Pertuzumab and Its Accelerated Approval: Evolving Treatment Paradigms and New Challenges in the Management of HER2-Positive Breast Cancer

March 15, 2014

This article discusses the development of pertuzumab to date, with a particular focus on the accelerated approval decision. We highlight the need to identify reliable biomarkers of sensitivity and resistance to HER2-targeted therapy, which would make possible the individualization of treatment for patients with HER2-positive breast cancer.

The addition of trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), to standard chemotherapy in patients with HER2-positive breast cancer has resulted in major improvements in breast cancer outcomes, including improved survival, in both the adjuvant and metastatic settings. However, some patients experience disease relapse despite adjuvant trastuzumab-containing therapy, and resistance to trastuzumab develops in the majority of patients in the metastatic setting. An understanding of the molecular mechanisms underlying trastuzumab resistance has aided the development of novel HER2-targeted therapies. In June 2012, the HER2 dimerization inhibitor pertuzumab was approved by the US Food and Drug Administration (FDA) for use with chemotherapy and trastuzumab in the first-line treatment of metastatic HER2-positive breast cancer. In September 2013, accelerated approval was granted for use of pertuzumab in the neoadjuvant setting, representing a landmark decision by the FDA. This article discusses the development of pertuzumab to date, with a particular focus on the accelerated approval decision. We highlight the need to identify reliable biomarkers of sensitivity and resistance to HER2-targeted therapy, which would make possible the individualization of treatment for patients with HER2-positive breast cancer.

Background

Amplification and/or overexpression of the human epidermal growth factor receptor 2 (HER2) gene (ERBB2) is present in approximately 15% to 20% of breast cancers and was historically associated with aggressive disease and a poor prognosis.[1] HER2 is a member of the epidermal growth factor receptor (EGFR or ErbB) family of receptor tyrosine kinases and is a key target for targeted therapy.[1,2] The humanized monoclonal antibody trastuzumab was approved by the US Food and Drug Administration (FDA) for use in the metastatic setting in 1998 based on improved clinical benefit and overall survival (OS).[3] Further investigation led to approval in the adjuvant setting in 2006; the combination of trastuzumab and chemotherapy reflected a new standard of care for patients with HER2-positive early breast cancer.[4]

Despite significant progress in the management of HER2-positive breast cancer, resistance to trastuzumab is a common clinical dilemma. Approximately 15% of women treated with adjuvant chemotherapy and trastuzumab experience disease relapse, and the majority of patients with metastatic breast cancer develop resistance to trastuzumab within 1 year of starting treatment.[5] In addition, other patients exhibit de novo resistance to trastuzumab where the disease is unresponsive to treatment from the time trastuzumab is first introduced. Continuation of trastuzumab beyond disease progression can result in clinical benefit for some patients when combined with a chemotherapy or another HER2-targeted therapy.[6,7] However, the need to elucidate the molecular mechanisms underlying trastuzumab resistance has become evident.

Dysregulation of downstream signaling pathways; alternative receptor tyrosine kinase signaling; and accumulation of the truncated kinase, active p95-HER2, have all been implicated in trastuzumab resistance.[8] Based on these observations and extensive preclinical and clinical development, three additional HER2-targeted therapies are now available for patients with HER2-positive breast cancer. These include the dual tyrosine kinase inhibitor lapatinib, the antibody chemotherapy conjugate ado-trastuzumab emtansine (T-DM1) and the HER2/HER3 dimerization inhibitor pertuzumab. Pertuzumab, which is the focus of this review, is approved for treatment of patients with HER2-positive metastatic breast cancer, and it recently received accelerated approval for use in the neoadjuvant setting.

