Description
Pertuzumab (Perjeta), a monoclonal antibody, is a human epidermal growth factor receptor 2 (HER2) antagonist. It is approved by the U.S. Food and Drug Administration in combination with trastuzumab and docetaxel for (1) treatment of HER2-positive, metastatic breast cancer; and (2) as neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage breast cancer. The combination of 2 HER2-active agents targeting different subdomains of HER2 (pertuzumab targets subdomain II and trastuzumab targets subdomain IV) may provide a more comprehensive blockade of HER2 protein and its pathways and, thus, may lead to greater treatment effect.

For individuals who have HER2-positive locally recurrent or metastatic breast cancer who receive pertuzumab in combination with trastuzumab and a taxane, the evidence includes a 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 plus trastuzumab alone, and reported a statistically significant improvement of 6.1 months in progression-free survival 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 were diarrhea, rash, mucosal inflammation, neutropenia, febrile neutropenia, and dry skin. These trial results have indicated a strong likelihood that health outcomes are improved when pertuzumab is added to standard treatment for locally recurrent or metastatic breast cancer. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-positive locally advanced, inflammatory, or early-stage operable breast cancer who receive preoperative pertuzumab in combination with trastuzumab and a taxane (neo-adjuvant therapy), the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The NeoSphere pivotal trial supported the efficacy of pertuzumab in the neoadjuvant setting using a surrogate outcome (pathologic complete response); the validity of pathologic complete response as a surrogate for survival outcomes was deemed reasonable by the Food and Drug Administration. In NeoSphere, there was a 17.8% absolute difference in pathologic complete response for the pertuzumab group, a statistically significant difference. In stratified analysis, the treatment effect was greater for hormone receptor‒negative patients (24.6% absolute difference) vs hormone receptor-positive patients (10.0% absolute difference). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-positive early-stage breast cancer who receive postoperative pertuzumab in combination with trastuzumab and a taxane (adjuvant therapy), the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Although the large adequately powered APHINITY trial, which randomized 4,805 patients with a median follow-up of 45 months, met its statistically significant threshold for the primary end point of invasive disease-free survival in favor of pertuzumab, the effect size was small, with an absolute decrease of 0.9 percentage points in the rate of recurrence or death at 3 years; the upper bound of confidence interval of the hazard ratio included 1. Further, the trial showed no statistically significant improvement in overall survival with pertuzumab compared with control. While the safety analysis showed a consistently increased incidence of adverse events in the pertuzumab arm vs the placebo arm, the differences were small and not statistically significant, except for the incidence of diarrhea. However, the safety analysis was biased in favor of pertuzumab arm, because the patients in whom cardiac toxicity from anthracycline treatment precluded HER2-targeted treatment in the pertuzumab arm were excluded from the analysis, while toxic effects were reported in their entirety for all patients randomized to placebo. On average, 62.5 patients would have to receive pertuzumab treatment instead of standard of care for one additional patient not to have any invasive disease event while, on average, 14.5 patients would have to receive pertuzumab instead of standard of care for one additional patient to have an adverse event greater than grade 3. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have HER2-positive non-breast cancer malignancies who receive pertuzumab, the evidence includes RCTs, uncontrolled trials, and case series. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The phase 3 PENELOPE trial found that adding pertuzumab to chemotherapy did not significantly improve progression-free survival in patients with platinum-resistant ovarian carcinoma. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background  
BREAST CANCER
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‒melanoma skin cancer and ranks second for cancer mortality after lung cancer. In 2014 (the most recent year numbers are available), 236,968 women and 2,141 men in the United States were diagnosed with breast cancer, and 41,211 women and 465 men in the United States died from breast cancer.¹ 

Multimodality therapy delivered in a multidisciplinary setting involving surgical, radiation, and medical oncology specialists is the current approach to invasive breast cancer care. The recommendations for treatment are based on histopathologic type and stage at presentation. Staging is according to the Tumor, Node, Metastasis (TNM) system. Also, the American Joint Committee on Cancer has recommended the use of the prognostic staging system for breast cancer that incorporates biomarkers, the status of estrogen and progesterone receptors, and expression of the human epidermal growth factor 2 (HER2) receptor. This staging system will be effective in the United States on January 1, 2018.²  

HER2 Protein
Approximately 20% to 25% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with tyrosine kinase activity. HER2, previously called HER2/neu, or erbB-2,3 belongs to the HER family of transmembrane tyrosine kinase receptors (HER1 [epidermal growth factor receptor], 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 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.⁴  

HER2 overexpression is associated with reduced time to disease recurrence and poorer prognosis. Before the advent of HER2-targeted therapy, HER2 overexpression was associated with shorter disease-free and overall survival 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.⁵

Metastatic Breast Cancer
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, 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).⁶ 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.⁷

The goals of treatment for metastatic breast cancer are primarily to prolong survival, alleviate symptoms, and maintain or improve quality of life. Treatment is primarily with chemotherapeutic and other antitumor drugs including targeted therapies. Recommended agents used in combination with trastuzumab are paclitaxel with or without carboplatin, docetaxel, vinorelbine, and capecitabine.

Locally Advanced, Inflammatory, and Early-Stage 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 treated with chemotherapy plus trastuzumab, relapse-free survival now exceeds 80%.8 The National Comprehensive Cancer Network 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.9 Although breast conservation rates are higher after neoadjuvant chemotherapy, a survival advantage has not been shown compared with adjuvant (postoperative) chemotherapy.^10,11

Inflammatory breast cancer is rare, aggressive, and 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.   

REGULATORY STATUS
In June 2012, pertuzumab (Perjeta^®; Genentech, South San Francisco, CA) was approved by the U.S. Food and Drug Administration (FDA) through the biologics license application (125409) for the treatment of metastatic breast cancer. Pertuzumab is a HER2/neu receptor antagonist indicated in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.¹² 

In September 2013, a supplemental application for the use of pertuzumab for neoadjuvant treatment of breast cancer was granted accelerated approval by FDA. 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." 

Postmarketing commitments associated with this accelerated approval included the following¹²:

• Submission of the final efficacy (disease-free survival) and safety results from Adjuvant Pertuzumab and Herceptin^® IN Initial TherapY of Breast Cancer (APHINITY NCT 01358877).  

HER2 Testing
Detection of HER2 protein overexpression is necessary for selection of patients appropriate for pertuzumab therapy. Table 1 summarizes the FDA-approved HER2 testing kits indicated as aids in the assessment of patients for whom HER2 -targeted treatment is being considered.  

Table 1. FDA-Approved HER2 Testing Kits¹³

Drug (Trade Name)	BLA			Device		PMA	Device Manufacturer		Intended Use		Test Type
Trastuzumab (Herceptin®; Genentech, South San Francisco, CA)	103792			INFORM HER-2/NEU		P940004/S001	Ventana Medical Systems (Tucson, AZ)		Qualitative presence of Her-2/Neu gene amplification FFPE human breast tissue		FISH
					INFORM HER2 DUAL ISH DNA Probe Cocktai	P100027/S001-S01	Ventana Medical Systems		Determining HER2 gene status by enumeration of the ratio of the HER2 gene to chromosome 17		CISH
					Bond Oracle Her2 IHC System	P090015S001	Leica Biosystems (Buffalo Grove, IL)		Semi-quantitative IHC assay to determine Her2 oncoprotein status in FFPE breast cancer tissue		IHC
					INSITE HER-2/NEU KI	P040030	BioGenex Laboratories (Fremont, CA)		Her-2/neu mouse monoclonal antibody (clone C1B11) IHC semi-quantitatively localize by light microscopy the overexpression of Her-2/neu in normal and neoplastic tissue sections		IHC
Trastuzumab (Herceptin®)Pertuzumab (Perjeta®) ado-trastuzumab emtansine (Kadcyla®; Genentech, South San Francisco, CA)	103792 125409 125427				HER2 FISH PharmDx Kit	P040005/S001-S010	Agilent Technologies (Santa Clara, CA)		HER2 IQFISH PharmDx for quantitative determination of HER2 gene amplification in FFPE breast cancer, metastatic gastric or GE junction tissues, adjunct for estimating prognosis in stage II, node-positive breast cancer patients		FISH
Trastuzumab (Herceptin®)	103792			HER2 CISH PharmDx Kit		P100024/S001-S005	Agilent Technologies		Quantitatively determine HER2 gene status in FFPE breast cancer tissue, adjunct for estimating prognosis in stage II, node-positive breast cancer patients		CISH
Trastuzumab(Herceptin®) Pertuzumab (Perjeta®)ado-trastuzumab emtansine (Kadcyla®)	103792 125409 125427			HERCEPTEST™		P980018/S001-S018	Agilent Technologies		Quantitative IHC to determine HER2 protein overexpression in FFPE breast cancer, metastatic gastric or GE junction tissues		IHC
Trastuzumab (Herceptin®)	103792			SPOT-LIGHT® HER2 CISH Kit		P050040/S001-S003	Thermo Fisher Scientific (Waltham, MA)		Quantitatively determine HER2 gene amplification in FFPE breast carcinoma tissue		CISH

CISH: chromogenic in situ hybridization; BLA: biologics license application; FFPE: formalin-fixed, paraffin embedded; FISH: fluorescence in situ hybridization; GE: gastroesophageal; FDA: U.S. Food and Drug Administration; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemical; PMA: premarket approval.  

