Name of Policy: Perjeta® (pertuzumab)

Policy #: 661 Effective Date: September 30, 2016 Category: Pharmacy Latest Review Date: August 2016

Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.

Page 1 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 Description of Procedure or Service: Perjeta® (pertuzumab) is a that is a human epidermal receptor 2 (HER2) antagonist. Pertuzumab inhibits the HER2 signaling pathways which can result in the arrest of tumor cell growth as well as cell death. Pertuzumab also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). As a single agent, pertuzumab inhibited the growth of human tumor cells, while the combination of pertuzumab and had complementary mechanisms of action and resulted in enhanced antitumor activity.

Perjeta® (pertuzumab) is approved by the U.S. Food and Drug Administration (FDA) in combination with trastuzumab and as neoadjuvant treatment for individuals with HER2-positive, locally advanced, inflammatory, or early stage (either greater than 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer. The combination of two HER2-active agents targeting different subdomains of HER2 (pertuzumab targets subdomain II and trastuzumab targets subdomain IV) may result in a more comprehensive blockade of HER2 and its pathways, and thus may lead to greater treatment effect.

The approval was based on improvement of the primary endpoint of pathological complete response (pCR) in the breast, which was defined as the absence of invasive neoplastic cells at microscopic examination of the primary tumor at surgery. The label reported "No data are available demonstrating improvement in event-free survival or overall survival."

Description of Disease Breast cancer accounts for nearly 1 in 3 cancer diagnoses in women in the United States. Among women, breast cancer is the second most common cancer after non‒ skin cancer and ranks second for cancer mortality after lung cancer. In 2016, an estimated 246,660 new cases of breast cancer will be diagnosed among women, and approximately 40,450 women are expected to die from breast cancer.

Policy: Effective for dates of service on or after September 30, 2016 Perjeta® (pertuzumab) meets Blue Cross and Blue Shield of Alabama’s medical criteria for coverage for treatment of individuals who meet Criteria (A) AND either (B), (C), OR (D) as follows: A. The breast tumor is HER2-positve (HER2+) as documented by one of the following: 1. Immunohistochemistry (IHC) is 3+; or 2. In situ hybridization (ISH) positive by any of the following: a. Single probe average HER2 copy number greater than or equal to 6.0 signals/cell; or b. Dual-probe HER2/CEP 17 ratio greater than or equal to 2.0; or c. Dual-probe HER2/CEP 17 ratio less than 2.0 with an average HER2 copy number greater than or equal to 6.0 signals/cell; AND B. The individual has metastatic breast cancer and both of the following:

Page 2 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 1. Pertuzumab will be used in combination with trastuzumab and either docetaxel* or paclitaxel*, and 2. The combination chemotherapy with pertuzumab will be used as single-line anti- HER2 chemotherapy for metastatic disease until progression. *Note: If docetaxel or paclitaxel treatment is discontinued (for example, related to toxicity), treatment with pertuzumab and trastuzumab may continue. OR C. The individual has operable early stage, locally advanced, or inflammatory breast cancer and will undergo neoadjuvant (prior to surgery) therapy and all of the following are met: 1. Primary tumor is larger than 2 cm in diameter or individual is node positive (clinically evident by palpation or imaging); and 2. ECOG performance status 0-2; and 3. Used in combination therapy with trastuzumab and one of the following: a. Docetaxel with or without carboplatin; or b. Paclitaxel; and 4. Not continued post-operatively (adjuvant).

OR D. The individual has early stage or locally advanced breast cancer and will undergo adjuvant systemic therapy and all of the following are met: 1. Pertuzumab used for a maximum of 6 cycles; and 2. Pertuzumab was not used as neoadjuvant therapy; and 3. Primary tumor measures 2 cm or more in diameter or individual lymph node positive; and 4. Used in combination with 12 months (52 weeks) course of trastuzumab and one of the following a. Docetaxel with or without carboplatin; or b. Paclitaxel

Perjeta® (pertuzumab) does not meet Blue Cross and Blue Shield of Alabama’s medical criteria for coverage and is considered investigational for treatment of individuals who do not meet the criteria listed above.

Perjeta® (pertuzumab) does not meet Blue Cross and Blue Shield of Alabama’s medical criteria for coverage and is considered investigational if it is administered after trastuzumab is discontinued or as part of a regimen without trastuzumab.

Concomitant use of pertuzumab with other targeted biologic agents not otherwise noted in the criteria above, including but not limited to , , , , , and ziv- does not meet Blue Cross and blue Shield of Alabama’s medical criteria for coverage and is considered investigational.

