Medical Policy. Description/Scope. Position Statement

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1 L Subject: Document #: Current Effective Date: 01/05/2016 Status: Revised Last Review Date: 11/05/2015 Description/Scope This document addresses the indications for trastuzumab (Herceptin, Genentech, Inc., San Francisco, CA), a humanized recombinant DNA monoclonal antibody that targets tumor cells overexpressing the human epidermal growth factor receptor 2 (HER2) protein and/or amplification of the HER2 gene. Note: Please see the following for additional information: DRUG Pertuzumab (Perjeta ) DRUG Ado-trastuzumab emtansine (Kadcyla ) Position Statement Medically Necessary: I. Breast Cancer Trastuzumab is considered medically necessary for individuals with breast cancer who meet criteria (A) and one or more of the indications listed in (B) below: A) Individuals whose breast tumors are HER2-positive as documented by one of the following: 1. Immunohistochemistry (IHC) is 3+; or 2. In situ hybridization (ISH) positive by any of the following: a. Single probe average HER2 copy number greater than or equal to 6.0 signals/cell; or b. Dual-probe HER2/CEP 17 ratio greater than or equal to 2.0; or c. Dual-probe HER2/CEP17 ratio less than 2.0 with an average HER2 copy number greater than or equal to 6.0 signals/cell; AND B) Individuals meet one or more of the following indications: 1. As a component of neoadjuvant therapy prior to surgical treatment; 2. As adjuvant treatment of breast cancer to complete a 12-month (52 weeks) course of trastuzumab; 3. In combination therapy with pertuzumab when the criteria to treat breast cancer in DRUG Pertuzumab (Perjeta ) are met; 4. In combination therapy with lapatinib as a treatment of metastatic breast cancer when both of the following criteria are met: a. Individual has received or is receiving trastuzumab-based therapy; and b. Disease has progressed on or after trastuzumab therapy; 5. As treatment of metastatic breast cancer, as a single agent or in combination with chemotherapy (any chemotherapy approved for use in breast cancer, except when the combination is addressed in another Page 1 of 17

2 medically necessary or investigational and not medically necessary statement below) either in treatment-naive individuals or individuals already receiving chemotherapy. II. Gastric, Esophageal and Gastroesophageal Adenocarcinoma Trastuzumab is considered medically necessary for individuals with advanced gastric, esophageal or gastroesophageal (GE) junction adenocarcinoma who meet criteria: (A) and in addition, both of the criteria listed in (B) below: A) Individuals whose tumors have HER2 protein overexpression documented by one of the following: 1. Immunohistochemistry (IHC) 3+; or 2. Fluorescent in situ hybridization (FISH) HER2 gene copy is greater than 6; or 3. FISH ratio of HER2 gene/chromosome 17 ratio is greater than or equal to 2.0; AND B) Individuals meet the following criteria: 1. Used in combination treatment; and 2. Trastuzumab is used in only one line of therapy. Investigational and Not Medically Necessary: Trastuzumab is considered investigational and not medically necessary when the above criteria are not met and for all other indications, including but not limited to: lung cancer, osteosarcoma, and pancreatic cancer. Concomitant use of trastuzumab with other targeted biologic agents not otherwise noted in the criteria above (including but not limited to erlotinib, cetuximab, panitumumab, and bevacizumab) is considered investigational and not medically necessary. Rationale Breast Cancer Trastuzumab originally received approval in 1998, by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with metastatic breast cancer whose tumors overexpressed HER2 (referred to as HER2+) and who had received one or more chemotherapy regimens for the metastatic disease. Additionally, trastuzumab in combination with paclitaxel as part of a first-line regimen for metastatic disease was also approved. In 2006 and 2008, trastuzumab received additional FDA approval for use in the adjuvant setting in combination therapy for individuals with positive lymph nodes or node-negative disease with high-risk features, or as a single agent following multi-modality anthracycline based therapy. Although there are different FDA approved dosing recommendations, the maximum treatment period for adjuvant therapy is 52 weeks. Treatment for metastatic breast cancer may continue until disease progression (Product Information, 2015). These indications were based on the results of a variety of randomized controlled trials studying the role of trastuzumab as a treatment of metastatic breast disease, as neoadjuvant therapy or adjuvant therapy. The trials examined the use of trastuzumab as monotherapy or in combination with a variety of other therapies and all reported improved disease free survival. Page 2 of 17