Related Policies
50112 Trastuzumab

Policy
In patients who have HER2-positive breast cancer, the use of pertuzumab in combination with trastuzumab and a taxane (e.g., docetaxel, paclitaxel) may be considered MEDICALLY NECESSARY:

• For neoadjuvant treatment of locally advanced, inflammatory or early stage (either > 2 cm in diameter or node positive) breast cancer.
• For treatment of locally recurrent or metastatic breast cancer if pertuzumab was not previously administered.

The use of pertuzumab is considered INVESTIGATIONAL for all other indications, including, but not limited to, HER2-positive gastric, colorectal, non-small-cell lung and ovarian cancers; HER2-positive cancers of the gastro-esophageal junction; and HER2-negative cancers.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

Policy Guidelines
Pertuzumab has shown fetotoxicity in animal studies. Women of childbearing age should be on effective contraception before starting pertuzumab.

Pertuzumab dose reductions are not recommended. If trastuzumab is discontinued, pertuzumab should be discontinued.

The use of pertuzumab may be associated with LV (left ventricular) dysfunction, similar to trastuzumab.

• In the CLEOPATRA trial of patients with metastatic breast cancer, baseline LV ejection fraction (EF) of ≥ 50 was required for trial entry.
• If LVEF decreases to 45 percent to 49 percent with a 10 percent or greater decrease below pretreatment values, or if LVEF decreases to less than 45 percent, both pertuzumab and trastuzumab should be held for at least three weeks. If the LVEF does not improve or continues to decline after three weeks of holding the drugs, both pertuzumab and trastuzumab should be discontinued.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that certain FDA-approved devices, drugs or biologics may not be considered investigational, and, thus, these devices may be assessed only on the basis of their medical necessity. 

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Treatment For HER2-POSITIVE Locally Recurrent or Metastatic Breast Cancer
Clinical Context and Test Purpose
The purpose of pertuzumab in combination with trastuzumab and a taxane is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HER2-positive locally recurrent or metastatic breast cancer.

The question addressed in this evidence review is: Does the use of pertuzumab in combination with trastuzumab and a taxane, as a treatment for HER2-positive malignancies, improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with HER2-positive locally recurrent or metastatic breast cancer.

Interventions
The therapy being considered is pertuzumab in combination with trastuzumab and a taxane.

Comparators
The following therapy is currently being used to make treat HER2-positive malignancies:trastuzumab and a taxane alone.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival, treatment-related mortality, and treatment-related morbidity.

Timing
Follow-up to monitor outcomes varies from the short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Setting
Pertuzumab would be administered in an oncology outpatient setting

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Systematic Reviews
The systematic reviews of targeted therapy for metastatic breast cancer have mostly combined results of pertuzumab and other targeted agents (e.g., trastuzumab, lapatinib).^16,17,18,19 These systematic reviews and meta-analyses have concluded that targeted agents have efficacy, but do not offer more specific conclusions for pertuzumab, other than those from the pivotal Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. A network meta-analysis evaluated direct and indirect comparisons of different regimens.¹⁷ It included 21 trials (total N = 11,276 patients). Six 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 trastuzumab emtansine (T-DM1), were superior to a combination of lapatinib plus trastuzumab and to any single agent regimens.

Randomized Controlled Trials
A single phase 3 trial (CLEOPATRA), a pivotal multicenter, double-blind RCT, has compared pertuzumab plus a current standard care regimen (trastuzumab plus docetaxel) with trastuzumab plus docetaxel alone.²⁰ Eligible patients (N = 808) had histologically or cytologically confirmed human epidermal growth factor 2 (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. A baseline left ventricular ejection fraction (LVEF) of 50% or more was required for trial entry. Centrally designated laboratories confirmed HER2 status using fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC), which were considered positive for a FISH amplification ratio greater than 2.0 or IHC score of 3+. Patients who had received systemic neoadjuvant therapy (i.e., previous trastuzumab) for nonmetastatic breast cancer were eligible if treatment was at least 1 year before trial entry.

Patients were randomized to the following intravenous (IV) cycles:

• 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 6 cycles.

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

The primary efficacy outcome was progression-free survival (PFS), determined by independent review. Secondary outcomes included OS, objective response rate (ORR), investigator-determined PFS, and safety. Independent reviewers evaluated all radiographic and cytologic data for disease progression and tumor response. Tumor response was assessed every 9 weeks. Analysis of PFS was performed in the intention-to-treat population, stratified by prior treatment status (previous adjuvant or neoadjuvant chemotherapy vs none) and region. The median follow-up was 30 months in both groups (Kaplan-Meier estimate).²¹

Patient demographic and baseline characteristics were balanced between treatment arms. The median age was 54 years, and 59% of the patients were white, 32% were Asian, and 4% were black. Seventeen percent of patients were enrolled in North America, 14% in South America, 38% in Europe, and 31% in Asia. The efficacy outcomes are summarized in Table 2. The primary intention-to-treat analysis found statistically improved PFS in the pertuzumab. The results of subgroup analyses were consistent across strata with the exception of nonvisceral disease (hazard ratio [HR], 0.96; 95% confidence ratio [CI], 0.61 to 1.52; n = 178 patients). After an additional year of follow-up during which crossover was not allowed and poststudy 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).²¹ Independent review of overall response rate (complete response plus partial response) was 80% in the pertuzumab group and 69% in the control group.⁴ There was no statistical difference between the 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 cancer subscales of the Functional Assessment of Cancer Therapy-Breast questionnaire).²²

In post hoc exploratory analyses of central nervous system metastases, Swain et al. (2014) reported that the incidence of central nervous system metastases as the site of first disease progression was similar between treatment groups (13.7% in the pertuzumab group vs 12.6% in the control group; p = 0.64).²³ The median time to develop central nervous system metastases as the site of first disease progression was longer in the pertuzumab group (15.0 months) than in the control group (11.9 months; HR = 0.58; 95% CI, 0.39 to 0.85; p = 0.005).

A subsequent publication by Swain et al. (2015) reported final prespecified OS results from the CLEOPATRA trial, with a median follow-up of 50 months.²⁴ As shown in Table 2, median OS was 15.7 months longer in the pertuzumab group. The median PFS and median duration of response were unchanged from the 30-month interim analysis estimates.

Table 2. Summary of Outcomes from the Pivotal Trial (CLEOPATRA)

Outcomes	Pertuzumab  (n = 402)	Placebo  (n = 406)	Treatment Effect  (N = 808)	p
Median PFS by independent assessment, mo	18.5	12.4	6.1
HR (95% CI)			0.62 (0.51 to 0.75)	< 0.001
Median PFS by investigator assessment, mo	18.5	12.4	6.1
HR (95% CI)			0.65 (0.54 to 0.78)	< 0.001d
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)	< 0.001d
No. of deaths (%), (50-mo FU)	168 (41.8)	221 (54.4)	53
Median OS, mo (50-mo FU)	56.5	40.8	15.7
HR (95% CI)			0.68 (0.56 to 0.84)	< 0.001
Overall response, %
Objective responseb	80.2	69.3
Difference (95% CI)			10.8 (4.2 to 17.5)	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, mo	20.2c	12.5c

Adapted from Baselga et al. (2012)²⁰ and Swain et al. (2013, 2015).^21,24
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.^21
b Complete response plus partial response.
^c From pertuzumab prescribing information.^25
d Interim analysis was considered significant. Observed data crossed the O’Brien-Fleming stopping boundary of the Lan-DeMets alpha spending function (HR≤0.739, p≤0.0138).

