Medical Policy

Policy Num:      05.001.026
Policy Name:    Pertuzumab for Treatment of Malignancies
Policy ID:           [05.001.026]  Ac / B / M+ / P+]  [5.01.20]

Last Review:     November 12, 2024
Next Review:     November 20, 2025
 

Related Policies:  None

Pertuzumab for Treatment of Malignancies

summary

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 (FDA) for (1) treatment of HER2-positive metastatic breast cancer in combination with trastuzumab and docetaxel (2) as neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage breast cancer in combination with trastuzumab and chemotherapy and (3) as adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence in combination with trastuzumab and chemotherapy. 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 the HER2 protein and its pathways and, thus, may lead to greater treatment effect.

Summary of Evidence

For individuals who have human epidermal growth factor receptor 2 (HER2)-positive locally recurrent or metastatic breast cancer who receive pertuzumab in combination with trastuzumab and a taxane, the evidence includes systematic reviews, a pivotal randomized controlled trial (RCT) comparing pertuzumab plus docetaxel and trastuzumab with docetaxel plus trastuzumab alone, and several other RCTs comparing other combinations. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. The pivotal RCT, CLEOPATRA, reported a statistically significant 6.1-month improvement in progression-free survival (PFS) for the pertuzumab group. After a median follow-up of 30 months, the rate of OS was also significantly improved in the pertuzumab group. The MARIANNE trial assessed PFS for trastuzumab plus taxane versus trastuzumab emtansine (T-DM1) plus placebo versus T-DM1 plus pertuzumab. Results showed little difference in PFS among the 3 groups. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have HER2-positive locally advanced, inflammatory, or early-stage breast cancer who receive preoperative pertuzumab in combination with trastuzumab and a taxane (neoadjuvant therapy), the evidence includes systematic reviews and an RCT. Relevant outcomes are OS, 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 [pCR]); the validity of pCR as a surrogate for survival outcomes was deemed reasonable by the FDA. 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) versus hormone receptor-positive patients (10.0% absolute difference). The evidence is sufficient to determine that the technology results in an 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 a systematic review and an RCT. Relevant outcomes are OS, 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 endpoint of invasive disease-free survival (DFS) 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 the confidence interval (CI) for the hazard ratio (HR) included 1. Further, the trial showed no statistically significant improvement in OS with pertuzumab compared with control. Similar results were observed in the 6-year follow-up data. While the safety analysis showed a consistently increased incidence of adverse events in the pertuzumab arm versus 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 the 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 1 additional patient not to have an invasive disease event while, on average, 14.5 patients would have to receive pertuzumab instead of standard of care for 1 additional patient to have an adverse event greater than grade 3. These trial results have been widely reviewed and the use of pertuzumab for this indication has been updated in the FDA labeling as well as national oncology guidelines. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

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 OS, disease-specific survival, and treatment-related mortality and morbidity. Ongoing phase 2a multiple basket studies (MyPath way) have shown promise in using pertuzumab in patients with advanced colorectal cancer and metastatic biliary tract cancer. Conversely, the phase 3 PENELOPE trial found that adding pertuzumab to chemotherapy did not significantly improve PFS in patients with platinum-resistant ovarian carcinoma. Likewise, results of a RCT (JOSHUA) in patients with advanced gastric cancer and another RCT (JACOB) in patients with advanced gastric and gastroesophageal-junction cancer were unfavorable for use of pertuzumab in these populations. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether pertuzumab as a treatment for human epidermal growth factor receptor 2-positive malignancies improves the net health outcome.

POLICY statements

In patients who have human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the use of pertuzumab may be considered medically necessary:

• in combination with trastuzumab and a taxane (eg, docetaxel, paclitaxel) for treatment of locally recurrent or metastatic breast cancer if pertuzumab was not previously administered; or

• for neoadjuvant treatment of locally advanced, inflammatory, or early-stage (either >2 cm in diameter or node-positive) breast cancer; or

• the adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

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 gastroesophageal junction; and HER2-negative cancers.