3 In 2012, the FDA approved pertuzumab (Perjeta, Genentech, Inc., San Francisco, CA) in combination with trastuzumab and docetaxel, for individuals with HER2+ metastatic breast cancer who have not previously received anti-her2 therapy or chemotherapy treatment for the metastatic disease. The approval was based on the significantly improved progression-free survival (PFS) results from the phase III, double-blind, placebo-controlled Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. A total of 808 participants with HER2+ metastatic breast cancer were enrolled into the study. Participants were eligible if they did not receive prior chemotherapy for the metastatic disease. One hormonal treatment prior to randomization was allowed. The median PFS was 18.5 months for those randomized to the group treated with trastuzumab, pertuzumab and docetaxel compared to a median PFS of 12.4 months in the control group treated with placebo plus trastuzumab and docetaxel. The control group had more frequent left ventricular systolic dysfunction (8.3%) compared to the treatment group combining trastuzumab and pertuzumab (4.4%) (Baselga, 2012). Gianni and colleagues (2011) reported updated results from the ongoing phase III, randomized, open-label, multicenter international HERA (Herceptin Adjuvant) trial comparing trastuzumab treatment for 1 year and 2 years with observation after standard neoadjuvant and/or adjuvant therapy in women with early breast cancer. The interim analysis at a median 1-year follow-up demonstrated a significantly improved disease-free survival (DFS) with trastuzumab compared to chemotherapy alone (hazard ratio [HR] 0.54; 95% confidence interval [CI], ). As a result, the protocol was amended in 2005, to allow individuals from the control group who had not relapsed to cross over and receive trastuzumab. Based on recommendations from the independent data monitoring committee, the 2-year trastuzumab group data are not being released until the final event-driven analysis. Planned data updates occur every 2 years for the 1-year trastuzumab treatment and the observation group. With a median follow-up of 48.4 months, Gianni presented updated data for the 1-year and observation cohorts. The 4-year disease-free survival rate in the 1-year trastuzumab treatment group was 78.6% compared to 72.2% (HR 0.76; 95% CI, ; p<0.0001) for the observation group. The 4-year overall survival (OS) rate was not statistically significant with 89.3% for the trastuzumab group and 87.7 % (p=0.11) in the observation group. Of the 1698 participants in the observation group, 885 (52%) of the individuals crossed over and began trastuzumab treatment. In a comparison of the individuals in the selective crossover group, the estimated HR for fewer disease free survival events was significant (p=0.0077) compared to the observation cohort. The authors concluded that although the OS benefit was no longer statistically significant, the benefit from 1-year treatment with trastuzumab is maintained with longer follow-up. The data from treatment with 2-years of trastuzumab is still pending. It should be noted the majority of randomized studies of trastuzumab as adjuvant therapy enrolled individuals with breast cancer and positive axillary nodes, or individuals with negative nodes but with a primary tumor measuring greater than 1 cm in greatest dimension. The size limitation in individuals with negative nodes was based on the assumption that small tumors (less than 1 cm in diameter) were at low risk of recurrence such that trastuzumab would not be beneficial, particularly considering the cardiac side effects. However, in 2008, data presented at the San Antonio Breast Cancer Symposium challenged this assumption. Gonzalez-Angulo and colleagues (2009) performed a retrospective review of 1390 individuals with early breast cancer no larger than 1 cm in any dimension and negative axillary nodes in the Breast Cancer Management Database at the University of Texas M.D. Anderson Cancer Center (MDACC). A total of 965 individuals were eligible for the study. A second set of 350 individuals who met identical clinical criteria at 2 other institutions in Belgium and Austria were used to validate the MDACC results. Individuals were divided into three groups: triple negative (i.e., negative hormone receptors and negative HER2), HER 2+ (regardless of hormone status) and hormone receptor-positive and HER2 negative. Individuals with HER2+ breast cancer had a significantly worse relapse free survival compared to individuals with hormone- Page 3 of 17