Several early-phase RCTs and a phase 3 RCT have evaluated pertuzumab with or without trastuzumab in combination with chemotherapy agents other than docetaxel as well as other targeted therapies. For example, Perez et al. (2017) reported the primary results of the phase 3 MARIANNE trial (NCT01120184).²⁶ This industry-supported study was designed to assess whether the addition of T-DM1 to standard of care (trastuzumab plus taxane) or pertuzumab monotherapy was superior in patients with HER2-positive, advanced breast cancer and no prior therapy for advanced disease. Trastuzumab plus taxane chemotherapy was considered first-line treatment for metastatic disease at the time of study onset. Results showed that T-DM1 treatment resulted in noninferior, but not superior, PFS compared with trastuzumab plus a taxane in patients with locally advanced or metastatic HER2-positive breast cancer. The median PFS was 13.7 months for trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab. The addition of pertuzumab to T-DM1 did not improve PFS (HR=0.91; 95% CI, 0.73 to 1.13) for T-DM1 plus pertuzumab vs T-DM1.

Krop et al. (2016) reported on the results of a phase 1b/2a study evaluating pertuzumab in combination with T-DM1 and paclitaxel in HER2-positive metastatic breast cancer.²⁷ The maximum tolerated dose of T-DM1 plus paclitaxel was determined in 60 patients using a 3+3 dose-escalation approach. In phase 2a, 44 patients were randomized (1:1) to T-DM1 3.6 mg/kg every 3 weeks plus weekly paclitaxel 80 mg/m² (group A) or to T-DM1 3.6 mg/kg every 3 weeks plus weekly paclitaxel 80 mg/m² and pertuzumab with a loading dose of 840 mg on day 1 of cycle 1 followed by 420 mg every 3 weeks in subsequent cycles (group B). Including both phase 1b and 2a patients, common all-grade adverse events were peripheral neuropathy (91%) and fatigue (80%). Seventy-seven percent experienced grade 3 or 4 adverse events, most commonly neutropenia (25%) and peripheral neuropathy (18%). There were 5 deaths, of which two were considered treatment-related. Among the 42 phase 2a patients, the median follow-up was 6.2 months. Among the phase 2a patients with measurable disease, the ORR was 48% (95% CI, 28% to 70%) in group A and 52% (95% CI, 30% to 72%) in group B.

Dang et al. (2015), at a single U.S. center, evaluated pertuzumab in combination with trastuzumab and weekly paclitaxel 80 mg/m² (instead of docetaxel) in 69 patients with metastatic disease.²⁸ Fifty-one (74%) patients were treated in the first-line setting and 18 (26%) 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 to 38 months), median investigator-assessed PFS was 19.5 months overall (95% CI, 14 to 26 months), 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 left ventricular (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.

Nonrandomized Trials
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.²⁹ Ninety-five percent of patients had received trastuzumab in a prior treatment regimen for advanced disease or as adjuvant or neoadjuvant therapy. The median duration of follow-up was not reported but was described as “limited” and may have been approximately 8 months (estimated 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. The 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). The median PFS was 6.6 months overall, 7.7 months in the first-line setting, and 5.5 months in the second-line setting. The incidence of grade 3 or 4 thrombocytopenia and grade 3 or 4 fatigue were 13% and 11%, respectively. Two (3%) patients experienced grade 2 infusion reactions, including 1 anaphylactic reaction; both were attributed to T-DM1 infusion. Six (9%) patients experienced LV systolic dysfunction.

Section Summary: Treatment for HER2-Positive Locally Recurrent or Metastatic Breast Cancer
The evidence on the efficacy of pertuzumab in combination with trastuzumab and a taxane as a treatment for HER2-positive, locally recurrent or metastatic breast cancer includes a pivotal RCT comparing pertuzumab plus docetaxel and trastuzumab with docetaxel plus trastuzumab alone; the trial reported a statistically significant 6.1-month improvement in PFS for the pertuzumab group; and systematic review. There was a 9.8% absolute difference in OS, a statistically and clinically significant result.

NEOadjuvant Treatment of Locally Advanced, Inflammatory, or Early-Stage Breast Cancer
Clinical Context and Test Purpose
The purpose of preoperative pertuzumab in combination with trastuzumab and a taxane (neoadjuvant therapy) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer.

The question addressed in this evidence review is: Does use of preoperative pertuzumab in combination with trastuzumab and a taxane, as a treatment for HER2-positive locally advanced, inflammatory, or early-stage breast cancer, improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with HER2-positive locally advanced, inflammatory, or early-stage breast cancer.

Interventions
The therapy being considered is preoperative pertuzumab in combination with trastuzumab and a taxane (neoadjuvant therapy).

Comparators
The following therapy is currently being used to treat HER2-positive locally advanced, inflammatory, or early-stage breast cancer: trastuzumab and a taxane alone.

Outcomes
The general outcomes of interest are OS, disease-specific survival, treatment-related mortality, and treatment-related morbidity.

Timing
symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Setting
Patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer are actively managed by oncologists in an outpatient setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Randomized Controlled Trials
Pertuzumab was given accelerated U.S. Food and Drug Administration (FDA) approval in the neoadjuvant (preoperative) setting based on 2 phase 2 trials: NeoSphere and TRYPHAENA. These trials used a novel surrogate end point, pathologic complete response (pCR).^30,31 Trial investigators defined pCR as “the absence of invasive neoplastic cells at microscopic examination of the primary tumor at surgery.” However, after completion of these trials, FDA issued guidance for industry proposing the following definitions of pCR for regulatory purposes³²:

“Pathologic complete response (pCR) is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.”

OR

“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, based on a meta-analysis by Cortazar et al. (2014) that assessed the relation between pCR and long-term outcome, reflects the evolving paradigm in the surgical management of the axilla.³³ The magnitude of increase in pCR needed to predict a survival benefit with 1 treatment over another is unknown.

In the NeoSphere trial, 417 treatment-naive patients with locally advanced (32%), inflammatory (7%), or early-stage operable (61%) HER2-positive, breast cancer were randomized in an open-label manner to treatment with docetaxel in combination with trastuzumab, pertuzumab, or both, or combination trastuzumab plus pertuzumab only.³⁰ Seven percent of patients were from North America; 73% were white and 23% were Asian. All patients had at least 1 primary tumor larger than 2 cm in diameter and baseline LVEF of at least 55%. Patients were stratified by hormone receptor status. Doses were:

• Pertuzumab: 840 mg IV load, then 420 mg every 3 weeks
• Trastuzumab: 8 mg/kg IV load, then 6 mg/kg every 3 weeks
• Docetaxel: 75 mg/m² IV every 3 weeks, escalating as tolerated to 100 mg/m² every 3 weeks.

After completing 4 cycles of neoadjuvant treatment, eligible patients (94%) underwent surgery. Results are summarized in Table 3. The incidence of pCR (FDA definition; blinded review) was significantly greater in patients who received neoadjuvant pertuzumab plus trastuzumab and docetaxel (39.3%). 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. Subsequently, a 5-year analysis of NeoSphere secondary outcomes (PFS, disease-free survival [DFS], safety) was reported by Gianni et al. (2016).³⁴ After surgery, NeoSphere patients received additional chemotherapy and adjuvant trastuzumab. Analyses of PFS were performed on the intention-to-treat population, analyses of DFS were performed on all patients who underwent surgery, and safety analyses were performed on the as-treated population. Median follow-up time was 60 months. By 5 years, 87 (21%) of 417 patients had progressed or died — 19 (18%) of 107 in group A (trastuzumab plus docetaxel), 17 (16%) of 107 in group B (pertuzumab plus trastuzumab and docetaxel), 27 (25%) of 107 in group C (pertuzumab plus trastuzumab), and 24 (25%) of 96 in group D (pertuzumab plus docetaxel). PFS and DFS results are shown in Table 3. NeoSphere was powered for the primary outcome (pCR) and not PFS or DFS outcomes. Although PFS and DFS at 5-year follow-up had large and overlapping CIs, the results supported the primary results for pCR and would suggest that neoadjuvant pertuzumab combined with trastuzumab and docetaxel is beneficial. An exploratory analysis of the association between total pCR and PFS was also presented. Five-year PFS was 85% (95% CI, 76% to 91%) for patients who achieved total pCR vs 76% (95% CI, 71% to 81%) in patients who did not (HR=0.54; 95% CI, 0.29 to 1.00), combining all treatment arms.

