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Keywords:

  • human epidermal growth factor receptor 2 (HER2)-positive;
  • metastatic;
  • breast;
  • cancer;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

The successful development of therapies targeting the human epidermal growth factor receptor 2 (HER2) has altered the natural progression of disease among patients with HER2-positive metastatic breast cancer. The monoclonal antibody trastuzumab was the first HER2-directed agent and it was associated with significantly improved outcomes for patients. Subsequently, other HER2-directed agents such as the monoclonal antibody pertuzumab, the tyrosine kinase receptor inhibitor lapatinib, and the immunoconjugate trastuzumab emtansine were developed to overcome resistance to trastuzumab and provide additional treatment options for patients. Recent data have demonstrated that the use of these HER2-directed agents improves outcomes. However, with the emergence of new HER2-targeted agents, the optimal sequencing of treatment remains unclear. Ongoing research is investigating new HER2 combinations, the role of sequencing, novel HER2-directed agents, and combinations with other targeted agents to overcome resistance. Cancer 2015;121:17–24. © 2014 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

Breast cancer is the most common cancer in women, and the second-leading cause of cancer-related mortality among women. Despite improvements in early detection and treatment, nearly 40,000 women in the United States were estimated to die of metastatic breast cancer in 2013.[1] Among patients diagnosed with breast cancer, approximately 20% will have overexpression of the human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase receptor that belongs to the epidermal growth factor receptor (EGFR) family. The normal function of HER2 is to regulate cell growth and survival, as well as adhesion, migration, differentiation, and other cellular responses. HER2 overexpression was historically associated with a poor clinical outcome.[2] However, the addition of HER2-directed therapy has significantly improved the outcomes for patients with HER2-positive metastatic breast cancer. This review focuses on the HER2-directed agents currently available in clinical practice for patients with metastatic disease, and the literature regarding optimal sequencing of these agents.

HER2-Directed Agents

Trastuzumab

Trastuzumab (Herceptin; Genentech, San Francisco, Calif), a humanized monoclonal antibody targeted against HER2, was to our knowledge the first HER2-directed agent available for use in the treatment of patients with metastatic HER2-positive breast cancer.[3] Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 receptor. Several mechanisms of action have been supported by the literature, including antibody-dependent, cell-mediated cytotoxicity; blocking HER2 cleavage; and inhibiting ligand-independent activation of downstream signaling pathways. The addition of trastuzumab to taxane-based chemotherapy significantly improved time to disease progression and overall survival (OS), leading to the approval of trastuzumab for the first-line treatment of patients with metastatic HER2-positive breast cancer by the US Food and Drug Administration (FDA) in 1998.[4] Although subjects on the control arm were allowed to cross over to trastuzumab at the time of disease progression, the median OS was improved from 20.3 months to 25.1 months. The main toxicity associated with trastuzumab has been an increased risk of symptomatic congestive heart failure or asymptomatic reductions in left ventricular ejection fraction, as well as a low risk of infusion reactions.

Despite the clinical success of trastuzumab as a single agent[5] or in combination with chemotherapy[6] or endocrine therapy[7] in treating first-line metastatic disease, patients still develop disease progression. Progression may be caused by the development of resistance to either trastuzumab or to chemotherapy. Continuing treatment with trastuzumab beyond disease progression in combination with an alternative chemotherapeutic agent has demonstrated benefit. The German Breast Group (GBG) 26/Breast International Group (BIG) 03-05 trial compared capecitabine with capecitabine in combination with trastuzumab in patients with metastatic breast cancer who had developed disease progression while receiving trastuzumab. Patients were permitted to receive up to 1 line of therapy in the metastatic setting. The continuation of trastuzumab demonstrated an improvement in the response rate and progression-free survival (PFS). An OS advantage was not observed in this trial, possibly due to its closure before the completion of accrual and the large number of patients in the control arm who received subsequent HER2-directed agents.[8] Currently, continued HER2-directed therapy is considered the standard of care.

