POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY

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1 Original Issue Date (Created): August 28, 2012 Most Recent Review Date (Revised): May 20, 2014 Effective Date: August 1, 2014 POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY I. POLICY The use of pertuzumab may be considered medically necessary in the treatment of breast cancer when all of the following conditions are met: Patient has HER2 positive metastatic breast cancer Pertuzumab is used in combination with trastuzumab and a taxane (e.g., docetaxel, paclitaxel) The use of pertuzumab is considered investigational for all other indications, including but not limited to locally advanced breast cancer, local recurrences of breast cancer following treatment, HER2-positive gastric cancers, and HER2-positive cancers of the gastro-esophageal junction. There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure. Policy Guidelines: Disease is HER2 positive, where overexpression of HER2 is confirmed by: Immunohistochemistry (IHC) assay 3+ OR Fluorescence in situ hybridization (FISH) assay >2.2 If IHC is 2+, must confirm with FISH assay >2.2 HER-2 overexpression/testing should be assessed only by facilities with demonstrated proficiency in the specific assay being used. If appropriate quality control/assurance procedures are in place for a laboratory, either the IHC or the FISH method may be used to determine HER2 tumor status. If the laboratory does not have control/assurance procedures in place, the sample should be sent to a reference laboratory that does meet the quality control/assurance procedures. Page 1

2 Pertuzumab has shown fetotoxicity in animal studies. Women of childbearing age should be on effective contraception prior to starting pertuzumab. The use of pertuzumab may be associated with LV (left ventricular) dysfunction, similar to trastuzumab. The CLEOPATRA trial had the following inclusion criteria and recommendations for monitoring: LV ejection fraction >50% at start of therapy If LVEF is <40% during monitoring (or 40-45% with an absolute change from pretreatment value of more than 10%), both pertuzumab and trastuzumab should be withheld. If the LV ejection fraction does not improve or continues to decline after 3 weeks of holding the drugs, both pertuzumab and trastuzumab should be discontinued. Cross-reference: MP Trastuzumab (Herceptin) MP Off-Label Use of Prescription Drug and Medical Devices II. PRODUCT VARIATIONS TOP [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] Capital Cares 4 Kids [N] PPO [N] HMO [N] SeniorBlue HMO (see note) [N] SeniorBlue PPO (see note) [N] Indemnity [N] SpecialCare [N] POS [Y] FEP PPO* Note: Off-label use of FDA approved drugs and biologicals used in an anti-cancer chemotherapeutic regimen for medically accepted indications may be covered under Medicare if the indications are supported in either one or more Medicare recognized compendia or in peerreviewed literature. Refer to Medicare Benefit Policy Manual (100-2, Chapter 15, Section Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen) for the compendia list. * Refer to FEP Medical Policy Manual MP Perjeta. The FEP Medical Policy manual can be found at: Page 2

3 III. DESCRIPTION/BACKGROUND TOP Pertuzumab (Perjeta ) is a monoclonal antibody that is a HER2 receptor antagonist. It has received U.S. Food and Drug Administration (FDA)-approval for use in combination with trastuzumab and docetaxel for the treatment of HER2 positive, metastatic breast cancer. The combination of 2 HER2-active agents targeting different subdomains of HER2 may result in a more comprehensive blockade of HER2 and its pathways, and thus may lead to a greater treatment effect. Description of Disease. 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. After lung cancer, breast cancer ranks second for cancer mortality. In 2012, an estimated 229,000 new cases of invasive breast cancer will be diagnosed among women, and approximately 40,000 women are expected to die from breast cancer. (1) Metastatic breast cancer has a poor prognosis. In a cohort of 3,524 women with de novo Stage IV or relapsed breast cancer diagnosed between 1992 and 2007, the median overall survival was 39.2 months among patients with de novo Stage IV and 27.2 months among patients with relapsed disease (estimates independent of HER2 status).(2) Factors associated with reduced survival for patients with metastatic breast cancer include age 50 years, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status.(3) Systemic treatment for metastatic breast cancer is mainly palliative. The goals of treatment are to prolong survival, alleviate symptoms, and maintain or improve quality of life. Treatment is primarily with chemotherapeutic and other anti-tumor drugs. The National Comprehensive Cancer Network (NCCN) guidelines on treatment of metastatic breast cancer include specific recommendations for first-line treatment of HER2-positive metastatic breast cancer. (1, 4) All of the recommended treatment regimens in the guidelines include trastuzumab. Recommended agents that are used singly or in combination with trastuzumab are paclitaxel, docetaxel, vinorelbine, capecitabine, and carboplatin. HER2. HER2, previously called HER2/neu, or ErbB-2, (5) is part of the HER tyrosine kinase receptor family that includes 4 transmembrane receptors (HER1 [EGFR], HER2, HER3, and HER4). These receptors mediate tumor cell growth, survival, and differentiation. The 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, to and through 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) and that initiate tyrosine kinase signaling without ligand stimulation. (6) 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. Prior to the advent of HER2 targeted therapy, HER2 overexpression was Page 3