Table 3. Summary of Outcomes from the Pivotal Trial (NeoSphere) 

Outcomes	Group A (n=107)	Group B (n = 107)	Group C (n = 107)	Group D (n = 96)
pCR, n (%)	23 (21.5)	42 (39.3)	12 (11.2)	17 (17.7)
p	-	0.006 (vs A)	0.022 (vs A)	0.002 (vs B)
Hormonereceptor-positivesubgroupa
pCR, n/N (%)	6/50 (12.0)	11/50 (22.0)	1/51 (2.0)	4/46 (8.7)
Hormone receptor-negative subgroupa
pCR, n/N (%)	17/57 (29.8)	31/57 (54.4)	11/55 (20.0)	13/50 (26.0)
PFS, n (%)	19 (18)	17 (16)	27 (25)	24 (25)
HR  (95% CI)	-	0.69  (0.34 to 1.40; vs A)	1.25  (0.68 to 2.30; vs A)	2.05  (1.07 to 3.93; vs B)
DFS, n (%)	18 (18)	15 (15)	19 (20)	22 (24)
HR  (95% CI)	-	0.60  (0.28 to 1.27; vs A)	0.83  (0.42 to 1.64; vs A)	2.16  (1.08 to 4.32; vs B)

Adapted from Gianni et al. (2012)³⁰ and Cortazar et al. (2014).³³
Group A: trastuzumab plus docetaxel; group B: pertuzumab plus trastuzumab and docetaxel; group C: pertuzumab plus trastuzumab; group D: pertuzumab plus docetaxel.
CI: confidence interval; DFS: disease-free survival; HR: hazard ratio; pCR: pathologic complete response (as defined by the U.S. Food and Drug Administration); PFS: progression-free survival.
^a Subgroups stratified by hormone receptor status (estrogen or progesterone receptor-positive vs estrogen and progesterone receptor-negative).

Baseline breast cancer stage and type were reported in supplementary data: operable early-stage (n = 254), locally advanced (n = 134), and inflammatory breast cancer (n = 29). The participants were evenly distributed across the 4 intervention arms with the exception of inflammatory breast cancer, presumably due to small numbers. None of the outcome studies cited reported results, either pCR or PFS, for any stage or type subgroup.

The phase 2 TRYPHAENA trial was a cardiac safety study of neoadjuvant pertuzumab in combination with anthracycline chemotherapy.³¹  TRYPHAENA was an international open-labeled 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 LVEF of at least 55%. Patients were stratified by hormone receptor status and randomized 1:1:1 to receive 6 cycles of neoadjuvant chemotherapy with pertuzumab and trastuzumab administered concurrently or sequentially, as follows: 

• Group A (n = 73): 5-fluorouracil plus epirubicin plus cyclophosphamide for 3 cycles followed by docetaxel for 3 cycles, with trastuzumab and pertuzumab given concurrently throughout
• Group B (n = 75): 5-fluorouracil plus epirubicin plus cyclophosphamide for 3 cycles followed by docetaxel plus trastuzumab and pertuzumab for 3 cycles
• Group C (n = 77): docetaxel plus trastuzumab and pertuzumab and carboplatin for 6 cycles (see Table 4).

Primary safety end points were the incidence of investigator-assessed symptomatic LV systolic dysfunction (congestive heart failure) and a decline in LVEF of 10 percentage points or more from baseline to an absolute value less than 50%. As shown in Table 7 in the Safety section, the incidence of LV dysfunction was similar across all 3 treatment groups. The secondary outcome (pCR) did not differ statistically  across treatment groups. In an informal comparison with NeoSphere, pCR occurred more commonly in all 3 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.^25,35,36 Table 4 also shows that, like NeoSphere, pCR occurred more commonly in hormone receptor-negative patients than in hormone receptor-positive patients.

Table 4. Pathologic Complete Response in TRYPHAENA 

Outcomes	Group A (n = 73)	Group B (n = 75)	Group C (n = 77)
pCR, n (%)	41 (56.2)	41 (54.7)	49 (63.6)
p	-	0.85 (vs A)	0.35 (vs A); 0.26 (vs B)
Hormonereceptor-positivesubgroupb
pCR, n/N (%)	16/39 (41.0)	16/35 (45.7)	19/40 (47.5)
Hormone receptor-negative subgroupb
pCR, n/N (%)	25/34 (73.5)	25/40 (62.5)	30/37 (81.1)

Adapted from Genentech (2017)²⁵ and Food and Drug Administration (2013).³⁶
Group A received FEC for 3 cycles followed by docetaxel for 3 cycles, with trastuzumab and pertuzumab given concurrently throughout; group B received FEC for 3 cycles followed by docetaxel plus trastuzumab and pertuzumab for 3 cycles; group C received docetaxel plus trastuzumab and pertuzumab and carboplatin for 6 cycles.
FEC: 5-fluorouracil, epirubicin, and cyclophosphamide; pCR: pathologic complete response, as defined by the U.S. Food and Drug Administration.

^b Subgroups stratified by hormone receptor status (estrogen or progesterone receptor-positive vs estrogen and progesterone receptor-negative).

Nonrandomized Trials
Swain et al. (2018) published the BERENICE trial, a phase 2 cardiac safety study of neoadjuvant pertuzumab in combination with trastuzumab and chemotherapy.³⁷ BERENICE was an international nonrandomized study of patients with local advanced, inflammatory, or an early breast cancer. Patients were assigned to one of two groups, treated in the neoadjuvant period as follows:

• Group A (n = 199): dose-dense doxorubicine plus cyclophosphamide for 4 cycles, followed by 12 weekly paclitaxel injections. Four cycles of trastuzumab and pertuzumab were started with taxane therapy.
• Group B (n = 201): fluorouracil, epirubicin, and cyclophosphamide for 4 cycles, followed by docetaxel for 4 cycles. Four cycles of trastuzumab and pertuzumab were started with taxane therapy.

Treatment with trastuzumab and pertuzumab was continued in the adjuvant setting, up to one year. Primary safety endpoints were the incidence of New York Heart Association (NYHA) class III and IV heart failure and LVEF decline (defined as decline of ≥ 10% from baseline, to an absolute value < 50%); results are noted in Table 7. The reporting period for these adverse events extended from onset of treatment to the day before the first dose of a study drug, following surgery. The main efficacy endpoint was pathologic complete response in the breast and lymph nodes, which was 62% for Group A and 61% for Group B. Study limitations included nonrandomized study design and absence of a placebo treatment.

Section Summary: Neoadjuvant Treatment of Locally Advanced, Inflammatory, or Early-Stage Breast Cancer
For individuals who have HER2-positive, locally advanced, inflammatory, or early-stage operable breast cancer who received pertuzumab in combination with trastuzumab and a taxane, the evidence includes a pivotal RCT (NeoSphere) that supported the efficacy of pertuzumab in the neoadjuvant setting. In NeoSphere, there was a 17.8% absolute difference in pCR for the pertuzumab group, a statistically significant difference. In stratified analysis, the treatment effect was greater for hormone receptor-negative patients (24.6% absolute difference)  vs  hormone receptor-positive patients (10.0% absolute difference). The 5-year results on PFS and DFS had wide overlapping CIs but directionally support the primary results for pCR and would suggest that neoadjuvant pertuzumab combined with trastuzumab and docetaxel may be beneficial.

Adjuvant treatment of early-stage breast cancer
Clinical Context and Test Purpose
The purpose of postoperative pertuzumab in combination with trastuzumab and a taxane (adjuvant therapy) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HER2-positive early-stage breast cancer.

The question addressed in this evidence review is: Does the use of postoperative pertuzumab in combination with trastuzumab and a taxane, as a treatment for HER2-positive early-stage breast cancer, improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with HER2-positive early-stage breast cancer.

Interventions
The therapy being considered is postoperative pertuzumab in combination with trastuzumab and a taxane (adjuvant therapy).

Comparators
The following therapy is currently being used to treat HER2-positive early-stage breast cancer: trastuzumab and a taxane alone.

