| Coverage Policy Manual | |
| Policy #: | 2014014 |
| Category: | Pharmacy |
| Initiated: | June 2014 |
| Last Review: | December 2023 |
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| Pertuzumab (e.g., Perjeta) | |
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| Description: |
Pertuzumab is a monoclonal antibody that is a human epidermal growth factor receptor 2 (HER2) antagonist. It is approved by the U.S. Food and Drug Administration (FDA) 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 result in a more comprehensive blockade of HER2 and its pathways, and thus may lead to greater treatment effect.
Background
Description of Disease. Breast cancer accounts for nearly 1 in 3 cancer diagnoses in women in the U.S. Among women, breast cancer is the second most common cancer after nonmelanoma skin cancer and ranks second for cancer mortality after lung cancer. In 2013; an estimated 232,000 new cases of invasive breast cancer will be diagnosed among women, and approximately 40,000 women are expected to die from breast cancer (NCI, 2014).
Metastatic Breast Cancer
Metastatic breast cancer has a poor prognosis. In a cohort of 3524 women with de novo Stage IV or relapsed breast cancer diagnosed between 1992 and 2007, median overall survival was 39.2 months among individuals with de novo Stage IV and 27.2 months among individuals with relapsed disease (estimates independent of HER2 status) (Dawood, 2010). Factors associated with reduced survival for individuals with metastatic breast cancer include age 50 years or older, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status (Chang, 2003).
Systemic treatment for metastatic breast cancer is mainly palliative. Goals of treatment are to prolong survival, alleviate symptoms, and maintain or improve quality of life. Treatment is primarily with chemotherapeutic and other antitumor drugs. The National Comprehensive Cancer Network (NCCN) guidelines on treatment of breast cancer recommend specific regimens for first-line treatment of HER2-positive metastatic disease, all of which include trastuzumab (NCCN, 2014). Recommended agents used in combination with trastuzumab are paclitaxel with or without carboplatin, docetaxel, vinorelbine, and capecitabine.
Early Stage and Inflammatory Breast Cancer
Treatment for operable (locally invasive or early stage) breast cancer includes surgery and/or radiation therapy 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 who are treated with chemotherapy plus trastuzumab, relapse-free survival now exceeds 80% (Krop, 2012). Current guidelines from the National Comprehensive Cancer Network (NCCN) 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 (NCCN, 2014). Although breast conservation rates are higher after neoadjuvant chemotherapy, a survival advantage has not been shown compared with adjuvant (postoperative) chemotherapy (Rastogi, 2008; Mieog, 2007).
Inflammatory breast cancer is a rare, aggressive breast cancer that accounts for 1% to 6% of U.S. breast cancer cases. Inflammatory breast cancer is characterized by erythema and edema of the skin (peau d’orange) that has a palpable border and is commonly hormone receptor-negative and HER2-positive. Based on retrospective and prospective studies, current NCCN guidelines recommend preoperative chemotherapy with an anthracycline-based regimen (eg, doxorubicin plus cyclophosphamide followed by a taxane). For individuals with HER2-positive disease, NCCN recommends adding trastuzumab for up to 1 year (NCCN, 2014).
HER2. 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, (Hudis, 2007) belongs to the HER family of transmembrane tyrosine kinase receptors (HER1 [EGFR], HER2, HER3, HER4). These receptors mediate tumor cell growth, survival, and differentiation. HER receptors, when activated by extracellular ligand binding, dimerize, and activate cell signaling through the phosphatidyl inositol-3 (PI3)-kinase/AKT pathway, which regulates tumor cell survival, and the mitogen-activated protein kinase (MAPK) pathway, which regulates cellular proliferation. HER2 has no known ligand; it forms active heterodimers (particularly HER2:HER3) and, when overexpressed, homodimers (HER2:HER2) that constitutively activate tyrosine kinase signaling (Baselga, 2010).
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 (Press, 2005).