4 associated with shorter disease-free and overall survival than women with either lymph nodenegative or lymph node-positive breast cancers, with lack of responsiveness to tamoxifen therapy, and with altered responsiveness to cytotoxic chemotherapy. (7) Testing for HER2 overexpression and/or amplification is recommended as a routine part of the diagnostic work-up on all primary breast cancers. (8) The main benefit of HER2 testing is its predictive value for response to targeted therapy. Two testing procedures are used, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tests are positive, negative, or equivocal (see Table 1). When carefully validated testing is performed, neither is considered a superior predictor of benefit from anti-her2 therapy. IHC is often used first because it is less expensive. FISH testing is reserved for the up to 15% of tumor samples with equivocal IHC values (2+). If FISH testing is equivocal, samples should be confirmed by counting additional cells or repeating the FISH test. If FISH remains equivocal, confirmatory IHC is recommended so that HER2 protein expression is known for the sample. (8) In an analysis of tumor samples for several large trastuzumab breast cancer trials, only 40 of 2,502 (1.6%) breast cancer specimens had FISH ratios between 1.80 and (7) Table 1. Testing for HER2 Overexpression and/or Amplification Result Immunohistochemistry Fluorescence in situ hybridization Negative 0 or 1+: no staining or weak, incomplete membrane staining in any proportion of tumor cells Ratio of HER2 /CEP17 a is <1.8 Or An average of <4 copies of HER2 gene per nucleus b Positive 3+: at least 30% of tumor cells exhibit intense membrane staining Ratio of HER2 /CEP17 is >2.2 Or An average of >6 copies of HER2 gene per nucleus b Equivocal 2+: complete membrane staining that is either nonuniform or weak in intensity but with obvious circumferential distribution in at least 10% of cells Ratio of HER2/CEP 17 is between 1.8 and 2.2 or Page 4

5 An average of 4 to 6 copies of HER2 gene per nucleus b Abbreviations: CEP, chromosome enumeration probe; HER2, human epidermal growth factor receptor 2. a CEP 17 is a centromeric probe for chromosome 17 (internal control probe) b Signals/nucleus for those test systems without an internal central probe Regulatory Status Pertuzumab (Perjeta ) received U.S. Food and Drug Administration (FDA) approval for metastatic breast cancer in June Labeled indications are for use in combination with trastuzumab and docetaxel for the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer who have not received prior anti-her2 therapy or chemotherapy for metastatic disease. IV. RATIONALE TOP Literature Review A single Phase 3 trial was submitted in support of the approval of Perjeta : A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA). Two Phase 2 trials that were conducted in patients with HER2+ early breast cancer (neoadjuvant treatment with trastuzumab and docetaxel, NEOSPHERE) and in patients with trastuzumab-resistant HER2+ metastatic breast cancer (also in combination with trastuzumab and docetaxel, B [not identified by NCT trial number]) were submitted as supporting documents for the pivotal Phase 3 trial. The CLEOPATRA trial is the single randomized controlled trial (RCT) completed to date. (10) CLEOPATRA (N=808) was a randomized, double-blind placebo controlled multicenter trial of pertuzumab plus a current standard of care regimen of trastuzumab and docetaxel versus trastuzumab and docetaxel alone. Eligible patients had histologically or cytologically confirmed HER2- positive adenocarcinoma of the breast with locally recurrent or metastatic disease (including de-novo Stage IV), and were candidates for chemotherapy but not curative surgery. The majority of the patients (78.2%) had visceral disease, which is defined as metastatic disease to an internal organ, and the remaining patients (22.2%) had locally advanced disease or metastases to the skin, bone, bone marrow, lymph nodes, or soft tissue. Eleven percent of patients received prior trastuzumab in the adjuvant setting. Patients were randomized to pertuzumab + trastuzumab + docetaxel or placebo + trastuzumab + docetaxel, cycled every 3 weeks and dosed as follows: Page 5