Outcomes
The general outcomes of interest are OS, disease-specific survival, treatment-related mortality, and treatment-related morbidity.

Timing
Follow-up to monitor outcomes varies from the short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Setting
Patients with HER2-positive early-stage breast cancer are actively managed by oncologists in an outpatient setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Randomized Controlled Trials
Von Minckwitz et al. (2017) reported on the results of the pivotal APHINITY RCT in which 4,805 node-positive or high-risk node-negative HER2-positive, operable breast cancer patients were randomized to pertuzumab (n = 2400) or placebo (n = 2405) added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab.³⁸ The primary end point was invasive DFS, defined as the time from randomization until the date of the first occurrence of any one of the following: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive disease, a distant disease recurrence, contralateral invasive breast cancer, or death from any cause. Note that this definition of invasive DFS differs from the standard definition of outcomes for adjuvant breast cancer trials proposed as part of the STEEP system.³⁹ The definition of invasive DFS in the APHINITY trial excluded second primary nonbreast cancer as events. The secondary end points included OS, DFS (including noninvasive breast cancers), invasive DFS (including second primary nonbreast cancer, per the STEEP definition), relapse-free interval and distant relapse-free interval, safety, and health-related quality of life. All other analyses including any post hoc subgroup analysis should be considered exploratory.

As per the trial protocol, the overall α-level was controlled for the 4 planned interim analyses for OS with the first reported comparison tested at an adjusted 2-sided significance level. To control for the overall significance level of the secondary end points, the trialists used a hierarchical testing procedure with secondary end points tested in the following order if the primary end point was statistically significant: invasive DFS including second primary nonbreast cancer, DFS, OS, recurrence-free survival, and distant relapse-free interval. The published results did not conform to this hierarchical statistical plan enumerated in the protocol because the OS was not statistically significant and yet multiple subsequent secondary end points were tested and reported. Results are summarized in Table 5 as per the protocol statistical analysis plan.

Table 5. Summary of Key RCT Efficacy Results: APHINITY 

Outcomes	Pertuzumab (n = 2400)	Placebo (n = 2405)	HR (95% CI)	p
Primary end point
3-year IDFS rate, %	94.1	93.2	0.81 (0.66 to 1.00)	0.045
n (%) with event	171 (7.1)	210 (8.7)	-
Secondary end points
IDFS (STEEP)
3-year rate, %	93.5	92.5	0.82 (0.68 to 0.99)	0.043
n (%) with event	189 (7.9)	230 (9.6)	-
Disease-free survival
3-year rate, %	93.4	92.3	0.81 (0.67 to 0.98)	0.033
n (%) with event	192 (8.0)	236 (9.8)	-
Overall survival
n (%) with event	80 (3.3)	89 (3.7)	0.89 (0.66 to 1.21)	0.47
Recurrence-free survival
3-year rate, %	95.2	94.3	a
n (%) with event	138 (5.8)	173 (7.2)
Distant relapse-free interval
3-year rate, %	95.7	95.1	a
n (%) with event	119 (5.0)	145 (6.0)

CI: confidence interval; HR: hazard ratio; IDFS: invasive disease-free survival; RCT: randomized controlled trial.
^a These secondary outcomes were not analyzed for statistical significance because of a predefined hierarchical testing procedure precluded further testing.

The APHINITY trial met the primary end point as evident by the statistically significant increase in invasive DFS with the addition of pertuzumab to the standard of care (i.e., chemotherapy plus trastuzumab). However, the effect size was small, with an absolute decrease of 0.9 percentage point in the rate of recurrence or death at 3 years, and the upper bound of CI of the HR includes 1 among HER2-positive, node-positive or node-negative early breast cancer patients. The Fragility Index proposed by Walsh et al. (2014) is intended to help identify less robust results from an RCT with binary outcomes.⁴⁰ This index identifies the number of events that would need to change to nonevents in the control group in order to change statistically significant results to nonsignificant results. A higher Fragility Index indicates more robust results. Given that the 95% CI of the HR for the primary outcome included 1, BCBSA calculated the Fragility Index for the APHINITY trial, and the results showed that if 2 patients in the control arm were converted from not having the primary end point to having the primary end point, the study would not be statistically significant (p > 0.05). Though the effect size of invasive DFS was relatively larger (1.8 percentage points) among a subgroup of patients with lymph node involvement, it still confers only a marginal benefit. Further, results from this subgroup analysis are exploratory and therefore only hypothesis generating. This small statistically meaningful benefit in invasive DFS has to be balanced against the risk associated with adding pertuzumab to the standard of adjuvant care. A greater proportion of patients in the pertuzumab arm discontinued treatment for safety reasons (7.8%) compared with the placebo arm (6.4%). A similar trend of increased cardiac events was reported in the pertuzumab arm (17 [0.7%]) vs placebo arm (8 [0.3%]). Among the subgroup of patients treated with an anthracycline-based chemotherapy, the proportion of patients with at least 1 adverse event greater than grade 3 was higher in the arm receiving pertuzumab (61.8% [1133/1834]) compared with the placebo arm (57.0% [1080/1894]). The individual adverse events including neutropenia, febrile neutropenia, neutrophil count decreased, diarrhea, and anemia were all numerically higher (data not shown) in the pertuzumab arm. The incidence of diarrhea greater than grade 3 was 2.5 times higher in the pertuzumab arm (9.8% [232/2364]) than in the placebo arm (3.7% [90/2405]). While such data showed a marginal numeric higher burden of toxicity lacking statistical significance, the analysis was biased in favor of pertuzumab arm. This bias was because the patients in whom cardiac toxicity resulting from anthracycline treatment precluded HER2-targeted treatment in the pertuzumab arm were excluded from the analysis (n = 36) while toxic effects were reported in their entirety for all patients randomized to placebo. In an editorial accompanying the article, Miller (2017) reported on a worst-case scenario that if all 36 patients whose toxic effects were discounted had a primary cardiac event, the risk of cardiac toxic effects in the pertuzumab group would increase to 2.3%.⁴¹ In addition to the above limitations, there was no information in the analyses on the utilization of hormone therapy for estrogen receptor-positive disease, nor was there information on adjuvant radiotherapy when clinically indicated or the type of surgery (breast-conserving vs mastectomy) in the study populations.

Section Summary: Adjuvant Treatment of Early-Stage Breast Cancer
The evidence for addition of pertuzumab to the standard of care in the adjuvant setting for early-stage breast cancer includes a large adequately powered APHINITY trial that randomized 4,805 patients with a median follow-up of 45 months. While the trial met the statistically significant threshold for the primary end point of invasive DFS in favor of pertuzumab, the results lacked robustness as indicated by a Fragility Index score of 2. While the safety analysis showed a consistently increased incidence of adverse events in pertuzumab arm vs placebo arm, the differences were small and not statistically significant, except for the incidence of diarrhea. However, the safety analysis was biased in favor of pertuzumab arm because the patients in whom cardiac toxicity from anthracycline treatment precluded HER2-targeted treatment in the pertuzumab arm were excluded from the analysis while toxic effects were reported in their entirety for all patients randomized to placebo. On an average, 62.5 patients would have to receive pertuzumab treatment instead of the standard of care for one additional patient not to have any invasive disease event while, on average, 14.5 patients would have to receive pertuzumab arm instead of the standard of care for one additional patient to have an adverse event greater than grade 3. Further, this trial showed no statistically significant improvement in OS with pertuzumab compared with control.

HER2-positive non-breast cancer malignancies
Clinical Context and Test Purpose
The purpose of pertuzumab is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HER2-positive non-breast cancer malignancies.

The question addressed in this evidence review is: Does the use of pertuzumab, as a treatment for HER2-positive nonbreast malignancies, improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with HER2-positive non-breast cancer malignancies.

Interventions
The therapy being considered is pertuzumab.

Comparators
The following therapy is currently being used to treat HER2-positive non-breast cancer malignancies: standard care without pertuzumab.

Outcomes
The general outcomes of interest are OS, disease-specific survival, treatment-related mortality, and treatment-related morbidity.