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Page 3 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 Effective for dates of service September 1, 2015 to September 29, 2016 Perjeta® (pertuzumab) meets Blue Cross and Blue Shield of Alabama’s medical criteria for coverage for treatment of individuals who meet Criteria (A) AND either (B), OR (C) as follows: A. The breast tumor is HER2-positve (HER2+) as documented by one of the following: 1. Immunohistochemistry (IHC) is 3+; or 2. In situ hybridization (ISH) positive by any of the following: a. Single probe average HER2 copy number greater than or equal to 6.0 signals/cell; or b. Dual-probe HER2/CEP 17 ratio greater than or equal to 2.0; or c. Dual-probe HER2/CEP 17 ratio less than 2.0 with an average HER2 copy number greater than or equal to 6.0 signals/cell; AND B. The individual has metastatic breast cancer and both of the following: 1. Pertuzumab will be used in combination with trastuzumab and either docetaxel* or paclitaxel*, and 2. The combination chemotherapy with pertuzumab will be used as single-line anti- HER2 chemotherapy for metastatic disease until progression. *Note: If docetaxel or paclitaxel treatment is discontinued (for example, related to toxicity), treatment with pertuzumab and trastuzumab may continue. OR C. The individual has early stage, locally advanced, or inflammatory breast cancer and will undergo neoadjuvant (prior to surgery) therapy and all of the following are met: 1. Primary tumor is larger than 2 cm in diameter or individual is node positive (clinically evident by palpation or imaging); and 2. ECOG performance status 0-2; and 3. Used in combination therapy with trastuzumab and one of the following: a. Docetaxel with or without carboplatin; or b. Paclitaxel; and 4. Not continued post-operatively (adjuvant).

Perjeta® (pertuzumab) does not meet Blue Cross and Blue Shield of Alabama’s medical criteria for coverage and is considered investigational for treatment of individuals who do not meet the criteria listed above.

Perjeta® (pertuzumab) does not meet Blue Cross and Blue Shield of Alabama’s medical criteria for coverage and is considered investigational if it is administered after trastuzumab is discontinued or as part of a regimen without trastuzumab.

Concomitant use of pertuzumab with other targeted biologic agents not otherwise noted in the criteria above, including but not limited to erlotinib, cetuximab, panitumumab, bevacizumab, lapatinib, and ziv-aflibercept does not meet Blue Cross and blue Shield of Alabama’s medical criteria for coverage and is considered investigational.

Page 4 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

Key Points: Metastatic Breast Cancer Metastatic breast cancer has a poor prognosis. In a cohort of 3524 women with de novo stage IV or relapsed breast cancer diagnosed between 1992 and 2007, median overall survival (OS) 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). Factors associated with reduced survival for patients with metastatic breast cancer include age 50 years or older, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status.

Systemic treatment for metastatic breast cancer is mainly palliative. Goals of treatment are to prolong survival, alleviate symptoms, and maintain or improve quality of life. Treatment is primarily with chemotherapeutic and other antitumor drugs. The National Comprehensive Cancer Network (NCCN) guidelines on treatment of breast cancer recommend specific regimens for first-line treatment of HER2- positive metastatic disease, all of which include trastuzumab. Recommended agents used in combination with trastuzumab are paclitaxel with or without carboplatin, docetaxel, vinorelbine, and capecitabine.

Early-Stage and Inflammatory Breast Cancer Treatment for operable (locally invasive or early-stage) breast cancer includes surgery and/or radiotherapy followed by adjuvant chemotherapy to reduce recurrence risk. Since the advent of treatments targeting the HER2 gene, outcomes for women with early-stage HER2-positive breast cancer have improved considerably. Among women with positive lymph nodes who are treated with chemotherapy plus trastuzumab, relapse-free survival now exceeds 80%. Current NCCN guidelines indicate that preoperative (neoadjuvant) chemotherapy may be appropriate for large tumors (>2 cm) in women with invasive breast cancer who are eligible for breast-conserving surgery. Although breast conservation rates are higher after neoadjuvant chemotherapy, a survival advantage has not been shown compared with adjuvant (postoperative) chemotherapy.

Inflammatory breast cancer is a rare, aggressive breast cancer that accounts for 1% to 6% of U.S. breast cancer cases. Inflammatory breast cancer is characterized by erythema and edema of the skin (peau d’orange) that has a palpable border and is commonly hormone receptor‒negative and HER2-positive. Based on retrospective and prospective studies, current NCCN guidelines recommend preoperative chemotherapy with an -based regimen (e.g., plus cyclophosphamide followed by a taxane). For patients with HER2-positive disease, NCCN recommends adding trastuzumab for up to 1 year.

Page 5 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 HER2 Approximately 20% to 25% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with activity. HER2, previously called HER2/neu, or ErbB-2, belongs to the HER family of transmembrane tyrosine kinase receptors (HER1 [EGFR], HER2, HER3, HER4). These receptors mediate tumor cell growth, survival, and differentiation. HER receptors, when activated by extracellular ligand binding, dimerize and activate cell signaling through the phosphatidyl inositol-3 (PI3)-kinase/AKT pathway, which regulates tumor cell survival, and the mitogen-activated protein kinase (MAPK) pathway, which regulates cellular proliferation. HER2 has no known ligand; it forms active heterodimers (particularly HER2:HER3) and, when overexpressed, homodimers (HER2:HER2) that constitutively activate tyrosine kinase signaling.

HER2 overexpression is associated with reduced time to disease recurrence and poorer prognosis. Before the advent of HER2-, HER2 overexpression was associated with shorter disease-free and OS than HER2-negative lymph node‒negative or lymph node‒positive breast cancers; with lack of responsiveness to tamoxifen therapy; and with altered responsiveness to cytotoxic chemotherapy.

Testing for HER2 overexpression and/or amplification is recommended as a routine part of the diagnostic work-up on all invasive (early-stage or recurrent) breast cancers. 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). If a reflex test (ordered after an initial equivocal HER2 test result and using the alternative technique) on the same specimen does not return a positive or negative result, histopathologic features should be reviewed, and testing should be repeated on the same specimen, on another block of the same specimen, or on another specimen (e.g., core biopsy, surgical resection, lymph node, and/or metastatic site). Repeat testing also should be considered if results seem discordant with other histopathologic findings. An indeterminate test result may be returned if technical issues prevent 1 or both tests from being reported as positive, negative, or equivocal, e.g., due to inadequate specimen handling or artifacts that prevent interpretation.