4 positive cancer or triple-negative breast cancer (p<0.0001). The authors concluded that individuals with even small (less than 1 cm) HER2+ tumors have a significant risk of relapse and that adjuvant systemic therapy with trastuzumab should be considered. Therefore, adjuvant trastuzumab is considered in any individual with HER 2+ early breast cancer regardless of nodal status or size of primary tumor. Blackwell and colleagues (2010) reported results from a phase III randomized study (EGF104900) of lapatinib alone or in combination with trastuzumab for women with HER2-positive, trastuzumab-refractory metastatic breast cancer. A total of 296 participants were enrolled with random assignment equally to each treatment arm. Assessments were completed every 4 weeks through week 16, and then every 8 weeks thereafter. Participants were allowed to cross over to combination therapy if objective disease progression was noted after receiving a minimum of 4 weeks of monotherapy with lapatinib. In 2012, the final planned analysis of OS included 291 participants who were available for efficacy analysis with 145 in the lapatinib monotherapy group and 146 in the combination lapatinib and trastuzumab group. After progression of disease while on lapatinib monotherapy, 77 participants were allowed to cross over and received combination therapy. The primary endpoint of PFS was significantly improved in the individuals who were treated with combination trastuzumab and lapatinib compared to lapatinib monotherapy (HR, 0.71; 95% CI, 0.58 to 0.94; p=0.011). Median PFS was 11.1 weeks with combination therapy compared to 8.1 weeks PFS for monotherapy with lapatinib. The median OS was 14 months for the combination therapy versus 9.5 months for lapatinib monotherapy (HR, 0.74; 95% CI, 0.57 to 0.96; p=0.021). Adverse events had similar incidence rates of 94% in the combination cohort compared to 90% in the single-agent group. A significantly higher rate of diarrhea was noted in participants in the combination arm versus the monotherapy arm (62% vs. 48%). Serious adverse events were reported by 26% in the cohort receiving combination therapy and 16% in the cohort receiving monotherapy. The authors noted the 4.5 month survival improvement with the trastuzumab combination supports the preclinical data that lapatinib plus trastuzumab combination has synergistic antiproliferative effects (Blackwell, 2012). In the GBG26/BIG 3-05 phase III RCT, participants were randomized to start single agent capecitabine or continue trastuzumab and start capecitabine at the time of progressive disease while on first-line regimens that included trastuzumab. Baselga and colleagues (2012) reported there was no significant survival difference in the final OS analysis between treatment arms. However, the post-hoc analysis demonstrated a better progression survival than those who did not receive third-line anti-her2 therapy. Post-progression survival of 18.8 months was noted in participants who continued or restarted anti-her2 therapy after second progression compared to 13.3 months in those who did not receive third-line anti-her2 therapy (p=0.02). The authors note that the results need to be confirmed in a larger meta-database analysis to overcome potential bias related to the post-hoc review. The authors concluded the use of anti-her2 therapy throughout multiple lines continues to be recommended. The clinical practice guideline (CPG) of the National Comprehensive Cancer Network (NCCN, 2015) recommends the use of trastuzumab to treat breast cancer. The CPG recommends continued trastuzumab following progression on first line-trastuzumab containing chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab in patients with long-term control of disease is unknown. In 2014, the American Society of Clinical Oncology (ASCO) clinical practice guideline (Ramakrishna) provided recommendations for management of individuals with brain metastasis from HER2+ breast cancer. The guideline includes a recommendation for individuals who developed an isolated progression in the brain while on single-agent trastuzumab, to treat the brain metastasis and continue the single-agent trastuzumab. Page 4 of 17

5 In a retrospective series of 80 individuals with brain metastases from breast cancer, the use of lapatinib and trastuzumab-based therapy significantly improved OS compared to chemotherapy or radiotherapy alone (Bartsch, 2012). Median OS was 13 months for those receiving trastuzumab with or without chemotherapy and at 24 months of follow-up, the median OS for lapatinib (with or without trastuzumab or chemotherapy) was not reached. A phase III randomized trial (GeparQuinto, GBG 44) enrolled individuals with untreated HER2-positive, operable or locally advanced breast cancer randomized to treatment with lapatinib (ECH-TL group) versus trastuzumab (ECH-TH group) in combination with neoadjuvant anthracycline-taxane-based chemotherapy. There were improved rates of pathologic complete response in the ECH-TH group with 93 (30.3%) of 307 participants compared to 70 (22.7%) of 308 participants in the ECL-TL (odds ratio [OR] 0.68 [95% CI, ]; p=0.04) (Untch, 2012). Baselga and colleagues reported results from NeoALTTO, an open-label, multicenter, phase III randomized trial of dual HER2 inhibition with lapatinib and trastuzumab versus lapatinib alone or trastuzumab alone in the neoadjuvant setting. Individuals received 6 weeks of the assigned biologic agent(s) followed by an additional 12 weeks of therapy in combination with paclitaxel prior to definitive breast surgery. A significantly higher (p=0.0001) pathologic complete response (pcr) was noted in the combination lapatinib and trastuzumab group (51.3%; 95% CI, ) compared to the group treated with trastuzumab alone (29.5%; ). Grade 3 and 4 adverse events were more frequent in the dual lapatinib and trastuzumab cohort (21.7%) compared to 1.3% in trastuzumab alone and 18.8% in the lapatinib group. Participants who were unable to complete the planned therapy due to side effects were higher in the groups treated with lapatinib alone (18.8%) and combination lapatinib and trastuzumab (39.5%) versus the trastuzumab alone group (8.1%). The authors noted the results support the proof of concept and with longer follow-up, DFS and OS will be reported. Additional long-term data and studies are needed to confirm dual inhibition of HER2 in the neoadjuvant setting is safe and effective. Event-free survival and overall survival were prespecified secondary endpoints in the phase III NeoALTTO trial. De Azambuja (2014a) and colleagues reported at an event follow-up of 3.77 years, there was no significant difference in event-free survival between the lapatinib and trastuzumab groups (HR 1.06, 95% CI, , p=0.81) and between the combination and trastuzumab groups (HR 0.78, 95% CI, , p=0.33). Similarly, there was no significant difference in the 3-year over-all survival 93% for lapatinib, 90% trastuzumab and 95% for combination therapy. However, the authors reported for the subset of participants that achieved pcr, the 3-year event free survival was significantly improved compared to those that did not achieve pcr (HR 0.38, 95% CI, , p=0.0003). Those that achieved pcr also had significantly improved overall survival when compared to those that did not achieve pcr (HR 0.35, 95% CI, , p=0.005). Clinical indications combining trastuzumab with lapatinib are a category 2A recommendation in the NCCN practice guidelines (2015) for individuals with HER2 overexpressing metastatic breast cancer that have received prior trastuzumab therapy. The CPG also notes the optimal neoadjuvant regimen for HER2-targeting remains uncertain. Gastric, Esophageal and Gastroesophageal Carcinoma In October 2010, the FDA approved trastuzumab in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of individuals with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease. Treatment for gastric cancer may continue until disease progression (Product Information, 2015). Page 5 of 17