Timing
Follow-up to monitor outcomes varies from the short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Setting
Patients with HER2-positive non-breast cancer malignancies are actively managed by oncologists in an outpatient setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Randomized and Nonrandomized Trials
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 unresectable or metastatic neuroendocrine carcinoma, platinum-resistant ovarian cancer, and cetuximab-refractory locally advanced or metastatic colorectal cancer; HER2 status is not an inclusion or exclusion criteria for any 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 (then called Omnitarg) showed limited activity as a single agent in ovarian, breast, and prostate cancers. Therefore, for our purposes, off-label use will include only trials with pertuzumab in combination with other agents.

There is limited published evidence available for HER2-positivenon-breast cancer uses of pertuzumab. Table 6 summarizes relevant studies published in peer-reviewed journals.

Table 6. Summary of Published Studies Using Combination Therapy With Pertuzumab for Off-Label Indications

Disease	Study; Trial	N	Design	Results
Platinum-resistant, advanced ovarian cancera	Kurzeder et al. (2016)42(PENELOPE)	156	Phase 3, multicenter, double-blind RCT; 135 patients with ovarian cancer who progressed during platinum therapy or within 6 mo of completing 4+ cycles of platinum-containing therapy were randomized to physician’s choice chemotherapy (topotecan plus paclitaxel or gemcitabine) plus pertuzumab or physician’s choice chemotherapy (topotecan plus paclitaxel or gemcitabine) plus placebo	Median PFS: 4.3 mo in pertuzumab group and 2.6 mo in placebo group (HR = 0.74; 95% CI, 0.50 to 1.11; p = 0.14) Median OS: 10.3 mo in pertuzumab group and 7.9 mo in placebo group (HR = 0.84; 95% CI, 0.53 to 1.32; p = 0.44) ORR: 11.5% in pertuzumab group and 7.2% in placebo group (RD = 4.3%; 95% CI, -6.7% to 15.2%) Grade ≥ 3 neutropenia, thrombocytopenia, diarrhea, nausea, and vomiting more common in pertuzumab group
Advanced neuroendocrine cancersd	Bendell et al. (2016)43	43	Phase 2, multicenter, single-arm, open-label study of bevacizumab, pertuzumab, and octreotide depot in patients with advanced, unresectable, or metastatic, well-differentiated neuroendocrine  carcinoma with documented evidence of disease progression	Toxicity: diarrhea (63%), fatigue (63%), hypertension (44%), nausea (44%); reversible G3 hypertension (26%), LVEF decline (9%) ORR=16% Median PFS = 6.5 mo Median OS = 26.4 mo
HER2-positive advanced gastric cancer	Kang et al. (2014)44	30	Phase 2a dose-finding and safety study of first-line pertuzumab, trastuzumab, capecitabine, and cisplatin	Safety profiles of 2 pertuzumab regimens (low-dose with load or high dose) were similar, but with lower dose, mean serum trough concentration was ≈ 37% lower than that in patients with metastatic breast cancer Higher dose pertuzumab regimen (840 mg every 3 wk) selected for phase 3 trials
Cetuximab-resistant, KRAS wild-type, metastatic CRC	Rubinson et al. (2014)45	13	Phase 1/2, multicenter, single-arm, open-label study; 13 patients with metastatic disease that progressed on ≥ 1 previous cetuximab-containing regimens received cetuximab plus pertuzumab at several dose levels in a 3+3 designc	6 (46%) of 13 patients experienced dose-limiting toxicities and study terminated Grade ≥ 3 dose-limiting toxicities included dermatitis (6 patients), mucositis (5 patients), and diarrhea (2 patients) Of 7 evaluable patients, 1 (14%) had partial response lasting 6 mo
Relapsed NSCLC	Hughes et al. (2014)46	41	Phase 2, multicenter, single-arm study of pertuzumab plus erlotinib in patients with relapsed, stage III – IV NSCLC	Grade 3-4 treatment-related AEs occurred in 68% of patients, terminating enrollment Investigator-assessed response rate at day 56 was 12%
Relapsed, platinum-sensitive ovarian cancera	Kaye et al. (2013)47	149	Phase 2, multicenter, open-label RCT; 149 patients first-relapse, platinum-sensitiveb advanced ovarian cancer were randomized to carboplatin and paclitaxel or gemcitabine x 6 cycles with or without pertuzumab x 17 cycles (11 additional cycles)	Median OS: 28.2 mo in pertuzumab group and not estimable in  placebo group (HR for death, 1.02; 80% CI, 0.74 to 1.41; p = 0.926) No treatment effect of pertuzumab in patients with low HER3mRNA Most patients experienced serious AEs (63% pertuzumab, 70% control) Grade ≥3 neutropenia and thrombocytopenia more common in control group (71% vs 64% and 32% vs 18%, respectively)
Locally advanced or metastatic NSCLC	Felip et al. (2012)48	15	Phase 1b, multicenter, single-arm, open-label study to assess maximum tolerated dose and dose-limiting toxicity; 15 patients with stage IIIb/IV NSCLC who failed chemotherapy received erlotinib for 8 d, then erlotinib plus pertuzumab (21-d cycles for 6 cycles)	No dose-limiting toxicities observed, AEs generally grade 1/2 and manageable ORR = 20% (3/15 patients) Median overall PFS = 9.3 wk A loading dose of pertuzumab 840 mg followed by 420 mg once every 3 wk plus daily erlotinib 150 mg appeared to be most appropriate regimen for this combination
Platinum-resistant, advanced ovarian cancera	Makhija et al. (2010)49	135	Phase 2, multicenter, double-blind RCT; 135 patients with ovarian cancer who had received ≤ 1 previous treatment for platinum-resistant recurrent cancer were randomized to gemcitabine plus pertuzumab or gemcitabine plus placebo	Median PFS: 2.9 mo in pertuzumab group and 2.6 mo in placebo group (HR = 0.66; 95% CI, 0.43 to 1.03; p = 0.07) Risk of progression was reduced in 61 patients with low (< median) HER3 mRNA expression (HR = 0.32; 95% CI, 0.17 to 0.59; p = 0.002) Grade ≥ 3 neutropenia, thrombocytopenia, diarrhea, and back pain more common in pertuzumab group

AE: adverse event; CI: confidence interval; CRC: colorectal cancer; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; LVEF: left ventricular ejection fraction; NSCLC: non-small-cell lung cancer; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; RCT: randomized controlled trial; RD: risk difference.
^a Includes epithelial ovarian, fallopian tube, or primary peritoneal cancer.
^b Initial response to and 6-mo minimum progression-free interval after completing a platinum-based regimen.
^c Dose escalation method in which a 3-patient cohort is treated at a starting dose considered to be safe based on animal data. If no patient experiences a dose-limiting toxicity, subsequent 3-patient cohorts are treated at increasing dose levels. If any patient experiences a dose-limiting toxicity, 3 additional patients are treated at the same dose. Dose escalation continues until ≥ 2 patients among a cohort of 3 to 6 patients (i.e., ≥ 33%) experience dose-limiting toxicities at a given dose level. The dose just below this toxic dose level is commonly recommended for phase 2 trials.^50
d Includes typical carcinoid, pancreatic islet cell, and other well-differentiated neuroendocrine carcinomas.

Section Summary: HER2-Positive Non-Breast Cancer Malignancies
For individuals who have HER2-positive non-breast cancer malignancies who receive pertuzumab, the evidence includes RCTs, uncontrolled trials, and case series. The phase 3 PENELOPE trial found that adding pertuzumab to chemotherapy did not significantly improve PFS in patients with platinum-resistant ovarian carcinoma. Evidence from pivotal trials in other cancers is not available.

Safety
During the CLEOPATRA trial (metastatic breast cancer), adverse events that occurred more frequently in pertuzumab-treated patients included diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. Grade 3, 4, or 5 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%).²¹ 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 next), did not increase with an additional year of follow-up.²¹

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) was neutropenia, which occurred in 52% of patients who received docetaxel and 1% of patients who did not. 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 0% who did not. One death due to fulminant hepatitis was possibly related to study treatment (pertuzumab plus trastuzumab and docetaxel).³⁰ In the 5-year follow-up of NeoSphere,⁵¹ there were no new or long-term safety concerns. During adjuvant treatment, adverse events of grade 3, 4 or 5 were highest in group C. During posttreatment follow-up, only 7% of patient in group A, 10% of patients in group B, 7% of patients in group C, and 7% of patients in group D reported adverse events. The most commonly reported adverse events were neutropenia and febrile neutropenia.