6 Pertuzumab: 840 mg IV load, then 420 mg IV every 3 weeks until disease progression or unmanageable toxicity Trastuzumab: 8 mg/kg IV load, then 6 mg/kg every 3 weeks until disease progression or unmanageable toxicity Docetaxel: 75 mg/m 2 IV every 3 weeks with dose adjustments up to 100 mg/m 2 or down by 25% for absence or emergence of intolerable toxicity, respectively, for at least 6 cycles. In the case of docetaxel discontinuation due to adverse effects, antibody therapy continued until disease progression or unmanageable toxicity. Centrally designated laboratories confirmed HER2 status, which was considered positive using either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) (FISH amplification ratio >2.0 or IHC 3+). Patients were eligible if they had received systemic neoadjuvant therapy (i.e. prior trastuzumab) for non-metastatic breast cancer greater than 1 year prior. Patients were from the U.S. (14.4%), Europe (37.9%), or Asia (31.3%). The majority of the patients were White (59.4%) and Asian (32.3%). The mean age was 53.5 years (median 54, range 22 to 89) at randomization. The primary efficacy outcome was progression-free survival (PFS), determined by independent review. Secondary outcomes included overall survival, objective response rate, PFS (determined by investigator), and safety. The independent reviewers evaluated all radiographic and cytologic data for progressive disease and overall tumor response. Tumor response was assessed every 9 weeks. The analysis of progression-free survival was performed using the intent-to-treat population. The difference in independent reviewerassessed PFS between the 2 treatment arms was compared using the log-rank test, stratified by prior treatment status and region. Median follow up was 19.3 months for both groups (Kaplan- Meier estimate). The efficacy outcomes are summarized in Table 2. The primary intent-to-treat analysis found statistically improved PFS (18.5 months vs months in the pertuzumab and control arms, respectively, hazard ratio [95% confidence interval (CI)]: 0.62 [0.51, 0.75], p<0.001). Results of subgroup analyses were consistent across strata with the exception of non-visceral disease (hazard ratio [95% CI]: 0.96 [0.61, 1.52], N=178 patients). After 165 events, interim analyses identified a trend toward statistically improved overall survival that did not cross the boundary for halting the trial (17.2% vs. 23.6% in the pertuzumab and control arms, respectively, hazard ratio [95% CI]: 0.64 [0.47, 0.88] p=0.005, with stopping boundary of p=0.0012). Independent review of overall response rate (complete response plus partial response) was 80% in the pertuzumab arm and 69% in the control arm. (6) Page 6

7 Table 2. Summary of Pivotal Trial Results (CLEOPATRA) (10) Pertuzumab (N=402) Placebo (N=406) Treatment effect (N=808) Median progression-free survival by independent assessment (mths) Hazard Ratio, 95% CI 0.62, 0.51 to 0.75 (p<0.001) Median progression-free survival by investigator assessment (mths) Hazard Ratio, 95% CI 0.65, 0.54 to 0.78 (p<0.001) c Overall mortality a, Number of deaths (%) 69 (17.2) 96 (23.6) Hazard Ratio, 95% CI 0.64, 0.47 to 0.88 (p=0.005) b Objective Response Rate, Objective response d, % , 4.2 to 17.5 (p=0.0001) c Complete response, % Page 7