Mechanism of Action

There are four transmembrane tyrosine kinase receptors in the HER2 family: epidermal growth factor receptor (EGFR/HER1/ErbB1), HER2 (HER2/neu or ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Each receptor is comprised of three domains: an extracellular domain, an alpha helical transmembrane domain, and an intracellular protein kinase domain. The extracellular domain consists of four further subdomains, including subdomain I (ligand-binding site), subdomain II (dimerization site), and subdomain IV (site for binding of trastuzumab).[9] The extracellular domain of HER2 has a constitutively open conformation such that it is permanently activated and ready to form homodimers (HER2/HER2) or heterodimers (HER2/HER3) when ligands engage other ErbB protein family surface receptors. This potentiates a series of intracellular events that control cell growth and proliferation.[10] Ligands may bind EGFR alone (eg, EGF), both EGFR and HER4 (eg, betacellulin), HER3 and HER4, or HER4 alone (eg, neuregulins such as heregulin). There is no known ligand for HER2.[11]

Trastuzumab binds to extracellular subdomain IV of the HER2 receptor, inhibits downstream signaling, and stimulates antibody-dependent cell-mediated cytotoxicity (ADCC).[9] It is becoming increasingly recognized that trastuzumab may also harness the immune system against HER2.[12] Pertuzumab is a humanized monoclonal antibody that binds to extracellular subdomain II of the HER2 receptor, preventing HER2 heterodimerization with HER1, HER3, and HER4.[13] Its mechanism of action is complementary to that of trastuzumab, in that it inhibits HER2/HER3 dimerization, thereby inhibiting HER2-mediated cell signaling via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (Figure 1).[2] Pertuzumab can also trigger ADCC independent of trastuzumab, and with comparable efficacy.[14]

Preclinical Development

It was observed in in vitro studies that pertuzumab inhibits heregulin-induced activation of the PI3K cell survival pathway, whereas trastuzumab does not.[2] This implied that pertuzumab was more effective than trastuzumab at preventing ligand-activated HER2 signaling. Activity of single-agent pertuzumab in breast, prostate, ovarian, and lung cancer cell lines was observed in human tumor xenograft models in mice.[2] The combination of pertuzumab and trastuzumab was found to have a greatly enhanced antitumor effect in HER2-positive breast cancer in in vitro studies as well as in xenografts, compared with either trastuzumab or pertuzumab monotherapy.[14,15] However, an association was noted, in mice, between dilated cardiomyopathy and cardiac restriction of HER2, prompting caution as clinical studies involving combination therapy were developed.[16]

Pharmacokinetics

In a phase I study, pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 to 25 mg/kg. In the dose range of 2 to 15 mg/kg, the mean elimination half-life was 18.9 +/− 8 days, and the mean clearance was 3.42mL/kg/day. At doses up to 15mg/kg, the maximum tolerated dose of pertuzumab was not reached.[17] Results from a phase Ib trial suggested that a loading dose of 840 mg IV (followed by 420 mg every 3 weeks) achieved a steady-state trough and peak concentration by the second cycle of treatment.[18] Pharmacokinetic analysis from the CLEOPATRA (Clinical Evaluation of Pertuzumab And TRAstuzumab) trial indicated that docetaxel and trastuzumab did not affect the pharmacokinetics of pertuzumab.[19]

Clinical Development

Advanced breast cancer

Pertuzumab has been evaluated in phase I clinical studies as monotherapy, in combination with other HER2-targeted agents, and with chemotherapy (eg, docetaxel, paclitaxel, and capecitabine). In a dose-escalation study (n = 21), the most common adverse events (AEs) were asthenia, vomiting, diarrhea, and an acneiform rash.[17] In a phase II study, the combination of pertuzumab and trastuzumab achieved a clinical benefit rate of 50% in patients with HER2-positive disease whose disease had progressed on prior trastuzumab-containing therapy.[6] To confirm that this result was due to dual HER2-targeted therapy, a third cohort (n = 29) of patients was recruited to receive pertuzumab monotherapy. The median progression-free survival (PFS) was 17.4 weeks for those patients who received dual therapy vs 7.1 weeks for those who received monotherapy. The general conclusion from these phase II trials was that pertuzumab was synergistic with trastuzumab and was associated with acceptable toxicity.

