therapy of patients with HER2-positive early-stage breast cancer. When the first interim results were reported in 2005, there was interest in offering Trastuzumab to patients who would otherwise meet criteria, but who had already completed adjuvant therapy prior to the announcement of trial results. This group of patients still has not been formally studied, but patients in the HERA trial started Trastuzumab a median 8 months after surgery. At the time, investigators suggested that patients who completed adjuvant chemotherapy within the prior 6 months might be considered reasonable candidates.
Concurrent Versus Sequential Therapy
At present, data are inadequate to determine the optimal regimen of trastuzumab within the overall regimen of adjuvant therapy, specifically whether concurrent or sequential Trastuzumab is preferred. The NCCTG N9831 trial (see the Rationale section) includes two arms given Trastuzumab, one concurrent with and the other following paclitaxel. Results for this comparison have not been published.
The FDA-approved label recommends that left ventricular ejection fraction (LVEF) should be measured before starting trastuzumab therapy, and shown to be within the treating institution’s normal range. Continued therapy should depend on periodic monitoring (e.g., at 3, 6, and 12 months) without an unacceptable decrease (e.g., greater than 15%) from baseline LVEF.
Breast cancer patients considered for preoperative (neoadjuvant or primary systemic) chemotherapy may have early-stage disease, but larger tumors (stages IIA, IIB or operable T3N1M0), or may have locally advanced but non-metastatic (M0) disease.
Safety Concerns with Ado-Trastuzumab Emtansine
Although there are no absolute contraindications to ado-trastuzumab emtansine, there are a number of additional safety considerations:
Dosing Considerations with Ado-Trastuzumab Emtansine
Ado-trastuzumab emtansine is administered at a dose of 3.6 mg/kg intravenously every 3 weeks.
The first infusion is administered over 90 minutes with slowing or interruptions for fever, chills, or other infusion-associated symptoms, followed by 90 minutes of observation and vital sign monitoring. If the first infusion is well tolerated (i.e., without any signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.
Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation
The human epidermal growth factor receptor 2 (HER2) gene located on chromosome 17q, encodes a transmembrane ligand orphan receptor tyrosine kinase that amplifies the signal provided by other members of the HER family (HER1/EGFR, HER3, and HER4) by forming heterodimers with them. HER2 activation and dimerization causes alterations in several complex downstream-signaling cascades that are involved in regulation of cell growth, proliferation, migration, adhesion, and survival, and thus has been implicated in oncogenesis.
The HER2 gene is amplified and overexpressed in 20–30% of breast cancers, a finding which has been associated with more aggressive disease and higher relapse and mortality rates. HER2 is also overexpressed in other epithelial cancers, including ovarian, thyroid, lung, salivary gland, stomach, colon, and prostate, making it a logical target for antibody-mediated therapy.
Trastuzumab has only received U.S. Food and Drug Administration (FDA) marketing approval for specific patients with breast cancer. However, its activity has been investigated in the preoperative (neoadjuvant) setting for breast cancer, in combination with regimens besides those specified in the FDA-approved product label, and in a wide range of other types of cancer that overexpress HER2.
Trastuzumab (Herceptin®) is a humanized monoclonal antibody against the extracellular domain of HER2. Trastuzumab has received FDA marketing approval for treatment of HER2-positive breast cancer in both the adjuvant and metastatic settings. It first received FDA approval in September 1998 for use in metastatic breast cancer, as a first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy.
In November 2006, trastuzumab received FDA marketing approval as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel (AC→P) for the adjuvant treatment of HER2-positive, node-positive early stage breast cancer.
In January 2008, FDA granted marketing approval for trastuzumab as a single agent for the adjuvant treatment of early stage HER2-positive node-positive breast cancer or node-negative (ER/PR-negative or with one high-risk feature) disease following multi-modality, anthracycline-based therapy. Trastuzumab also was approved to be administered as a single agent in an every-3-week dosing schedule for 1 year.