NCCN 2A positioning category for Off label indications:

Extensive Brain Metastases

Used in combination with high-dose trastuzumab as treatment for limited brain metastases in patients with HER2 positive breast cancer may be considered as initial treatment in select patients (eg, patients with small asymptomatic brain metastases) consider as treatment for recurrent brain metastases treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options

Biliary Tract Cancers: Gallbladder Cancer

Subsequent treatment in combination with trastuzumab for progression on or after systemic treatment for unresectable or metastatic disease that is HER2-positive (useful in certain circumstances)

Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma

Subsequent treatment in combination with trastuzumab for progression on or after systemic treatment for unresectable or metastatic disease that is HER2-positive (useful in certain circumstances)

Salivary Gland Tumors

Useful in certain circumstances, in combination with trastuzumab, as systemic therapy for human epidermal growth factor receptor 2 (HER2)-positive recurrent disease with distant metastases in patients with a performance status (PS) of 0-3 unresectable locoregional recurrence or second primary with prior radiation therapy

Colon Cancer

Therapy in combination with trastuzumab (HER2-amplified and RAS and BRAF wildtype) if intensive therapy not recommended and no previous treatment with a HER2 inhibitor as primary treatment for locally unresectable or medically inoperable disease as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction for synchronous unresectable metastases of other sites as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy

Therapy in combination with trastuzumab in patients (HER2-amplified and RAS and BRAF wild-type) if intensive therapy not recommended as adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in patients who have received previous chemotherapy as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy.

Subsequent therapy in combination with trastuzumab for progression of advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type) not previously treated with HER2 inhibitor, in patients previously treated with oxaliplatin-based therapy without irinotecan with irinotecan-based therapy without oxaliplatin with oxaliplatin and irinotecan without irinotecan or oxaliplatin without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

Initial systemic therapy for advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type) in combination with trastuzumab if intensive therapy not recommended and no previous treatment with a HER2 inhibito

Subsequent therapy in combination with trastuzumab for progression of advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type) not previously treated with HER2 inhibitor, in patients previously treated with oxaliplatin-based therapy without irinotecan with irinotecan-based therapy without oxaliplatin with oxaliplatin and irinotecan without irinotecan or oxaliplatin without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

Rectal Cancer

Therapy in combination with trastuzumab in patients (HER2-amplified and RAS and BRAF wild-type) if intensive therapy not recommended and no previous treatment with a HER2 inhibitor as primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant or total neoadjuvant therapy as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction as primary treatment for synchronous unresectable metastases of other sites as primary treatment for unresectable isolated pelvic/anastomotic recurrence as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy

Therapy in combination with trastuzumab in patients (HER2-amplified and RAS and BRAF wild-type) if intensive therapy not recommended as adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy

Subsequent therapy in combination with trastuzumab for progression of advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type) not previously treated with HER2 inhibitor, in patients previously treated with oxaliplatin-based therapy without irinotecan with irinotecan-based therapy without oxaliplatin with oxaliplatin and irinotecan without irinotecan or oxaliplatin without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

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 left ventricular dysfunction, similarly to trastuzumab.

• In the CLEOPATRA trial of patients with metastatic breast cancer, baseline left ventricular ejection fraction (LVEF) of ≥50% was required for trial entry.

• If LVEF decreases to 45% to 49% with a 10% or greater decrease below pretreatment values, or if LVEF decreases to less than 45%, both pertuzumab and trastuzumab should be withheld for at least 3 weeks. If LVEF does not improve or continues to decline after 3 weeks of withholding the drugs, pertuzumab and trastuzumab should be discontinued.

Coding

Please see the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Breast Cancer

Among women in the U.S., breast cancer has the highest rate of new cancer cases of all other cancers and ranked second for cancer mortality after lung cancer. In 2021, there were 272,454 new cases of breast cancer in women , and in 2022,42,211 women died of the disease.^1,

Staging

Multimodal 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 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 receptor 2(HER2). This staging system went into effect in the U.S. in January 2018.^2,

