Pertuzumab in the Treatment of HER2 + Breast Cancer

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1 Focused Review 591 Pertuzumab in the Treatment of HER2 + Breast Cancer Komal Jhaveri, MD, and Francisco J. Esteva, MD, PhD Abstract Pertuzumab, a humanized monoclonal antibody and the first in the class of agents called the HER2 dimerization inhibitors, impairs the ability of HER2 to bind to other members of the HER family. It has a unique and complimentary mechanism of action compared with trastuzumab, and the combination has resulted in the enhanced blockade of the HER signaling pathway. When pertuzumab was used in combination with docetaxel and trastuzumab in the first-line treatment of metastatic HER2 + breast cancer, it led to an overall survival benefit. Pertuzumab has therefore been approved by the FDA and is currently used as a standard of care for this indication. It is also the first agent in oncology to receive accelerated FDA approval in the neoadjuvant setting. Randomized trials showed that the addition of pertuzumab to trastuzumabbased chemotherapy improves pathologic complete response rates in HER2 + early-stage breast cancer. A randomized phase III clinical trial with disease-free survival as the primary end point is evaluating the safety and efficacy of pertuzumab in the adjuvant setting. This article describes the preclinical data, synthesizes available data from phase I III clinical trials of pertuzumab in early stage and metastatic settings, and puts them into perspective with current treatment recommendations and future research developments. (J Natl Compr Canc Netw 2014;12: ) NCCN: Continuing Education Accreditation Statement This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation. This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity. All clinicians completing this activity will be issued a certificate of participation. To participate in this journal activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at node/43680; and 4) view/print certificate. Release date: April 11, 2014; Expiration date: April 11, 2015 Learning Objectives Upon completion of this activity, participants will be able to: Describe the unique and complimentary mechanism of action of pertuzumab with trastuzumab resulting in enhanced blockade of the HER signaling pathway Evaluate the safety and efficacy of pertuzumab in the management of HER2 + breast cancer in the neoadjuvant and metastatic settings From New York University Cancer Institute, New York, New York. Submitted January 20, 2014; accepted for publication February 14, Dr. Jhaveri has disclosed that she has served as a consultant for Genentech. Dr. Esteva has disclosed that he has served as a consultant for Genentech. Correspondence: Francisco J. Esteva, MD, PhD, New York University Cancer Institute, 160 East 34th Street, New York, NY Francisco.Esteva@nyumc.org EDITOR Kerrin M. Green, MA, Assistant Managing Editor, JNCCN Journal of the National Comprehensive Cancer Network Ms. Green has disclosed that she has no relevant financial relationships. AUTHORS Deborah J. Moonan, RN, BSN, Director, Continuing Education & Grants Ms. Moonan has disclosed that she has no relevant financial relationships. Ann Gianola, MA, Manager, Continuing Education & Grants Ms. Gianola has disclosed that she has no relevant financial relationships. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations Ms. Gregory has disclosed that she has no relevant financial relationships.