6 Bang (2010) and colleagues reported results from ToGA (trastuzumab for gastric cancer) a multicenter, phase III randomized trial investigating trastuzumab as first-line treatment of locally advanced, recurrent or metastatic gastric and gastroesophageal adenocarcinoma. A total of 3807 individuals with gastric carcinoma were tested for HER2. Eligibility for inclusion in the study was HER2 positivity defined as IHC 3+ or FISH positive (defined as HER2: CEP17 ratio 2.0) (Bang, 2010). Of these, 594 individuals had HER2+ tumors and were randomized to a control group receiving chemotherapy or to a treatment group receiving chemotherapy plus trastuzumab. Chemotherapy consisted of either 5-fluorouracil or capecitabine in conjunction with cisplatin every 3 weeks, for 6 cycles. The treatment group received 6 cycles of chemotherapy plus trastuzumab on day 1 of each cycle and trastuzumab was continued every 3 weeks until disease progression. The median number of trastuzumab cycles was 8 (range 1-49). At 18.6 months of follow-up, the median OS was 13.5 months in the trastuzumab arm, compared to 11.1 months OS in the control group (p=0.0048) at a median follow-up of 17.1 months. The overall response rate (ORR) was also significantly improved for the trastuzumab group compared to controls, 47.3% vs. 34.5%, respectively. The NCCN practice guideline for gastric cancer (2015) and the National Cancer Institute PDQ (2015) for gastric cancer list the use of trastuzumab as a part of combination therapy for HER2-positive advanced gastric, esophageal and gastroesophageal adenocarcinoma. In a Cochrane Review of chemotherapy for gastric cancer (Wagner, 2010), the authors recommended HER2 overexpression testing for all gastric cancers and use of trastuzumab in combination therapy with cisplatin and 5FU for HER2-positive gastric carcinomas. HER2 overexpression The key selection criterion for trastuzumab is HER2 overexpression. In the pivotal breast cancer clinical trials, HER2 overexpression was determined by scores of 2+ or 3+ resulting from the IHC Clinical Trial Assay (CTA), which is utilized in research settings. Individuals with scores of 0 or 1+ were not included in the trials. Subsequently, the FDA has approved commercially available IHC tests to determine HER2 overexpression, which include Herceptest (Dako Corp., Glostrup, Denmark) and Pathway (Ventana Medical Systems, Tucson, AZ). In addition, FDA approved tests which measure fluorescent in situ hybridization (FISH) of the HER2/neu protein including PharmDx (Dako Corp., Glostrup Denmark), Dako HER2 FISH PharmDx test kit (Dako Corp., Glostrup, Denmark), PathVysion (Abbott-Vysis Inc, Downers Grove, IL) and INFORM (Ventana Medical Systems, Tucson, AZ). In 2007, 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 2013 (Wolff 2007; 2013). The guideline was established to promote complete and standardized reporting of malignant pathology to Improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer (Wolff, 2013). The guideline recommends all individuals with newly diagnosed and recurrent invasive breast cancer should have tumors HER2 tested by laboratories that are accredited to perform HER2 testing. The updated guideline defines the results of HER2 testing as follows: Positive HER2: IHC 3+ based on circumferential membrane staining that is complete, intense. (Observed in a homogeneous and contiguous population and within >10% of the invasive tumor cells). ISH positive based on: o Single-probe average HER2 copy number 6.0 signals/cell* Page 6 of 17