When carefully validated testing is performed, neither test is considered a superior predictor of benefit from anti-HER2 therapy. IHC often is used first because it is less expensive. FISH testing is reserved for the up to 15% of tumor samples with equivocal IHC values (2+). In an analysis of tumor samples from several large trastuzumab breast cancer trials, 40 of 2502 breast cancer specimens (1.6%) had equivocal FISH ratios.

Table 1: Testing for HER2 Overexpression and/or Amplification Result Immunohistochemistry Fluorescence In Situ Hybridization Negative 0 or 1+: No membrane staining or • Single-probe mean HER2 copy incomplete and number is <4 signals/cell faint/barely perceptible staining in Or invasive tumor • Dual-probe HER2/CEP17a ratio cells is <2.0 with mean

Page 6 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 HER2 copy number <4 signals/cell Positive 3+: More than 10% of invasive • Single-probe mean HER2 copy tumor cells exhibit number is ≥6 signals/cell intense circumferential membrane Or staining • Dual-probe HER2 /CEP17a ratio is ≥2.0 or, if mean HER2 copy number is ≥6 signals/cell, <2.0 Equivocal • 2+: Circumferential membrane • Single-probe mean HER2 copy staining is incomplete and/or or number is ≥4 and <6 signals/cell weak in intensity in >10% of Or invasive tumor cells • Dual-probe HER2 /CEP17a Or ratio is <2.0 with mean HER2 • Circumferential membrane copy number ≥4 and <6 staining is complete and intense signals/cell in ≤10% of invasive tumor cells CEP: chromosome enumeration probe; HER2: human epidermal 2 gene. a CEP 17 is a centromeric probe for chromosome 17 (internal control probe).

Treatment of Metastatic Breast Cancer Systematic Reviews and Meta-Analyses Systematic reviews of targeted therapy for metastatic breast cancer have been published, most of which combine results of pertuzumab other targeted agents such as trastuzumab and lapatinib. These meta-analyses conclude that targeted agents have efficacy, but do not generally offer any more specific conclusions for pertuzumab, other than those from the pivotal CLEOPATRA trial. One of these studies was a network meta-analysis, in which direct and indirect comparisons of different regimens were made. This study included 21 trials with a total of 11,276 patients. A total of 6 targeted treatment regimens were compared with each other and with standard care (nontargeted treatment). Results reported that 2 regimens, a combination of pertuzumab plus trastuzumab and (T-DM1), were superior to a combination of lapatinib plus trastuzumab and to any single agent regimens.

Randomized Controlled Trials A single Phase III trial was submitted in support of the approval of pertuzumab: A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA). Two Phase II studies, one conducted in patients with HER2-positive early breast cancer (neoadjuvant treatment with trastuzumab and docetaxel, NeoSphere) and the other in patients with trastuzumab-resistant HER2+ metastatic breast cancer (also in combination with trastuzumab and docetaxel) were submitted as supporting documents for the pivotal Phase III trial.

The CLEOPATRA trial was a multicenter, double-blind RCT comparing pertuzumab plus a current standard care regimen (trastuzumab plus docetaxel) with trastuzumab plus docetaxel alone. Eligible patients (N=808) 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 for curative surgery. Most patients

Page 7 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 (78%) had visceral disease, defined as metastases to an internal organ, and the remaining patients (22%) had locally advanced disease or metastases to the skin, bone, bone marrow, lymph nodes, or soft tissue. Eleven percent of patients had received trastuzumab in the adjuvant setting. Baseline left ventricular (LV) ejection fraction of 50% or more was required for trial entry. Patients were randomized to pertuzumab + trastuzumab + docetaxel or placebo + trastuzumab + docetaxel, cycled every three weeks and dosed as follows: • 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/m2 IV every 3 weeks with dose adjustments up to 100 mg/m2 or down by 25% for absence or emergence of intolerable toxicity, respectively, for at least six cycles

In the case of docetaxel discontinuation due to adverse effects, antibody therapy is continued until disease progression or unmanageable toxicity.

Centrally designated laboratories confirmed HER2 status using either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC), which were considered positive for FISH amplification ratio greater than 2.0 or IHC 3+. Patients who had received systemic neoadjuvant therapy (i.e., previous trastuzumab) for nonmetastatic breast cancer were eligible if treatment was at least one year before trial entry. Patients were from the U.S. (14%), Europe (38%), or Asia (31%). Most patients were white (59%) or Asian (32%). Mean age at randomization was 54 years (median, 54years; range, 22-89).

The primary efficacy outcome was progression-free survival (PFS), determined by independent review. Secondary outcomes included overall survival (OS), objective response rate, investigator-determined PFS, and safety. Independent reviewers evaluated all radiographic and cytologic data for disease progression and tumor response. Tumor response was assessed every nine weeks. Analysis of PFS was performed in the intent-to-treat population using the log-rank test, stratified by prior treatment status (previous adjuvant or neoadjuvant chemotherapy vs none) and region. Median follow up was 30 months in both groups (Kaplan-Meier estimate).