2 592 Focused Review Jhaveri and Esteva Background Approximately 20% of breast cancers have amplification or overexpression of human epidermal growth factor receptor 2 (HER2), a member of the receptor tyrosine-protein kinase erbb family of receptors that also includes epidermal growth factor receptor (EGFR or erbb1), erbb3/her3, and erbb4/ HER4. 1 Historically, HER2 overexpression was associated with an increased risk of recurrence with a poor prognosis. 2 4 This is because aberrant HER2 activity and activation of the HER2 receptor leads to formation of homodimers or heterodimers (eg, HER2/HER3), which activate a variety of molecular pathways (the phosphatidylinositol 3-kinase [PI3K] and mitogen-activated protein kinase [MAPK] pathways), ultimately leading to cellular proliferation and survival. 5,6 The advent of trastuzumab, a monoclonal antibody against the extracellular domain IV of HER2, has revolutionized the management of this subgroup of patients and significantly improved their survival in the adjuvant and metastatic settings. 7,8 Unfortunately, most patients with metastatic breast cancer (MBC) still develop acquired resistance to trastuzumab, 9 12 thereby highlighting a need to develop other effective anti-her2 directed therapies. 13 Pertuzumab is a humanized, recombinant monoclonal antibody that is distinct and complimentary to trastuzumab, in that it binds the extracellular domain II of the HER2 receptor and prevents the dimerization of HER2 with the other erbb/her receptors. 14 In fact, it is the first among a new class of agents called HER2 dimerization inhibitors. 15 Similar to trastuzumab, pertuzumab activates antibodydependent cellular cytotoxicity, with equivalent efficacy, leading to cancer cell death. 16,17 Preclinical Data The HER2/HER3 heterodimer functions as the most potent complex of the HER family of proteins and can cause robust pro-oncogenic signaling and resistance to trastuzumab-based therapy. 18 Pertuzumab (initially known as 2C4) led to ligand-dependent inhibition of HER2 in both HER2-expressing and non HER2-expressing tumors, and also effectively blocked HER2/HER3 heterodimers. 19 In the BT474 HER2-overexpressing cell lines, the combination of trastuzumab plus pertuzumab was synergistic. This combination reduced HER2/EGFR and HER2/HER3 heterodimer formation, inhibited PI3K and MAPK signal transduction, and resulted in induction of apoptosis in vitro. 20 These results were also reproduced in HER2 xenograft models. 16 Interestingly, tumor mass reduction was noted in tumors that had progressed on single-agent trastuzumab and were later treated with both pertuzumab and trastuzumab. 16 Pharmacokinetics Pharmacokinetic simulations from rodents and cynomolgus monkeys suggested that dosing of pertuzumab at 5 to 15 mcg/kg every 3 weeks would achieve a target trough concentration of 20 mcg/ml, which was optimal to experience antitumor activity. 15,21 Two phase I trials supported administration once every 3 weeks. 21,22 The volume of distribution was similar to serum volume. The mean elimination half-life was 18.9 ± 8.0 days. 21 The maximum tolerated dose (MTD) was not achieved at doses up to 25 mg/kg. 22 Pharmacokinetic simulations using weight-based dosing, fixed dosing, or body surface area (BSA) based dosing suggested that the weight-based and BSA-based dosing did not improve steady-state exposure, and therefore the fixed dosing regimen of 840 mg intravenously followed by 420 mg every 3 weeks was recommended. 23 The fixed dosing regimen was estimated to achieve steady state by the end of the second cycle of treatment. Phase I Trials: Clinical Efficacy and Safety Pertuzumab was evaluated in a phase I dose escalation trial ( mg/kg) of 21 patients with advanced solid tumors. 21 The MTD was not reached and pertuzumab was well tolerated, with mostly grade 1 or 2 toxicities of asthenia (62%), vomiting (52%), nausea (48%), abdominal pain (48%), rash (43%), diarrhea (43%), and anemia (33%). One event of grade 3 dose-limiting toxicity (DLT), consisting of a gastrointestinal bleed, occurred in a patient with preexisting esophageal varices. Another patient had a grade 1 hypersensitivity reaction after the fifth cycle. No decline in left ventricular ejection fraction less than 50% in the first 2 cycles was reported. Partial responses were reported in 2 patients: one with ovarian cancer and the other with islet cell carcinoma of the pancreas. Notably, tumors from both of these patients did not overexpress HER2.