Testing for HER2 overexpression and/or amplification is recommended as a routine part of the diagnostic work-up on all invasive (early stage or recurrent) breast cancers (Wolff, 2014). The main benefit of HER2 testing is its predictive value for response to targeted therapy. Two testing procedures are used, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tests are positive, negative, or equivocal. If a reflex test (ordered after an initial equivocal HER2 test result and using the alternative technique) on the same specimen does not return a positive or negative result, histopathologic features should be reviewed, and testing should be repeated on the same specimen, on another block of the same specimen, or on another specimen (e.g., core biopsy, surgical resection, lymph node, and/or metastatic site). Repeat testing also should be considered if results seem discordant with other histopathologic findings (Wolff, 2014). An indeterminate test result may be returned if technical issues prevent one or both tests from being reported as positive, negative, or equivocal, ego, due to inadequate specimen handling or artifacts that prevent interpretation.
When carefully validated testing is performed, neither test is considered a superior predictor of benefit from anti-HER2 therapy. IHC often is used first because it is less expensive. FISH testing is reserved for the up to 15% of tumor samples with equivocal IHC values (2+). In an analysis of tumor samples from several large trastuzumab breast cancer trials, 40 of 2502 breast cancer specimens (1.6%) had equivocal FISH ratios (Press, 2005).
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.
The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) developed joint guideline recommendations for HER2 testing in breast cancer and the guideline was updated in 2018. NCCN guidelines for breast cancer (2019) have incorporated the updated ASCO/CAP recommendations for HER2 status into the treatment algorithms for HER2 targeted therapy.
Positive HER2:
Equivocal HER2:
Negative HER2 if a single test (or both tests) performed show:
Regulatory Status
Pertuzumab (e.g., Perjeta®) received FDA approval for metastatic breast cancer in June 2012. Labeled indications are for “use in combination with trastuzumab and docetaxel for treatment of individuals with HER2 [human epidermal growth factor receptor 2] –positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease” (Genentech, 2013).
In September 2013, FDA granted accelerated approval to pertuzumab for neoadjuvant treatment of breast cancer. Labeled indications are for “use in combination with trastuzumab and docetaxel in individuals 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. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival. Limitations of use:
Data from the Phase 3 APHINITY trial (expected in 2023) are required to convert accelerated approval for this indication to full approval.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Effective December 13, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Labeled Indications
The use of pertuzumab in combination with trastuzumab and a taxane (e.g., docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of those individuals who have HER2-positive breast cancer* (FDA, Perjeta, 2012):
Off-Label Indications
The use of pertuzumab meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for off-label use for treatment of the following conditions:
Breast Cancer
Central Nervous System Cancers-Extensive Brain Metastases
Colon Cancer
Rectal Cancer
Head and Neck-Salivary Gland Tumors
Biliary Tract Cancers-Gallbladder Cancer/ Intrahepatic Cholangiocarcinoma/Extrahepatic Cholangiocarcinoma
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
The initial Pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30–60-minute intravenous infusion.
MBC: Administer pertuzumab, trastuzumab or trastuzumab hyaluronidase-oysk, and docetaxel every 3 weeks.
Neoadjuvant: Administer pertuzumab, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for 3 to 6 cycles.
Adjuvant: Administer pertuzumab, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy postoperatively every 3 weeks for a total of 1 year (up to 18 cycles).
Pertuzumab is available as an injection: 420 mg/14 mL single-dose vial.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab for any indication or circumstance not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of pertuzumab, for any indication or circumstance not described above, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2022 to December 12, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Labeled Indications
The use of pertuzumab in combination with trastuzumab and a taxane (e.g., docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of those individuals who have HER2-positive breast cancer* (FDA, Perjeta, 2012):
*HER2 positive as defined by:
** High risk of recurrence as defined by:
Off-Label Indications
The use of pertuzumab meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for off-label use for treatment of the following conditions:
Breast Cancer
Colon Cancer
Head and Neck-Salivary Gland Tumors
Rectal Cancer
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The initial Pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30–60-minute intravenous infusion.
MBC: Administer pertuzumab, trastuzumab or trastuzumab hyaluronidase-oysk, and docetaxel every 3 weeks.
Neoadjuvant: Administer pertuzumab, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for 3 to 6 cycles.
Adjuvant: Administer pertuzumab, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy postoperatively every 3 weeks for a total of 1 year (up to 18 cycles).