Lapatinib

The development of tumor resistance to trastuzumab led to the development of alternative approaches to block signaling through the HER2 pathway. Lapatinib (Tykerb; GlaxoSmithKline, London, UK) is an orally active, reversible, dual tyrosine kinase inhibitor of EGFR (HER1) and HER2. Lapatinib was initially approved by the FDA in 2007 in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer whose disease progressed while receiving trastuzumab-based chemotherapy. The approval was based on results from a phase 3 clinical trial that demonstrated that the addition of lapatinib to capecitabine significantly improved the median time to disease progression when compared with capecitabine alone (8.4 months vs 4.4 months; P < .001).[9]

The MA.31 trialrandomized 652 patients between lapatinib and trastuzumab in combination with taxane-based therapy in the first-line setting. The median PFS was inferior in the lapatinib arm compared with the trastuzumab arm (8.8 months vs 11.4 months) (hazards ratio [HR], 1.33 [95% confidence interval (95% CI), 1.06-1.67]; P = .001).[10] Although this first-line study favored trastuzumab, lapatinib has also been studied in combination with trastuzumab in patients with trastuzumab-refractory metastatic breast cancer. Patients were heavily pretreated, receiving a median of 3 prior trastuzumab regimens for metastatic disease. The combination of trastuzumab and lapatinib demonstrated improved clinical benefit (24.7% vs 12.4%; P = .01) and PFS compared with lapatinib alone (12.1 weeks vs 8.1 weeks; P = 0.008).[11] Longer follow-up also demonstrated a median OS advantage of 4.5 months.[12] The most common adverse events observed with lapatinib were diarrhea, rash, nausea, vomiting, and fatigue. The incidence of cardiac toxicity in a pooled analysis of > 3600 patients treated with lapatinib on 44 clinical trials did not demonstrate a significant increase in cardiac events compared with control arms (1.6% vs 0.7%).[13]

Pertuzumab

Pertuzumab (Perjeta; Genentech) is a humanized monoclonal antibody that binds to the extracellular domain of the HER2 receptor at a different epitope than trastuzumab.[14] Activation of the HER2 pathway is initiated by dimerization of HER2 with other receptors in this family, such as HER3 and HER1. Although binding of pertuzumab to subdomain II of the HER2 receptor also stimulates antibody-dependent cell-mediated cytotoxicity, its synergy with trastuzumab has primarily been demonstrated through its ability to block the potential escape pathways through HER3/HER2 and HER2/HER2 dimerization.[9] The combination of trastuzumab and pertuzumab results in more comprehensive blockade of signaling through the HER2 pathway, resulting in enhanced antitumor activity in tumor models.[15]

As a single-agent after disease progression while receiving trastuzumab-based therapy, pertuzumab has shown limited clinical activity.[16] However, in a phase 2 trial of patients with HER2-positive metastatic breast cancer who developed disease progression while receiving prior trastuzumab-based therapy, the combination of pertuzumab and trastuzumab demonstrated an objective response rate of 24% and a clinical benefit rate of 50%. The median PFS was 5.5 months.[17] In the first-line setting, the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study compared the combination of trastuzumab, pertuzumab, and docetaxel with the use of trastuzumab and docetaxel alone. The primary endpoint of median PFS was improved from 12.4 months to 18.5 months by the addition of pertuzumab (HR, 0.62; P < .001).[18] OS was also found to be improved, with the median not yet reached in the pertuzumab arm at the time of last follow-up and an OS of 37.6 months reported in the placebo group (HR, 0.66; P = .0008).[19] It is interesting to note that approximately one-half of the patients in the study had received no prior adjuvant chemotherapy and only 10% had received prior adjuvant trastuzumab. Additional analysis of the CLEOPATRA trial demonstrated a similar magnitude of benefit among patients receiving pertuzumab, regardless of whether they had previously received (neo)adjuvant trastuzumab.[20]

Overall, pertuzumab has been reported to be well tolerated in clinical trials. The observed rates of grade 3 or greater (National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0) diarrhea and febrile neutropenia were higher in the CLEOPATRA study compared with the pertuzumab arm. The rate of asymptomatic or symptomatic left ventricular cardiac dysfunction was not increased by the addition of pertuzumab. Based on the results of the CLEOPATRA trial, pertuzumab in combination with trastuzumab and docetaxel was approved by the FDA in 2012 for the first-line treatment of patients with metastatic HER2-positive breast cancer. The National Comprehensive Cancer Network guidelines currently recommend the combination of pertuzumab, trastuzumab, and a taxane as the preferred regimen for the first-line treatment of patients with HER2-positive metastatic breast cancer.[21]