7 o Dual-probe HER2/CEP 17 ratio 2.0* with an average HER2 copy number 4.0 signals/cell o Dual-probe HER2/CEP17 ratio 2.0* with an average HER2 copy number < 4.0 signals/cell o Dual-probe HER2/CEP17 ratio < 2.0* with an average HER2 copy number 6.0 signals/cell *Observed in a homogeneous and contiguous population and within >10% of the invasive tumor cells. By counting at least 20 cells within the area. Equivocal HER2: IHC 2+ based on circumferential membrane staining that is incomplete and/or weak/moderate and within > 10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within 10% of the invasive tumor cells. ISH equivocal based on: o Single-probe average HER2 copy number 4.0 and < 6.0 signals/cell o Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number 4.0 signals/cell Negative HER2 if a single test (or both tests) performed show: IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of the invasive tumor cells IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within 10% of the invasive tumor cells ISH negative based on: o Single-probe average HER2 copy number < 4.0 signals/cell o Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signal/cell For individuals with equivocal results, the guidelines (Wolff, 2013) recommend additional testing with a reflex test (on the same specimen using the alternative test) or a new test (new specimen if available, using same or alternative test). NCCN guidelines for breast cancer (2015) have incorporated the updated ASCO/CAP recommendations for HER2 status into the treatment algorithms for HER2 targeted therapy. Specific IHC scoring criteria were developed for gastric carcinoma based on the identification of basolateral membrane staining of gastric tumor specimens obtained surgically or via biopsy. Staining of surgical specimens with strong complete, basolateral or lateral membranous reactivity in 10% of tumor cells was deemed IHC 3+ and HER2 positive (Bang, 2010). Staining of biopsy specimens with tumor cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells stained were deemed IHC 3+ and HER2 positive (Bang, 2010). Equivocal results were categorized as IHC 2+ with staining of surgical specimens weak to moderate complete, basolateral or lateral membranous reactivity in 10% of tumor cells (Bang, 2010). Equivocal HER2 was determined if staining on biopsy specimens included cancer cell cluster with a weak to moderate complete, basolateral, or lateral membranous reactivity irrespective of percentage of cancer cells was HER2 equivocal (Bang, 2010). Cardiac Function Trastuzumab is associated with a risk of cardiac dysfunction. The practice guidelines from the NCCN (2015) recommend baseline cardiac monitoring and intermittent cardiac function testing during the course of therapy. Page 7 of 17

8 Additionally, the product label states treatment with trastuzumab should only start or continue if the left ventricular ejection fraction (LVEF) is above the institutional lower limit of normal. Jones and colleagues (2009) noted patients with metastatic disease have a very different oncology risk profile to those receiving adjuvant treatment; the monitoring strategy and thresholds for treatment discontinuation should thus be individualized in consultation with the oncologist and cardiologist when appropriate. De Azambuja and colleagues (2014b) reported long-term cardiac safety results from the randomized phase III, Herceptin Adjuvant (HERA, BIG1-01) trial. At a median follow-up of 8 years, there was a low incidence of cardiac events noted in participants treated with trastuzumab for 1 year and for 2 years. LVEF decreased in the 3 study arms (2-year and 1-year trastuzumab therapy, and observation) by 7.2%, 4.1% and 0.9%, respectively. There were no incidences of severe congestive heart failure (CHF) in the observation group, and there was 0.8% for both trastuzumab treatment groups. There were 3 cardiac deaths in the 2-year treatment arm, none in the 1-year arm and 2 cardiac deaths in the observation arm. Acute recovery from any cardiac endpoint was achieved in 118 (87.2%) individuals in the 2-year trastuzumab arm and in 66 (79.5%) individuals in the 1-year trastuzumab treatment arm. The authors concluded the use of trastuzumab in the adjuvant setting had a low incidence of cardiac endpoints, and most were reversible with discontinuation of trastuzumab. Other Uses As a result of clinical trials demonstrating the effectiveness of trastuzumab with chemotherapy, additional clinical trials are studying the efficacy of adding trastuzumab to specific targeted biologic agents. However, at this time, there is no evidence to support the safety and efficacy of combining trastuzumab with other biologic agents not discussed above. The updated NCCN clinical practice guideline (2015) for non-small cell lung cancer notes trastuzumab may be used as a targeted agent for individuals with HER2 mutations, the recommendations are based on 2B* category of evidence. The National Cancer Institute (NCI) notes the incidence of HER2-positive NSCLC is less than 2% (NCI, 2015). Two randomized phase II studies investigating trastuzumab in combination with chemotherapy to treat NSCLC did not observe clinically significant benefit of adding trastuzumab to the standard chemotherapeutic regimens (Gatzemeier, 2004; Krug, 2005). Mazieres (2014) reported results from a retrospective review of consecutive series of individuals identified with NSCLC and HER2 positivity from three participating centers. A total of 65 individuals (1.7%) out of 3800 individuals tested had the HER2 mutation, and 16 of these individuals received treatment with anti-her2 therapy. Four individuals were treated with two or more anti-her2 therapies. The authors recommended large prospective trials to evaluate the efficacy and safety of trastuzumab and other anti- HER2 therapy in the treatment of adenocarcinoma of the lung. The NCI does not recommend trastuzumab as a treatment for NSCLC (2015). There are ongoing trials investigating the use of trastuzumab and other anti-her2 therapies to treat NSCLC. The Children s Oncology Group reported results from a phase II trial of combination therapy of trastuzumab and chemotherapy as a treatment for high-risk osteosarcoma with HER2 over-expression (Ebb, 2012). Of the 96 evaluable individuals with newly diagnosed metastatic osteosarcoma, 41 individuals had HER2-positive tumors. All participants received 10 weeks of induction therapy with doxorubicin, cisplatin, methotrexate, ifosfamide, and etoposide followed by 21 weeks of post-induction therapy. Those with HER2-positive tumors received trastuzumab for a total of 34 doses. At a median follow-up of 41.6 months, there were no statistically significant differences in OS and event-free survival (EFS) between the HER2-positive and the HER2-negative cohorts. The 30-month EFS was 32% (95% CI, 18% to 46%), with 30-month OS of 59% (95% CI, 43% to 73%) in the group Page 8 of 17