Human Epidermal Growth Factor Receptor 2 Protein

Approximately 20% to 25% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with tyrosine kinase activity.^3,This receptor, previously called HER2/neu, or ERBB-2, belongs to the human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinase receptors (HER1, HER2, HER3, HER4).^4, These receptors mediate tumor cell growth, survival, and differentiation. The HER receptors, when activated by extracellular ligand binding, dimerize and activate cell signaling through the phosphatidyl inositol-3-kinase/AKT pathway, which regulates tumor cell survival, and the mitogen-activated protein kinase pathway, which regulates cellular proliferation. There is no known ligand for HER2; it forms active heterodimers (particularly HER2:HER3) and, when overexpressed, homodimers (HER2:HER2) that constitutively activate tyrosine kinase signaling.^5,

Overexpression of HER2 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 survival (DFS) and overall survival (OS) than HER2-negative lymph node-negative or lymph node-positive breast cancers; with a lack of responsiveness to tamoxifen therapy; and with altered responsiveness to cytotoxic chemotherapy.^6,

Health and Health Outcome Disparities for Select Human Epidermal Growth Factor Receptor 2 Positive Non-Breast Cancer Malignancies

Health and health outcome disparities exist across racial and ethnic groups or socioeconomic status (SES) groups for a variety of malignancy types. A meta-analysis by Karanth et al (2019) included 41 studies evaluating the role of race, SES, or health-care access on disparities in ovarian cancer treatment or survival.^7, Investigators found that there was a 25% decrease (relative risk [RR], 0.75; 95% confidence interval [CI], 0.66 to 0.84) in administration of guideline-directed ovarian cancer treatment and an 18% increased risk (RR, 1.18; 95% CI, 1.11 to 1.26) of mortality in Black individuals compared to White individuals with ovarian cancer. Administration of adherent ovarian cancer treatment was 15% lower (RR, 0.85; 95% CI, 0.77 to 0.94) in the lowest versus the highest SES groups and 30% lower (RR, 0.70; 95% CI, 0.58 to 0.85) among patients at lower versus higher hospital volumes.

Regulatory Status

In 2012, pertuzumab (Perjeta^®; Genentech) 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 the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.^7,

In 2013, pertuzumab was granted accelerated approval by the FDA for neoadjuvant treatment of 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 in combination with trastuzumab and chemotherapy.^8,

In 2017, pertuzumab labeling was further expanded to include adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence in combination with trastuzumab and chemotherapy.

In 2020, the FDA approved PHESGO, a combination of pertuzumab and trastuzumab, HER2/neu receptor antagonists, and hyaluronidase, an endoglycosidase for subcutaneous administration. It is labeled for the following indications: Use in combination with chemotherapy as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer, adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence, use in combination with docetaxel for treatment of patients with HER2­ positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This product is not specifically reviewed in this policy.

HER2 Testing

Detection of HER2 protein overexpression is necessary for the 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 Kits

Adapted from the U.S. Food and Drug Administration (2022 ).10,BLA: biologics license application; CISH: chromogenic in situ hybridization; FDA: U.S. Food and Drug Administration; FFPE: formalin-fixed, paraffin-embedded; FISH: fluorescence in situ hybridization; GEJ: gastroesophageal junction; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemical; PMA: premarket approval.

RATIONALE

This evidence review was created in December 2012 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 16, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the 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 1 or more intended clinical use 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. Randomized controlled trials 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No 1

Treatment For Human Epidermal Growth Factor Receptor 2-Positive Locally Recurrent or Metastatic Breast Cancer

Clinical Context and Therapy Purpose

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 human epidermal growth factor receptor 2 [HER2] status).^11, In 2020, the 5-year survival rates for women and men with metastatic breast cancer were estimated at 27% and 22%, respectively. 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.^12,

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.

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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are 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 treat HER2-positive malignancies: trastuzumab and a taxane alone.

Outcomes

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

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 long-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.

Review of Evidence

The systematic reviews of targeted therapy for metastatic breast cancer have mostly combined results of pertuzumab and other targeted agents (eg, trastuzumab, lapatinib).^{13,14,15,16,17,18,} 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.^14, It included 21 trials (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. Another network meta-analysis that included 20 trials (N=7094) likewise found that progression-free survival (PFS) was longer with pertuzumab and trastuzumab plus docetaxel compared to trastuzumab and docetaxel (hazard ratio [HR], 0.65; 95% credible interval [CrI], 0.43 to 0.98).^19,

Randomized Controlled Trials

flone.^20, 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 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 FISH amplification ratio greater than 2.0 or IHC score of 3+. Patients who had received systemic neoadjuvant therapy (ie, previous trastuzumab) for nonmetastatic breast cancer were eligible if treatment was at least 1 year before trial entry.

