MP 5.01.12

Trastuzumab

Medical Policy
Section Prescription Drugs	Original Policy Date 07/16/1999	Last Review Status/Date Reviewed with literature search/11:2008
Issue 11:2008		Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

Description

Policy

Breast Cancer
Metastatic
Trastuzumab as a single agent may be considered medically necessary for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.*
Trastuzumab may be considered medically necessary in combination with paclitaxel for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease.*
Adjuvant
Trastuzumab may be considered medically necessary for the adjuvant treatment of patients with HER2-overexpressing node-positive disease, HER2-overexpressing node-negative disease with at least one high-risk feature (see Policy Guidelines) as part of a treatment regimen consisting of: doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; docetaxel and carboplatin; or, as a single agent following multi-modality anthracycline based therapy.*
Neoadjuvant
Trastuzumab may be considered medically necessary as a component of preoperative (neoadjuvant or primary systemic) therapy, followed by additional postoperative adjuvant trastuzumab to complete a full year of treatment, for patients with HER2-positive breast cancer undergoing medically appropriate preoperative chemotherapy.
For additional guidance on combination therapy involving trastuzumab, see the section Policy Guidelines.

Non-Breast Cancer
Trastuzumab is considered investigational for the treatment of other malignancies, including, but not limited to osteosarcoma, non-small-cell lung, ovarian, prostate, head and neck, esophageal, gastric, pancreatic, colorectal, endometrial, or urothelial cancers.
*Indications included in the FDA-approved label.

Policy Guidelines

Benefit Application

BlueCard/National Account Issues

State and Federal mandates (e.g., FEP) requiring coverage of FDA-approved drugs may supercede this policy.

For example, Medicare coverage policy on cancer-related drugs is proscribed by an amendment to the Social Security Act, (1) which specifies sources of information that Medicare must consider in reviewing appropriateness of treatment. Medicare's requirement that a drug or biologic used in an anticancer chemotherapeutic regimen for a medically accepted indication is defined as:

·         the use is supported by 1 or more citations that are included (or approved for inclusion) in 1 or more of the following compendia: the American Hospital Formulary Service- Drug Information, the American Medical Association Drug Evaluations (note: no longer published), the US Pharmacopoeia-Drug Information, and other authoritative compendia as identified by the Secretary, unless the Secretary has determined the use is not medically appropriate or the use is identified as not indicated in 1 or more such compendia, or

·         the carrier involved determines, based on guidance from the Secretary to carriers for determining accepted uses of drugs, that such use is medically accepted based on supportive clinical evidence in peer-reviewed medical literature apperaing in publications that have been identified for purposes of this subclass by the Secretary

The Secretary may revise the list of compendia as is appropriate for identifying medically accepted indications for drugs.

Rationale

Breast Cancer
Metastatic
The initial 1998 FDA approval 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 one 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 nonapproved 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, although no data from randomized trials are available to critically evaluate such combinations.
Adjuvant
Results from 5 randomized trials provide data on clinical outcomes of adjuvant trastuzumab therapy: the Breast Cancer International Research Group 006 trial (BCIRG 006, 'n=3,222) (8); the Herceptin Adjuvant Trial (HERA, 'n=5,090) (9); the North Central Cancer Treatment Group N9831 trial (NCCTG N9831, 'n=3,505) (10); the North American National Surgical Adjuvant Breast and Bowel Project B31 trial (NSABP B31, 'n=2,030 ) (11); and, the Finnish Herceptin Study (FinHer, 'n=232) (12). All women enrolled in these studies tested positive for HER2 using either IHC or FISH assays. There were important differences in patient characteristics, trial design, and implementation, as reviewed in depth elsewhere. (7, 13-16). The following Table summarizes the design and results of those trials.

Trial (ref)	Tumor Characteristics	Design	Trastuzumab Schedule	F/U (median, years)	DFS HR vs. controls [95% CI] (p)	OS HR vs. controls [95% CI] (p)
BCIRG (8)	node-positive, or high-risk node-negative	AC→D AC→DH DCH	Q1wk w.CTx Q3wk postCTx	3	AC→DH:0.61 [0.48-0.76]('<0.0001)DCH:0.67 [0.54-0.83] (0.0003)	AC→DH:0.59 [0.42-0.85] (0.004) DCH:0.66 [0.47-0.93] (0.0115)
HERA (9)	node-postive, or node-negative with tumor ≥cm	Accepted CTx CTx→H (1yr) CTx→H (2yrs)	Q3wk postCTx	2	0.64 [0.43-0.57] ('<0.0001)	0.66 [0.47-1.23]  (0.0115)
NCCTG N9831 (10)	node-positive, or if node-negative, with primary tumor '>1 cm if ER/PR-negative, or '>2cm if ER/PR-positive	AC→P AC→P→H AC→PH	Q1wk w/CTx Q1wk post CTx	2	combined data: 0.48 [0.39-0.59] ('<0.0001)	combined data: 0.67 [0.48-0.93] (0.015)
NSABP B31 (11)	node-positive	AC→P AC→PH	Q1wk w/CTx Q1wk post CTx	2
FinHer (12)	node-positive, or node-negative and ≥2cm and PR-negative	D or V→FEC DH or VH→FEC	Q1wk w/CTx	3	0.42 [0.21-0.83] (0.01)	0.41 [0.16-1.08] (0.07)
AC: doxorubicin + cyclophosphamide; CI: confidence interval; cm: centimeter; CTx: chemotherapy; DCH: docetaxel + carboplatin + trastuzumab; DFS: disease-free survival; ER/PR: estrogen receptor/progesterone receptor; FEC: 5-fluorouracil + epirubicin + cyclophosphamide; FU: follow-up; H: Herceptin® (trastuzumab); HR: hazard ratio; OS: overall survival; P: paclitaxel; Q: every; V: vinorelbine; w/: with;