Pertuzumab is available as an injection: 420 mg/14 mL single-dose vial.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, 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.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 2022 to November 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Labeled Indications
The use of pertuzumab in combination with trastuzumab and a taxane (eg, docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of those individuals who have HER2-positive breast cancer* (FDA, Perjeta, 2012):
*HER2 positive as defined by:
** High risk of recurrence as defined by:
Off-Label Indications
The use of pertuzumab meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for off-label use for treatment of the following conditions:
Breast Cancer
Colon Cancer
Head and Neck-Salivary Gland Tumors
Rectal Cancer
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, 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.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 2020 through December 31, 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
In patients who have HER2-positive breast cancer*, the use of pertuzumab in combination with trastuzumab and a taxane (eg, docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
* HER2 positive as defined by:
** High risk of recurrence as defined by:
Off-labeled Indications
For those members subject to Arkansas state law (Act 270) requiring coverage of drugs that are deemed to be safe and effective for a specific cancer by the National Comprehensive Cancer Network (NCCN), the use of pertuzumab for NCCN Category 1 and 2a recommendations in accordance with Coverage Policy #2000030 meet member benefit certificate primary coverage criteria and is covered in patients who have HER2-positive breast cancer.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Dosage and administration
Per FDA label guidelines.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, 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.
Effective December 2019 to February 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
In patients who have HER2-positive breast cancer, the use of pertuzumab in combination with trastuzumab and a taxane (eg, docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
Off-labeled Indications
For those members subject to Arkansas state law (Act 270) requiring coverage of drugs that are deemed to be safe and effective for a specific cancer by the National Comprehensive Cancer Network (NCCN), the use of pertuzumab for NCCN Category 1 and 2a recommendations in accordance with Coverage Policy #2000030 meet member benefit certificate primary coverage criteria and is covered in patients who have HER2-positive breast cancer.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Dosage and administration:
Per FDA label guidelines.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, 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.
Effective March 2019 to November 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
In patients who have HER2-positive breast cancer, the use of pertuzumab in combination with trastuzumab and a taxane (eg, docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Dosage and administration:
Per FDA label guidelines.
Off-labeled Indications
For those members subject to Arkansas state law (Act 270) requiring coverage of drugs that are deemed to be safe and effective for a specific cancer by the National Comprehensive Cancer Network (NCCN) the use of pertuzumab for the following off-label indications meet member benefit certificate primary coverage criteria and is covered in patients who have HER2-positive breast cancer:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, 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.
Effective June 2014 - February 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
In patients who have HER2-positive breast cancer, the use of pertuzumab in combination with trastuzumab and a taxane (eg, docetaxel, paclitaxel) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
Off-labeled Indications
For those members subject to Arkansas state law (Act 270) requiring coverage of drugs that are deemed to be safe and effective for a specific cancer by the National Comprehensive Cancer Network (NCCN) the use of pertuzumab for the following off-label indications meet member benefit certificate primary coverage criteria and is covered in patients who have HER2-positive breast cancer:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of pertuzumab 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, 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.
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| Rationale: |
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In post-hoc exploratory analyses of central nervous system (CNS) metastases, the incidence of CNS metastases as the site of first disease progression was similar between treatment groups (13.7% vs 12.6% in the pertuzumab and control groups, respectively; chi-square test, p=0.64) (Swain, 2014). Median time to development of CNS metastases as the site of first disease progression was longer in the pertuzumab group compared with the control group (15.0 months vs 11.9 months; HR=0.58 [95% CI, 0.39 to 0.85]; log-rank test, p=0.005).
A subsequent publication reported final prespecified OS results from the CLEOPATRA trial with a median follow-up of 50 months (Swain, 2015). Median OS was 15.7 months longer in the pertuzumab group compared with the control group (median OS=56.5 months vs 40.8 months; HR=0.68 [95% CI, 0.56 to 0.84]; p<0.001). Median PFS and median duration of response were unchanged from the 30-month interim analysis estimates.