The primary efficacy outcome was PFS, determined by an 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 demographics 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 group. The results of subgroup analyses were consistent across strata with the exception of non-visceral disease (HR, 0.96; 95% confidence interval [CI], 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, a second interim (ie, confirmatory) analysis 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,

An independent review of the overall response rate (complete response plus partial response) was 80% in the pertuzumab group and 69% in the control group.^20, 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=.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=.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, The 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 secondary interim analysis estimates.

Swain et al (2020) published end-of-study results from the CLEOPATRA trial.^25, After a median follow-up of 99 months, patients who received pertuzumab had a statistically significant 6.3-month improvement in PFS and a statistically significant 16.3-month improvement in OS.

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

Adapted from Baselga et al (2012)20, and Swain et al (2013 ).21,CI: confidence interval; HR: hazard ratio; NR: not reached; OS: overall survival; PFS: progression-free survival.a Second interim (confirmatory) analysis after 267 deaths.21,b 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≤.0138). c First interim analysis after 165 deaths. d Complete response plus partial response.e From pertuzumab prescribing information.9,

Several early-phase RCTs and phase 3 RCTs 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 randomized 1095 patients to 1 of 3 treatment groups: trastuzumab plus taxane (control), T-DM1 plus placebo, or T-DM1 plus pertuzumab to assess which was superior for 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 treatment with T-DM1 plus placebo resulted in noninferior, but not superior, PFS compared with trastuzumab plus a taxane. For PFS, both experimental arms were noninferior, but not superior, to trastuzumab plus taxane: the median PFS was 13.7 months for trastuzumab plus taxane, 14.1 months with T-DM1 plus placebo, and 15.2 months with T-DM1 plus pertuzumab. The addition of pertuzumab to T-DM1 also did not improve PFS compared with T-DM1 plus placebo (stratified HR, 0.91; 95% CI, 0.73 to 1.13).

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 2 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.

Urruticoechea et al (2018) reported on results of the Pertuzumab Herceptin Evaluation with Xeloda (PHEREXA), a phase 3 RCT in 446 patients.^28, Arm A (n=224) was treated with oral capecitabine and intravenous (IV) trastuzumab; Arm B (n=228) was treated with oral capecitabine, IV trastuzumab, plus IV pertuzumab. Median PFS for Arm A was 9.0 months and 11.8 months for Arm B (HR, 0.83; 95% CI, 0.68 to 1.02). The median OS for Arm A was 28.1 months and 37.2 months for Arm B (HR, 0.76; 95% CI, 0.60 to 0.98). The final data, presented at the 2018 American Society of Clinical Oncology Annual Meeting, concluded that “PHEREXA is formally a negative study” and does not change the standard of care for HER2-positive metastatic breast cancer.

A phase 2, multicenter, randomized, open-label trial (N=258) evaluated the efficacy and safety of trastuzumab plus an aromatase inhibitor (anastrozole or letrozole) with or without pertuzumab in patients with HER2-positive and hormone receptor-positive advanced breast cancer in the first-line setting (PERTAIN). In the primary analysis, induction chemotherapy with a taxane was permitted in both treatment arms, and median follow-up was 31 months.^29, The primary outcome of PFS was 18.89 months in patients who received pertuzumab and 15.8 months in those who did not (HR, 0.65; 95% CI, 0.48 to 0.89); the median OS was not reached in either group. Serious adverse events were more likely in the pertuzumab group (33.1 % vs 19.4 %). Arpino et al (2023) conducted a follow-up analysis (>6 year follow-up).^30, At data cut-off, the median follow-up was 71.1 months. The median PFS was 20.6 months in patients who received pertuzumab versus 15.8 months in those who did not (stratified HR, 0.67; 95% CI, 0.50 to 0.89; p=.006). Median OS was 60.2 months in patients who received pertuzumab versus 57.2 months in those who did not (stratified HR, 1.05; 95% CI, 0.73 to 1.52; p=.783). Any-grade adverse event incidence rates were similar between the pertuzumab group and control group (96.1% vs. 98.4%); serious adverse events were more likely to occur in the pertuzumab group (36.2% vs. 22.6%).

