The successful development of trastuzumab validated the treatment approach of targeting HER2. The following three other anti-HER2 targeted agents have been subsequently developed: lapatinib, pertuzumab, and T-DM1. Even more recently, a better understanding of the mechanisms of resistance to anti-HER2 therapy has led to the development of novel therapeutic agents such as neratinib.

Adjuvant setting

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Trastuzumab is the first and so far the only targeted agent approved for the adjuvant treatment of patients with early-stage HER2-positive breast cancer.2,4 The benefit of adding trastuzumab to chemotherapy was evaluated in the following five main randomized studies: HERA,26–29 NSABP-B31 and NCCTG N9831,30–32 BCIRG 006,33,34 and FNCLCC-PACS 0435 trials. Among these studies, the joint analysis of two major North American Cooperative Group trials (NSABP B31 and NCCTG N9831) established the superiority of combining chemotherapy (doxorubicin plus cyclophosphamide followed by paclitaxel) with trastuzumab over the arms that did not contain the anti-HER2 agent, with the largest benefit shown with concurrent administration of taxanes and trastuzumab.36 Although with a more strict patient selection and close cardiac assessment the incidence of trastuzumab-related cardiac events has been reduced over the past years, cardiotoxicity remains a significant problem in clinical practice.37 Hence, trastuzumab was also developed and showed important efficacy results when combined with nonanthracycline-based regimens as in the BCIRG 006 trial.33,34 Therefore, in patients with cardiac risk factors, the use of this regimen can now be considered to overcome any potential cardiac side effects.38 The HERA trial confirmed that the standard duration of adjuvant trastuzumab is 12 months.28,29 A Cochrane review that included eight randomized control trials with 11,991 patients with HER2-positive tumors confirmed the superiority of trastuzumab-containing regimens in terms of both disease-free survival (DFS; hazard ratio [HR] 0.60; 95% confidence intervals [CIs] 0.50–0.71; P<0.0001) and overall survival (OS; HR 0.66; 95% CI 0.57–0.77; P<0.00001).39 Trastuzumab administration was associated with a significant increased risk of congestive heart failure (risk ratio [RR] 5.11; 90% CI 3.0–8.7; P<0.00001) and left ventricular ejection fraction decline (RR 1.8; 90% CI 1.4–2.5; P=0.0008).39 Nevertheless, in more recent studies, with a strict patient selection and close cardiac assessment, the risk of cardiac events with the use of trastuzumab-based regimens has decreased significantly.37 As shown in the HERA trial, the majority of cardiac events occurred during treatment and were reversible in ~80% of the cases.40

If trastuzumab is a monoclonal antibody that interferes with HER2 outside of the cell, lapatinib is an oral tyrosine kinase inhibitor that reversibly inhibits both HER1 and HER2 at the intracellular level.41 Lapatinib has been investigated in two trials of patients with HER2-positive early-stage breast cancer.13

The TEACH study compared lapatinib with placebo in 3,147 trastuzumab-naive patients and failed to show a statistically significant difference in DFS (HR 0.83; 95% CI 0.7–1.0; P=0.053).42,43 The central review of HER2 status revealed that only 79% of the randomized patients were actually HER2 positive. In this group of patients, an improved DFS was observed with the use of lapatinib (HR 0.82; 95% CI 0.7–1.0; P=0.04). Treatment-related grade 3–4 toxicities included diarrhea (6%), rash (5%), and hepatobiliary disorders (2%). Of note, in this trial, the level of HER2 positivity was specified according to the cutoff used for trastuzumab approval.