3 Focused Review 593 Pertuzumab in HER+ Breast Cancer In another phase I trial, 18 Japanese patients with advanced solid tumors 22 were treated with pertuzumab at 5 to 25 mg/kg every 3 weeks. MTD was not reached and 1 patient had a DLT consisting of elevated gamma-glutamyl transpeptidase. Limited evidence showed antitumor activity, with 2 patients experiencing stable disease (SD): one with rectal cancer and the other with non small cell lung cancer. Portera et al 24 reported a phase I trial of pertuzumab and trastuzumab in 11 patients with HER2 + MBC treated with up to 3 prior trastuzumab-based regimens. The partial response and SD rates were 18.2% and 27.3%, respectively, and progression-free survival () was 1.5 months. Grade 3 toxicities included allergic reaction and left ventricular systolic dysfunction (LVSD) in 9% of patients. Notably, of the 6 patients who experienced any grade of LVSD, all had received prior anthracyclines and most had also experienced LVSD with prior trastuzumab therapy. Synergistic interaction without additive toxicity was noted between pertuzumab and docetaxel in a phase Ib trial. 25 One patient with prostate cancer experienced a partial response and more than 50% of patients experienced SD after 4 cycles of treatment with combination therapy. DLTs of grade 3 diarrhea and grade 4 febrile neutropenia were noted in 2 of 2 patients treated with 75 mg/m 2 of docetaxel and 1050 mg of pertuzumab every 3 weeks. Of 5 patients, 2 who received 100 mg/m 2 of docetaxel and 420 mg of pertuzumab (after a loading dose of 840 mg) every 3 weeks experienced DLTs of grade 3 fatigue and grade 4 febrile neutropenia. 25 Based on the DLT noted in this trial and other phase II data available that showed no difference in toxicity or efficacy between the 2 doses of pertuzumab, the recommended phase II doses were 75 mg/m 2 of docetaxel and 420 mg of pertuzumab (after a loading dose of 840 mg) every 3 weeks. 25 A phase I trial was conducted of pertuzumab at 1050 mg on day 1 plus capecitabine at 825, 1000, or 1250 mg/m 2 twice daily for the first 14 days of a 21-day cycle. 26 No DLTs were seen at any dose level, and the most common adverse event was grade 3 asthenia observed in 2 patients. SD was reported in 11 patients. 26 All of the phase II trials of pertuzumab in patients with HER2 +, HER2, or HER2-unknown status are summarized in Table 1. Overall, single-agent pertuzumab has modest antitumor activity, but improved efficacy was noted when combined with other anti-her2 agents (dual HER2 blockade) or in combination with other chemotherapy agents Although preclinical results showed that pertuzumab could prove effective in the treatment of non HER2-expressing tumors, clinical results were disappointing, especially in patients with prostate and ovarian cancer The neoadjuvant setting has been used to assess treatment response and resistance in patients with triple-negative and HER2 + breast cancer. The pathologic complete response (pcr) rate has been a primary end point in various neoadjuvant trials of HER2 + breast cancer. 34 In the neoadjuvant setting, pertuzumab was evaluated in 2 trials: NeoSphere (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) 35 and TRYPHAENA (Trastuzumab Plus Pertuzumab in Neoadjuvant HER2-Positive Breast Cancer). 36 In the NeoSphere trial, 417 treatment-naïve patients with HER2-overexpressing breast cancer received 4 cycles of varying combinations of pertuzumab (P; 840 mg loading dose followed by 420 mg every 3 weeks), trastuzumab (T; 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks), and docetaxel (D; 75 mg/m 2, escalating if tolerated to 100 mg/m 2 every 3 weeks). Patients were randomized to 1 of 4 treatment groups: T+D, P+T+D, P+T, or P+D. The primary end point was pcr in the breast. Patients who received P+T+D had a significant improvement in pcr (45.8%) compared with T+D (29.0%; P=.0141), P+D (24.0%; P=.003), and P+T (16.8%; P<.001). Notably, in patients treated with P+T+D, the pcr rate was higher in patients with estrogen receptor (ER) negative tumors (63.2%) compared with those with ER + tumors (27.3%). 