 

Despite substantial differences in trial design and patient characteristics, the latest available data on all 5 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 versus overall incidence) and duration of follow-up.
Neoadjuvant
One randomized, controlled trial has been published on benefits of adding trastuzumab to neoadjuvant chemotherapy. (17) 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. (18) 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. (18) At a median follow-up of 36.1 months for randomized patients, 3 in the chemotherapy-only arm experienced recurrence (one 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. (17, 18) Analyses from randomized, controlled trials (19-21) and single-arm studies (22-24) 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.
Non-Breast Cancer
Uncontrolled pilot studies have reported preliminary results for outcomes of trastuzumab combined with chemotherapy for patients with advanced non-small-cell lung cancer (25, 26) and for advanced androgen-dependent or androgen-independent prostate cancer (27, 28) 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, required for study eligibility. (29) Another study reported treatment with trastuzumab as a single agent demonstrated poor efficacy in 18 patients with advanced hormone-refractory prostate cancer. (30) 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. (31) In addition, a study of trastuzumab in patients with recurrent or refractory ovarian or primary peritoneal carcinoma found a low rate of clinical response to treatment. (32) Three reports were identified from phase II trials of trastuzumab plus chemotherapy to treat non-small cell lung cancer. (33-35) 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. (36) 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. (37) 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). (38, 39) A phase II trial that treated 44 patients with HER2–positive, advanced urothelial carcinoma with a combination of trastuzumab, paclitaxel, carboplatin, and gemcitabine. showed thirty-one (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. (40)
No reports of randomized clinical trials of trastuzumab therapy for any cancer other than breast cancer have been published, nor have any other studies demonstrated substantial tumor control efficacy.
National Cancer Institute Physician Data Query Database (PDQ)
In November 2008, 95 phase II/III trials were underway that involve trastuzumab therapy in adjuvant, neoadjuvant, and metastatic breast cancer, in combinations containing cytotoxic, endocrine and targeted therapies (http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=5355729).
The PDQ database included no active phase III trials on the use of trastuzumab (alone or in combination) to treat malignancies other than breast cancer. Four phase II trials are active: one on transitional cell bladder cancer (NCT00238420); one on gallbladder or bile duct cancer (NCT00478140); one on B-cell ALL (NCT00724360); and one on non-small cell lung cancer (NCT00758134).
National Comprehensive Cancer Network (NCCN) Guideline
The current NCCN guideline (v.2.2008) recommends 1 year of trastuzumab (with cardiac monitoring) as part of adjuvant therapy for patients with node-positive breast cancer that overexpresses HER2. The guideline also suggests considering trastuzumab for patients with HER2-positive node negative tumors 1 cm diameter or greater. The guideline advises clinicians to either use the AC→paclitaxel + trastuzumab regimen or to give trastuzumab after adjuvant chemotherapy is completed. It counsels against giving trastuzumab concurrently with doxorubicin, because of cardiac toxicity. (http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf)
The NCCN guideline also recommends that clinicians and patients with HER2 positive breast tumors staged as IIA, IIb, or T3N1M0 consider preoperative chemotherapy incorporating trastuzumab. Although it lists only one neoadjuvant regimen for such patients (paclitaxel plus trastuzumab followed by FEC plus trastuzumab), a current NCI-sponsored phase III RCT (ACOSOG Z1041 or NCT00513292) is comparing this regimen with an alternative that also incorporates trastuzumab. Another U.S.-based trial (NSABP B-41 or NCT00486668) is comparing different neoadjuvant regimens using HER2-targeted therapies (trastuzumab, lapatinib, or both). Additional trials outside the U.S. also are comparing different neoadjuvant regimens that use trastuzumab (e.g., NCT00288002, NCT00553358). Each of these trials limits eligibility to HER2 positive patients with larger tumors.
The NCCN breast cancer guideline indicates paclitaxel with or without carboplatin, docetaxel with or without carboplatin, or vinorelbine is the preferred chemotherapy for use in combination with H to treat HER2 overexpressing metastatic disease.
As of November 2008, use of trastuzumab has not been addressed by any of the NCCN guidelines for malignancies other than breast cancer, including osteosarcoma or non-small-cell lung, ovarian, prostate, head and neck, esophageal, gastric, pancreatic, colon, rectal, endometrial, or urothelial cancers. Additionally, breast cancer is the only malignancy for which trastuzumab use is recommended in the NCCN Drugs and Biologics Compendium.

 

References:

 

 

Index

Breast Cancer, Treatment with Trastuzumab
Herceptin
Trastuzumab 

Policy History