Two single-arm studies investigated pertuzumab in off-label combinations for HER2-positive advanced breast cancer. Dang and colleagues (2014) at a single U.S. center evaluated pertuzumab in combination with trastuzumab and weekly paclitaxel (instead of docetaxel) 80 mg/m2 in 69 patients with metastatic disease (NCT01276041) (Miller, 2014). Fifty-one patients (74%) were treated in the first-line setting and 18 (26%) were treated in the second-line setting; of those previously treated for metastatic disease, 14 (78%) had received trastuzumab. At median follow-up of 21 months (range, 3-38), median investigator-assessed PFS was 19.5 months overall (95% CI, 14 to 26), 24.2 months in the first-line setting (95% CI, 14 to not reached), and 16.4 months in the second-line setting (95% CI, 8.5 to not reached). Six-month PFS was 86% overall, 89% in the first-line setting, and 78% in the second-line setting, which exceeded a prespecified threshold for efficacy and further study. No patients experienced febrile neutropenia or symptomatic LV systolic dysfunction. The incidence of grade 3-4 fatigue was 6%, and incidences of grade 3-4 diarrhea, peripheral neuropathy, and palmar-plantar erythrodysesthesia syndrome were 3% each.
Miller et al (2014) conducted an international study of 64 patients with HER2-positive metastatic breast cancer who received trastuzumab emtansine plus pertuzumab in the first-line (33%) or second-line (67%) setting (Miller, 2014). Ninety-five percent of patients had received trastuzumab either in a prior treatment regimen for advanced disease or as adjuvant or neoadjuvant therapy. Median duration of follow-up was not reported but was described as “limited” and may have been approximately 8 months (rough estimate from Kaplan-Meier survival plot). Objective response (the primary efficacy end point) was observed in 41% of all patients, 57% of those in the first-line setting, and 33% of those in the second-line setting. Median duration of response was 13.9 months overall (95% CI, 6.9 to not reached), 13.9 months in the first-line setting (95% CI, 5.9 to not reached), and 11.8 months in the second-line setting (95% CI, 5.4 to not reached). Median PFS was 6.6 months overall, 7.7 months in the first-line setting, and 5.5 months in the second-line setting. Incidence of grade 3-4 thrombocytopenia and grade 3-4 fatigue was 13% and 11%, respectively. Two patients (3%) experienced grade 2 infusion reactions, including 1 anaphylactic reaction; both were attributed to trastuzumab emtansine infusion. Six patients (9%) experienced LV systolic dysfunction.
Neoadjuvant Treatment of Locally Advanced, Inflammatory, or Early Stage Breast Cancer
Pertuzumab is the first drug the U.S. Food and Drug Administration (FDA)-approved for neoadjuvant (preoperative) treatment of breast cancer. Accelerated approval was granted based on 2 phase 2 Trials (Gianni, 2012; Schneeweiss, 2013) that used a novel surrogate end point, pathologic complete response (pCR). 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 purposes (FDA, 2014):
This recommendation, based on a meta-analysis25 assessed the relationship between pCR and long-term outcome, reflects the evolving paradigm in surgical management of the axilla. The magnitude of increase in pCR needed to predict a survival benefit with one treatment over another is unknown (Cortazar, 2013).
Published Studies Using Pertuzumab in Combination With Other Anti-HER2 Therapy for Off-Label Indications
Kang and colleagues performed a phase 2 multicenter, single-arm, open-label study on 66 patients with advanced HER2-positive breast cancer that progressed during prior trastuzumab-based therapy. These patients received trastuzumab plus pertuzumab combination therapy. The conclusions of the study showed an Objective response rate was 24.2%; five patients (7.6%) achieved a complete response, 11 (16.7%) achieved a partial response, 17 (25.8%) achieved stable disease of ≥6 mo.; median PFS was 5.5 mo; overall, the combination was well tolerated, and adverse events were mild to moderate (Kang, 2014).
Hughes and colleagues performed a phase 2 multicenter, single-arm study of pertuzumab plus erlotinib in 41 patients with relapsed, stage III-IV NSCLC. The conclusions of the study showed grade 3-4 treatment-related AEs occurred in 68% of patients, terminating enrollment; Investigator-assessed response rate at day 56 was 12% (Hughes, 2013).