In May 2008, the FDA approved two new trastuzumab containing regimens for the adjuvant treatment of early-stage HER2-positive node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer. The first regimen is in combination with docetaxel and carboplatin (also known as TCH for Taxotere®, carboplatin, and Herceptin®), which does not contain an anthracycline (doxorubicin) component. The second is part of a treatment regimen containing anthracycline (doxorubicin), cyclophosphamide, and docetaxel (AC-TH).
Other HER2 Inhibitors
Lapatinib (Tykerb®) is a small molecule 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.
Lapatinib is indicated for use in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
Pertuzumab (Perjeta®) Pertuzumab is a HER dimerization inhibitor recently approved by the FDA for use in combination with trastuzumab and docetaxel in patients with HER2-positive metastatic cancer who are treatment naïve or whose disease has recurred after adjuvant therapy.
Ado-trastuzumab emtansine (Kadcyla™), also known as trastuzumab-DM1 or T-DM1, is an antibody-drug conjugate comprising trastuzumab and emtansine (DM1). It is a HER2 antagonist that is intended as treatment for patients with breast cancers that overexpress HER2, and it may also have applications for other HER-2 positive malignancies. 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 linkage. T-DM1 binds HER2 with an affinity comparable to that of trastuzumab. 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. Ado-trastuzumab emtansine has been shown to preserve the antitumor activity of trastuzumab (described above). Death of HER2-expressing cells therefore results from effects of both active moieties of ado-trastuzumab emtansine.
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The initial 1998 approval by the U.S. Food and Drug Administration (FDA) for trastuzumab in metastatic breast cancer was based on results from 2 pivotal clinical trials. In one trial, single-agent trastuzumab was given to women (n=222) who had received 1 or 2 courses of cytotoxic chemotherapy, yielding an objective response rate (ORR) of 15% and a median duration of response of 9.1 months. (1) In a second randomized trial (n=469), trastuzumab was evaluated as part of a first-line combination regimen consisting of either doxorubicin (A) plus cyclophosphamide (C) or paclitaxel (P). (2) The addition of trastuzumab to chemotherapy resulted in an increased response rate (50% vs. 32%, p<0.001), longer median response duration (9.1 vs. 6.1 months, p<0.001), and prolonged overall survival (OS) (25.1 months vs. 20.3, p=0.046) compared to chemotherapy alone. Because a significantly higher incidence of New York Heart Association (NYHA) class III or IV cardiotoxicity was reported in this trial among patients who received AC plus trastuzumab, compared to AC, paclitaxel/trastuzumab, or paclitaxel, the FDA and others subsequently cautioned against using a regimen that combined trastuzumab with doxorubicin. (3, 4)
Similar efficacy results have been subsequently reported with the combination of trastuzumab with docetaxel (D) in 188 patients with metastatic breast cancer. (5) Further studies of other trastuzumab combination regimens have included its use with capecitabine, vinorelbine, gemcitabine, and platinum salts, achieving response rates ranging from 27% to 86%. (reviewed in 6, 7) These early studies also have shown that trastuzumab can be combined with non-approved chemotherapy regimens while adding little to the overall toxicity profile in the metastatic setting. Similarly, trastuzumab is being evaluated in combinations with hormonal modalities such as tamoxifen or aromatase inhibitors.
Kaufman and colleagues reported the results of the first randomized phase III trial combining a hormonal agent (aromatase inhibitor anastrozole) and trastuzumab without chemotherapy. (8) Patients were postmenopausal with HER2 and hormone receptor-positive metastatic disease (patients with CNS metastases were excluded). Patients were randomized to receive trastuzumab plus anastrozole (n=103) or anastrozole alone (n=104). Baseline characteristics were balanced between the two groups. The primary endpoint was progression free survival (PFS), defined as the time from randomization and the date of disease progression or death. There were a total of 187 withdrawals from the trial treatment, most frequently due to progressive disease. In the anastrozole-only arm, 70% of the patients who experienced progressive disease subsequently crossed over to receive a trastuzumab containing regimen. Progression free survival was significantly improved in the trastuzumab plus anastrozole arm with a median PFS of 4.8 months (95% confidence interval [CI]: 3.7 to 7.0 months) versus 2.4 months (95% CI: 2.0 to 4.6 months) in the anastrozole-only arm (hazard ration [HR] =0.63; 95%CI: 0.47-0.84; p=0.0016). Grade 3 and 4 adverse events were 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1% in the anastrozole-only arm.
