Policy No: dru281. Medication Policy Manual. Date of Origin: September 24, Topic: Perjeta, pertuzumab. Next Review Date: May 2015

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1 Medication Policy Manual Topic: Perjeta, pertuzumab Committee Approval Date: May 9, 2014 Policy No: dru281 Date of Origin: September 24, 2012 Next Review Date: May 2015 Effective Date: June 1, 2014 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Pertuzumab (Perjeta) is a monoclonal antibody used in the treatment of HER2-positive metastatic breast cancer. It is given via intravenous infusion in combination with trastuzumab (Herceptin) plus chemotherapy. dru281.4 Page 1 of 6

2 Policy/Criteria I. Most contracts require prior authorization approval of pertuzumab prior to coverage. Pertuzumab may be considered medically necessary in patients with breast cancer when criterion A or B below is met: A. Metastatic Breast Cancer: A diagnosis of HER2-positive metastatic breast cancer when: 1. Pertuzumab is used concomitantly with trastuzumab (Herceptin) and chemotherapy (e.g. docetaxel). AND 2. Pertuzumab is used in one of the two treatment settings described below: a. Patient has had no prior therapy for metastatic breast cancer. OR b. Patient has received one prior therapy for metastatic breast cancer that included trastuzumab (Herceptin) plus chemotherapy in the absence of pertuzumab. OR B. Neoadjuvant Use in Breast Cancer: A diagnosis of HER2-positive locally advanced, inflammatory, or early stage breast cancer when: 1. Pertuzumab is used preoperatively prior to resection of the breast tumor (neoadjuvant setting). AND 2. Pertuzumab is used concomitantly with trastuzumab (Herceptin) and chemotherapy (e.g. docetaxel). II. Administration, Quantity Limitations, and Authorization Period A. RegenceRx does not consider pertuzumab to be a self-administered medication. B. When prior authorization is approved, pertuzumab may be approved as follows: 1. Metastatic setting: Initial dose of 840 mg, followed by subsequent doses of 420 mg every 3 weeks. 2. Neoadjuvant setting: Initial dose of 840 mg, followed by 420 mg every 3 weeks for up to six doses prior to surgery. C. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. dru281.4 Page 2 of 6

3 III. Pertuzumab is considered investigational when: A. It is not administered in conjunction with trastuzumab (Herceptin). B. Used beyond the second-line treatment setting for metastatic breast cancer. C. Used in the adjuvant treatment setting for HER2-positive breast cancer. IV. Pertuzumab is considered investigational when used for all other conditions, including but not limited to: A. Gastric cancer. B. HER2-negative breast cancer. C. Ovarian cancer. Position Statement - Pertuzumab, a monoclonal antibody that prevents growth of cancer cells via its blockade of HER2 receptors, is approved for the treatment of HER2-positive metastatic breast cancer (mbc) and as a neoadjuvant therapy (used prior to surgical resection of a tumor) for locally advanced, inflammatory, or early stage HER2-positive breast cancer. - Pertuzumab binds to a different area on HER2 receptors than trastuzumab. The two medications are used in combination to provide greater antitumor activity than either agent alone. - In a large study of patients with HER2-positive mbc, the combination of pertuzumab/ trastuzumab/docetaxel significantly improved progression-free survival as compared with trastuzumab/docetaxel alone in the first-line metastatic setting. An interim analysis reports a survival advantage with pertuzumab at 3 years; however, median overall survival is not yet mature. - The evidence for pertuzumab in the second-line HER2-positive mbc setting is of poor quality. However, as it is rapidly becoming the standard of care, coverage is provided in the second-line setting when pertuzumab was not used with trastuzumab plus chemotherapy in the first-line mbc setting. - Evidence for pertuzumab in the neoadjuvant setting (when given for 3 to 6 doses prior to surgical resection of the breast tumor) is based on a surrogate endpoint (the absence of invasive cancer in the breast and lymph nodes). It is not known if it improves survival. - Pertuzumab has not been shown to be effective when used alone (i.e. not in combination with trastuzumab) or in the treatment of other types of cancer. - Pertuzumab has been shown to be safe and effective when dosed as follows: an initial dose of 840 mg via intravenous infusion, followed by 420 mg every three weeks. dru281.4 Page 3 of 6