Section Summary: Treatment for Human Epidermal Growth Factor Receptor 2 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 systematic reviews, a pivotal RCT comparing pertuzumab plus docetaxel and trastuzumab with docetaxel plus trastuzumab alone, and several other RCTs comparing other combinations. The pivotal RCT, CLEOPATRA, reported a statistically significant 6.1-month improvement in PFS for the pertuzumab group. After a median follow-up of 30 months, the rate of OS was also significantly improved in the pertuzumab group. The MARIANNE trial assessed PFS for trastuzumab plus taxane versus T-DM1 plus placebo versus T-DM1 plus pertuzumab. Results showed little difference in PFS among the 3 groups.

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 systematic reviews, a pivotal randomized controlled trial (RCT) comparing pertuzumab plus docetaxel and trastuzumab with docetaxel plus trastuzumab alone, and several other RCTs comparing other combinations. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. The pivotal RCT, Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA), reported a statistically significant 6.1-month improvement in progression-free survival (PFS) for the pertuzumab group. After a median follow-up of 30 months, the rate of OS was also significantly improved in the pertuzumab group. The MARIANNE trial assessed PFS for trastuzumab plus taxane versus trastuzumab emtansine (T-DM1) plus placebo versus T-DM1 plus pertuzumab. Results showed little difference in PFS among the 3 groups. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No 2

Neoadjuvant Treatment of Locally Advanced, Inflammatory, or Early-Stage Breast Cancer

Clinical Context and Therapy Purpose

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 HER2, outcomes for women with early-stage HER2-positive breast cancer have improved considerably. Among women with positive lymph nodes treated with chemotherapy plus trastuzumab and pertuzumab, relapse-free survival now exceeds 80%.^31, 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, in addition to patients with inoperable breast cancer whose tumors possess certain characteristics.^32, Although breast conservation rates are higher after neoadjuvant chemotherapy, a survival advantage has not been shown compared with adjuvant (postoperative) chemotherapy.^33,34,32,

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.

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 individuals with HER2-positive locally advanced, inflammatory, or early-stage breast cancer.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are 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. The 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.

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 long-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.

Review of Evidence

Systematic reviews

Fazal et al (2023) performed a systematic review and meta-analysis that evaluated the efficacy and safety of neoadjuvant therapy with chemotherapy plus trastuzumab, with or without pertuzumab, in patients with HER2-positive, early-stage breast cancer (3 trials; N=840).^35, The primary outcome was the rate of pathologic complete response (pCR) achieved. The incidence of pCR was higher in the pertuzumab group (45%) compared to the control group (32%) (odds ratio [OR], 2.10; 95% CI, 1.56 to 2.83; I²=0%).

Yu et al (2020) performed a systematic review and meta-analysis that evaluated the efficacy and safety of chemotherapy plus trastuzumab, with or without pertuzumab, in patients with HER2-positive, early-stage breast cancer (N=15,284).^36, Seven trials evaluated outcomes in the neoadjuvant setting and 3 trials evaluated outcomes in the adjuvant setting. In the neoadjuvant setting, the addition of pertuzumab did not improve event-free survival/invasive disease-free survival (DFS; HR, 0.75; 95% CI, 0.49 to 1.13; p=.17) or OS (HR, 0.62; 95% CI, 0.35 to 1.10; p=.10). However, the addition of pertuzumab significantly improved pCR (relative risk [RR], 1.34; 95% CI, 1.15 to 1.57; p=.0002). Overall, patients receiving pertuzumab had an increased risk of grade 3/4 diarrhea, nausea, vomiting, hepatotoxicity, and skin disorders.

Chen et al (2019) performed a systematic review and meta-analysis that compared the efficacy and safety of chemotherapy plus trastuzumab or T-DM1, with or without pertuzumab, in patients with HER2-positive breast cancer (N=9,872).^18, In the neoadjuvant setting (n=1,738), the addition of pertuzumab significantly improved pCR compared to chemotherapy plus trastuzumab alone (absolute difference, 11.0%; OR, 1.33; 95% CI, 1.08 to 1.63; p=.006). The most common adverse events in all included patients were rash, diarrhea, myalgia, epistaxis, and mucosal inflammation. Among adverse events of grade 3 or higher, neutropenia, diarrhea, and anemia were the most common.