Efficacy outcomes are summarized in Table 2. The primary intent-to-treat analysis found statistically improved PFS (18.5 months vs 12.4 months in the pertuzumab and control groups, respectively; hazard ratio [95% confidence interval (CI)], 0.62 [0.51 to 0.75, p<0.001). Results of subgroup analyses were consistent across strata with the exception of nonvisceral disease (hazard ratio, HR [95% CI], 0.96 [0.61 to 1.52]; n=178 patients). After an additional year of follow-up during which crossover was not allowed and post study treatments were similar between groups, interim analyses identified statistically improved OS that crossed a prespecified boundary for halting the trial (deaths in 28% vs 38% of the pertuzumab and control groups, respectively; HR [95% CI], 0.66 and 0.52 to 0.84]; <0.001, with stopping boundary of 0.0138). Independent review of overall response rate (complete response plus partial response) was 80% in the pertuzumab group and 69% in the control group (p=0.001). There was no statistical difference between the two groups in health-related quality of life, as measured by time to a clinically significant change in a composite scale (physical well-being, functional well-being, and breast Page 8 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 cancer subscales of the Functional Assessment of Cancer Therapy-Breast [FACT-B] questionnaire). In post hoc exploratory analyses of central nervous system (CNS) metastases, the incidence of CNS metastases as the site of first disease progression was similar between treatment groups (13.7% vs 12.6% in the pertuzumab and control groups, respectively; χ2 test, p=0.64). Median time to development of CNS metastases as the site of first disease progression was longer in the pertuzumab group than in the control group (15.0 months vs 11.9 months; HR=0.58; 95% CI, 0.39 to 0.85; log-rank test, p=0.005).

A subsequent publication reported final prespecified OS results from the CLEOPATRA trial with a median follow-up of 50 months. As shown in Table 2, median OS was 15.7 months longer in the pertuzumab group than in the control group (56.5 months vs 40.8 months; HR=0.68; 95% CI, 0.56 to 0.84; p<0.001). Median PFS and median duration of response were unchanged from the 30-month interim analysis estimates.

Table 2: Summary of Pivotal Trial Results (CLEOPATRA) Outcomes Pertuzumab Placebo Treatment effect (n=402) (n=406) (N=808) Median PFS by independent assessment (mths) 18.5 12.4 6.1

HR (95%CI) 0.62 (0.51 to 0.75) p<0.001 Median PFS by investigator assessment (mths) 18.5 12.4 6.1 HR (95%CI) 0.65 (0.54 to 0.78) p<0.001 d Overall mortality No. of deaths (%), 30-mo FUa 113 (28.1) 154 (37.9) 41 Median OS, mo NR 37.6 HR (95% CI) 0.66 (0.52 to 0.84), No. of deaths (%), (50-mo FU) 168 (41.8%) 221 (54.4%) p<0.001d Median OS, mo (50-mo FU) 56.5 40.8 53 HR (95% CI) 15.7 0.68 (0.56 to 0.84), p<0.001

Overall Response (%) Objective responseb 80.2 69.3 Difference (95% CI) 10.8 (4.2 to 17.5) p=0.001 Complete response 5.5 4.2 Partial response 74.6 65.2 Stable disease 14.6 20.8 Progressive disease 3.8 8.3 Median duration of response 20.2 mths 12.5 mths CI: confidence interval; FU: follow-up; HR: hazard ratio; NR: not reached; OS: overall survival; PFS: progression-free survival. a Second interim analysis after 267 deaths. b Complete response plus partial response. c From pertuzumab prescribing information. d Interim analysis was considered significant. Observed data crossed the O’Brien–Fleming stopping boundary of the Lan- DeMets alpha spending function (HR ≤.739, p≤.0138).

Page 9 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 Two single-arm studies investigated pertuzumab in off-label combinations for HER2-positive advanced breast cancer. Dang et al (2015) at a single U.S. center evaluated pertuzumab in combination with trastuzumab and weekly paclitaxel (instead of docetaxel) 80 mg/m2 in 69 patients with metastatic disease (NCT01276041). Fifty-one patients (74%) were treated in the first-line setting and 18 (26%) were treated in the second-line setting; of those previously treated for metastatic disease, 14 (78%) had received trastuzumab. At median follow-up of 21 months (range, 3-38 months), median investigator-assessed PFS was 19.5 months overall (95% CI, 14 to 26), 24.2 months in the first-line setting (95% CI, 14 to not reached), and 16.4 months in the second-line setting (95% CI, 8.5 to not reached). Six-month PFS was 86% overall, 89% in the first-line setting, and 78% in the second-line setting, which exceeded a prespecified threshold for efficacy and further study. No patients experienced febrile neutropenia or symptomatic LV systolic dysfunction. The incidence of grade 3 or 4 fatigue was 6%, and incidences of grade 3 or 4 diarrhea, peripheral neuropathy, and palmar-plantar erythrodysesthesia syndrome were 3% each.