The ALTTO study investigated the efficacy of lapatinib alone, the sequence of trastuzumab followed by lapatinib, or the dual anti-HER2 blockade (lapatinib plus trastuzumab) as compared to standard trastuzumab for 1 year in 8,381 patients.44 At interim analysis, due to futility in demonstrating noninferiority of lapatinib versus trastuzumab, the lapatinib arm was closed and trastuzumab was offered to disease-free patients. As compared to trastuzumab alone, dual anti-HER2 blockade with lapatinib and trastuzumab was not associated with a significant improved DFS (HR 0.84; 95% CI 0.7–1.02; P=0.048) at the 0.025 significance level foreseen in the statistical analysis plan of the study. As compared with patients treated with trastuzumab, those who underwent lapatinib experienced more diarrhea, cutaneous rash, and hepatic toxicity.44

Pertuzumab is a monoclonal antibody that inhibits the HER2–HER3 heterodimerization.45 Pertuzumab had been demonstrated to significantly improve OS by 15.7 months in the metastatic setting when added to a regimen containing docetaxel plus trastuzumab.46 In the adjuvant setting, the Phase III APHINITY trial (NCT01358877) is currently evaluating the benefit of its addition to trastuzumab. A press release on March 1, 2017, confirmed a significant improvement in invasive DFS (iDFS) with the addition of pertuzumab to trastuzumab in patients with early-stage HER2-positive breast cancer. Full results of the study are expected to be reported at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in June.

T-DM1 is an anti-HER2 antibody–drug conjugate that combines emtansine (a cytotoxic agent) to trastuzumab to further increase the toxicity of the monoclonal antibody by targeting its activity directly to cancer cells.47 T-DM1 administration improves progression-free survival and OS in the metastatic setting in case of trastuzumab-resistant HER2-positive breast cancer.48,49 So far, no data are yet available in early-stage breast cancer, but the compound is actually being investigated in three Phase III trials.13 The KATHERINE study is comparing 14 cycles of adjuvant T-DM1 with trastuzumab in patients with residual disease following neoadjuvant chemotherapy combined with trastuzumab (NCT01772472). The KAITLIN trial is comparing the combination of T-DM1 and pertuzumab with a taxane after surgery and anthracycline-based chemotherapy (NCT01966471). Finally, the ATEMPT trial is comparing T-DM1 alone with paclitaxel plus trastuzumab followed by trastuzumab in stage I HER2-positive breast cancer (NCT01853748).

Neoadjuvant setting

The use of trastuzumab in the neoadjuvant setting of HER2-positive early-stage breast cancer has revolutionized the management of these patients leading to the clinical development of new anti-HER2 targeted therapies in this setting.

The first of the large Phase III trials that supported the combination of trastuzumab and anthracycline-based chemotherapy was the NOAH trial.50,51 The study included 235 patients with locally advanced breast cancers and confirmed a beneficial effect of adding trastuzumab to chemotherapy in improving both pathological complete response (pCR) rate and survival outcomes. Subsequent studies confirmed that the addition of trastuzumab as part of neoadjuvant therapy significantly increases pCR with no additional toxicity and is currently the standard of care in this setting.52 As shown in the ACOSOG Z1041 trial, trastuzumab should be administered concurrently to taxane-based chemotherapy, while the administration with anthracyclines should be avoided.53 More recently, the HannaH trial validated the subcutaneous route of administration of trastuzumab as an alternative option.54–56

The combination of lapatinib and trastuzumab has been evaluated in multiple randomized trials.57 When combining the results from the six randomized studies that investigated this combination, the dual blockade with trastuzumab and lapatinib was particularly active only in patients with hormone receptor-negative disease and treated with taxane chemotherapy. Nevertheless, the increased pCR rates with the use of this combination did not translate in survival benefit.58

Pertuzumab has been evaluated in two Phase II neoadjuvant trials (ie, NeoSphere and TRYPHAENA studies) in which patients received a combination of trastuzumab and chemotherapy with or without pertuzumab.59–61 As compared to the use of chemotherapy and trastuzumab alone, dual anti-HER2 blockade with pertuzumab and trastuzumab was associated with a significant improvement in pCR rate and a trend toward increased survival. Safety was confirmed with low rates of cardiac dysfunction in the investigational arms.