Given the promising phase II results, the phase III CLEOPATRA trial randomly assigned 808 treatment-naive patients with HER2-positive metastatic breast cancer to treatment with docetaxel and trastuzumab, plus either placebo or pertuzumab.[20] The primary endpoint of the trial was PFS; secondary endpoints were OS, overall response rate, and safety. The median PFS was 12.4 months in the placebo arm and 18.5 months in the pertuzumab arm (P < .001). Differences in AEs between the placebo and pertuzumab arms were as follows: diarrhea, 46.3% vs 66.8%; rash, 24.2% vs 33.7%; mucositis, 19.9% vs 27.8%; febrile neutropenia, 7.6% vs 13.8%; and dry skin, 4.3% vs 10.6%. The majority of the toxicities were grade 1 or 2, and left ventricular systolic dysfunction (LVSD) of grade III or higher was noted in 1.2% of patients in the placebo arm compared with 2.8% of patients in the pertuzumab arm. The second interim OS analysis confirmed that docetaxel/trastuzumab/pertuzumab significantly improved OS in patients with HER2-positive metastatic breast cancer compared with those who did not receive pertuzumab.[21] Median OS was 37.6 months (95% confidence interval [CI], 34.3–NE [not estimable]) in the placebo arm and has not been reached (95% CI, 42.4–NE) in the pertuzumab arm (hazard ratio [HR], 0.66; 95% CI, 0.52–0.84; P = .0008).

The pivotal CLEOPATRA trial led to FDA approval of the investigational regimen and established a new standard of care in the first-line metastatic breast cancer setting. It is likely, however, that not all patients need dual HER2-targeted therapy combined with chemotherapy as initial therapy. Treatment decisions should also reflect the performance status of the patient, comorbidities, disease burden, and presence or absence of visceral disease (Figure 2). Thus, the administration of pertuzumab and trastuzumab without chemotherapy may be considered in the first-line setting. Based on the phase II trial described above,[6] patients who experience disease progression after trastuzumab-based therapy without pertuzumab may consider pertuzumab plus trastuzumab (with or without chemotherapy) beyond the first-line setting. However, further research is needed regarding the optimal sequencing of HER2-targeted therapies.

In order to further define the role of pertuzumab in patients with HER2-positive metastatic breast cancer, a number of studies are ongoing or in clinical development. These are investigating the combination of pertuzumab with standard chemotherapies, endocrine therapies, and other HER2-targeted therapies (Table 1). Because the combination of anastrozole and trastuzumab resulted in a PFS benefit in patients with hormone receptor (HR)-positive and HER2-positive metastatic breast cancer, the PERTAIN (PERtuzumab Trastuzumab Aromatase Inhibitors) study will assess whether adding pertuzumab to this regimen will result in further benefit. An exciting combination that is now being investigated is T-DM1 and pertuzumab, with interim reports indicating encouraging antitumor activity and an acceptable toxicity profile.[22] (T-DM1 was approved by the FDA in February 2013 as a single agent for treatment of patients with HER2-positive MBC previously exposed to trastuzumab.[23]) This type of approach, combining dual HER2-targeted therapies, may result in significant efficacy with minimal toxicity for patients, compared with chemotherapy-based approaches.

Neoadjuvant clinical trials

The results of studies performed in the metastatic setting have significantly contributed to the design of neoadjuvant studies of pertuzumab in patients with HER2-positive disease. NeoSphere (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) randomly assigned 417 women to receive trastuzumab/docetaxel, pertuzumab/trastuzumab/docetaxel, pertuzumab/trastuzumab, or pertuzumab/docetaxel.[24] Patients treated with pertuzumab/trastuzumab/docetaxel achieved a pathologic complete response (pCR) rate of 45.8%, compared with a pCR rate of 29% in patients who received trastuzumab/docetaxel, or a rate of 24% in those who received pertuzumab/docetaxel. Interestingly, 16.8% of patients who received pertuzumab/trastuzumab experienced a pCR, implying that chemotherapy could in the future potentially be omitted in a subgroup of patients. Further subgroup analysis in patients with HR-negative disease noted a pCR rate of 63% in those treated with pertuzumab/trastuzumab/docetaxel, and a rate of 27% in those treated with pertuzumab/trastuzumab alone. Neutropenia and febrile neutropenia were the most common serious AEs (SAEs). There was no additional cardiotoxicity when pertuzumab was added to trastuzumab, and no patient had a left ventricular ejection fraction decrease to less than 40% at any time during the study.