35 Grade 3 through 5 toxicities in the P+T+D arm included neutropenia (45%), febrile neutropenia (8%), leukopenia (5%), diarrhea (6%), asthenia (2%), granulocytopenia (1%), rash (2%), irregular menstruation (1%), hypersensitivity reaction (1%), pyrexia (1%), fulminant hepatitis (1%), and death (1%). 35 In the TRYPHAENA trial, 225 women with HER2 + tumors were randomized to 1 of 3 arms: Arm A received FEC-100 (fluorouracil at 500 mg/m 2, epirubicin at 100 mg/m 2, and cyclophosphamide at 600 mg/m 2 ) for 3 cycles, followed by docetaxel (75 mg/m 2, escalating to 100 mg/m 2 if tolerated) plus P+T for 3 cycles; Arm B received FEC+P+T followed by docetaxel plus P+T for 3 cycles; and Arm C received docetaxel (100 mg/m 2 ) and carboplatin (area under the curve 6) with P+T for 6 cycles. The primary end point of this trial was cardiac safety. All grades of

4 594 Focused Review Jhaveri and Esteva Table 1 Summary of Phase II Trials of Pertzumab in Patients With HER2 + and HER2 MBC Trial Cohort Regimen and Schema N End Point Results Grade 3/4 Toxicities Cortes et al 27 HER2 + P followed by P+T; patients with MBC that previously progressed on trastuzumabbased therapy; up to 3 prior chemotherapy regimens Baselga et al 28 HER2 + P+T vs P alone; patients with MBC that progressed during trastuzumab-based therapy; up to 3 prior chemotherapy regimens Dieras et al 29 HER2 + P+T-DM1; patients with MBC treated with prior T, no prior T-DM1 or P allowed Gianni et al 30 HER2 Arm A P, 420 mg q3wk (840 mg loading dose) Arm B 1050 mg q3wk (840 mg loading dose); MBC treated with up to 2 prior lines of chemotherapy and had prior anthracyclines either in the adjuvant or metastatic setting Iyengar et al 46 HER2 + Pac, 80 mg/m 2 qwk P, 420 mg q3wk (840 mg loading dose) T, 6 mg/kg q3wk (8 mg/kg loading dose); HER2 + MBC treated with up to 1 prior line of therapy in the metastatic setting 29 (17 combinations) RR RR: 3.4% (17.6%) SD: 6.9% (23.5%) : mo (4.35) 66 RR and CBR RR: 24.2% CR: 7.6% SD: 25.8% CBR: 50.0% : 5.5 mo 67 (first-line: 22; relapsed: 45) Safety and tolerability pharmacokinetics RR First-line: 9/22 (41%) Relapsed: 19/45 (42%) 79 a Safety and RR Arm A (n=41) PR: 2 (4.9%) SD: 18 (44.0%) : mo Arm B (n=37) SD: 14 (38%) 67 at 6 mo 6-mo : 82% (95% CI, 62% 87%) CR: 11% PR: 46% SD: 25% Pertuzumab monotherapy: Diarrhea (3%), fatigue (6%), oropharyngeal pain (3%), abdominal pain (3%), femur fracture (3%), ocular icterus (3%), syncope (3%). Combination treatment: Diarrhea (6%), fatigue (6%), back pain (6%), pain (6%), osmotic demyelination syndrome (6%) Diarrhea (3%), rash (2%), asthenia (2%), pruritus (2%) Thrombocytopenia (11.9%), fatigue (9.0%), increased ALT (7.5%), increased AST (6.0%); 1 grade 5 pneumonia Arm A Diarrhea (7.3%), fatigue (2.4%), vomiting (2.4%) Arm B Diarrhea (5.4%) Fatigue (6%), diarrhea (3%), peripheral neuropathy (3%), AST/ ALT elevation (3%), dry skin (2%), nausea (2%), neutropenia (3%), handfoot syndrome (3%) a Only 78 patients were included in the intent-to-treat analysis, because 1 patient did not receive the study medication. Abbreviations: ALT, alanine aminotransferase; AST, aspartate transaminase; CBR, clinical benefit rate; CR, complete response; MBC, metastatic breast cancer; P, pertuzumab; Pac, paclitaxel;, progression-free survival; PR, partial response; RR, response rate; SD, stable disease; T, trastuzumab. LVSD were low across all 3 study arms: 5.6%, 4.0%, and 2.6% in Arms A, B, and C, respectively. Grade 3 or higher LVSD was observed in 2.7% of patients in Arm A but not in Arms B and C. pcr rates in the breast were 57.3%, 61.6%, and 66.2%, respectively. 36 Based on these exciting results, pertuzumab was granted FDA-accelerated approval in the neoadjuvant setting in Pertuzumab is the first anticancer drug approved before definitive surgery for a nonmetastatic solid tumor, validating pcr as an acceptable end point in oncology drug development. Phase III Trials in the Metastatic and Adjuvant Settings Pertuzumab was first approved in the metastatic setting by the FDA in 2012 based on the encouraging results of the Clinical Evaluation of Pertuzumab