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 endpoint, pCR.^37,38, 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, the FDA issued guidance for industry proposing the following definitions of pCR for regulatory purposes^39,:

“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.^40, The magnitude of increase in pCR needed to predict a survival benefit with one 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.^37, 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^37,. 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% 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, DFS, safety) was reported by Gianni et al (2016).^41, 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). Progression-free survival 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 a 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 versus 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)

Adapted from Gianni et al (2012)37, and Cortazar et al (2014).40,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 versus 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.^38, 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 endpoints were the incidence of investigator-assessed symptomatic left ventricular (LV) systolic dysfunction (congestive heart failure) and a decline in LVEF of 10% or more from baseline to an absolute value less than 50%.^38, 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, the FDA reviewers found this evidence insufficient to support concomitant administration of pertuzumab with an anthracycline.^9,42,43, 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

Adapted from Genentech (2020) 9, and U.S. Food and Drug Administration (2013).43,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.a The p-values calculated by BCBSA.b Subgroups stratified by hormone receptor status (estrogen or progesterone receptor-positive versus 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.^44, BERENICE was an international nonrandomized study of patients with locally advanced, inflammatory, or early breast cancer. Patients were assigned to 1 of 2 groups, treated in the neoadjuvant period as follows:

• Group A (n=199): dose-dense doxorubicin 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 1 year. Primary safety endpoints were the incidence of New York Heart Association class III and IV heart failure and LVEF decline (defined as a 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 pCR 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 systematic reviews and a pivotal RCT (NeoSphere) that supported the efficacy of pertuzumab in the neoadjuvant setting. In NeoSphere, there was a statistically significant 17.8% absolute difference in pCR for the pertuzumab group. In stratified analysis, the treatment effect was greater for hormone receptor-negative patients (24.6% absolute difference) versus 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.

For individuals who have HER2-positive locally advanced, inflammatory, or early-stage breast cancer who receive preoperative pertuzumab in combination with trastuzumab and a taxane (neoadjuvant therapy), the evidence includes systematic reviews and an RCT. Relevant outcomes are OS, 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 [pCR]); the validity of pCR as a surrogate for survival outcomes was deemed reasonable by the FDA. 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) versus hormone receptor-positive patients (10.0% absolute difference). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No 3

Adjuvant Treatment of Early-Stage Breast Cancer

Clinical Context and Therapy 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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are 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. The 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.

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 long-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.

Review of Evidence

Systematic Reviews

Yu et al (2020) performed a systematic review and meta-analysis that evaluated the efficacy and safety of chemotherapy plus trastuzumab, with or without pertuzumab, in patients with HER2-positive, early-stage breast cancer.^36, Seven trials evaluated outcomes in the neoadjuvant setting and 3 trials evaluated outcomes in the adjuvant setting. In the adjuvant setting, the addition of pertuzumab improved event-free survival/invasive DFS (HR, 0.86; 95% CI, 0.78 to 0.94; p=.001) and was on the margin of statistical significance for improvement in OS (HR, 0.87; 95% CI, 0.65 to 1.00; p=.05). Overall, patients receiving pertuzumab had an increased risk of grade 3/4 diarrhea, nausea, vomiting, hepatotoxicity, and skin disorders.

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=2,400) or placebo (n=2,405) added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab.^45, The primary endpoint was invasive DFS, defined as the time from randomization until the date of the first occurrence of any 1 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 standardized definitions for efficacy endpoints (ie, standardized definitions for efficacy end points [STEEP]) system.^46, The definition of invasive DFS in the APHINITY trial excluded second primary nonbreast cancer as events.^45, The secondary endpoints 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 alpha-level of 0.05 was controlled for in 3 planned interim analyses for OS, with the first reported comparison tested at an adjusted t 2-sided significance level of 0.00001.^45, To control for the overall significance level of the secondary endpoints, the trialists used a hierarchical testing procedure with secondary endpoints tested in the following order if the primary endpoint 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 the hierarchical statistical plan enumerated in the protocol because the OS was not statistically significant and yet multiple subsequent secondary endpoints 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

CI: confidence interval; DFS: disease-free survival; HR: hazard ratio; OS: overall survival; RCT: randomized controlled trial; STEEP: standardized definitions for efficacy end points.a These secondary outcomes were not analyzed for statistical significance because a predefined hierarchical testing procedure precluded further testing.