TRYPHAENA (Trastuzumab Plus Pertuzumab in Neoadjuvant HER2-Positive Breast Cancer) was a multicenter, randomized phase II study of neoadjuvant trastuzumab and pertuzumab given concurrently or sequentially with anthracycline-based or non–anthracycline-based chemotherapy, in women with stage II/III HER2-positive breast cancer (N = 225).[25] Patients in arms A and B received 3 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC), with patients in arm A also receiving concurrent pertuzumab and trastuzumab. Both arms then received 3 cycles of docetaxel, pertuzumab, and trastuzumab. Patients in arm C received 6 cycles of docetaxel and carboplatin with concurrent pertuzumab and trastuzumab. Surgery was scheduled after the completion of chemotherapy, and trastuzumab was continued for 1 year. The most frequently reported SAEs were neutropenia, febrile neutropenia, and leukopenia; the incidence of SAEs was highest in patients in arm C (35.5%), followed by arm A (27.8%) and arm B (20.0%). Grade 3 or higher symptomatic LVSD was noted in 2.7% of women overall, and diarrhea was the most common AE. The pCR rates (in breast) were similar across all treatment arms, ranging from 57% to 66%. Overall, these neoadjuvant phase II studies demonstrated that dual HER2-targeted therapy was superior to single-agent pertuzumab or trastuzumab, with minimal additional cardiotoxicity; the results highlighted the importance of studies investigating predictive biomarkers of response in this setting (Table 2). In addition, these findings confirm the results that were seen in the metastatic setting (CLEOPATRA trial).

Accelerated Approval

Based on the neoadjuvant trials just described, the FDA granted accelerated approval in late 2013 to pertuzumab for use preoperatively in combination with a complete chemotherapy regimen for patients with HER2-positive breast cancer.[26] Accelerated approval allows drugs to be approved based on a surrogate or intermediate clinical endpoint, in situations where the drug is intended for use for serious conditions and fills an unmet medical need. The rationale for accelerated approval is that it makes important drugs available to patients more quickly than in the past. Confirmatory trials are required to verify clinical benefit (eg, by showing an OS benefit), and if results are positive, they may lead to full approval of the agent.

The trials submitted to the FDA to support the neoadjuvant indication for pertuzumab included NeoSphere, TRYPHAENA (supportive neoadjuvant) and CLEOPATRA (supportive metastatic). Per the label, pertuzumab may be administered for 3 to 6 cycles neoadjuvantly to patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (> 2 cm or node-positive) with one of three chemotherapy backbones: preoperative pertuzumab/trastuzumab/docetaxel × 4, followed by FEC × 3 postoperatively; preoperative FEC × 3, followed by pertuzumab/trastuzumab/docetaxel; and pertuzumab in combination with docetaxel, carboplatin, and trastuzumab.[26] It is noted that there is insufficient evidence to recommend concomitant anthracycline/pertuzumab or sequential use of doxorubicin with pertuzumab.

The confirmatory phase III trial required for full approval of neoadjuvant pertuzumab has already completed accrual, with initial results expected in 2016. APHINITY (Adjuvant Pertuzumab and Herceptin IN IniTial therapY of breast cancer) randomizes 4,800 patients with stage I-III HER2-positive breast cancer to standard chemotherapy (non-anthracycline– or anthracycline-based) concurrent with pertuzumab/trastuzumab, or to standard chemotherapy concurrent with trastuzumab.[27] In both arms, the same HER2-targeted therapy is administered post-chemotherapy, to complete 1 year of therapy. Invasive disease-free survival is the primary endpoint of this trial, and secondary endpoints include OS, disease-free survival, and cardiac safety. If the results of APHINITY are positive, the addition of pertuzumab to chemotherapy in the adjuvant setting will likely become standard of care.