Trastuzumab Emtansine

Trastuzumab emtansine (T-DM1) (Kadcyla; Genentech) is an immunoconjugate that combines trastuzumab with the microtubule-targeting agent emtansine (DM1; a derivative of maytansine). Trastuzumab is stably linked to DM1 with a nonreducible thioether linker.[22] Previously, maytansines had been investigated as potent antimitotic agents, similar to vinca alkaloids, in the prevention of microtubule assembly. However, a poor therapeutic window limited their initial development. This was overcome by conjugation with the monoclonal antibody trastuzumab, thereby allowing for targeted intracellular drug delivery.[23]

Early-phase clinical trials of T-DM1 in patients with HER2-positive metastatic breast cancer whose disease progressed after treatment with HER2-directed therapy demonstrated promising clinical activity. A single-arm phase 2 trial of T-DM1 among 112 patients who had received a median of 5 prior regimens in the metastatic setting demonstrated an objective response rate of 25.9% and a median PFS of 4.6 months.[24] In contrast to this study, in which approximately 60% of patients had received lapatinib, a phase 2 trial performed among 110 patients who had received a median of 8.5 prior regimens including lapatinib demonstrated an objective response rate of 34.5% and a median PFS of 6.9 months.[25]

The EMILIA studywas a randomized phase 3 trial comparing T-DM1 with lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer who had received prior treatment with trastuzumab in combination with a taxane. Approximately 61% of patients in the EMILIA trial had received no lines or 1 line of therapy in the metastatic setting. Approximately 84% of patients had received trastuzumab in either the metastatic setting, early-stage setting, or both; 16% of patients had received trastuzumab only in the early-stage setting. The primary endpoint of median PFS was 3.2 months longer in the group receiving T-DM1 (9.6 months vs 6.4 months; P < .001). OS was also found to be significantly better with T-DM1 compared with lapatinib plus capecitabine (30.9 months vs 25.1 months; P < .001).[26] Based on the positive results of the EMILIA trial, T-DM1 was approved by the FDA in 2013 for the treatment of patients with metastatic HER2-positive breast cancer who received prior therapy with trastuzumab in combination with a taxane.

The results from the randomized phase 3 Th3RESA trial comparing T-DM1 with a treatment of the physician's choice were recently presented. The 602 patients included in the trial had received a median of 4 prior chemotherapy regimens in the metastatic setting, including trastuzumab and lapatinib. The median PFS was significantly higher with T-DM1 compared with a treatment of the physician's choice (6.2 months vs 3.3 months) (HR, 0.53 [95% CI, 0.42-0.66]; P < .0001).[27] Based on the promising results observed in patients who had received prior treatment in the metastatic setting, a randomized phase 2 trial comparing T-DM1 with docetaxel plus trastuzumab was performed among 137 patients in the first-line setting. The median PFS was significantly higher with T-DM1 compared with docetaxel plus trastuzumab (14.2 months vs 9.2 months; HR, 0.59 [95% CI, 0.36-0.97]).[28] MARIANNE, a phase 3 trial comparing T-DM1, T-DM1 plus pertuzumab, and trastuzumab plus a taxane in the first-line treatment of patients with metastatic HER2 positive breast cancer, is currently ongoing.

Intracellular delivery of the cytotoxic agent DM1 to HER2-overexpressing cells minimized the toxicity noted in other tissues. The most common adverse events associated with T-DM1 were thrombocytopenia and an elevation of liver enzymes. The majority of patients were able to continue on treatment after dose modification for grade 3 or 4 events. Cardiac toxicity was comparable to treatment with trastuzumab.

Special Consideration for Patients With Hormone Receptor-Positive, HER2-Positive Disease

For patients whose tumors are hormone receptor (estrogen receptor and progesterone receptor) -positive and HER2-positive, non–chemotherapy-based approaches with dual targeting of these pathways have also been studied. The addition of trastuzumab to first-line therapy with anastrozole has demonstrated improved PFS (4.8 months vs 2.4 months; P = .0016).[7] Likewise, the addition of lapatinib to first-line therapy with letrozole also improved clinical benefit and PFS (8.2 months vs 3.0 months; P = .019).[29] The addition of HER2-directed therapy with either trastuzumab or lapatinib to endocrine therapy should be considered as a lower-toxicity first-line treatment for patients without symptomatic metastases or visceral crisis.[30] Although the combination of lapatinib plus letrozole offers the advantage of being an oral regimen, it is also associated with increased gastrointestinal toxicity due to the increased incidence of diarrhea.