8 Partial Response, % Stable disease, % Progressive disease, % Median Response (mths) Abbreviations: CI, confidence interval; mths, months a Interim analysis after 165 events b Interim analysis is considered not significant. Observed data did not cross O Brien Fleming stopping boundary of the Lan-DeMets alpha spending function (Hazard Ratio [p value], [ ]). Subsequent [unpublished] analyses indicate that overall survival was improved, but no values were reported and the new results will be presented at an [unspecified] upcoming medical meeting. c Hierarchical hypothesis testing used (PFS-independently assessed, overall survival, objective response rate), since overall survival did not cross prespecified stopping boundaries, the subsequent testing is considered exploratory only. d Complete response plus partial response Safety The CLEOPATRA trial is the major source of safety information for pertuzumab. During the trial, adverse events that occurred more frequently in the pertuzumab treated arm included: diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. Grade 3 or higher diarrhea (7.9% and 5.0% in the pertuzumab and control groups, respectively) and febrile neutropenia (13% and 7% in the pertuzumab and control groups, respectively) were reported more often in the pertuzumab treated group. Death associated with adverse events, mostly infection-related, occurred in 2.5% of the control group and 2.0% of the pertuzumab group. Left ventricular function was prospectively monitored because trastuzumab is associated with left ventricular dysfunction. Left ventricular systolic dysfunction of any grade was reported more frequently in the control group than the pertuzumab group (8.3% vs. 4.4%). Events of grade 3 or higher occurred in 2.8% of the control group and 1.2% of the pertuzumab group. Off-Label Use The potential off-label use of pertuzumab will likely be strongest for conditions in which trastuzumab is indicated, which includes virtually all other HER2-positive breast cancer and Page 8

9 metastatic gastric or gastroesophageal junction adenocarcinomas. Non-breast cancer indications under study include unresectable or metastatic neuroendocrine carcinoma, and cetuximab-refractory locally advanced or metastatic colorectal cancer; HER2 status is not an inclusion or exclusion criteria for either of these trials. Trials in metastatic or locally-advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction also are ongoing. In 2005, a Genentech press release acknowledged that Phase 2 trials of pertuzumab (Perjeta, called Omnitarg at the time) showed limited activity as a single agent in ovarian, breast, and prostate cancers. Therefore, off-label use for the purposes of this report will include only trials with pertuzumab in combination with another anti-her2 agent. There is limited published evidence available for off-label uses. Table 3 summarizes the studies that are currently published in peer-reviewed journals. The 2 aforementioned Phase 2 trials submitted by Genentech in support of the pertuzumab (Perjeta ) application are the NeoSphere trial and the Baselga 2010 trial called BO17929.(11, 12) The NeoSphere trial (11) was a Phase 2 trial of 4 neoadjuvant regimens of pertuzumab, trastuzumab, and docetaxel involving 417 patients with locally advanced, inflammatory or early-stage operable HER2- positive breast cancer. After 12 weeks, a significantly higher proportion of patients achieved a pathologic complete response to the neoadjuvant pertuzumab and trastuzumab plus docetaxel arm compared to the neoadjuvant trastuzumab and docetaxel arm (45.8% vs. 29.0%, p=0.014). The BO17929 trial studied combination pertuzumab and trastuzumab in 66 trastuzumabresistant HER2-positive metastatic breast cancer patients. The objective response rate was 24% in the combination group and 3% in the pertuzumab-alone group. (12) Table 3. Summary of Published Trials Using Pertuzumab in Combination with Other Anti-HER2 Therapy for Indications Other Than Previously Untreated HER2+ Metastatic Breast Cancer Disease Trial N Study Design Conclusions Locally advanced, inflammatory or early-stage HER2- positive breast cancer (nonmetastatic) Gianni 2012 (NeoSphere)(11) 417 Phase 2, multicenter, randomized, open-label study in treatment-naive women with HER2-positive breast cancer assigned (1:1:1:1) to A) trastuzumab + docetaxel, B) pertuzumab+ trastuzumab + docetaxel, C) pertuzumab + trastuzumab, or D) pertuzumab + docetaxel. Pertuzumab and trastuzumab plus docetaxel group (B) had a significantly improved pathologic complete response rate (49 of 107 patients; 45 8%) compared to the trastuzumab plus docetaxel group (A); 31 of 107; 29 0%; p=0 0141) 23 of 96 (24 0%) women given pertuzumab plus docetaxel (D) had a pathological complete response, as did 18 of 107 (16 8%) given pertuzumab and trastuzumab (C). Page 9