Miller et al (2014) conducted an international study of 64 patients with HER2-positive metastatic breast cancer who received T-DM1 plus pertuzumab in the first-line (33%) or second-line (67%) setting. Ninety-five percent of patients had received trastuzumab either in a prior treatment regimen for advanced disease or as adjuvant or neoadjuvant therapy. Median duration of follow- up was not reported but was described as “limited” and may have been approximately 8 months (rough estimate from Kaplan-Meier survival plot). Objective response (the primary efficacy end point) was observed in 41% of all patients, 57% of those in the first-line setting, and 33% of those in the second-line setting. Median duration of response was 13.9 months overall (95% CI, 6.9 to not reached), 13.9 months in the first-line setting (95% CI, 5.9 to not reached), and 11.8 months in the second-line setting (95% CI, 5.4 to not reached). Median PFS was 6.6 months overall, 7.7 months in the first-line setting, and 5.5 months in the second-line setting. Incidence of grade 3 or 4 thrombocytopenia and grade 3 or 4 fatigue were 13% and 11%, respectively. Two patients (3%) experienced grade 2 infusion reactions, including 1 anaphylactic reaction; both were attributed to T-DM1 infusion. Six patients (9%) experienced LV systolic dysfunction.

Neoadjuvant Treatment of Locally Advanced, Inflammatory, or Early Stage Breast Cancer Pertuzumab is the first drug FDA-approved for neoadjuvant (preoperative) treatment of breast cancer. Accelerated approval was granted based on two Phase II trials that used a novel surrogate end point, pathologic complete response. Trial investigators defined pathologic complete response as “the absence of invasive neoplastic cells at microscopic examination of the primary tumor at surgery.” However, after completion of these trials, FDA issued draft guidance for industry proposing the following definition of pathologic complete response for regulatory purposes: “Pathologic complete response (pCR) is defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy.”

OR

Page 10 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 “Pathological complete response (pCR) is defined as the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.”

This recommendation was based on meta-analysis that assessed the relation between pCR and long-term outcome, reflects the evolving paradigm in surgical management of the axilla. The magnitude of increase in pCR needed to predict a survival benefit with 1 treatment over another is unknown.

NeoSphere was an international, open label RCT in 417 treatment-naïve patients with locally advanced (32%), inflammatory (7%), or early stage operable (61%) HER2-positive breast cancer. Seven percent of patients were from North America; 73% were white, and 23% were Asian. All patients had at least one primary tumor larger than 2 cm in diameter and baseline left ventricular (LV) ejection fraction (by echocardiography or multiple gated acquisition [MUGA] scan) of at least 55%. Patients were stratified by hormone receptor status and randomized 1:1:1:1 to receive four cycles of neoadjuvant treatment with docetaxel in combination with trastuzumab, pertuzumab, or both, or combination trastuzumab/pertuzumab only. Doses were: • Pertuzumab: 840 mg IV load, then 420 mg every three weeks • Trastuzumab: 8 mg/kg IV load, then 6 mg/kg every three weeks • Docetaxel: 75 mg/m2 IV every three weeks, escalating as tolerated to 100 mg/m2 every three weeks

After completing four cycles of neoadjuvant treatment, eligible patients (94%) underwent surgery. The incidence of pCR (FDA definition; blinded review) was significantly greater in patients who received neoadjuvant pertuzumab/trastuzumab/docetaxel than in those who received neoadjuvant trastuzumab/docetaxel alone (39.3% vs 21.5%; p=0.006). As previously noted, the clinical significance of a 17.8 percentage point difference in pCR is uncertain. Consistent with other studies of HER2 treatments for breast cancer, the incidence of pCR was greater in hormone receptor-negative patients than in hormone receptor-positive patients in all treatment groups (see Table 3).

Table 3: Summary of Pivotal Trial Results (NeoSphere) A: Trastuzumab/ B: C: Pertuzumab/ D: Pertuzumab/ docetaxel Pertuzumab/trastuzumab/ trastuzumab docetaxel n=107 docetaxel n=107 n=96 n=107 pCR, n (%) 23 (21.5%) 42 (39.3%) 12 (11.2%) 17 (17.7%)

P value -- 0.006 (vs A) 0.022 (vs A) 0.002 (vs B) Hormone receptor-positive subgroupa pCR, n (%) 6/50 (12.0) 11/50 (22.0) 1/51 (2.0) 4/46 (8.7) Hormone receptor-negative subgroupa pCR, n (5) 17/57 (29.8) 31/57 (54.4) 11/55 (20.0) 13/50 (26.0) pCR, pathologic complete response as defined by FDA a Subgroups stratified by hormone receptor status (estrogen or progesterone receptor positive versus estrogen and progesterone receptor negative).

Page 11 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661

The Phase 2 TRYPHAENA trial was a cardiac safety study of neoadjuvant pertuzumab in combination with anthracycline chemotherapy. TRYPHAENA was an international unblinded RCT in 225 patients with locally advanced (25%), inflammatory (6%), or early stage operable (69%) HER2-positive breast cancer. As in NeoSphere, all patients had a primary tumor size of 2 cm or greater and baseline LV ejection fraction of at least 55%. Patients were stratified by hormone receptor status and randomized 1:1:1 to receive six cycles of neoadjuvant chemotherapy with pertuzumab and trastuzumab administered concurrently or sequentially, as follows: • Group A (n=73): 5-fluorouracil plus epirubicin plus cyclophosphamide (FEC) for three cycles followed by docetaxel for three cycles, with trastuzumab and pertuzumab given concurrently throughout • Group B (n=75): FEC for three cycles followed by docetaxel plus trastuzumab plus pertuzumab for three cycles • Group C (n=77): docetaxel plus trastuzumab plus pertuzumab plus carboplatin for six cycles Primary safety end points were incidence of investigator-assessed symptomatic LV systolic dysfunction (congestive heart failure) and decline in LV ejection fraction of 10 percentage points or more from baseline to an absolute value less than 50%. As shown in Table 5, the incidence of LV dysfunction was similar across all three treatment groups. pCR was a secondary outcome and did not differ statistically across treatment groups (see Table 4). In informal comparison with NeoSphere, pCR occurred more commonly in all three treatment groups in TRYPHAENA, possibly due to the use of anthracycline-containing neoadjuvant regimens. However, because TRYPHAENA was a small trial of short duration, FDA reviewers found this evidence insufficient to support concomitant administration of pertuzumab with an anthracycline. Table 4 also shows that, like NeoSphere, pCR occurred more commonly in hormone-receptor negative patients than in hormone-receptor positive patients.