Ongoing and Unpublished Clinical Trials
Ongoing
Breast Cancer Trials
(NCT01966471) Industry sponsored Randomized, Multicenter, Open-Label, Phase III Trial Comparing Trastuzumab plus Pertuzumab Plus a Taxane Following Anthracyclines Versus Trastuzumab Emtansine plus Pertuzumab Following Anthracyclines as Adjuvant Therapy in Patients with Operable HER2-Positive Primary Breast Cancer; planned enrollment of 2500 patients and projected completion date of Jan 2024.
(NCT01572038) Industry sponsored Multicenter, Open-label, Single-arm Study of a Pertuzumab in Combination With Trastuzumab and a Taxane in First Line Treatment of Patients With HER2- Positive Advanced (Metastatic or Locally Recurrent) Breast Cancer (PERUSE); planned enrollment of 1095 and projected completion date of ay 2018.
(NCT02132949) Industry sponsored A Multicenter, Multinational, Phase II Study to Evaluate Pertuzumab in combination With Trastuzumab and Standard Neoadjuvant Anthracycline-based Chemotherapy in Patients With
HER2-Positive, Locally Advanced, Inflammatory, or Early-StageBreast Cancer planned enrollment of 400 and projected completion date of Feb 2021.
Nonbreast cancer trials
(NCT02205047) Integration of Trastuzumab, with or Without Pertuzumab, Into peri-operatiVe chemotherapy of HER-2 positive stomach cancer: the INNOVATION-TRIAL with planned enrollment of 220 patients and projected completion date of Dec 2021.
(NCT02120911) Industry sponsored Feasibility Study of Chemoradiation, Trastuzumab and Pertuzumab in Resectable HER2+Esophageal Carcinoma: the TRAP Study with planned enrollment of 40 patients and projected completion date of Jan 2016.
Unpublished
(NCT00947167) Industry sponsored Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Tumors with planned enrollment of 4 that was terminated (toxicity).
Two small single-arm studies examined pertuzumab in off-label combinations (eg, without trastuzumab or docetaxel) for metastatic breast cancer. One study supported the use of pertuzumab in a paclitaxel containing regimen, and this regimen is considered medically necessary. The other study of trastuzumab emtansine (T-DM1) provided insufficient evidence for efficacy and safety that is comparable with the U.S. Food and Drug Administration (FDA)-approved regimen. The large, phase 3 MARIANNE trial is evaluating pertuzumab in combination with T-DM1 for metastatic breast cancer, with results expected in 2016.
Neoadjuvant Therapy
Current NCCN guidelines (version 2.2015) state that a pertuzumab-containing regimen may be administered to patients with HER2-positive, early-stage breast cancer who have tumor size 2 cm or greater or regional lymph node metastasis. Patients who have not received a neoadjuvant pertuzumab containing regimen may receive adjuvant pertuzumab (Hudis, 2007).
Other Cancers
Pertuzumab is not included in current NCCN guidelines for gastric (NCCN, 2015a) colon (NCCN, 2015b) rectal (NCCN, 2015c) non-small cell Lung (NCCN, 2015d) ovarian (NCCN, 2015e) or esophageal cancers, including gastroesophageal junction cancers (NCCN, 2015f).
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement.
2019 Update
A literature search conducted through February 2019 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
A literature search conducted through February 2019 did not reveal any new information that would prompt a change in the coverage statement.
Urruticoechea et al (2018) reported on results of the PHEREXA trial, a phase III RCT that assessed the combination of trastuzumab and capecitabine (an antimetabolite) with or without pertuzumab in 446 patients with HER2-positive metastatic breast cancer. Arm A (n=224) was treated with oral capecitabine and 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 (hazard ratio[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 (ASCO) Annual Meeting, concluded that “PHEREXA is formally a negative study” and does not change the standard of care for HER2-positive metastatic breast cancer (Bartsch and Bergen 2018).
Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting.
In the ongoing multicentre single-arm phase IIIb PERUSE study (Bachelot T et al. 2019), patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS).
Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At the preliminary analysis, 52 months’ median follow-up, median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.