10 The most frequently occurring adverse events were alopecia, neutropenia, diarrhea, nausea, fatigue, rash, and mucosal inflammation. Advanced HER2- positive breast cancer that progressed during prior trastuzumabbased therapy Baselga 2010(12) 66 Phase 2, multicenter, open-label, single-arm study; 66 patients with advanced HER2-positive breast cancer that progressed during prior trastuzumab-based therapy. Received trastuzumab and pertuzumab combination therapy. The objective response rate was 24.2%. Five patients (7.6%) achieved a complete response, 11 (16.7%) achieved a partial response, and 17 (25.8%) achieved stable disease of 6 months. Median progression-free survival was 5.5 months. Overall, the combination was well-tolerated, and adverse events were mild to moderate. Locally advanced or metastatic NSCLC Felip 2012(13) 15 Phase Ib, open-label, multicenter study to assess maximum tolerated dose and dose-limiting toxicity. 15 patients with stage 2Ib/IV NSCLC who failed chemotherapy received erlotinib (days -8 to -1), then combination therapy of erlotinib and pertuzumab (21-day cycles for 6 cycles). No dose-limiting toxicities were observed, and AEs were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients). The median overall progression-free survival was 9.3 weeks. A loading dose of pertuzumab 840 mg followed by 420 mg once every 3 weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination. HER: Human epidermal growth factor receptor; NSCLC: Non-small-cell lung cancer; AE: Adverse event Clinical Input Received through Physician Specialty Societies and Academic Medical Centers While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Page 10

11 Responses were received from 3 academic medical centers and one specialty society. In general, there was agreement on the medically necessary indications and agreement on the investigational indications. However, reviewers disagreed with some of the criteria listed for pertuzumab use. There was consensus that pertuzumab should not be restricted to patients who are naïve to other HER2 antagonists, specifically trastuzumab. There was also consensus that pertuzumab should be medically necessary in combination with paclitaxel in addition to docetaxel. Summary There is one RCT evaluating the efficacy of pertuzumab as a treatment for HER2-positive metastatic breast cancer. This study compared pertuzumab plus docetaxel/trastuzumab to docetaxel/trastuzumab alone and reported a statistically significant 6.1 month improvement in progression-free survival for the pertuzumab group. There was a 6.4% absolute difference in overall survival that did not quite meet the prespecified significance for interim analysis. While progression-free survival as a clinical (non-surrogate) endpoint is controversial for cancer trials since it is subject to several biases, the protocol for the CLEOPATRA trial addressed some of these concerns by employing double-blinding, using short and equal assessment intervals and establishing that there was not differential loss to follow-up. Adverse events that were more common in the pertuzumab group were diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. The results of this trial indicate a strong likelihood that health outcomes are improved when pertuzumab is added to standard treatment for metastatic breast cancer, and therefore, pertuzumab may be considered medically necessary for this indication when criteria are met as listed in the policy statement. For other HER2-positive malignancies, the evidence is not sufficient to form conclusions. There is one additional RCT that evaluated pertuzumab for locally advanced breast cancer, but this was a Phase II trial in which the primary outcomes were response rates rather than survival, resulting in uncertainty as to whether clinically relevant outcomes are improved. A number of RCTs are ongoing that are evaluating pertuzumab in different populations of breast cancer patients, and for other types of malignancy that are HER2-positive. At the present time, these off-labeled uses of pertuzumab are considered investigational. Practice Guidelines and Position Statements Current clinical practice guidelines published by the National Comprehensive Cancer Network (NCCN) include pertuzumab among its preferred regimens for first-line treatment of HER2- positive metastatic breast cancer.(4) Pertuzumab in combination with trastuzumab and docetaxel received a category 1 recommendation (based on high-level evidence with uniform consensus that the intervention is appropriate), and pertuzumab in combination with trastuzumab and weekly paclitaxel received a category 2A recommendation (based on lowerlevel evidence with uniform consensus that the intervention is appropriate). The latter recommendation was based on a single-arm, Phase II study currently in progress (NCT ). In contrast to the prescribing information, the guideline supports the secondline use of pertuzumab in combination with trastuzumab with or without chemotherapy (e.g., Page 11