Table 4: Pathological Complete Response in TRYPHAENA A: FEC x 3 cycles then B: FEC x 3 cycles then C: Pertuzumab/trastuzumab/ docetaxel x 3 cycles; pertuzumab/trastuzumab/ docetaxel/carboplatin x 6 cycles pertuzumab/trastuzumab docetaxel x 3 cycles throughout, n=73 n=75 n=77 pCR, n (%) 41 (56.2%) 41 (54.7%) 49 (63.6%) p valuea -- 0.85 (vs A) 0.35 (vs A); 0.26 (vs B) Hormone receptor-positive subgroupb pCR, n (%) 16/39 (41.0%) 16/35 (45.7%) 19/40 (47.5%) Hormone receptor-negative subgroupb pCR, n (%) 25/34 (73.5%) 25/40 (62.5%) 30/37 (81.1%) FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; pCR: pathological complete response, as defined by FDA a p values calculated by report author (χ2 test). b Subgroups stratified by hormone receptor status (estrogen or progesterone receptor positive versus estrogen and progesterone receptor negative).

Safety During the CLEOPATRA trial in patients with metastatic breast cancer, adverse events that occurred more frequently in pertuzumab-treated patients included diarrhea, rash, mucosal Page 12 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 inflammation, febrile neutropenia, and dry skin. Grade 3 or higher adverse events that occurred more commonly in the pertuzumab group were diarrhea (9% vs 5%), neutropenia (49% vs 46%), and febrile neutropenia (14% vs 8%). Deaths associated with adverse events, mostly infection- related, occurred in 2.0% of the pertuzumab group and 2.5% of the control group. The incidence of adverse events, including cardiac adverse events (discussed further in later section), did not increase with an additional year of follow-up.

In the NeoSphere trial (neoadjuvant setting), adverse events of all grades were less common in the group that did not receive docetaxel. Diarrhea was the only adverse event that occurred in 20% or more of patients in all groups (50% pertuzumab plus docetaxel [with or without trastuzumab]; 34% trastuzumab plus docetaxel; 28% pertuzumab plus trastuzumab). The most commonly occurring serious adverse event (Grade 3 or higher) was neutropenia, which occurred in 52% of patients who received docetaxel and 1% of patients who did not receive docetaxel. Other common serious adverse events were febrile neutropenia, leukopenia, and diarrhea, all of which occurred in 6% to 8% of patients who received docetaxel and no patients who did not. One death due to fulminant hepatitis was possibly related to study treatment (pertuzumab plus trastuzumab plus docetaxel).

In the TRYPHAENA trial (neoadjuvant setting), diarrhea, alopecia, and nausea (all grades) were reported in more than 50% of patients in all three treatment groups. As in NeoSphere, the most common serious adverse event (Grade 3 or higher) was neutropenia, which occurred in approximately 45% of patients across groups. Other common serious adverse events were febrile neutropenia and leukopenia. No death was reported during neoadjuvant treatment.

LV Dysfunction Because trastuzumab is associated with LV dysfunction, LV function was prospectively monitored in clinical trials (See Table 5). • In CLEOPATRA (metastatic breast cancer), LV systolic dysfunction of any grade was reported more frequently in the control group than in the pertuzumab group (8.3% vs 4.4%); Grade 3 or higher events also occurred more frequently in the control group (2.8% vs 1.2%). Among patients who developed symptomatic LV systolic dysfunction (congestive heart failure), 73% were exposed to previous anthracycline therapy (median cumulative dose approximately 250 mg/m2) compared with 39% of patients who did not develop congestive heart failure. Previous radiotherapy also was associated with congestive heart failure, but this was not a stratified covariate. Eighty-nine percent of patients who experienced dysfunction (defined as a 10% or more decrease in baseline ejection fraction [EF] to an absolute EF <50%) recovered to an EF of 50% or more. • In NeoSphere (neoadjuvant therapy), incidences of LV dysfunction and congestive heart failure were higher in the pertuzumab-trastuzumab-docetaxel group than in other groups (see Table 5). LVEF recovered to 50% or more in all six patients who developed LV dysfunction (previously defined). • Incidences of LV dysfunction and congestive heart failure were higher in TRYPHAENA than in NeoSphere (see Table 5). LV dysfunction (previously defined) occurred more commonly in patients who received anthracycline-containing neoadjuvant regimens. Of 11 patients who developed LV dysfunction, EF recovered to 50% or more in all.