Optimal Sequencing of HER2-Directed Agents

The incorporation of HER2-directed therapy has led to significant improvements in response rates and OS for patients with HER2-positive metastatic breast cancer (Fig. 1). The CLEOPATRA trial, in which patients received dual antibody therapy with trastuzumab and pertuzumab in combination with docetaxel, demonstrated a superior median PFS and OS, thereby establishing this as the current standard of care for the first-line treatment of patients with HER2-positive metastatic breast cancer (Table 1).[18, 19] Preliminary reports from ongoing studies evaluating the dual antibody combination with paclitaxel suggest this is a safe and effective combination as well.[31]

image

Figure 1. Schematic for human epidermal growth factor receptor 2 (HER2)-directed agents is shown. HER2 is a transmembrane tyrosine kinase receptor. Homodimerization or heterodimerization leads to phosphorylation of the intracellular tyrosine kinase domain, inducing cell proliferation and survival. Once phosphorylated, the HER2 receptor activates phosphatidylinositol 3-kinase (PI3KK), which then leads to the activation of the enzyme Ak transforming factor (AKT), inducing cell survival. HER2 also activates the rat sarcoma (RAS) enzyme, which then activates mitogen-activated protein kinase (MAPK), inducing cell proliferation. Trastuzumab is a monoclonal antibody directed against HER2. Pertuzumab is a humanized monoclonal antibody that binds to the dimerization domain of the HER2 receptor at a different epitope than trastuzumab. T-DM1 is an immunoconjugate that combines trastuzumab with the microtubule-targeting agent emtansine. Lapatinib and neratinib are oral tyrosine kinase inhibitors of epidermal growth factor receptor (HER1) and HER2. BKM120 is an oral PI3K inhibitor. MK-2206 is an oral selective inhibitor of AKT. Everolimus is an orally available mammalian target of rapamycin (mTOR) inhibitor.

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Table 1. Trials of Novel HER2-Directed Agents in the First-Line Setting
TrialDrugsNo. of SubjectsNeoadjuvant or Adjuvant TrastuzumabPFS, MonthsHR (95% CI)
  1. Abbreviations: 95% CI, 95% confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazards ratio; PFS, progression-free survival.

CLEOPATRA[18]Docetaxel plus trastuzumab40610.1%12.40.62 (0.51-0.75) P<.001
40211.7%18.5
Docetaxel plus trastuzumab plus pertuzumab   
MA.31[10]Taxane plus trastuzumab31818%11.41.33 (1.06-1.67) P=.001
Taxane plus lapatinib31818%8.8
Hurvitz[28]Trastuzumab emtansine6717.9%14.20.59 (0.36-0.97)
Docetaxel plus trastuzumab7027.1%9.2

Several ongoing clinical trials will potentially impact the optimal sequencing of therapy. The MARIANNE trial compares T-DM1, T-DM1 plus pertuzumab, and trastuzumab plus a taxane in the first-line setting. This study was designed before the results of the CLEOPATRA study, and therefore the control arm of a taxane plus trastuzumab does not contain pertuzumab. Although it is exciting to consider a nontraditional chemotherapy approach for the first-line treatment of patients with HER2-positive breast cancer, many questions are likely to result from this study. Comparisons of outcome between patients treated on the T-DM1 and T-DM1 plus pertuzumab arms with the currently preferred first-line regimen of docetaxel, trastuzumab, and pertuzumab will be challenging. Furthermore, if T-DM1 alone is determined to be the best approach, the role of second-line pertuzumab and trastuzumab with chemotherapy combinations will also need to be evaluated. Currently, there are limited data regarding the use of pertuzumab outside of the first-line setting and reimbursement may be challenging.[17]

Multiple treatment options are available at the time of disease progression after first-line therapy (Table 2).[8, 9, 24] Before the FDA approval of T-DM1, patients typically received subsequent lines of chemotherapy in combination with trastuzumab or capecitabine and lapatinib in combination. Decisions regarding the sequencing of therapy typically took multiple variables into account such as prior toxicities, ease of scheduling, and patient preference. The EMILIA trial clearly demonstrated that T-DM1 was superior and less toxic than the combination of capecitabine and lapatinib. The National Comprehensive Cancer Network currently recommends that T-DM1 should be the preferred second-line regimen after disease progression occurs during treatment with pertuzumab, trastuzumab, and taxane-based therapy.