von Minckwitz and colleagues investigated whether trastuzumab should be given beyond disease progression in women with HER2-positive locally-advanced or metastatic breast cancer. (9) Patients were randomly assigned to chemotherapy (capecitabine) alone (n=78) or to capecitabine plus trastuzumab (n=78). Follow-up was 15.6 months, during which time there were 38 deaths in the capecitabine arm versus 33 in the capecitabine plus trastuzumab group. The primary end point in the study was time to progression, which was defined as the time period between randomization and documented disease progression or disease-related death. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the combined therapy group; hazard ratio 0.69 (95% CI: 0.48 to 0.97; p=0.0338). Differences in OS were not significant at 20.4 months (95% CI: 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI: 19.0 to 30.7) in the combined therapy group (p=0.257).
Results from randomized trials provide data on clinical outcomes of adjuvant trastuzumab therapy: the Breast Cancer International Research Group 006 trial (BCIRG 006, n=3,222) (10); the Herceptin Adjuvant Trial (HERA, n=5,090) (11); the North Central Cancer Treatment Group N9831 trial (NCCTG N9831, n=3,505) (12); the North American National Surgical Adjuvant Breast and Bowel Project B31 trial (NSABP B31, n=2,030 ) (13); and, the Finnish Herceptin Study (FinHer, n=232) (14). All women enrolled in these studies tested positive for HER2 using either immunohistochemical assays (IHC) or fluorescence in situ hybridization assays (FISH) assays. There were important differences in patient characteristics, trial design, and implementation, as reviewed in depth elsewhere. (7, 15-18). The following table summarizes the design and results of those trials.
Despite substantial differences in trial design and patient characteristics, the latest available data from adjuvant trials of trastuzumab demonstrate consistent, clinically significant improvements in DFS. The combined analysis of the NSABP B31, NCCTG N9831, BCIRG, and HERA trials shows significant improvement in OS versus controls in patients given adjuvant trastuzumab. Although only HERA reported that trastuzumab improved DFS in a subgroup with high-risk, node-negative disease, 3 other trials included similar patients and found better outcomes in the trastuzumab arm. While few patients were node negative in NCCTG N9831 and FinHer, 29% of each arm was node negative in BCIRG 006. Note that all trials excluded patients with small (<1 cm) node-negative tumors. Thus, there is no evidence that adjuvant trastuzumab benefits this subgroup of HER2-positive patients. The benefits of trastuzumab were independent of estrogen-receptor status or the type of prior chemotherapy. These data do not settle the issue of optimal timing and duration of trastuzumab therapy, but data from the FinHer study suggest that even a short course (9 weeks) may be beneficial in reducing the risk of recurrence and death in women with HER2-positive, early-stage disease. Furthermore, final results for the 2-year trastuzumab regimen arm in HERA are not yet available.
Grade III/IV congestive heart failure (CHF) or cardiac-related death for patients receiving trastuzumab-containing adjuvant regimens ranged from 0 (FinHer) to 4.1% (NSABP B31) overall, with age and baseline left-ventricular ejection fraction related to the risk for cardiac dysfunction. Concurrent use of trastuzumab and a taxane following 4 cycles of AC resulted in the highest rates of CHF (1.5%, 2.4%, and 3.4% for the BCIRG, N9831, and B31 trials, respectively). Sequential administration of anthracyclines, taxanes, and trastuzumab resulted in CHF rates of 1.4% and 0.5% for the N9831 and HERA trials, respectively. The non-anthracycline arm of the BCIRG trial had the lowest rate (0.3%) of CHF. While the acceptable rate of cardiac events overall was likely related to rigorous monitoring during the trials, cross-trial comparisons and conclusions are difficult due to differences in definitions of cardiac events, evaluations for cardiac safety, analysis of cardiac endpoints (cumulative vs. overall incidence) and duration of follow-up.