9 with HER2-positive tumors who received trastuzumab therapy. The HER2-negative group had a 30-month EFS of 32% (95% CI, 20% to 45%) with a 30-month OS of 50% (95% CI, 36% to 63%). Ebb and colleagues (2012) noted there is controversy regarding the reliability, consistency, and predictive value of HER2 expression levels in osteosarcoma. There is currently an ongoing study to determine if HER2 has a prognostic impact for osteosarcoma. The researchers noted the consistent validation of HER2 expression in osteosarcoma also needs to be established, and then a randomized controlled trial should be done to compare the effects of treatment with trastuzumab versus without trastuzumab. In a phase II study of 212 individuals with metastatic pancreatic cancer, Harder and colleagues (2012) investigated the significance of HER2 expression and the potential use of trastuzumab as an agent to target HER2 overexpression when given in combination with capecitabine. The single-arm, open-label trial screened 212 individuals at 9 different institutions. Tumor specimens were available for HER2 expression and gene amplification testing in 207 participants, of which 22 (11%) had IHC grade 3. Seventeen participants with HER2 IHC 3+ were eligible for assessment after 12 weeks of treatment. Progressive disease (PD) occurred in 13 of the 17 participants, with a primary endpoint of PFS rate estimated after 12 weeks of 23.5%. The study was terminated early with 4 participants alive and without evidence of PD after 12 weeks. In a post hoc FISH analysis of the IHC 3+ pancreatic tumor tissue, the HER2 gene amplification was inconsistent and contrary to other tumor types such as breast and gastric cancer. The authors concluded the HER2 gene amplification in pancreatic cancer was very low and OS and PFS were not improved with treatment of trastuzumab and capecitabine. Therefore further evaluation of anti-her2 treatment in patients with metastatic pancreatic cancer was not recommended (Harder, 2012). Additionally, investigators continue to study the prevalence and role of HER2 in other malignancies. However, there have been no large randomized controlled trials demonstrating the safety and efficacy of trastuzumab versus current standard therapies for malignancies other than breast, gastric, esophageal and gastroesophageal cancers. Background/Overview The human epidermal growth factor receptor 2 gene ERBB2 is commonly referred to as HER2. Other names for this gene include NEU, Her-2, HER-2/neu and c-erb B2. Initially, the HER2 gene was detected in frozen breast tumor samples. Amplification of the HER2 gene was later correlated to overexpression of protein levels in samples of breast cancer. The HER2 overexpression is present in approximately 18%-25% of all early breast cancers and is associated with aggressive disease, shortened DFS and OS (Baselga, 2006; Robert, 2006; Wolff, 2007; Wolff, 2013). According to the National Cancer Institute (NCI, 2014), approximately 10% to 20% of all new gastric cancer cases are diagnosed at an early stage of disease. The remaining individuals are diagnosed with regional or distant metastatic disease. A review by Gravalos (2008) noted HER2 overexpression in gastric cancer ranged from 9%- 38% in reported series. Adverse Events and Warnings: The Product Information Label (2015) for trastuzumab includes the following Black Box warnings: Cardiomyopathy Page 9 of 17

10 Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function. Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Embryo-fetal Toxicity Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Other serious adverse reactions caused by trastuzumab include diarrhea, exacerbation of chemotherapy-induced neutropenia and infection. Definitions Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone or biological therapy. Anti-HER2 therapy: Agents that target the HER2 receptor (for example, lapatinib, pertuzumab, and trastuzumab). Disease free survival (DFS): The interval between a complete disappearance of the cancer (complete response) and the time of relapse. Line of therapy: First-line therapy: The first or primary treatment for the diagnosis. This may include surgery, chemotherapy, radiation therapy or a combination of these therapies. Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression. Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (secondline therapy) are not effective or there is disease progression. Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread. Page 10 of 17