Neratinib is an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level.62,63 This small molecule has shown promising results in both the metastatic and early settings including when administered to patients who have previously received trastuzumab-based treatment.62,63

Adjuvant setting

Up to one-third of patients with HER2-positive early-stage breast cancer develop recurrent disease even when adequately treated.29,32 Hence, attempts to escalate the standard treatment with chemotherapy and 1 year of trastuzumab should be considered of crucial importance for this subgroup of patients. Among these attempts, extending the duration of trastuzumab up to 2 years and the combination of trastuzumab and bevacizumab or lapatinib have failed.13 The ExteNET trial challenged another way to escalate treatment in this subgroup of patients by using neratinib at the completion of standard chemotherapy and 1 year of trastuzumab.64

The ExteNET study was a randomized, double-blind, placebo-controlled, Phase III trial that included a total of 2,840 patients with HER2-positive stage I–III breast cancer who had previously completed 1 year of adjuvant trastuzumab. Eligible patients were randomized to an additional 12 months of treatment with oral neratinib (240 mg/day) or matching placebo. Randomization was performed in a 1:1 ratio and was generated with permuted blocks stratified by hormonal receptor status, nodal status, and trastuzumab mode of administration. A total of 31.5% of patients had tumors of ≤2 cm, 24% of them had node-negative disease, and 57% of the patients had hormone receptor-positive disease. After a median follow-up of 2 years, DFS was 93.9% in the neratinib arm and 91.6% in the placebo arm, favoring the use of tyrosine kinase inhibitor (HR 0.67; 95% CI 0.5–0.91; P=0.0091). The cumulative incidence of central nervous system recurrence was not different in the two arms (0.91% in the neratinib arm and 1.25% in the placebo arm, P=0.44), but longer follow-up is foreseen for acquiring better insight on this endpoint. The most common grade 3–4 adverse events in the neratinib arm included diarrhea (40%), vomiting (3%), and nausea (2%). Furthermore, patients reported to have an altered quality of life in the first month of treatment by neratinib followed by recovery toward baseline levels afterward.

Of note, in comparison to the HERA trial, which failed to show a DFS improvement by increasing anti-HER2 treatment duration from 1 to 2 years, the ExteNET study enrolled patients with lower incidence of lymph node involvement (24 vs 32%, respectively) and administered more commonly trastuzumab with concurrent chemotherapy (62 vs 0%, respectively) and more frequently the combination of anthracyclines and taxanes as adjuvant chemotherapy (68 vs 26%, respectively). It is noteworthy also the presence of 4.5 months between the end of trastuzumab and the initiation of neratinib in the ExteNET trial, while this delay was not present in the HERA trial for trastuzumab initiation after chemotherapy (89 days). The authors attributed the positive results of the ExteNET trial to the oncogenic addiction of HER2-positive tumors to the HER2 pathway with the recurrence of breast cancer being secondary to an acquired resistance to trastuzumab that can lead to a possible re-activation of the HER2 pathway after continuous inhibition. Adding neratinib would overcome this resistance especially in the absence of cross-resistance with trastuzumab. Interestingly, a prespecified subgroup analysis of iDFS according to hormone receptor status showed that neratinib provided greater benefit to patients with hormone receptor-positive breast cancer (HR 0.51; 95% CI 0.33–0.77; P=0.0013) than to those with hormone receptor-negative tumors (HR 0.93; 95% CI 0.6–1.43; P=0.74; P for interaction =0.054). Longer follow-up data from the study are awaited to better understand the potential role of neratinib in this setting.

In terms of toxicity, diarrhea is the most important side effect observed with the administration of neratinib (in the ExteNET trial, 55 and 40% of patients developed grade 1–2 and grade 3–4 diarrhea, respectively).64 To overcome this issue, intensive loperamide prophylaxis during the first month of treatment has been shown to effectively reduce the occurrence of diarrhea and improves the overall tolerability to the drug.65 An open-label Phase II study is currently assessing the incidence and severity of diarrhea when routine use of intensive loperamide prophylaxis is administered during the first month of neratinib therapy (NCT02400476).