The APHINITY trial met the primary endpoint as evident by the statistically significant increase in invasive DFS with the addition of pertuzumab to the standard of care (ie, 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 95% 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.^47, 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 endpoint to having the primary endpoint, the study would not be statistically significant (p>.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%]) versus placebo arm (8 [0.3%]). Among the subgroup of patients treated with 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% [1,133/1,834]) compared with the placebo arm (57.0% [1,080/1,894]). 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% [232/2,364]) than in the placebo arm (3.7% [90/2,405]). 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%.^48,

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.

Additional 6-year follow-up data was reported for the APHINITY trial.^49, The OS at 6 years was not significantly different with pertuzumab (95%) compared to placebo (94%; HR, 0.85; 95% CI, 0.67 to 1.07). However, invasive DFS was improved with pertuzumab compared to placebo (91% vs 88% of patients were event-free; HR, 0.76; 95% CI, 0.64 to 0.91). One additional primary cardiac event occurred in the 6-year follow-up period.

Section Summary: Adjuvant Treatment of Early-Stage Breast Cancer

The evidence for the addition of pertuzumab to the standard of care in the adjuvant setting for early-stage breast cancer includes a systematic review and RCT. The large adequately powered APHINITY trial randomized 4,805 patients with a median follow-up of 45 months. While the trial met the statistically significant threshold for the primary endpoint 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 versus 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 1 additional patient not to have any invasive disease event, and 14.5 patients would have to receive pertuzumab instead of the standard of care for 1 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. Similar results were observed in the 6-year follow-up data.

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 a systematic review and an RCT. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. Although the large adequately powered Adjuvant Pertuzumab and Herceptin in Initial Therapy in Breast Cancer (APHINITY) trial, which randomized 4,805 patients with a median follow-up of 45 months, met its statistically significant threshold for the primary endpoint of invasive disease-free survival (DFS) 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 the confidence interval (CI) for the hazard ratio (HR) included 1. Further, the trial showed no statistically significant improvement in OS with pertuzumab compared with control. Similar results were observed in the 6-year follow-up data. While the safety analysis showed a consistently increased incidence of adverse events in the pertuzumab arm versus 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 the 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 1 additional patient not to have an invasive disease event while, on average, 14.5 patients would have to receive pertuzumab instead of standard of care for 1 additional patient to have an adverse event greater than grade 3. These trial results have been widely reviewed and the use of pertuzumab for this indication has been updated in the FDA labeling as well as national oncology guidelines. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No 4

Human Epidermal Growth Factor Receptor 2-Positive Non-Breast Cancer Malignancies

Clinical Context and Therapy 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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are 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. The 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.

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 long-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.

Review of Evidence

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. A trial in metastatic or locally advanced HER2-positive adenocarcinoma of the stomach is 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-positive non-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

CI: confidence interval; DoR, duration of response; HER: human epidermal growth factor receptor; HERACLES-B: HER2 Amplification for Colo-rectal Cancer Enhanced Stratification, cohort B; HR: hazard ratio; IV: intravenous; LVEF: left ventricular ejection fraction; mRNA: messenger ribonucleic acid; NCI-MATCH: National Cancer Institute-Molecular Analysis for Therapy Choice; NCT: national clinical trial; NSCLC: non-small-cell lung cancer; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; RCT: randomized controlled trial; RD: risk difference; T-DM1: trastuzumab emtansine.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 dose-limiting toxicity, subsequent 3-patient cohorts are treated at increasing dose levels. If any patient experiences 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 (ie, ≥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.66,d Includes typical carcinoid, pancreatic islet cell, and other well-differentiated neuroendocrine carcinomas.e Results unpublished but are posted on clinicaltrials.gov.