Table 2. Trials of HER2-Directed Therapy in the Second-Line Setting and Beyond
TrialTreatmentNo. of SubjectsPrior TherapyPFS, MonthsHR (95% CI)
  1. Abbreviations: 95% CI, 95% confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazards ratio; NR, not reported; PFS, progression-free survival; T-DM1, trastuzumab emtansine.

EMILIA[26]T-DM149561%, 0-1 lines9.60.65 (0.55-0.77) P<.001
Lapatinib plus capecitabine49639%, >1 line6.4
TH3RESA[27]T-DM1602 (2:1)Median of 4 prior lines6.20.53 (0.42-0.66) P<.0001
Treatment of physicians' choice3.3
Burris 2011[24]T-DM1112Median of 5 prior lines4.6NR
Krop[25]T-DM1110Median of 8.5 prior lines6.9NR
BOLERO-3[46]Vinorelbine plus trastuzumab plus everolimus284Median of 3-4 prior lines7.00.78 (0.65-0.95) P = .0067
Vinorelbine plus trastuzumab2855.8
Von Minckwitz 2011[8]Capecitabine plus trastuzumab781 prior line of therapy allowed8.20.69 (0.48-0.97) P = .0338
Capecitabine785.6
Geyer 2006[9]Capecitabine plus lapatinib163Prior taxane, anthracyline, trastuzumab required8.40.49 (0.34-0.71) P<.001
Capecitabine1614.1
Blackwell[12]Lapatinib plus trastuzumab148Median of 3 prior lines12 wk0.74 (0.58-0.94) P = .011
Lapatinib1488.1 wk
Baselga[17]Pertuzumab plus trastuzumab66Mean duration of prior trastuzumab: 16.2 mo5.5NR

To the best of our knowledge, there are currently no data regarding the role of continued trastuzumab after disease progression occurs while patients are receiving treatment with a taxane with pertuzumab and trastuzumab-based therapy in the first-line setting and T-DM1 in the second-line setting. Extrapolation from prior studies suggests that patients should continue to receive HER2-directed therapy.[8] However, more research is needed to understand the mechanisms of resistance to these newer HER2-targeted agents and to better define the best approach in this setting. The optimal sequencing for later lines is also unclear. Trastuzumab has been combined with several cytotoxic agents such as vinorelbine, capecitabine, eribulin, liposomal doxorubicin, and gemcitabine in clinical trials, and has demonstrated clinical efficacy.[32-35] Patients who prefer an oral regimen could opt for therapy with capecitabine plus lapatinib. A nonchemotherapy option would include lapatinib with trastuzumab.[11] In the absence of evidence establishing the optimal sequence of therapy in the third-line or later setting, patients and their physicians should weigh their options and the potential side effects of therapy.

New HER2-Directed Agents Currently in Development

Neratinib (Pfizer, New York, NY) and afatinib are orally available, irreversible, tyrosine kinase inhibitors of EGFR (HER1) and HER2 receptors. Early-phase clinical trials have demonstrated their clinical activity as a single agent.[36-38] Neratinib has also been combined with trastuzumab, paclitaxel, and vinorelbine with promising results, with response rates of 38% to 41% reported.[39, 40] Diarrhea has been the most frequently observed toxicity, and has been managed with antidiarrheal medications and dose reductions. A phase 2 trial comparing neratinib monotherapy with lapatinib plus capecitabine was unable to demonstrate the noninferiority of neratinib. The median PFS was 4.5 months on the neratinib arm and 6.8 months on the lapatinib plus capecitabine arm (HR, 1.19; 95% CI, 0.89-1.60).[37] There are several ongoing clinical trials with afatinib and neratinib, including a phase 3 study comparing the combination of neratinib and capecitabine with lapatinib and capecitabine.

Other novel HER2-directed therapies currently in development include antibodies directed toward HER3 as single agents and in combination with HER2-directed therapy, radioimmunotherapy with trastuzumab, and vaccines targeting the HER2 protein.