5 Focused Review 595 Pertuzumab in HER+ Breast Cancer and Trastuzumab (CLEOPATRA) trial. 37 This trial assessed the safety and efficacy of pertuzumab plus trastuzumab plus docetaxel (N=406) compared with placebo plus trastuzumab plus docetaxel (N=402) as first-line treatment in patients with HER2 + MBC. The primary end point was. Median was improved in the pertuzumab arm compared with the placebo arm (18.5 vs 12.4 months; hazard ratio [HR], 0.62; 95% CI, ; P<.001). Notably, only 10% patients had received prior trastuzumab. In this exploratory analysis, the was 16.9 months in the pertuzumab arm compared with 10.4 months the placebo arm (HR, 0.62). A confirmatory overall survival analysis was reported for the CLEOPATRA trial, with an HR of 0.66 (P=.0008). 38 The median overall survival was not reached for the pertuzumab arm, and was 37.6 months in the placebo arm (Figure 1). All-grade toxicities in the placebo and pertuzumab arms, respectively, were diarrhea (46.3% vs 66.8%), rash (24.2% vs 33.7%), mucosal inflammation (19.9% vs 27.8%), febrile neutropenia (7.6% vs 13.8%), and dry skin (4.3% vs 10.6%). Grade 3 or higher events were notable for febrile neutropenia (7.6% vs 13.8%) and LVSD (2.8% vs 1.2%). 37 Pertuzumab is also being evaluated in the adjuvant setting in the Adjuvant Pertuzumab and Herceptin in Initial Therapy of Breast Cancer (APHIN- ITY) trial, the results of which are eagerly awaited. Several other phase II and III trials are currently ongoing and have been summarized in Table 2. Adverse Events of Special Interest Overall, pertuzumab is well tolerated with no need for dose adjustments. The most frequent grade 1/2 toxicities include diarrhea, nausea/vomiting, fatigue, and rash. Rash, diarrhea, and risk of cardiotoxicity are adverse events of special interest and are detailed herein. Skin rash with pertuzumab is perhaps related to its mechanism of action and is usually of papulopustular (acneiform) phenotype similar to that associated with EGFR inhibitors. A recent meta-analysis evaluating the incidence of rash included 1726 patients from 8 clinical trials in different tumor types, including different combination regimens and different dosing schedules of pertuzumab. 39 All-grade and grade 3/4 toxicities of rash were 24.6% and 1.1%, respectively. Pertuzumab had an increased relative risk of rash compared with controls (1.53; 95% CI, ; Overall Survival (%) Pertuzumab, trastuzumab, docetaxel Placebo, trastuzumab, docetaxel P = Time (mo) Number at Risk Pertuzumab Placebo Figure 1 Kaplan-Meier estimates of overall survival (intention-totreat population) in the CLEOPTARA trial. Patients are stratified by previous treatment status and region. Tick marks indicate censoring events. From 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 2013;14:464; with permission. P=.007). 39 Although no guidelines exist for the treatment of rash specifically from pertuzumab, the same prevention and treatment principles from EGFR inhibitors could be applied. Although the rash associated with pertuzumab is milder compared with that associated with EGFR inhibitors, early recognition and treatment may improve quality of life and adherence to therapy. 39 Diarrhea is usually grade 1/2 and is easily manageable. The increased incidence of diarrhea with pertuzumab could be a result of HER1:HER2 heterodimer inhibition. Rates of all-grade and grade 3/4 diarrhea ranged between 27.0% and 72.0% and 3.0% and 7.9%, respectively, among various studies of pertuzumab. 40 HER signaling pathways are involved in not only oncogenic cell proliferation and survival but also myocardial homeostasis, which justifies the concern regarding the undesirable risk of cardiotoxicity from anti-her2 agents. 40 A meta-analysis of randomized adjuvant trials of trastuzumab in HER2 + breast cancer demonstrated that the incidence of cardiotoxicity in these patients was 2.45-fold higher than in those not receiving trastuzumab. 41 Most LVSD was asymptomatic, and normalized with discontinuation of trastuzumab. 42 A pooled analysis of 598 patients treated with pertuzumab evaluated cardiac safety. 43 Specifically, 6.9%, 3.4%, and 6.5% of patients treated with pertuzumab