In the TRYPHAENA trial (neoadjuvant setting), diarrhea, alopecia, and nausea (all grades) were reported in more than 50% of patients in all 3 treatment groups. As in NeoSphere, the most common serious adverse event (grade ≥ 3) 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.³¹

LV Dysfunction
Because trastuzumab is associated with LV dysfunction, LV function was prospectively monitored in clinical trials (see Table 7).

In CLEOPATRA (metastatic breast cancer), LV systolic dysfunction of any grade was reported more frequently in the control group (8.3%) than in the pertuzumab group (4.4%); grade 3 or higher events also occurred more frequently in the control group (2.8% vs 1.2%).²⁰ Among patients who developed symptomatic LV systolic dysfunction (congestive heart failure), 73% were exposed to previous anthracycline therapy (median cumulative dose, ≈ 250 mg/m²) compared with 39% of patients who did not develop congestive heart failure. The previous radiotherapy was also associated with congestive heart failure but was not a stratified covariate.⁵² Eighty-nine percent of patients who experienced dysfunction (defined as a ≥10% decrease in baseline ejection fraction to an absolute ejection fraction < 50%) recovered to an ejection fraction of 50% or more.²¹

In NeoSphere (neoadjuvant therapy), incidences of LV dysfunction and congestive heart failure were higher in the pertuzumab plus trastuzumab and docetaxel group than in other groups (see Table 7). LVEF recovered to 50% or more in all 6 patients who developed LV dysfunction (previously defined).³⁰ During the adjuvant period, there was 1 additional case of grade 3 or worse LV dysfunction or congestive heart failure in the pertuzumab plus trastuzumab plus docetaxel group.³⁴

Incidences of LV dysfunction and congestive heart failure were higher in TRYPHAENA than in NeoSphere (see Table 7). LV dysfunction (previously defined) occurred more commonly in patients who received anthracycline-containing neoadjuvant regimens. Of 11 patients who developed LV dysfunction, ejection fraction recovered to 50% or more in all.³¹ 

Table 7. Summary of LV Dysfunction Adverse Events 

Trial/Treatment Duration	LV Dysfunction, %a	Symptomatic LV Systolic Dysfunction (CHF), %
CLEOPATRA20/15 mob
Pertuzumab/trastuzumab/docetaxel	3.8	1.0
Trastuzumab/docetaxel	6.6	1.8
NeoSphere34/5-y (overall treatment and posttreatment)
Trastuzumab/docetaxel	2.0	0
Pertuzumab/trastuzumab/docetaxel	8.8	1.0
Pertuzumab/trastuzumab	4.0	1.0
Pertuzumab/docetaxel	7.0	0
TRYPHAENA31/18 wk
FEC x 3 cycles then docetaxel x 3 cycles; pertuzumab/trastuzumab throughout	5.6	0
FEC x 3 cycles then pertuzumab/trastuzumab/docetaxel x 3 cycles	5.3	2.7
Pertuzumab/trastuzumab/docetaxel/carboplatin x 6 cycles	3.9	0
BERENICE/6 mo
Doxorubicine/cyclophosphamide x 4 cycles then paclitaxel (12 injections) with trastuzumab/pertuzumab x 4 cycles	6.5%	1.5
FEC x 4 cycles then docetaxel/ trastuzumab/pertuzumab x 4 cycles	2.0%	0

Adapted from Genentech (2017).²⁵
CHF: congestive heart failure; FEC: 5-fluorouracil, epirubicin, and cyclophosphamide; LV: left ventricular; NR: not reported.
^a Decrease in LV ejection fraction of ≥ 10 percentage points from baseline to an absolute value < 50%
^b A mean of 19.9 pertuzumab cycles was administered.

Serious adverse events were also identified and characterized in the primary results of the APHINITY trial.³⁸ In the pertuzumab group (n = 2364), there were 17 (0.7%) primary cardiac events (defined as New York Heart Association class III or IV heart failure) and substantial decrease in LVEF and definite or probable cardiac death compared with 8 (0.3%) events in the placebo group (n = 2405). Additional descriptive analysis is available in the published supplemental appendix and is summarized in Table 8.

Using the data in Table 8, one may compare the primary cardiac events in the trial populations exposed to anthracycline chemotherapy in the intervention vs placebo arms. The primary cardiac event rate for the population presumably at highest risk for cardiac adverse events (pertuzumab plus trastuzumab plus anthracycline) is 15 (0.8%) compared with 7 (0.4%) in the placebo (plus trastuzumab and anthracycline). This could be interpreted as a signal that combination HER2 therapy with pertuzumab has an effect on cardiac toxicity beyond the known risks associated with the single agent trastuzumab and anthracycline chemotherapy. The primary cardiac event rates in the smaller study populations that did not receive an anthracycline were comparable between pertuzumab and placebo. Heart failure or LVEF decline accounted for most of the cardiac events in these comparisons.

Table 8. Summary of Key Hematologic and Cardiac Safety Results: APHINITY

	Targeted Therapy and Chemotherapy
Adverse Events	Regimen Aa (n = 1834), n (%)	Regimen Bb (n = 1894), n (%)	Regimen Cc (n = 528), n (%)	Regimen Dd (n = 510), n (%)
At least 1 grade ≥ 3 adverse event	1133 (61.8)	1080 (57.0)	384 (72.7)	299 (58.6)
Hematologic adverse events
Neutropenia	301 (16.4)	304 (16.1)	84 (15.9)	73 (14.3)
Febrile neutropenia	235 (12.8)	204 (10.8)	51 (9.7)	62 (12.2)
Decreased neutrophil count	193 (10.5)	197 (10.4)	35 (6.6)	33 (6.5)
Anemia	74 (4.0)	56 (3.0)	89 (16.9)	57 (11.2)
Fatal adverse evente	12 (0.7)	16 (0.8)	6 (1.1)	4 (0.8)
Primary cardiac eventf	15 (0.8)	7 (0.4)	9 (1.7)	7 (1.4)
Heart failure (NYHA III or IV) and significant LVEF declineg	13 (0.7)	5 (0.3)	2 (0.4)	1 (0.2)
Definite or probable cardiac death	2 (0.1)	2 (0.1)	0	0

Adapted from von Minckwitz et al (2017).³⁸
LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.
^a A: pertuzumab plus trastuzumab plus anthracycline.
^b B: placebo plus trastuzumab plus anthracycline.
^c C: pertuzumab plus trastuzumab plus nonanthracycline.
^d D: placebo plus trastuzumab plus nonanthracycline.
^e Fatal adverse events involving all body systems and procedural complications.
^f Primary cardiac events were counted over the whole study period, including posttreatment follow-up.
^g Significant LVEF decline defined as a decline of ≥ 10% points to a value < 50%.

Section Summary: Safety
Adverse events occurring more commonly with pertuzumab are diarrhea, rash, mucosal inflammation, neutropenia, febrile neutropenia, and dry skin. In NeoSphere, incidences of LV dysfunction and congestive heart failure were higher in the pertuzumab plus trastuzumab and docetaxel group than in other groups, but this increased risk of LV dysfunction was not observed in CLEOPATRA. In TRYPHAENA, LV dysfunction in patients who received pertuzumab was more common in patients who also received anthracycline-containing neoadjuvant regimens. In APHINITY, LVEF deterioration and New York Heart Association class III and IV heart failure were observed at rates consistent with other trials.

