Pertuzumab in the Treatment of HER2+ Breast Cancer

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 trastuzumab-based 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.

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 CE 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 http://education.nccn.org/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

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 antibody-dependent 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 (0.5-15.0 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.

In another phase I trial, 18 Japanese patients with advanced solid tumors22 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 al24 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 (PFS) 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/m2 of docetaxel and 1050 mg of pertuzumab every 3 weeks. Of 5 patients, 2 who received 100 mg/m2 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/m2 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/m2 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.27-30

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.31-33

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/m2, escalating if tolerated to 100 mg/m2 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/m2, epirubicin at 100 mg/m2, and cyclophosphamide at 600 mg/m2) for 3 cycles, followed by docetaxel (75 mg/m2, escalating to 100 mg/m2 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/m2) 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 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 2013. 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.

Table 1

Summary of Phase II Trials of Pertzumab in Patients With HER2+ and HER2- MBC

Table 1

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 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 PFS. Median PFS was improved in the pertuzumab arm compared with the placebo arm (18.5 vs 12.4 months; hazard ratio [HR], 0.62; 95% CI, 0.51-0.75; P<.001). Notably, only 10% patients had received prior trastuzumab. In this exploratory analysis, the PFS 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 (APHINITY) 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, 1.12-2.09; 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

Figure 1
Figure 1

Kaplan-Meier estimates of overall survival (intention-to-treat 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.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 4; 10.6004/jnccn.2014.0059

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 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.

Table 2

Ongoing Trials of Pertuzumab in the Early-Stage or Metastatic Setting

Table 2

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 PFS 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 PFS of 21.8 versus 13.8 months (HR, 0.67) and those with PI3KCA mutations had a time to median PFS 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

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. Lastly, with the expansion of the therapeutic armamentarium of anti-HER2 agents, identifying the right combination and sequencing of these various novel agents (eg, trastuzumab-DM1) will be imperative to optimize the clinical outcomes in these patients.

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.

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.

CE 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.

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Correspondence: Francisco J. Esteva, MD, PhD, New York University Cancer Institute, 160 East 34th Street, New York, NY 10016. E-mail: Francisco.Esteva@nyumc.org

Supplementary Materials

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    Kaplan-Meier estimates of overall survival (intention-to-treat 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.

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