The majority of the focus of drug development for patients with HER2-positive breast cancer has now shifted to combinations targeting the mechanisms of resistance. Resistance to trastuzumab-based therapy affects most patients with metastatic HER2-positive breast cancer. Activation of the phosphatidylinositol 3-kinase (PI3K)/Ak transforming factor (AKT)/mammalian target of rapamycin (mTOR) pathway is common in patients with HER2-positive breast cancer. The Cancer Genome Atlas Network reported that 39% of patients with HER2-positive breast cancer harbor a PIK3CA mutation.[41] Furthermore, activation of this pathway has been associated with resistance to HER2-based therapies[42] and agents targeting this pathway can reverse this resistance in preclinical models.[43]

Clinical data are emerging to support these laboratory findings. In the CLEOPATRA trial, PIK3CA mutations were associated with a poorer prognosis in both treatment arms.[18] The addition of everolimus, an orally available mTOR inhibitor, to HER2-directed therapy demonstrated encouraging activity in both phase 1 and 2 clinical trials.[44, 45] A randomized phase 3 clinical trial (BOLERO-3) evaluating the addition of everolimus to trastuzumab plus vinorelbine in heavily pretreated patients with HER2-positive metastatic breast cancer demonstrated significant improvements in PFS (7.0 months vs 5.8 months; P < .01), although this was somewhat modest in terms of clinical benefit. Longer follow-up is needed to evaluate OS in this trial.[46] BOLERO-1 is an ongoing trial evaluating the addition of everolimus to first-line therapy with trastuzumab and paclitaxel. Whether mTOR inhibition will be more important in overcoming acquired resistance to trastuzumab or will play a role in the first-line setting will be important to define from these studies.

AKT and PI3K inhibitors also are being studied in combination with trastuzumab and lapatinib. A phase 1 study of MK-2206, an oral selective inhibitor of AKT, in combination with trastuzumab demonstrated that the combination was safe and clinical activity was observed in heavily pretreated patients.[47] An ongoing phase 1 study of MK-2206 in combination with lapatinib was also recently completed (NCT01245205). BKM120 (buparlisib) is an oral PI3K inhibitor that has been studied in a phase Ib study in combination with trastuzumab. The combination was tolerable at the single-agent maximum tolerated dose of buparlisib and clinical activity was observed in patients with trastuzumab-resistant disease.[48] Multiple other PI3K inhibitors or dual PI3K/mTOR inhibitors also are being studied in combination with trastuzumab, lapatinib, and T-DM1.[49]9

Conclusions and Future Directions

The development of HER2-directed agents, including trastuzumab, pertuzumab, lapatinib, and T-DM1, has significantly improved long-term outcomes for patients with HER2-positive metastatic breast cancer. Currently, trastuzumab, pertuzumab, and taxane-based therapy are recommended for first-line treatment. T-DM1 is the preferred regimen in the second-line setting. In the third-line setting and beyond, several options are recommended, including lapatinib in combination with capecitabine or trastuzumab or other trastuzumab-based combinations with chemotherapy (Figure 2). Novel HER2-directed agents are in various stages of clinical development. Results from ongoing clinical trials of currently available agents and novel agents could impact the optimal sequencing of HER2-directed therapies in the metastatic setting (Table 3). The evolving use of HER2-directed therapies in the setting of early-stage disease, such as the recent FDA approval of pertuzumab for neoadjuvant therapy, could also impact the choice of first-line therapy in the metastatic setting.

image

Figure 2. Sequencing of Her2-Directed Therapy for Advanced Breast Cancer.

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Table 3. Ongoing Randomized Trials of HER2-Directed Therapy for Patients With Advanced Breast Cancer
TrialTreatmentEstimated EnrollmentSetting
  1. Abbreviations: HER2, human epidermal growth factor receptor 2; T-DM1, trastuzumab emtansine.

MARIANNET-DM1 plus pertuzumab1095First-line
T-DM1
Taxane plus trastuzumab
BOLERO-1Paclitaxel plus trastuzumab  ± everolimus719First-line
LUX-Breast 1Vinorelbine plus afatinib508Second-line
Vinorelbine plus trastuzumab
PUMACapecitabine plus neratinib600Third-line
Capecitabine plus lapatinib

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICT OF INTEREST DISCLOSURES
  6. REFERENCES
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