4 Clinical Efficacy - There is fair confidence in the evidence that the addition of pertuzumab to a standard trastuzumab-containing regimen improves progression-free survival (PFS) in HER2- positive metastatic breast cancer. It is not known if this improvement in PFS will translate to improved overall survival. * A single, phase III pivotal trial compared pertuzumab plus trastuzumab plus docetaxel to trastuzumab plus docetaxel alone in the HER2-positive metastatic breast cancer setting. [1] - The trial enrolled patients who had no prior chemotherapy or trastuzumab in the metastatic setting. Prior trastuzumab was allowed in the adjuvant or neoadjuvant setting if 12 months had passed between completion of adjuvant/neoadjuvant therapy and diagnosis of metastatic breast cancer. [1] - Median PFS was prolonged by approximately 6 months in the pertuzumab treatment arm. Interim survival data at 3 years favors the pertuzumab arm; however, median overall survival has not yet been reached. [2] * The evidence for pertuzumab in patients who have had progression while receiving prior HER2-blocking therapy is of poor quality. [3] - An uncontrolled study trial evaluated the combination of pertuzumab and trastuzumab in patients who had progression of their HER2-positive metastatic breast cancer on prior trastuzumab-based therapy. - The evidence from this trial is of poor quality because there was no comparator arm or blinding employed in the study. The effects of bias, confounding, and chance cannot be ruled out. - The study evaluated overall response rates (ORR) in 58 patients. - The authors reported a 24% ORR and a median PFS of 5.5 months. - The evidence of efficacy for pertuzumab in the neoadjuvant setting for locally advanced, inflammatory, or early stage breast cancer is of low quality. [4,5] * An open-label trial evaluated pathological complete response (pcr) rates for the combination of pertuzumab/trastuzumab/docetaxel versus trastuzumab/docetaxel alone as neoadjuvant therapy for women with early stage HER2-positive breast cancer. * Therapy was given preoperatively for 3 to 6 cycles prior to tumor resection (pertuzumab was administered every 3 weeks for 3 to 6 doses). * Pathological complete response is defined as the absence of invasive cancer in the breast and lymph nodes. It is unknown if pcr is an accurate predictor of overall survival in breast cancer. * The effect of neoadjuvant pertuzumab on overall survival has not been evaluated. dru281.4 Page 4 of 6

5 - Early phase II trials that studied pertuzumab (previously referred to as Omnitarg ) showed that it had only limited activity as a single agent in ovarian, breast, and prostate cancers. [6] It is, therefore, unlikely to be effective when used alone. - There is interest in using pertuzumab in other cancers where HER2 receptors may play a role in the disease process (e.g. some gastric cancers). A recently published phase II trial found no benefit in adding pertuzumab to standard chemotherapy in women with recurrent ovarian cancer. [7] - The National Comprehensive Cancer Network (NCCN) breast cancer guideline lists the combination of pertuzumab plus trastuzumab plus docetaxel as a category 1 recommendation for the first-line treatment of HER2-positive metastatic breast cancer. The guideline also states that pertuzumab may be given in combination with trastuzumab in the second-line metastatic treatment setting if patients were previously treated in the first-line metastatic setting with trastuzumab plus chemotherapy in the absence of pertuzumab (category 2A recommendation). Use of pertuzumab in the neoadjuvant setting was given a category 2A recommendation when administered concomitantly with a taxane plus trastuzumab. [8] RegenceRx performs independent analyses of oncology medications. The RegenceRx analysis and coverage policy may differ from NCCN clinical practice guidelines. Safety - Pertuzumab carries a boxed warning for embryo-fetal death and birth defects and is listed as a pregnancy Category D. [5] - Common adverse effects when pertuzumab is combined with trastuzumab plus docetaxel (> 30% incidence) include diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. [5] - Pertuzumab should be withheld for a left ventricular ejection fraction (LVEF) of < 40% or for a LVEF of 40% to 45% with a 10% absolute decrease below pretreatment values. [5] Dosing - The initial dose of pertuzumab is 840 mg administered as a 60-minute infusion. This is followed every 3 weeks thereafter with 420 mg doses administered over 30 to 60 minutes. [5] - In the neoadjuvant HER2-positive breast cancer setting, pertuzumab is given preoperatively every 3 weeks for 3 to 6 doses. The safety of pertuzumab given for more than 6 doses for early breast cancer has not been established. [5] dru281.4 Page 5 of 6

6 Cross References Pertuzumab for Treatment of HER2-Positive Malignancies; BlueCross BlueShield Association Medical Policy, Review Date: 12/2012. Tykerb, lapatinib, RegenceRx Medication Policy Manual, Policy No. 145 Kadcyla, ado-trastuzumab emtansine, RegenceRx Medication Policy Manual, Policy No. 298 Codes Number Description HCPCS J9306 Injection, pertuzumab, 1 mg ICD , 174.8, 174.9, 175.0, Malignant neoplasm of the breast References 1. Baselga, J, Cortes, J, Kim, SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med Jan 12;366(2): PMID: Swain, SM, Kim, SB, Cortes, J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol May;14(6): PMID: Baselga, J, Gelmon, KA, Verma, S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol Mar 1;28(7): PMID: Gianni, L, Pienkowski, T, Im, YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol Jan;13(1): PMID: Perjeta [package insert]. South San Francisco, CA: Genentech, Inc.; September Genentech, Inc. Press Release: Data From Omnitarg Clinical Program Presented at American Society of Clinical Oncology Meeting: Limited Activity Shown in Single-Agent Trials; Phase II Study of Omnitarg in Combination with Chemotherapy in Ovarian Cancer Currently Enrolling Patients; May 15, [cited 7/25/2012]; Available from: 7. Kaye, SB, Poole, CJ, Danska-Bidzinska, A, et al. A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer. Ann Oncol Jan;24(1): PMID: NCCN Clinical Practice Guidelines in Oncology. Breast Cancer v [cited 4/16/2014]; Available from: dru281.4 Page 6 of 6