Page 13 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 Table 5: Summary of Left Ventricular Dysfunction Adverse Events Trial/Treatment Duration LV Dysfunctiona, % Symptomatic LV Systolic Dysfunction (CHF), % CLEOPATRA/15 monthsb Pertuzumab/trastuzumab/docetaxel 3.8 1.0 Trastuzumab/docetaxel 6.6 1.8 NeoSphere/12 weeks Trastuzumab/docetaxel 1.0 0 Pertuzumab/trastuzumab/docetaxel 2.8 0.9 Pertuzumab/trastuzumab 1.0 0 Pertuzumab/docetaxel 1.0 0 TRYPHAENA/18 weeks FEC x 3 cycles then docetaxel x 3 cycles; 5.6 0 pertuzumab/trastuzumab throughout FEC x 3 cycles then pertuzumab/trastuzumab/ 5.3 2.7 docetaxel x 3 cycles Pertuzumab/trastuzumab/docetaxel/carboplatin x 6 3.9 0 cycles Abbreviations: CHF, congestive heart failure; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; LV, left ventricular a Decrease in left ventricular ejection fraction (LVEF) of ≥10 percentage points from baseline to an absolute value <50%. b A mean of 19.9 pertuzumab cycles was administered.

Other Uses Multiple phase 2 clinical trials are currently investigating the use of pertuzumab as a treatment for other solid tumors (for example, colorectal cancer, gastric cancer, neuroendocrine tumors, non-small cell lung cancer, and prostate cancer) and in combination with other drugs and targeted therapies. However, the data demonstrating safety and efficacy from these trials have not been published.

As a result of clinical trials demonstrating the effectiveness of pertuzumab with chemotherapy, additional clinical trials are studying the efficacy of adding pertuzumab to specific targeted biologic agents and/or with other chemotherapy agents. However, at this time, there is no evidence to support the safety and efficacy of combining pertuzumab with other biologic agents not discussed above.

Additionally, investigators continue to study the prevalence and role of anti-HER2 therapy in other malignancies. However, there have been no large randomized controlled trials to draw reasonable conclusions regarding the safety and efficacy of pertuzumab versus current standard therapies for malignancies other than breast cancers. NCCN guidelines for gastric cancer (2015) do not recommend the use of pertuzumab to treat gastric cancer.

Summary The evidence on the efficacy of pertuzumab as a treatment for HER2-positive, locally recurrent or metastatic breast cancer includes 1 randomized controlled trial (RCT). Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The RCT compared pertuzumab plus docetaxel and trastuzumab with docetaxel and trastuzumab alone, and reported a statistically significant 6.1-month improvement in progression-free survival

Page 14 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 for the pertuzumab group. There was a 9.8% absolute difference in overall survival, a statistically and clinically significant result. Adverse events occurring more commonly in the pertuzumab group was diarrhea, rash, mucosal inflammation, neutropenia, febrile neutropenia, and dry skin. These trial results indicate a strong likelihood that health outcomes are improved when pertuzumab is added to standard treatment for locally recurrent or metastatic breast cancer. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence on the efficacy of pertuzumab as a neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage operable breast cancer includes 1 RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The NeoSphere pivotal trial supported efficacy of pertuzumab in the neoadjuvant setting using a surrogate outcome (pathologic complete response [pCR]); the validity of pCR as a surrogate for survival outcomes was deemed reasonable. In NeoSphere, there was a 17.8% absolute difference in pCR for the pertuzumab group, a statistically significant difference. In stratified analysis, treatment effect was greater for hormone receptor‒negative patients (24.6% absolute difference) versus hormone receptor‒positive patients (10.0% absolute difference). Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence on the efficacy of pertuzumab as a treatment for other HER2-positive and HER2- negative tumors includes uncontrolled trials and case series. Relevant outcomes are overall survival, disease specific survival, and treatment-related mortality and morbidity. Two small single-arm studies examined pertuzumab in off-label combinations (e.g., without trastuzumab or docetaxel) for metastatic breast cancer. One study supported the use of pertuzumab in a paclitaxel-containing regimen, and this regimen is considered medically necessary. The other study of trastuzumab emtansine (T-DM1) provided insufficient evidence for efficacy and safety that is comparable with the Food and Drug Administration‒approved regimen. The large, phase 3 MARIANNE trial is evaluating pertuzumab in combination to T-DM1 for metastatic breast cancer, with results expected in 2016. The evidence is insufficient to determine the effects of the technology on health outcomes expected in 2016. The evidence is insufficient to determine the effects of the technology on health outcomes.

Key Words: Metastatic breast cancer, HER2-positive, neoadjuvant breast cancer treatment, Perjeta, pertuzumab

Approved by Governing Bodies: In June 2012, pertuzumab (Perjeta®) was approved by the U.S. Food and Drug Administration (FDA) for metastatic breast cancer. Labeled indications are for “use in combination with trastuzumab and docetaxel for treatment of patients with HER2 [human receptor 2]–positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.”

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In September 2013, pertuzumab was granted accelerated approval by FDA for neoadjuvant treatment of breast cancer. Labeled indications are for “use in combination with trastuzumab and docetaxel in patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathologic complete response rate. No data are available demonstrating improvement in event-free survival or OS [overall survival]. Limitations of use:

• The safety of pertuzumab as part of a doxorubicin-containing regimen has not been established. • The safety of pertuzumab administered for greater than 6 cycles for early breast cancer has not been established.”