A randomized, controlled trial has been published on the benefits of adding trastuzumab to neoadjuvant chemotherapy. (19) The study sequentially administered two neoadjuvant chemotherapy regimens followed by surgery to breast cancer patients with stage II to IIIA disease, and compared paclitaxel (four 3-week cycles) followed by fluorouracil, epirubicin, and cyclophosphamide (FEC; four 3-week cycles) with versus without trastuzumab. A data monitoring committee ended the trial after investigators randomized 42 patients, when a requested (but unplanned) analysis showed pathologic complete response (pCR) rates of 25% in the arm without and 66.7% in the arm with trastuzumab. Approximately the same proportion of patients in each arm (52.6% without and 56.5% with trastuzumab) received breast-conserving surgery, but patient choice likely influenced these results. A subsequent report of the same study included longer follow-up for randomized patients, and additional nonrandomized patients. (20) Results showed pCR in 26.3% (95% CI: 9–51%) of 19 patients randomized to neoadjuvant chemotherapy without trastuzumab, 65.2% (95% CI: 43–84%) of 23 patients randomized to the same neoadjuvant regimen plus trastuzumab, and 54.5% (95% CI: 32.2–75.6%) of 22 consecutive nonrandomized patients also given the same regimen plus trastuzumab. (20) At a median follow-up of 36.1 months for randomized patients, 3 in the chemotherapy-only arm experienced recurrence (1 of whom died), and none in the arm with added trastuzumab.
Although few recurrences or deaths have occurred thus far in this terminated randomized, controlled trial, the 2-fold increase in pCR rate is unlikely to be a chance result. (19, 20) Analyses from randomized, controlled trials (21-23) and single-arm studies (24-26) showed that patients with pCR after neoadjuvant chemotherapy (determined postoperatively) had significantly longer overall, disease-free, and/or recurrence-free survival than those who did not achieve pCR. This also was true when those who achieved pCR were compared with those who achieved clinically complete responses but were subsequently shown by postoperative pathology to have residual (microscopic) invasive disease. Thus, improving pCR rate by adding trastuzumab to neoadjuvant chemotherapy for HER2 patients with high-risk, larger tumors predicts improved overall and disease-free survival.
Additional reasoning supports considering neoadjuvant trastuzumab medically necessary for HER2-positive patients undergoing neoadjuvant chemotherapy, even if the one available randomized, controlled trial did not show it increased the proportion of patients given breast-conserving surgery. When used to reduce risk of recurrence for patients with operable breast cancer, chemotherapy is either completed before surgery or not begun until after. Those given preoperative chemotherapy rarely receive additional chemotherapy after resection, unless their breast cancer recurs or progresses. Although hormone-receptor-positive patients given neoadjuvant chemotherapy are given tamoxifen or an aromatase inhibitor after resection, most HER2-positive patients are hormone-receptor negative and would not receive hormone therapy. Whether chemotherapy is used pre- or postoperatively, it is given for 18-24 weeks depending on the regimen and trastuzumab currently is given for a full year. Trastuzumab administration was initiated concurrently with chemotherapy in most trials on adjuvant therapy. Consequently, it seems reasonable to initiate trastuzumab with chemotherapy for HER2-positive patients receiving neoadjuvant chemotherapy.
Trastuzumab in Non-Breast Cancer
One phase II and one phase III trial have been reported on the use of trastuzumab in advanced gastric cancer; the phase II trial is published in abstract form only. Cortés-Funes and colleagues reported preliminary results of a phase II study of 21 patients with advanced gastric cancer with overexpression/amplification of HER2. (27) Patients received trastuzumab in combination with chemotherapy (cisplatin) every 21 days until disease progression, unacceptable toxicity or withdrawal. Seventeen of the 21 patients were evaluable. Efficacy was reported as: 6 (35%) patients achieved response (1 CR, 5 PR), 3 (17%) had disease stabilization, 4 patients progressed and for 4 patients it was too early to report. The authors concluded that trastuzumab plus cisplatin is a well-tolerated regimen with promising activity in HER2/neu overexpressing gastric cancer.