11 Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN) Categories of Evidence and Consensus: Category 1: The recommendation is based on high level evidence, and there is uniform NCCN consensus. ** Category 2A: The recommendation is based on lower level evidence, including clinical experience and there is uniform NCCN consensus. * Category 2B: The recommendation is based on lower level evidence, including clinical experience and there is non-uniform NCCN consensus (but no major disagreement). Category 3: Based on any level of evidence but reflects major disagreement. All recommendations of the NCCN are Category 2A unless otherwise noted. Neoadjuvant therapy: Treatment given before the primary treatment which may include chemotherapy, radiation therapy, or hormone therapy. Off-label: Utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved label. Targeted biologic agent: A newer type of drug developed specifically to target genetic changes in cells that cause cancer. It works differently than standard chemotherapy drugs, often with different side effects. Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. When services may be Medically Necessary when criteria are met: HCPCS J9355 Injection; trastuzumab, 10 mg [Herceptin] ICD-10 Diagnosis C15.3-C15.9 Malignant neoplasm of esophagus C16.0-C16.9 Malignant neoplasm of stomach C C Malignant neoplasm of breast C78.89 Secondary malignant neoplasm of other digestive organs [specified as esophagus or Page 11 of 17

12 stomach] C79.32 Secondary malignant neoplasm of cerebral meninges C79.81 Secondary malignant neoplasm of breast D00.1 Carcinoma in situ of esophagus D00.2 Carcinoma in situ of stomach D05.00-D05.92 Carcinoma in situ of breast Z51.11-Z51.12 Encounter for antineoplastic chemotherapy and immunotherapy Z85.3 Personal history of malignant neoplasm of breast When services are Investigational and Not Medically Necessary: For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. References Peer Reviewed Publications: 1. Bang YJ, Van Cutsem E, Feyereislova A, et al.; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010; 376(9742): Bartsch R, Berghoff A, Pluschnig U, et al. Impact of anti-her2 therapy on overall survival in HER2- overexpressing breast cancer patients with brain metastases. Br J Cancer. 2012; 106(1): Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366(2): Baselga J, Perez E, Pienkowski T, Bell R. Adjuvant trastuzumab: a milestone in the treatment of HER-2- positive early breast cancer. Oncologist. 2006; 11 Suppl 1: Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010; 28(7): de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014a; 15(10): de Azambuja E, Procter MJ, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant Trial (BIG 1-01). J Clin Oncol. 2014b; 32(20): Dowsett M, Procter M, McCaskill-Stevens W, et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol. 2009; 27(18): Ebb D, Meyers P, Grier H, et al. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children's oncology group. J Clin Oncol. 2012; 30(20): Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004; 15(1): Page 12 of 17

13 11. Gianni L, Dafni U, Gelber RD, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4- year follow-up of a randomized controlled trial. Lancet Oncol. 2011; 12(3): Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010; 375(9712): Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2- positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014; 15(6): Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009; 27(34): Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008; 19(9): Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012; 106(6): Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer. 2009; 100(5): Krug LM, Miller VA, Patel J, et al. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma. Cancer. 2005; 104(10): Perez EA, Roche PC, Jenkins RB, et al. HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin Proc. 2002; 77(2): Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011; 29(25): Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353(16): Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) With ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2- positive breast cancer. J Clin Oncol. 2012; 30(31): Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353(16): Semiglazov V, Eiermann W, Zambetti M, et al. Surgery following neoadjuvant therapy in patients with HER2- positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) study. Eur J Surg Oncol. 2011; 37(10): Slamon D, Eiermann W, Robert N, et al.; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365(14): Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2- positive breast cancer: a randomised controlled trial. Lancet. 2007; 369(9555): Page 13 of 17

14 27. Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol. 2011; 29(25): Untch M, Loibl S, Bischoff J, et al.; GBG and the Arbeitsgemeinschat Gynakologische Onkologie-Breast (AGO-B) Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxanebased chemotherapy (GeparQuinto, GBG 44): a randomized phase 3 trial. Lancet Oncol. 2012; 13(2): von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2- positive advanced breast cancer: a German Breast Group 26/Breast International Group Study. J Clin Oncol. 2009; 27(12): von Minckwitz G, Schwedler K, Schmidt M, et al.; GBG 26/BIG Study Group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011; 47(15): Yamaguchi K, Sawaki A, Doi T, et al. Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study. Gastric Cancer. 2013; 16(2): Government Agency, Medical Society, and Other Authoritative Publications: 1. Balduzzi S, Mantarro S, Guarneri V, et al. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2014;(6):CD Giordano SH, Temin S, Kirshner JJ, et al; American Society of Clinical Oncology. Systemic therapy for patients with advanced human epidermal growth factor recptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014; 32(19): Herceptin [Product Information], San Francisco, CA. Genentech; April 23, Available at: Accessed on October 1, Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;(4):CD NCCN Clinical Practice Guidelines in Oncology 2014 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: Accessed on October 1, Breast Cancer (V ). Revised July 16, Esophageal and Esophagogastric Junction Cancers (V ). Revised March 23, Gastric Cancer (V ). Revised March 23, Non-Small Cell Lung Cancer (V ). Revised June 11, National Comprehensive Cancer Network. NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: Accessed on October 1, Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014; 32(19): Trastuzumab. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated September 15, Available at: Accessed on October 1, Trastuzumab Monograph. Lexicomp Online, American Hospital Formulary Service (AHFS ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 27, Accessed on October 1, Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2010;(3):CD Page 14 of 17