Although the approval of neoadjuvant pertuzumab has been welcomed by many, some questions have arisen regarding the use of the pertuzumab-containing regimens supported by the label. First, the studies that were performed incorporated chemotherapy backbones not commonly used in the United States and other parts of the world. Second, fewer patients completed the full course of therapy in the pertuzumab arm of NeoSphere than in the control arm (eg, 94% vs 100% for adjuvant FEC, 83% vs 92% for the complete course of trastuzumab).[28] The long-term implications of same are unclear, as is the question of whether the rates would differ outside of a clinical trial. The difference in the rates of therapy completion might be explained by the higher rates of AEs in the pertuzumab arms of these studies, including the higher rates of cardiac toxicity. It is also possible that, based on the AEs observed, the additional toxicity of these newly approved regimens may make them an inappropriate choice in some women. Determining who these women are upfront is an important area of investigation and is described elsewhere in this review. Third, it appears that patients with HR-positive disease obtain less benefit from pertuzumab-containing regimens than they do from non–pertuzumab-containing regimens. For example, in NeoSphere, the difference in pCR between the two arms for patients with HR-positive disease was 10%, compared with a 24% difference between the two arms in patients with HR-negative disease. Whether the potential additional toxicity of pertuzumab-containing regimens is outweighed by this magnitude of pCR benefit in unselected patients with HR-positive disease is an open question. Robust biomarkers that predict treatment response are urgently needed to help guide therapeutic decisions in this setting.

Finally, it is interesting to note that the Guidance to Industry drafted by the FDA in 2012 regarding the use of pCR as an endpoint to support accelerated approval is not reflected in the design of the studies that led to the recent accelerated approval of pertuzumab.[29] These studies, which were designed prior to the publication of the Guidance, did not utilize standard neoadjuvant chemotherapy backbones, included patients with HR-positive disease, defined pCR as the absence of residual invasive cancer in “breast” vs “breast and all sampled ipsilateral lymph nodes,” and incorporated statistical plans that do not necessarily meet regulatory standards. However, when deciding whether to grant accelerated approval for this indication, the potential for curing more patients with high-risk HER2-positive breast cancer was clearly felt to outweigh the potential risks and the lack of knowledge of the long-term efficacy and safety of neoadjuvant pertuzumab-containing regimens. Although increased LVSD was observed in the pertuzumab arms of the studies, this was predominantly asymptomatic and reversible. Additional clinical trials have been recommended by the FDA to further evaluate the cardiac safety of pertuzumab in combination with the approved chemotherapy backbones, as well as with more standard chemotherapy approaches.

Prognostic and Predictive Biomarkers

There is a proportion of patients for whom HER2-targeted therapy with or without chemotherapy provides no benefit, and the vast majority of those with advanced HER2-positive metastatic breast cancer eventually develop drug resistance. The development of robust prognostic markers-in addition to predictive biomarkers of sensitivity to, resistance to, and toxicity from HER2-targeted therapy-is therefore urgently needed.

The most important prognostic and predictive factor in managing patients with HER2-positive breast cancer is undoubtedly the presence of HER2 gene amplification and/or overexpression. The recently revised American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update reiterates the need for accurate HER2 testing in every primary invasive breast cancer, and at metastatic sites if specimens are available.[28]

It has been suggested that increased PI3K pathway activation (PTEN low and/or PIK3CA mutation) may confer resistance to HER2-targeted therapies, including pertuzumab. Biomarker analysis from the CLEOPATRA study indicated inferior outcomes in patients with PIK3CA gene mutations compared with outcomes in those with wild-type gene status.[31] PIK3CA mutational status did not, however, appear to predict treatment benefit in either arm. Interestingly, biomarker analysis from the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study found that in patients treated with the combination of lapatinib and trastuzumab, the pCR rate was 55.8% in those without PIK3CA mutations but only 28.6% in those with mutant tumors.[32] Future research will clarify whether PI3K pathway dysregulation is indeed associated with an inability to achieve pCR and/or with inferior clinical outcomes in patients treated with HER2-targeted therapies.

There has also been a surge in interest in the role of the immune system, and agents targeting the immune system, in breast cancer. The adaptive immune system and immune checkpoints were found to be associated with response to chemotherapy and to HER2-targeted therapy in a biomarker analysis of the NeoSphere study.[33] It was noted that a high level of an inhibitory receptor expressed on activated lymphocytes that regulates tolerance and autoimmunity (programmed cell death ligand 1 [PD-L1]) was consistently associated with lower pCR rates in each chemotherapy-containing arm, creating a rationale for combining immune-modulating agents with HER2-targeted therapies. Investigators are also evaluating whether immune gene expression signatures may predict response to HER2-targeted therapies.[34]

In trying to identify potential prognostic and predictive biomarkers, researchers must keep in mind that prospective randomized controlled trials remain the gold standard for biomarker validation. Ideally, serial imaging, tumor biopsies, and blood samples are incorporated into these studies to gain maximum information from precious resources. Well-designed retrospective validation studies using data from well-designed prospective clinical trials (“prospective-retrospective” studies) may also be acceptable as an alternative strategy.