Van Cutsem and colleagues reported the results of a Phase III, open-label, randomized, multicenter (122 centers in 24 countries) trial in which patients with HER2-positive, locally-advanced, recurrent, or metastatic gastroesophageal or gastric adenocarcinoma received chemotherapy consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin with or without trastuzumab. (28) Patients who received the trastuzumab were given it every three weeks for 6 cycles, until disease progression. The primary endpoint of the study was overall survival; secondary endpoints were overall response rate (ORR), PFS, time to progression, duration of response and safety. Median follow-up was 18.6 months in the chemotherapy plus trastuzumab group and 17.1 months in the chemotherapy-alone group. Tumors from 3,807 patients were tested for HER2 status; 22.1% were positive. Five-hundred ninety-four patients were randomized to the 2 treatment arms. Median OS for the group that received trastuzumab compared to those that did not was 13.8 months (95% CI: 12-16) versus 11.1 months (95% CI: 10-13) (p=0.0046; HR 0.74; 95%CI 0.60-0.91). ORR was 47.3% for those that received trastuzumab versus 34.5% for those that did not (p=0.0017). Rates of overall grade 3 or 4 adverse events (201 [68%] versus 198 [68%]) and cardiac adverse events (17 [6%] versus 18 [6%]) did not differ between the chemotherapy and trastuzumab versus chemotherapy alone groups.
Uncontrolled pilot studies have reported preliminary results for outcomes of trastuzumab combined with chemotherapy for advanced androgen-dependent or androgen-independent prostate cancer (29, 30) that is positive for HER2 overexpression or amplification. A study of trastuzumab and docetaxel for HER2-positive prostate cancer was closed as not feasible, since only 7 of 100 patients screened had 2+ or 3+ HER2 expression by immunohistochemistry, as required for study eligibility. (31) Another study reported treatment with trastuzumab as a single agent demonstrated poor efficacy in 18 patients with advanced hormone-refractory prostate cancer. (32)
Salivary Gland Cancer
A study to evaluate the use of trastuzumab in salivary gland cancer was closed early after it was found that the majority of salivary gland tumors did not overexpress HER2. (33)
Ovarian and Peritoneal Cancer
A study of trastuzumab in patients with recurrent or refractory ovarian or primary peritoneal carcinoma found a low rate of clinical response to treatment. (34)
Non-small cell lung cancer Three reports were identified from phase II trials of trastuzumab plus chemotherapy to treat non-small cell lung cancer. (35-37) Each of these studies reported that the addition of trastuzumab did not improve outcomes.
A randomized phase II comparison of docetaxel plus trastuzumab versus paclitaxel plus trastuzumab in chemotherapy-naive non-small cell lung cancer patients (n=65) reported no differences in objective response rates, median survival, or toxicity between arms. (38)
Median OS was 24 months in an uncontrolled phase I/II study (n=19) that combined trastuzumab with paclitaxel, cisplatin, and radiation for locally advanced, HER2 overexpressing esophageal cancer. (39)
Bladder and Kidney Cancer
Two uncontrolled small series were also reported on trastuzumab for metastatic transitional cell cancer of the bladder (n=7) or bladder and renal pelvis (n=6). (40, 41) A phase II trial that treated 44 patients with HER2–positive, advanced urothelial carcinoma with a combination of trastuzumab, paclitaxel, carboplatin, and gemcitabine, showed 31 (70%) patients responded, including 5 complete and 26 partial responses. Median time to progression and survival were 9.3 and 14.1 months, respectively. However, the study lacked controls given the same chemotherapy without trastuzumab. (42)
Targeted therapy using trastuzumab against human epidermal growth factor receptor type-2 (HER2) has shown survival benefit for primary and metastatic breast cancer, and has become the accepted and usual therapy for patients with HER-2 positive breast cancer.