Section Summary: Human Epidermal Growth Factor Receptor 2-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. Ongoing phase 2a multiple basket studies (MyPath way) have shown promise in using pertuzumab in patients with advanced colorectal cancer and metastatic biliary tract cancer. The MyPathway studies were open-label, single-arm studies with small sample sizes. However, a separate open-label, single-arm study found a low ORR with use of pertuzumab in patients with metastatic colorectal cancer. The phase 3 PENELOPE trial found that adding pertuzumab to chemotherapy did not significantly improve PFS in patients with platinum-resistant ovarian carcinoma. Likewise, results of an RCT (JOSHUA) in patients with advanced gastric cancer and another RCT (JACOB) in patients with advanced gastric and gastroesophageal-junction cancer were unfavorable for use of pertuzumab in these populations. 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.^21, 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%). 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.

In the NeoSphere trial (neoadjuvant setting), adverse events of all grades were less common in the group that did not receive docetaxel.^37, 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). In the 5-year follow-up of NeoSphere,^67, 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 patients 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.^38, 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.

Left Ventricular 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, approximately 250 mg/m²) compared with 39% of patients who did not develop congestive heart failure.^68, The previous radiotherapy was also associated with congestive heart failure but was not a stratified covariate. 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).^37, The LVEF recovered to 50% or more in all 6 patients who developed LV dysfunction (previously defined). 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.^41,

Incidences of LV dysfunction and congestive heart failure were higher in TRYPHAENA than in NeoSphere (see Table 7).^38, Left ventricular 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.

Table 7. Summary of Left Ventricular Dysfunction Adverse Events

Adapted from Genentech (2022 ).9,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.^45, In the pertuzumab group (n=2,364), 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=2,405). In the additional 6-year follow-up data, 1 more primary cardiac event occurred with pertuzumab.^49, Additional descriptive analysis of the APHINITY trial 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 versus placebo arms. The primary cardiac event rate for the population presumably at the 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

Adapted from von Minckwitz et al (2017).45,LVEF: left ventricular ejection fraction.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 of <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.

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 OS, disease-specific survival, and treatment-related mortality and morbidity. Ongoing phase 2a multiple basket studies (MyPath way) have shown promise in using pertuzumab in patients with advanced colorectal cancer and metastatic biliary tract cancer. Conversely, the phase 3 PENELOPE trial found that adding pertuzumab to chemotherapy did not significantly improve PFS in patients with platinum-resistant ovarian carcinoma. Likewise, results of a RCT (JOSHUA) in patients with advanced gastric cancer and another RCT (JACOB) in patients with advanced gastric and gastroesophageal-junction cancer were unfavorable for use of pertuzumab in these populations. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

In 2018, the American Society of Clinical Oncology issued recommendations on use of HER2-targeted therapy for patients with advanced HER2-positive breast cancer. ^69,  The guideline states, "Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the patient has a contraindication to taxanes (Type: evidence-based; Evidence quality: high; Strength of recommendation: strong)." In addition, it states, "If a patient's HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted therapy, but she has not received pertuzumab, clinicians may offer pertuzumab (Type: informal consensus; Evidence quality: insufficient; Strength of recommendation: weak."

These guidelines were updated in 2022, with no changes to the 2018 recommendations pertaining to pertuzumab. ^70,

National Comprehensive Cancer Network

Table 9. National Comprehensive Guideline Updates for Use of Pertuzumab

HER2: human epidermal growth factor receptor 2; IBC: inflammatory breast cancer.

HER2: human epidermal growth factor receptor 2.

National Institute for Health and Care Excellence

The NICE have made the following recommendations regarding pertuzumab in breast cancer: ^76,77,78,

• "Pertuzumab, in combination with trastuzumab and chemotherapy, is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of adults with human epidermal growth factor receptor 2 (HER2)‑positive breast cancer; that is, in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence."

• "Pertuzumab, with intravenous trastuzumab and chemotherapy, is recommended for the adjuvant treatment of human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer in adults, only if they have lymph node-positive disease."

• "Pertuzumab, in combination with trastuzumab and docetaxel, is recommended, within its marketing authorisation, for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer, in adults who have not had previous anti‑HER2 therapy or chemotherapy for their metastatic disease."

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVERAGE

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might impact this policy are listed in Table 10.

Table 10. Summary of Key Trials

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

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Policy History