6 596 Focused Review Jhaveri and Esteva Table 2 Ongoing Trials of Pertuzumab in the Early-Stage or Metastatic Setting Trial (ClinicalTrials.gov identifier) N Phase Cohort APHINITY (NCT ) MARIANNE (NCT ) VELVET (NCT ) PERTAIN (NCT ) PERUSE (NCT ) PHEREXA (NCT ) HELENA (NCT ) 4800 III HER2 + early-stage breast cancer 1095 III First-line treatment of HER2 + MBC 225 II First-line treatment of HER2 + MBC 250 II ER + and HER2 + MBC in first-line setting 1500 III First-line treatment of HER2 + MBC 450 II Patients with HER2 + MBC that progressed on first-line T-based chemotherapy 478 Observational First-line setting after progression on adjuvant T Regimen and Schema Arm A: adjuvant chemotherapy + P + T x 1 y Arm B: adjuvant chemotherapy + T + placebo x 1 y Arm A: T + taxane Arm B: T-DM1 + P Arm C: T-DM1 + placebo P + T + vinorelbine Arm A: P + T + AI Arm B: T + AI P + T + taxane Arm A: T + C Arm B: T + P + C P + T Primary End Point IDFS Safety Abbreviations: AI, aromatase inhibitor; C, capecitabine; ER, estrogen receptor; IDFS, invasive disease-free survival; MBC, metastatic breast cancer; P, pertuzumab;, progression-free survival; T, trastuzumab. alone, pertuzumab in combination with a non anthracycline-containing cytotoxic agent, or trastuzumab developed asymptomatic LVSD, and only 0.3%, 1.1%, and 1.1% developed symptomatic heart failure, respectively. Nevertheless, detailed cardiac risk factors should be considered when deciding on treatment with pertuzumab. Predictive Biomarkers Identifying a biomarker of response is of utmost importance in the development of an effective targeted agent. Several candidate biomarkers were explored in the CLEOPATRA trial, including PI3KCA status, HER1 3, HER2 mrna expression, and serum cher2, albeit none could specifically predict response to pertuzumab. Key findings from this analysis showed that HER2 is the only marker that predicts response to anti-her2 therapy, and that the presence of a PI3KCA mutation conferred a poor prognosis for but that patients maintained a response to pertuzumab. In particular, patients with PI3KCA wild-type treated with pertuzumab versus placebo had a time to median of 21.8 versus 13.8 months (HR, 0.67) and those with PI3KCA mutations had a time to median of 12.5 versus 8.6 months (HR, 0.64). This has important implications, because future clinical trials could focus on combining agents against the PI3K pathway with anti-her2 based therapies. 44 The NeoSphere trial studied 16 different biomarkers, including HER2 expression, PI3KCA mutation, p95her2, and insulin-like growth factor receptor expression. Although these biomarkers were expressed differently in the ER + subgroups compared with the ER subgroups, none could predict response to pertuzumab. 35 In patients with ovarian cancer treated with pertuzumab, the presence of HER2 phosphorylation and low HER3 mrna expression were associated with improved efficacy. 31,45