The addition of pertuzumab to trastuzumab and chemotherapy improves survival in HER2-positive early breast cancer and metastatic breast cancer. The efficacy and safety of pertuzumab versus placebo was assessed in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic gastric or gastro-oesophageal junction cancer. It was found that adding pertuzumab to trastuzumab and chemotherapy did not significantly improve overall survival in patients with HER2-positive metastatic gastric or gastro-oesophageal junction cancer compared with placebo. Further studies are needed to identify improved first-line treatment options in these types of cancer and to identify patients with HER2-driven tumours who might benefit from dual HER2-targeted therapy (Tabernero J et al. 2018).
Ongoing and Unpublished Clinical Trials
Ongoing Breast Cancer Trials
(NCT02514681) 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. Planned enrollment 370 with a completion date of Jul 20109
(NCT01491737) 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 FirstLine Patients With HER2-positive and Hormone Receptor-positive Advanced (Metastatic or Locally Advanced) Breast Cancer. Estimated completion date October 2019.
Nonbreast cancer trials
(NCT02205047) Integration of Trastuzumab, with or Without Pertuzumab, Into peri-operatiVe chemotherapy of HER-2 positive stomach cancer: the INNOVATION-TRIAL with planned enrollment of 220 patients and projected completion date of Sept 2024.
(NCT01774786) 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
(NCT02120911) Industry sponsored Feasibility Study of Chemoradiation, Trastuzumab and Pertuzumab in Resectable HER2+Esophageal Carcinoma: the TRAP Study with planned enrollment of 40 patients and projected completion date of Jan 2016.
Other Cancers
Pertuzumab is not included in current NCCN guidelines for gastric (NCCN, Version 2.2019); non-small cell Lung (NCCN, Version 7.2019); ovarian (NCCN, Version 2.2019) or esophageal cancers, including gastroesophageal junction cancers (NCCN, Version 2.2019).
2020 Update
A double-blind, randomized, placebo-controlled, phase 3 trial that was done at 204 centers in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randomization (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov, number NCT00567190.
Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9-106·4) and 98·7 months (90·9-105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50-72) in the pertuzumab group and 40·8 months (36-48) in the placebo group (hazard ratio 0·69, 95% CI 0·58-0·82); 8-year landmark overall survival rates were 37% (95% CI 31-42) in the pertuzumab group and 23% (19-28) in the placebo group. The most common grade 3-4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis.
Analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. (Swain SM, Miles D, Kim SB, et.al., 2020)
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
No standard options existed for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer that progresses after second line trastuzumab emtansine therapy before 2020. The purpose of this study was to examine the efficacy of pertuzumab retreatment after disease progression following pertuzumab-containing therapy for HER2-positive locally advanced or metastatic breast cancer for the first time. This randomized, open-label, multicenter phase III trial was undertaken in 93 sites in Japan. Eligible patients with HER2-positive breast cancer who had received pertuzumab, trastuzumab, and chemotherapy as first- and/or second-line therapy were randomly assigned (1:1) to: (i) pertuzumab, trastuzumab, and physician's choice chemotherapy (PTC), or (ii) trastuzumab and physician's choice chemotherapy (TC). The primary endpoint was investigator-assessed progression-free survival (PFS). Between August 1, 2015, and December 31, 2018, 219 patients were randomized to PTC (n = 110) or TC (n = 109). Median follow-up was 14.2 months (interquartile range, 9.0-22.2), and median PFS was 5.3 months (95% confidence interval [CI], 4.0-6.6) with PTC and 4.2 months (95% CI, 3.2-4.8) with TC (stratified hazard ratio 0.76 [95% CI upper limit 0.967]; p = 0.022). Progression-free survival was improved by adding pertuzumab in all prespecified subgroups. The PTC arm showed a trend towards better overall survival and duration of response, but similar objective response and health-related quality of life. The incidence of treatment-related adverse events was similar between groups except for diarrhea. Pertuzumab retreatment contributes to disease control for HER2-positive locally advanced or metastatic breast cancer previously treated with pertuzumab-containing regimens. (Yamamoto Y, Iwata H, Taira N, et.al., 2022)
2023 Update
The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Post surgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing.
The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (i.e., 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80).
The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC. (Krop IE, Im SA, Barrios C, et.al., 2021)
BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive.
Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively).
Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. (Swain SM, Ewer MS, Viale G, et.al., 2018)
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