Ongoing Challenges and Future Directions in the Management of HER2-Positive Breast Cancer

The FDA approval of trastuzumab revolutionized the way in which HER2-positive breast cancer has been managed in the last decade and a half. Now, pertuzumab has also enhanced the therapeutic landscape of HER2-positive breast cancer, and in combination with trastuzumab and chemotherapy is a standard of care in both the neoadjuvant and metastatic settings. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for breast cancer (“the Guidelines”) support the use of pertuzumab as a preferred first-line treatment option for patients with HER2-positive recurrent or metastatic breast cancer, in combination with trastuzumab and a taxane (docetaxel or paclitaxel).[35] We would suggest that the combination of pertuzumab and trastuzumab is another reasonable option in certain pertuzumab-naive patients who wish to avoid chemotherapy, in the first-line or subsequent settings. The Guidelines have also been recently updated to reflect the accelerated approval of neoadjuvant pertuzumab-containing therapies. Interestingly, the NCCN panel have indicated that they support the use of pertuzumab with a number of different neoadjuvant regimens, including those incorporating doxorubicin and paclitaxel. Although these regimens are commonly prescribed in many parts of the world, it must be noted that the safety (in particular the cardiac safety) of pertuzumab in combination with these agents in the early breast cancer setting has not been established. Results from ongoing or planned studies may help clarify this unanswered question. In addition, the Guidelines suggest that a patient who does not receive pertuzumab in the neoadjuvant setting may receive it adjuvantly, the presumption perhaps being that the outcomes with neoadjuvant and adjuvant chemotherapy are generally felt to be equivalent. We would recommend caution in choosing a neoadjuvant or adjuvant pertuzumab-based regimen in patients with a history of, or risk factors for, cardiac disease until further information is available from the ongoing APHINITY trial.

A challenge moving forward in managing patients with HER2-positive early breast cancer is to determine who needs a more aggressive treatment approach than the approved pertuzumab-based regimens offer. Although a high pCR rate is achieved with these regimens, in particular in patients with HR-negative disease, there is clearly a subgroup of patients who do not achieve a pCR or who relapse in the years following therapy. Future clinical trials may add novel agents, such as a PI3K inhibitor, to a neoadjuvant pertuzumab-containing backbone (Table 3). Such studies may benefit from evaluating patients with and without PI3K pathway aberrations separately. A National Surgical Adjuvant Breast and Bowel Project (NSABP) trial (NCT02003209) will investigate whether the addition of endocrine therapy to docetaxel, carboplatin, trastuzumab, and pertuzumab in women with HER2-positive, HR-positive disease will result in a higher pCR rate. Alternative pertuzumab-based combinations are also under investigation-for example, the combination of pertuzumab and T-DM1, which is being investigated in the MARIANNE trial.

The expansion of the pertuzumab label, and the approval of other HER2-targeted therapies, such as T-DM1, clearly have the capacity to improve outcomes for patients. A major challenge moving forward, however, is the burden these treatments do and will continue to place on healthcare systems worldwide. It is estimated that combination treatment with pertuzumab and trastuzumab could cost between $27,000 and $49,000 per patient, depending on the duration of therapy.[36] Therefore, the identification of reliable predictive biomarkers and the selection of candidates most appropriate for dual HER2-targeted therapy will be the next challenges. It is likely that there is a subgroup of patients with HER2-positive early breast cancer who would have very favorable outcomes with standard chemotherapy and trastuzumab and thus might not require the addition of pertuzumab.