7 Focused Review 597 Pertuzumab in HER+ Breast Cancer Conclusions and Future Perspectives A dual anti-her2 based treatment strategy with pertuzumab and trastuzumab results in a more comprehensive blockade of the HER signaling pathway than its single-agent counterparts. This combination has been FDA-approved in the metastatic setting and is the first to receive accelerated approval in the neoadjuvant setting. Results from the APHINITY study will establish the role of pertuzumab in the adjuvant setting. Although cardiotoxicity was an initial concern, no additive toxicity was noted with the combination of pertuzumab and trastuzumab. Despite these practice-changing advances that have transformed the landscape of HER2 + breast cancer, a few questions remain. Patients who will particularly benefit from pertuzumab, and the resistance mechanisms in those who will not, have yet to be identified. Furthermore, the subset of patients in whom chemotherapy can be omitted must be better identified. 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8 598 Focused Review Jhaveri and Esteva 28. 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 2010;28: Dieras V, Harbeck N, Albain K, et al. A phase Ib/II trial of trastuzumab-dm1 with pertuzumab for patients with HER2-positive, locally advanced or metastatic breast cancer: interim efficacy and safety results [abstracts]. Presented at the 2010 San Antonio Breast Cancer Symposium; December 8 12, 2010; San Antonio, Texas. 30. Gianni L, Llado A, Bianchi G, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010;28: Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhumab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 2006;24: de Bono JS, Bellmunt J, Attard G, et al. Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 2007;25: 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 2013;24: Jhaveri K, Dang C. Dual targeting of human epidermal growth factor receptor 2 (HER2) in neoadjuvant trials for operable HER2 positive (HER2+) disease. Curr Breast Cancer Rep 2013;5: Gianni L, Pienkowski T, Im YH, et al. 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Risk of rash with the anti-her2 dimerization antibody pertuzumab: a meta-analysis. Breast Cancer Res Treat 2012;135: Zagouri F, Sergentanis TN, Chrysikos D, et al. Pertuzumab in breast cancer: a systematic review. Clin Breast Cancer 2013;13: Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 2007;7: Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol 2006;24: Lenihan D, Suter T, Brammer M, et al. Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 2012;23: Baselga J, Cortes J, Im SA, et al. Biomarker analysis in CLEOPATRA: a phase III, placebo controlled study of pertuzumab in HER2- positive, first line metastatic breast cancer. Presented at the 2012 San Antonio Breast Cancer Symposium; December 4 8, 2012; San Antonio, Texas. 45. Makhija S, Amler LC, Glenn D, et al. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 2010;28: Iyengar N, Datko F, D Andrea G, et al. Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2- overexpressing metastatic breast cancer with cardiac biomarker data [abstract]. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10 14, 2013; San Antonio, Texas. Instructions for Completion To participate in this journal activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at node/43680; and 4) view/print certificate. After reading the article, you should be able to answer the following multiple- choice questions. Credit cannot be obtained for tests completed on paper. You must be a registered user on NCCN.org. If you are not registered on NCCN.org, click on New Member? Sign up here link on the left hand side of the Web site to register. Only one answer is correct for each question. Once you successfully answer all posttest questions you will be able to view and/or print your certificate. Software requirements: Internet Posttest Questions 1. In patients with HER2 + early-stage breast cancer, randomized neoadjuvant trials showed that the addition of pertuzumab to trastuzumab-based chemotherapy improves a. Pathologic complete response rates b. Overall survival c. Disease-free survival 2. Pertuzumab was first approved in the metastatic setting by the FDA in 2012 based on the encouraging results of which trial? a. TRYPHAENA b. NeoSphere c. CLEOPATRA d. APHINITY 3. The most frequently encountered and manageable adverse reactions associated with pertuzumab include: a. Diarrhea b. Nausea/vomiting c. Fatigue d. Rash e. Both a and d only f. All of the above