15 11. Wolff A, Hammond MEH, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013; 31(31): Wolff A, Hammond MEH, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007; 25(1): Websites for Additional Information 1. American Cancer Society. Available at: Accessed on October 1, National Cancer Institute. Available at: Accessed on October 1, Breast Cancer Treatment PDQ. Modified: July 24, Gastric Cancer Treatment PDQ. Modified: July 8, Non-small Cell Lung Cancer PDQ. Modified September 3, Index HER2; Her2-neu Herceptin Monoclonal antibody Trastuzumab The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. Document History Status Date Action Revised 11/05/2015 Medical Policy & Technology Assessment Committee (MPTAC) review. Revised 11/04/2015 Hematology/Oncology Subcommittee review. Revised investigational and not medically necessary statement to include all other indications, including but not limited to: lung cancer, osteosarcoma and pancreatic cancer. Updated Description, Rationale, Definitions, References and Websites sections. Removed ICD-9 codes from Coding section. Revised 11/13/2014 MPTAC review. Revised 11/12/2014 Hematology/Oncology Subcommittee review. Clarified metastatic breast cancer criterion B4b refers to trastuzumab. Updated Rationale, Coding, References and Websites sections. Revised 05/15/2014 MPTAC review. Revised 05/14/2014 Hematology/Oncology Subcommittee review. Revised HER2-positivity and how it is measured. Revised order of medically necessary breast cancer criteria and added the words "as a component of" prior to neoadjuvant therapy. Clarified criteria addressing combination therapy with pertuzumab for breast cancer by removing the word "metastatic." Updated Rationale, References and Websites sections. Page 15 of 17

16 Revised 05/09/2013 MPTAC review. Revised 05/08/2013 Hematology/Oncology Subcommittee review. Clarified medically necessary HER2 positive FISH criteria for both breast and gastric/ge adenocarcinoma to greater than or equal to 2.0. Added advanced to gastric/ge criterion. Updated Rationale, References and Websites. Revised 11/08/2012 MPTAC review. Revised 11/07/2012 Hematology/Oncology Subcommittee review. Clarified medically necessary criteria for combination therapy with FDA approved pertuzumab to treat metastatic breast cancer. Updated Rationale and References. Review 08/09/2012 MPTAC review. Revised 06/27/2012 MPTAC review. Revised 06/19/2012 Hematology/Oncology Subcommittee review. Added medically necessary criteria for combination therapy with new FDA approved pertuzumab to treat metastatic breast cancer. Updated Rationale and References. Revised 05/10/2012 MPTAC review. Revised 05/09/2012 Hematology/Oncology Subcommittee review. Clarified FISH ratio of HER2 gene/chromosome 17 ratio is greater than 2.0. Clarified neoadjuvant therapy. Removed criteria for baseline cardiac testing. Formatting changes to the Position Statements. Updated Rationale, Definitions, References and Websites. On 6/19/2012, Revised 05/19/2011 MPTAC review. Revised 05/18/2011 Hematology/Oncology Subcommittee review. Clarified medically necessary statement for breast cancer. Modified cardiac medically necessary statements. Updated Rationale, References and Websites. Revised 11/18/2010 MPTAC review. Revised 11/17/2010 Hematology/Oncology Subcommittee review. Clarified adjuvant therapy for breast cancer. Updated Rationale, References and Websites. Revised 05/13/2010 MPTAC review. Revised 05/12/2010 Hematology/Oncology Subcommittee review. Clarified HER2 testing criteria. Added medically necessary criteria for esophageal and gastroesophageal junction. Added medically necessary lapatinib combination with criteria. Deleted lapatinib from investigational and not medically necessary criteria. Updated Rationale, Coding, References and Websites. Revised 11/19/2009 MPTAC review. Revised 11/18/2009 Hematology/Oncology Subcommittee review. Revised cardiac criteria. Removed redundant medical necessary criteria for adjuvant breast cancer therapy. Updated rationale, references and websites. Revised 07/13/2009 MPTAC review. Revised 06/17/2009 Hematology/Oncology Subcommittee review. Added criteria for gastric cancer. Updated rationale, background and coding. Revised 05/21/2009 MPTAC review. Revised 05/20/2009 Hematology/Oncology Subcommittee review. Updated rationale, references, definitions and websites. Removed redundant adjuvant medically necessary criteria. Revised 02/26/2009 MPTAC review. Page 16 of 17