One Phase III trial has reported outcomes with the use of trastuzumab in advanced gastric or gastroesophageal cancer, with a 2 month OS benefit in the trastuzumab arm and no difference in severe adverse events between the group that received chemotherapy plus trastuzumab versus chemotherapy alone.
Studies examining the possible uses of trastuzumab in HER2-positive cancers other than breast and gastric/gastroesophageal cancers have consisted mainly of small uncontrolled series. For the most part, results have been disappointing, with little to no improvement in outcomes; studies have also suffered from the low percentage of HER2 overexpression in certain tumors.
The efficacy and safety of lapatinib in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) over-expressing (IHC 3+ or IHC 2+ confirmed by FISH), locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes, and trastuzumab.
Ado- trastuzumab emtansine.
Based on a literature search performed through March 2013, the evidence that was identified for this policy review consists of one RCT that was performed in support of application for FDA-approval, and two uncontrolled studies.
Randomized, controlled trial.
The Phase III EMILIA trial (N=991) was a randomized, stratified, active- controlled, open-label trial conducted in 26 countries (27% US). Patients had unresectable, locally advanced or metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane. Median age was 53 years, approximately 37% of patients had three or more metastatic sites, and 68% had visceral disease involvement. Patients were stratified (by world region, number of prior chemotherapy regimens for advanced disease, and visceral disease involvement) and randomized to one of 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. Potential bias introduced by the open-label trial design was minimized by assessor blinding of PFS and tumor response endpoints and by the use of an easily measured endpoint, OS.
Primary efficacy outcomes were PFS by independent review committee and overall survival (OS). PFS was 9.6 months in the ado-trastuzumab emtansine group and 6.4 months in the lapatinib+capecitabine group (hazard ratio [HR] 0.65 [95% CI: 0.55, 0.77]). Statistically nonsignificant differences in PFS were found in patients without visceral involvement and in patients from Asia and other parts of the world (stratified subgroups) and in patients 65 to 74 years of age and patients without measurable disease at baseline (prespecified subgroups). At a median follow-up of approximately19 months, an interim analysis of OS crossed the pre-determined stopping boundary, and the trial was discontinued. OS was 30.9 months in the ado-trastuzumab emtansine group and 25.1 in the lapatinib+capecitabine group (HR 0.68 [95% CI: 0.55, 0.85]).
Uncontrolled trials. Two single-arm, open-label, Phase II studies conducted in the US 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. Ninety-eight percent of patients were female, median age was 53 years, 74% of patients had three or more metastatic sites, and patients had received a median of 7 systemic treatments for metastatic disease. In TDM4258g (n=112), patients were previously treated with HER2-directed therapy (trastuzumab or lapatinib). Median age was 55 years, 75% of patients had three or more metastatic sites, and patients had received a median of 5 systemic treatments for metastatic disease. All patients in
both studies received ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks with dose modifications for adverse events.
Objective response rate (ORR, defined as complete responses plus partial responses) by independent radiologic facility (IRF) was the primary efficacy outcome in both studies. In TDM4374g (more pre- treatment), ORR was 35% (95% confidence interval [CI]: 26, 44). In TDM4258g (less pre-treatment), ORR was 26% (95% CI: 18, 34). There were no complete responses. Median progression-free survival (PFS),
a secondary outcome, was 6.9 months (95% CI: 4.2, 8.4) in TDM4374g and 4.6 months (95% CI: 3.9,
8.6) in TDM4258g.
Conference abstracts have presented results of several Phase I and Phase II studies of ado-trastuzumab emtansine for off-label uses. The main categories for off-label uses are for breast cancer at earlier stages or in various combination therapies for breast cancer, and for use in non-breast cancers.