Data from the phase 3 APHINITY trial (expected in 2023) are required to convert accelerated approval for this indication to full approval.

Benefit Application: Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable. ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: HCPCS Codes J9306 Injection, pertuzumab, 1 mg (effective 01/01/2014)

References: 1. Baselga J, Cortes J, Kim S, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366(2):109-119. 2. 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):1138-1144. 3. 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):489-491. 4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Pertuzumab (PerjetaTM). TEC Specialty Pharmacy Reports 2012; (#8-2012). 5. Carlson RW, Allred DC, Anderson BO et al. Metastatic Breast Cancer, Version 1.2012: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw 2012; 10(7):821-829.

Page 16 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 6. 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):545-553. 7. Chemotherapy regimens for recurrent or metastatic breast cancer. NCCN guidelines v. 2.2012. 8. Cortazar P, Zhang L, Untch M et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014. Jul 12 2014;384(9938):164-172. 9. Cortes J, Baselga J, Im YH et al. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol 2013; 24(10):2630-2635. 10. 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):1594-1600. 11. Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. Feb 10 2015;33(5):442-447. 12. 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):2169-2174. 13. 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):432-441. 14. , Inc. Perjeta® (pertuzumab) injection for intravenous use prescribing information, September 2013. Available online at: www.perjeta.com/. 15. 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):25- 32. 16. Giordano SH, Temin S, Kirshner JJ et al. Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. Jul 1 2014;32(19):2078-2099. 17. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357(1):39-51. 18. Kaye SB, Poole CJ, Danska-Bidzinska A et al. A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer. Ann Oncol 2013; 24(1):145-152. 19. Krop I, Winer EP. Further progress in HER2-directed therapy. Lancet Oncol 2012; 13(1):2- 3. 20. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 2009; 101(10):708-720. 21. Makhija S, Amler LC, Glenn D et al. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 2010; 28(7):1215-1223.

Page 17 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 22. Mates M, Fletcher GG, Freedman OC, et al. Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol. Mar 2015;22(Suppl 1):S114-122. 23. Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev 2007; (2):CD005002. 24. Miller KD, Dieras V, Harbeck N, et al. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol. May 10 2014;32(14):1437-1444. 25. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Breast Cancer. Available online at: seer.cancer.gov/statfacts/html/breast.html. 26. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, V.3.2016. Available online at: www.nccn.org/professionals/physician_gls/f_guidelines.asp. 27. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: gastric cancer, version 3.2015. http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. 28. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: colon cancer, version 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. 29. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: rectal cancer, version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. 30. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: non-small cell lung cancer, version 5.2015. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. 31. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. 32. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: esophageal and esophagogastric junction cancers, version 3.2015. http://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. 33. Perjeta (pertuzumab) package insert. Genentech, Inc. San Francisco, CA. 34. 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):6598-6607. 35. Rastogi P, Anderson SJ, Bear HD et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008; 26(5):778-785. 36. Rubinson DA, Hochster HS, Ryan DP et al. Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients. Invest New Drugs 2013. 37. Schneeweiss A, Chia S, Hickish T et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013; 24(9):2278-2284. Page 18 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 38. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2- positive metastatic breast cancer. N Engl J Med. Feb 19 2015;372(8):724-734. 39. Swain SM, Baselga J, Miles D, et al. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann Oncol. Jun 2014;25(6):1116-1121. 40. Swain SM, Ewer MS, Cortes J et al. Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study. Oncologist 2013; 18(3):257- 264. 41. Swain SM, Kim SB, Cortes J et al. Pertuzumab, trastuzumab, and docetaxel for HER2- positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013; 14(6):461-471. 42. Tsang RY, Finn RS. Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. British Journal of Cancer 2012; 106:6-13. 43. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125409Orig1s051 Summary Review - September 30, 2013. Available online at: www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125409_perjeta_toc.cfm. 44. US Food and Drug Administration. FDA Briefing Information for the September 12, 2013 Meeting of the Oncologic Drugs Advisory Committee. Available online at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsA dvisoryCommittee/ucm367753.htm. 45. US Food and Drug Administration. Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. /downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pd f. 46. US Food and Drug Administration. Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Draft Guidance: May 2013. Available online at: www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm064981.htm. 47. von Minckwitz G, Untch M, Blohmer J-U et al. Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. J Clin Oncol 2012; 30(15):1796-1804. 48. Wolff AC, Hammond ME, Hicks DG et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 2014; 138(2):241-256. 49. Wolff AC, Hammond ME, Schwartz JN et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline. J Clin Oncol 2007; 25(1):118-145. 50. Wu J, Qiu K, Zhu J, et al. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with breast cancer treated with HER2 blockade. Breast. Sep 12 2015. Page 19 of 20 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Medical Policy #661 51. Yu Q, Zhu Z, Liu Y, et al. Efficacy and safety of HER2-targeted agents for breast cancer with HER2-overexpression: a network meta-analysis. PLoS One. 2015;10(5):e0127404.

Policy History: Medical Policy Group: policy transferred to pharmacy with effective date September 1, 2015. Medical Policy Group, August 2016 (2): Updates to Description, Key Words, Approved by Governing Bodies, and References; Policy section updated to include criteria for adjuvant systemic therapy with early stage or locally advanced breast cancer; added references 11, 22, 24, 27-32, 38-39, 50-51.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case- by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

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