Summary of Evidence
For individuals who have HER2-positive locally recurrent or metastatic breast cancer who receive pertuzumab in combination with trastuzumab and a taxane, the evidence includes RCTs and a systematic review. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The RCT compared pertuzumab plus docetaxel and trastuzumab with docetaxel plus trastuzumab alone and reported a statistically significant improvement of 6.1 months in progression-free survival 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 were diarrhea, rash, mucosal inflammation, neutropenia, febrile neutropenia, and dry skin. These trial results have indicated a strong likelihood that health outcomes are improved when pertuzumab is added to standard treatment for locally recurrent or metastatic breast cancer. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-positive locally advanced, inflammatory, or early-stage operable breast cancer who receive preoperative pertuzumab in combination with trastuzumab and a taxane (neo-adjuvant therapy), the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The NeoSphere pivotal trial supported the efficacy of pertuzumab in the neoadjuvant setting using a surrogate outcome (pathologic complete response); the validity of pathologic complete response as a surrogate for survival outcomes was deemed reasonable by the Food and Drug Administration. In NeoSphere, there was a 17.8% absolute difference in pathologic complete response for the pertuzumab group, a statistically significant difference. In stratified analysis, the treatment effect was greater for hormone receptor-negative patients (24.6% absolute difference)  vs hormone receptor-positive patients (10.0% absolute difference). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-positive early-stage breast cancer who receive postoperative pertuzumab in combination with trastuzumab and a taxane (adjuvant therapy), the evidence includes an RCT. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Although the large adequately powered APHINITY trial, which randomized 4805 patients with a median follow-up of 45 months, met its statistically significant threshold for the primary end point of invasive disease-free survival in favor of pertuzumab, the effect size was small, with an absolute decrease of 0.9 percentage points in the rate of recurrence or death at 3 years; the upper bound of confidence interval of the hazard ratio included 1.Further, the trial showed no statistically significant improvement in overall survival with pertuzumab compared with control. While the safety analysis showed a consistently increased incidence of adverse events in the pertuzumab arm vs the placebo arm, the differences were small and not statistically significant, except for the incidence of diarrhea. However, the safety analysis was biased in favor of pertuzumab arm, because the patients in whom cardiac toxicity from anthracycline treatment precluded HER2-targeted treatment in the pertuzumab arm were excluded from the analysis, while toxic effects were reported in their entirety for all patients randomized to placebo. On average, 62.5 patients would have to receive pertuzumab treatment instead of the standard of care for one additional patient not to have any invasive disease event while, on average, 14.5 patients would have to receive pertuzumab instead of standard of care for one additional patient to have an adverse event greater than grade 3. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have HER2-positive non-breast cancer malignancies who receive pertuzumab, the evidence includes RCTs, uncontrolled trials, and case series. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The phase 3 PENELOPE trial found that adding pertuzumab to chemotherapy did not significantly improve progression-free survival in patients with platinum-resistant ovarian carcinoma. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input From 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.

2014 Input
In response to requests, input was received from 1 physician specialty society and 2 academic medical centers when this policy was under review in 2014. There was a consensus that pathologic complete response is a valid surrogate for survival outcomes and that pertuzumab triple-neoadjuvant therapy compares favorably with currently used neoadjuvant treatment regimens.

2012 Input
In response to requests, input was received from 1 specialty society and 3 academic medical centers when this policy was under review in 2012. 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 a consensus that pertuzumab should not be restricted to patients who are naive to other human epidermal growth factor 2 antagonists, specifically trastuzumab. There was also consensus that pertuzumab should be medically necessary in combination with paclitaxel in addition to docetaxel.

Practice Guidelines and Position Statements
National Comprehensive Cancer Network
Metastatic Disease
Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines (v.1.2018) include pertuzumab among its preferred regimens for first-line treatment of human epidermal growth factor 2 (HER2)-positive metastatic breast cancer.⁹ Pertuzumab in combination with trastuzumab and docetaxel received a category 1 recommendation, and pertuzumab in combination with trastuzumab and paclitaxel received a category 2A recommendation.

Neoadjuvant Therapy
Current NCCN guidelines (v.1.2018) support the preoperative administration of a pertuzumab-containing regimen to patients with HER2-positive, early-stage breast cancer who have a T2 or larger tumors or N1 or larger tumors (category 2A).⁹

Adjuvant Therapy
Current NCCN guidelines (v.1.2018) support the administration of a pertuzumab-containing regimen for adjuvant therapy in patients who have not received neoadjuvant pertuzumab (category 2A).⁹

Other Cancers
Pertuzumab is not included in current NCCN guidelines for rectal,⁵³ non-small-cell lung,⁵⁴ ovarian,⁵⁵ or esophageal cancers, including  astroesophageal junction cancers.⁵⁶ For gastric and colon cancer, pertuzumab is listed as a possible treatment of tumors with HER2 overexpression, with the note that “these approaches are currently considered investigational, and enrollment in a clinical trial is recommended.”^57,58

American Society of Clinical Oncology
For patients with early breast cancer, the American Society of Clinical Oncology (ASCO) published practice guidelines (2018) on adjuvant chemotherapy and targeted therapies.⁵⁹ The following relevant recommendation was made: 

• “Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer.” (Evidence: High; Strength of Evidence: moderate)

For patients with HER2-positive breast cancer and metastases, ASCO published clinical practice guidelines (2018) on disease management; pertuzumab was not mentioned.⁶⁰

For patients with advanced HER2-positive breast cancer, ASCO published practice guidelines (2018) on systemic therapy.⁶¹ The following relevant recommendations were made: 

• “Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the patient has a contraindication to taxanes” (Evidence: High; Strength of evidence: Strong)
• “If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment, but she has not received pertuzumab, clinicians may offer pertuzumab.” (Evidence: Insufficient; Strength of evidence: weak)

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might impact this policy are listed in Table 9.

Table 9. Summary of Key Trials 

NCT No.		Trial Name		Planned Enrollment	Completion Date
Metastatic breast cancer
Ongoing
NCT02514681a	A Randomized, Open-label Phase III Trial to Evaluate the Efficacy and Safety of Pertuzumab Retreatment in Previously Pertuzumab, Trastuzumab and Chemotherapy Treated Her2-Positive Metastatic Locally Advanced and Metastatic Breast Cancer			370	Jul 2019
NCT01491737a	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			258	Oct 2019
Unpublished
NCT01026142a	A Multicenter Randomized Phase III to Compare the Combination Trastuzumab and Capecitabine, With or Without Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer That Have Progressed After One Line of Trastuzumab-Based Therapy in the Metastatic Setting (PHEREXA)			452	Aug 2017 (completed)
Non-breast cancer trials
Ongoing
NCT01774786a			A Double-Blind, Placebo-Controlled, Randomized, Multicenter Phase III Study Evaluating The Efficacy And Safety Of Pertuzumab In Combination With Trastuzumab And Chemotherapy In Patients With Her2-Positive Metastatic Gastroesophageal Junction Or Gastric Cancer	780	Dec 2021
NCT02205047			Integration of Trastuzumab, with or without Pertuzumab, into perioperative chemotherapy of HER-2 positive stomach cancer: the INNOVATION TRIAL	220	Sep 2024
Unpublished
NCT01461057a			An Open-Label, Randomized, Multicenter Phase IIa Study Evaluating Pertuzumab in Combination With Trastuzumab and Chemotherapy in Patients With HER2-Positive Advanced Gastric Cancer	30	Oct 2017 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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43. Bendell JC, Zakari A, Lang E, et al. A phase II study of the combination of bevacizumab, pertuzumab, and octreotide LAR for patients with advanced neuroendocrine cancers. Cancer Invest. May 27 2016;34(5):213-219. PMID 27127841
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Coding Section 

Codes	Number	Description
HCPCS	J9171	Injection, docetaxel, 1 mg
	J9306	Injection, pertuzumab, 1 mg (new code 01/01/14)
	J9355	Injection, trastuzumab, 10 mg
ICD-9-CM Diagnosis	174.0-174.9	Malignant neoplasm of female breast
	175.0; 175.9	Malignant neoplasm of male breast
ICD-10-CM (effective 10/01/15)	C50.01-C50.929	Malignant neoplasm of breast, code range
ICD-10-PCS (effective 10/01/15)		Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for drugs.
	3E03305, 3E04305, 3E05305, 3E06305	Administration of other antineoplastic, percutaneous codes–code by central or peripheral and artery or vein
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

07/21/2022	Annual review, no change to policy intent.
02/11/2022	Interim review, updating rationale and references. No change to policy intent.
07/14/2021	Annual review, no change to policy intent.
10/29/2020	Interim review to add the statement: BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.
07/16/2020	Annual review, no change to policy intent.
07/01/2019	Annual review, no change to policy intent. Updating rationale and references.
08/03/2018	Annual review, no change to policy intent. Updating description, background, regulatory status, rationale and references.
07/28/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
07/11/2016	Annual review, no change to policy intent. Updating background, description, regulatory status, rationale, references and coding.
07/22/2015	Annual review, no change to policy intent. Updated background, description, rationale and references. Added benefit application and coded.
07/15/2014	Annual review. Updated title, background, description, regulatory status, rationale, references, policy guidelines and adding related policy. Updated policy verbiage to include medically necessary neoadjuvant therapy and treatment of locally recurrent disease, and investigational statement has been revised to include colorectal, non-small cell lung and ovarian cancers.