Earlier Stages of Breast Cancer. The MARIANNE trial, currently in progress, is a Phase III, three-arm trial comparing ado-trastuzumab emtansine, ado-trastuzumab emtansine plus pertuzumab, and trastuzumab plus a taxane for first-line treatment of metastatic breast cancer. GDC-0941 is an oral inhibitor of a downstream intracellular pathway regulated by HER2. Constitutive activation of this pathway is thought to contribute to trastuzumab insensitivity in HER2-positive breast cancer. A Phase Ib dose escalation study of this combination in patients with HER2-positive breast cancer who progressed on prior trastuzumab therapy is currently in progress.
Additional indications being studied include initial treatment of metastatic breast cancer, in combination with pertuzumab and/or paclitaxel for previously treated metastatic disease, or in patients previously treated with systemic chemotherapy.
Other cancer types. In preclinical studies of gastric cancer, ado-trastuzumab emtansine has shown efficacy. An ongoing Phase I study is assessing the combination of ado-trastuzumab emtansine plus capecitabine in patients with metastatic HER2-positive gastric cancer. A Phase III trial (N=412) comparing two different doses of ado-trastuzumab emtansine (3.6 mg/kg every three weeks or 2.4 mg/kg weekly) to standard taxane therapy in patients with HER2- positive advanced gastric cancer who experienced disease progression during or after first-line therapy is currently in progress.
2013 National Comprehensive Cancer Network (NCCN) Compendium Recommendations
The current NCCN Compendium recommends the use of trastuzumab as follows:
Preoperative therapy for patients with HER2-positive stage IIA, IIB, or T3, N1, M0 disease who desire breast preservation and fulfill criteria for breast-conserving surgery except for tumor size or for locally advanced disease (stage IIIA, IIIB, or IIIC) (Category 1):
HER2-positive, stage I, IIA, IIB, or T3, N1, M0 disease (ductal, lobular, mixed, or metaplastic histologies) that is pN0 (tumor greater than 0.5 cm), pN1mi, or node-positive or for locally advanced disease (stage IIIA, IIIB, or IIIC) (Category 1 for tumors > 1 cm; 2A if smaller):
Recurrent or Stage IV disease
Used in combination with aromatase inhibition for the treatment of recurrent or stage IV estrogen receptor-positive, human epidermal growth factor receptor 2-positive disease in postmenopausal women* who have received no prior endocrine therapy within one year. (Category 2A)
Male Breast Cancer
Men with breast cancer should be treated similarly to postmenopausal women, except that use of an aromatase inhibitor is ineffective without concomitant suppression of testicular steroidogenesis. (Category 2A)
Hormone Receptor-Negative or Endocrine Refractory Disease
HER2-positive recurrent or metastatic breast cancer that is hormone receptor-negative or hormone receptor-positive and endocrine therapy refractory as
Palliative therapy for patients with Karnofsky performance score ≥60% or ECOG performance score ≤2 in combination with systemic chemotherapy for the treatment of patients with advanced HER2-neu protein overexpressing gastric, esophageal or esophagogastric junction adenocarcinoma. (Category 1 for combination with cisplatin and fluorouracil or capecitabine for first-line therapy; 2A for combination with cisplatin and fluorouracil or capecitabine for second-line therapy; 2B otherwise.)
As of July 2013, use of trastuzumab has not been addressed the NCCN Compendium for other malignancies, including: osteosarcoma, ovarian, prostate, head and neck, pancreatic, colon, rectal, endometrial, urothelial or non-small cell lung cancers.
The current NCCN Compendium recommends the use of lapatinib as follows:
Used in combination with aromatase inhibition for the treatment of recurrent or stage IV estrogen receptor-positive, human epidermal growth factor receptor 2-positive disease in postmenopausal women* who have received no prior endocrine therapy within one year. Men with breast cancer should be treated similarly to postmenopausal women, except that use of an aromatase inhibitor is ineffective without concomitant suppression of testicular steroidogenesis. (Category 2A)
Used in combination with trastuzumab (without cytotoxic therapy) or capecitabine for human epidermal growth factor receptor 2-positive recurrent or metastatic trastuzumab-exposed disease. (Category 2A)
Consider for treatment in combination with capecitabine for recurrent brain metastases if active against primary tumor (breast). (Category 2A)
Preferred agent for human epidermal growth factor receptor 2-positive recurrent or metastatic trastuzumab-exposed disease. (Category 2A)
Updated to include new data on expanded indications of trastuzumab and addition of criteria for pertuzumab.