12 vinorelbine, docetaxel, or paclitaxel) in pertuzumab-naïve patients previously treated with trastuzumab. Cited evidence is from the Baselga Phase II study shown in Table 3 and another Phase II study of pertuzumab monotherapy in 29 trastuzumab-resistant patients. (14) Ongoing Trials A search of online site clinicaltrials.gov using the keyword pertuzumab returned 38 studies. The following is a summary of some of the key trials that are ongoing. These consist primarily of Phase 3 RCTs for treatment of breast cancer, and Phase 2 single-arm studies of pertuzumab in other types of cancer. Breast Cancer Trials NCT A Randomized Multicenter, Double-blind, Placebo-controlled Comparison of Chemotherapy Plus Trastuzumab Plus Placebo Versus Chemotherapy Plus Trastuzumab Plus Pertuzumab as Adjuvant Therapy in Patients With Operable HER2-positive Primary Breast Cancer. This RCT compares pertuzumab versus placebo in patients with non-metastatic breast cancer. NCT (MARIANNE study). A Study of Trastuzumab-DM1 Plus Pertuzumab Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE). This study compares trastuzumab + taxane (docetaxel or paclitaxel) versus trastuzumab + pertuzumab in HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. NCT (PHEREXA study). A Multicenter Randomized Study to Compare the Combination Trastuzumab and Capecitabine, With or Without Pertuzumab on Progression-Free Survival, as 2nd-line Treatment in Patients With HER2-positive Metastatic Breast Cancer That Has Progressed After Previous Treatment With Trastuzumab (PHEREXA). NCCT (TRYPHAENA study). A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Patients With HER2-Positive Breast Cancer (TRYPHAENA). This study is evaluating 3 regimens: pertuzumab + trastuzumab + docetaxel + 5-fluorouracil/epirubicin/cyclophosphamide OR carboplatin + trastuzumab (after surgery) in patients with locally advanced, inflammatory or early-stage HER2- positive breast cancer (neoadjuvant to surgery). NCT A Randomized, Two-arm, Open-label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab Plus an Aromatase Inhibitor in First Line Patients With HER2-positive and Hormone Receptor-positive Advanced (Metastatic or Locally Advanced) Breast Cancer. NCT A Two-cohort, Open-label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in First-Line Patients With HER2-positive Advanced (Metastatic or Locally Advanced) Breast Cancer. Page 12

13 Non-breast Cancer Trials NCT Combination of Bevacizumab,Pertuzumab, and Sandostatin for Adv. Neuroendocrine Cancers. This open-label Phase 2 study is testing a combination of bevacizumab, pertuzumab, and sandostatin for patients with unresectable or metastatic neuroendocrine tumors. NCT A Study of Pertuzumab in Combination With Trastuzumab and Chemotherapy in Patients With HER2-Positive Advanced Gastric Cancer. This openlabel Phase 2 study is testing a combination of pertuzumab, trastuzumab, and chemotherapy (cisplatin and capecitabine) for patients with metastatic or locallyadvanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction. NCT A Phase I/II Trial of Pertuzumab in Combination With Cetuximab in Cetuximab-Refractory Metastatic Colorectal Cancer. This open-label Phase 2 study is testing a combination of cetuximab and pertuzumab in patients with locally advanced or metastatic colorectal cancer that is refractory to Cetuximab. Medicare National Coverage None V. DEFINITIONS TOP N/A VI. BENEFIT VARIATIONS TOP The existence of this medical policy does not mean that this service is a covered benefit under the member's contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member s benefit information or contact Capital for benefit information. VII. DISCLAIMER TOP Capital s medical policies are developed to assist in administering a member s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. Page 13

14 VIII. REFERENCES TOP 1. Carlson RW, Allred DC, Anderson BO et al. Metastatic Breast Cancer, Version : Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw 2012; 10(7): Dawood S, Broglio K, Ensor J et al. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol 2010; 21(11): Chang J, Clark GM, Allred DC et al. Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 2003; 97(3): National Comprehensive Care Network. Breast Cancer. NCCN Clinical Practice Guidelines in Oncology 2012; version [Website]: Accessed April 11, Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357(1): Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010; 10(6): 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 2005; 11(18): Wolff AC, Hammond ME, Schwartz JN et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25(1): Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Pertuzumab (Perjeta ). TEC Specialty Pharmacy Reports 2012; (#8-2012). 10. Baselga J, Cortes J, Kim SB et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366(2): Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13(1): Baselga J, Gelmon KA, Verma S et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010; 28(7): Felip E, Ranson M, Cedres S et al. A Phase Ib, Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non-Small-Cell Lung Cancer. Clin Lung Cancer 2012; 13(6): Cortes J, Fumoleau P, Bianchi GV et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012; 30(14): Page 14