Updated to include ado-trastuzumab emtansine, which was recently approved by the FDA, and current NCCN Compendium recommendations.
Updated to include current NCCN Compendium recommendations for use of trastuzumab outside of breast cancer.
Injection, pertuzumab, 1 mg
Injection, trastuzumab, 10 mg
Type of Service
Place of Service
Add to Prescription Drug Section - New medical policy.
Replace Policy - Policy updated with new references; policy statement unchanged
Replace Policy - Policy reviewed; references added; current clinical trials and NCCN guidelines information added; policy statement unchanged.
Policy replaces BC.5.01.12 - New PR Policy. Policy statement changed to consider off-label uses of Trastuzumab medically necessary in tx of all stages of breast cancer with over-expressed HER-2/neu protein, or that are FISH positive. Trastuzumab to continue to be investigational for other malignancies.
Codes updated - No other changes.
Update Scope and Disclaimer - No other changes.
Replace Policy - Policy reviewed with literature search; no change to policy statement.
Replace Policy - Policy reviewed with literature search. New FDA labeled indication noted in the Description. References added. No change to policy statement.
Replace Policy - Policy reviewed with literature search. Policy no longer addresses only off-label uses. Renamed “HER2 Inhibitors”. Tykerb added as medically necessary when criteria are met. References and code added. Policy guidelines now state that HER2 overexpression testing is required.
Replace Policy - Policy reviewed with literature search. New indication: Herceptin is now considered medically necessary for gastric cancer.
Replace Policy - Herceptin, previously considered investigation for esophageal cancer, is now considered medically necessary.
Replace Policy - Policy rewritten and revised. Title changed from “HER-2 Inhibitors” to “Trastuzumab and Other HER2 Inhibitors.” Components of BC.5.01.12 Trastuzumab incorporated in large part into the policy with the following variations: Lapatinib indications added. ICD-10 codes added to policy.
Related Policies section updated; policy 2.04.76 added.
Replace policy. Policy reviewed with literature search; no change in policy statements.
Coding Section updated – ICD-10 codes are now effective 10/01/2014.
Replace policy. Policy updated with new data on expanded indications of trastuzumab, coverage is expanded for adjuvant treatment of HER2 positive as either part of several different combination therapy regimens or as a single agent following prior chemotherapy; addition of criteria for pertuzumab; and treatment of HER2 positive metastatic breast cancer in either combination therapy or as a single agent. A medically necessary policy statement has been added for pertuzumab in the treatment of previously untreated HER2-positive breast cancer or recurrent breast cancer after adjuvant therapy, when used in combination with trastuzumab and docetaxel; all other uses are now indicated as investigational.
Minor update. For clarification and improved readability, the medically necessary policy statement for Pertuzumab now appears within the section addressing HER-2 positive breast cancer. No changes have been made to the policy.
Replace Policy. Added Policy statements and Policy Guidelines information for ado-trastuzumab emtansine. Added clinical trial info for ado-trastuzumab emtansine to the Rationale section. Updated with current NCCN for all 3 drugs.
Coding update; HCPCS code J9306, effective 1/1/14, added to the policy.
Annual Review. Updated to include two medically necessary statements from current NCCN Compendium recommendations for use of trastuzumab outside of breast cancer. Codes removed with the exception of HCPCS J0306 and J9355; others are not utilized in adjudication of the policy.
Minor update. Clarification added to the medically necessary policy statement for pertuzumab: This includes use as adjuvant therapy, neoadjuvant therapy, and treatment of metastatic disease.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).