15 Other: Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual Publication Chapter 15 Sections 50, , Drugs and Biologicals Effective 10/01/03. [Website]: Accessed April 11, Genentech, Inc Perjeta Prescribing Information. Revised September [Website]: Accessed April 11, HercepTest and HER2Fish Test Companion Diagnostics. Dako, An Agilent Technologies Company. [Website]: Accessed April 11, Novitas Solutions Local Coverage Determination (LCD) L30538: Cytogenic Analysis. Effective 04/02/12. [Website]: Accessed April 11, IX. CODING INFORMATION TOP Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. HCPCS Code Description J9306 Injection, Pertuzumab 1 mg ICD-9-CM Diagnosis Description Code* Malignant Neoplasm of Female Breast Malignant Neoplasm of Male Breast *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. The following ICD-10 diagnosis codes will be effective October 1, 2015: ICD-10-CM Diagnosis Description Code* C Malignant neoplasm of nipple and areola, right female breast C Malignant neoplasm of nipple and areola, left female breast C Malignant neoplasm of nipple and areola, unspecified female breast C Malignant neoplasm of central portion of right female breast Page 15

16 ICD-10-CM Diagnosis Description Code* C Malignant neoplasm of central portion of left female breast C Malignant neoplasm of central portion of unspecified female breast C Malignant neoplasm of upper-inner quadrant of right female breast C Malignant neoplasm of upper-inner quadrant of left female breast C Malignant neoplasm of upper-inner quadrant of unspecified female breast C Malignant neoplasm of lower-inner quadrant of right female breast C Malignant neoplasm of lower-inner quadrant of left female breast C Malignant neoplasm of lower-inner quadrant of unspecified female breast C Malignant neoplasm of upper-outer quadrant of right female breast C Malignant neoplasm of upper-outer quadrant of left female breast C Malignant neoplasm of upper-outer quadrant of unspecified female breast C Malignant neoplasm of lower-outer quadrant of right female breast C Malignant neoplasm of lower-outer quadrant of left female breast C Malignant neoplasm of lower-outer quadrant of unspecified female breast C Malignant neoplasm of axillary tail of right female breast C Malignant neoplasm of axillary tail of left female breast C Malignant neoplasm of axillary tail of unspecified female breast C Malignant neoplasm of overlapping sites of right female breast C Malignant neoplasm of overlapping sites of left female breast C Malignant neoplasm of overlapping sites of unspecified female breast C Malignant neoplasm of unspecified site of right female breast C Malignant neoplasm of unspecified site of left female breast C50919 Malignant neoplasm of unspecified site of unspecified female breast *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. X. POLICY HISTORY TOP MP CAC 8/28/12 New policy. Pertuzumab (Perjeta) was FDA-approved in June of 2012 in combination with trastuzumab (Herceptin) and docetaxel for treatment of patients with HER-2 positive metastatic breast cancer who have not received prior anti-her2 therapy or chemotherapy for metastatic disease. 8/7/12 POLICY CODED. KLR 04/08/13- Admin code review-skb Page 16

17 CAC 7/30/13 Adopt BCBSA. No change to medically necessary policy statement. Added statement indicating the use of pertuzumab is considered investigational for all other indications, including but not limited to locally advanced breast cancer, local recurrences of breast cancer following treatment, HER2-positive gastric cancers, and HER2-positive cancers of the gastro-esophageal junction Added FEP variation to reference the FEP policy manual. Changed title from Pertuzumab (Perjeta ) to Pertuzumab for Treatment of HER2-Positive Malignancies. Deleted Medicare variation. Information related to off- label use changed to an informational note. 12/19/2013- New 2014 Code updates made. CAC 5/20/14 Consensus review. References updated. No changes to the policy statements. Coding reviewed. Top Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company, Capital Advantage Assurance Company and Keystone Health Plan Central. Independent licensees of the BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies. Page 17