Alternatively, there is clearly a subgroup of patients with HER2-positive early breast cancer who might benefit from HER2-targeted therapy alone-and thus be spared the toxicity of chemotherapy. In the NeoSphere study, patients with ER-negative disease treated with pertuzumab/trastuzumab alone (ie, with no chemotherapy) were noted to achieve a pCR rate of 27%. This result has prompted the development of clinical trials to investigate this subgroup of patients. The Translational Breast Cancer Research Consortium (TBCRC) 026 trial (NCT01937117) is a preoperative trial of pertuzumab and trastuzumab without chemotherapy that aims to identify a subgroup of HER2-positive patients for whom chemotherapy may be omitted. Potential early predictors of pCR will be evaluated using serial imaging (positron emission tomography), tumor biopsies, and blood-based markers (plasma tumor DNA), with a focus on the PI3K pathway and immune signatures. This is in stark contrast to the efforts described above, which aim to increase the efficacy of current HER2-targeted treatment regimens by adding additional agents, but at the price of additional toxicity.

Additional challenges regarding the role of pertuzumab in the management of patients with HER2-positive disease include the optimal combination with chemotherapy or other HER2-targeted agents, the sequencing of pertuzumab-based regimens with other HER2-targeted regimens (see Figure 2), and the appropriate duration of pertuzumab therapy, in particular in the neoadjuvant setting.[29,30] These outstanding questions are the focus of ongoing research with both FDA-approved options (eg, T-DM1 and lapatinib) and newer small-molecule tyrosine kinase inhibitors (eg, afatinib, neratinib, and everolimus). Consideration of the side-effect profiles of drug combinations may prove helpful in selecting appropriate regimens for individual patients.

Conclusions

The introduction of pertuzumab as a new treatment option for patients with HER2-positive breast cancer has resulted in clinically significant improvements in pCR rates in the neoadjuvant setting, and a survival advantage in patients with advanced breast cancer. Ongoing studies aim to gain further knowledge regarding the cardiac safety and longer-term benefits of this agent in early breast cancer in combination with standard trastuzumab-based treatment regimens. With the recent approval of other novel HER2-targeted therapies, such as T-DM1, the management paradigm has changed significantly for HER2-positive breast cancer, with overall acceptable toxicity profiles. A challenge moving forward is to determine the optimal clinical use and sequencing of the available HER2-targeted agents, and the identification of subgroups of patients who have poor outcomes with currently available therapies. Elucidating mechanisms of resistance to HER2-targeted therapies will help identify new oncogenic targets and ultimately, new treatment options for these patients. In addition, investigators should focus on identifying a subgroup of patients who may benefit from HER2-targeted therapy alone, without chemotherapy, or indeed any treatment at all. Therefore, while much progress has been made in the treatment of patients with HER2-positive breast cancer, perhaps the most exciting challenges are yet to come.

Financial Disclosure:Dr. Connolly has received research grants from Novartis, Puma Biotechnology, and Genentech; she also receives research support from QVC and the Fashion Footwear Association of New York. Dr. O’Sullivan has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Slamon DJ, Clark, GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-82.

2. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-37.

3. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-92.

4. US Food and Drug Administration. Herceptin (trastuzumab) label. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5256lbl.pdf. Accessed January 4, 2013.

5. Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:1800-8.

6. Cortes J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30:1594-600.

7. Gelmon KA, Mackey J, Verma S, et al. Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer. 2004;5:52-8; discussion 59-62.

8. De P, Hasmann M Leyland-Jones B. Molecular determinants of trastuzumab efficacy: What is their clinical relevance? Cancer Treat Rev. 2013;39:925-34.

9. Sarup JC, Johnson RM, King KL, et al. Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. Growth Regul. 1991;1:72-82.

10. Burgess AW, Cho HS, Eigenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12:541-52.

11. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366:2-16.

12. Nuti M, Bellati F, Visconti V, et al. Immune effects of trastuzumab. J Cancer. 2011;2:317-23.

13. Adams CW, Allison DE, Flagella K, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2006;55:717-27.

14. Scheuer W, Fries TZ, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330-6.

15. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 2004;64:2343-6.

16. Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459-65.

17. Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol. 2005;23:2534-43.

18. Attard G, Kitzen J, Blagden SP, et al. A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours. Br J Cancer. 2007;97:1338-43.

19. Cortes J, Swain SM, Kudaba I, et al. Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel. Anticancer Drugs. 2013;24:1084-92.

20. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

21. 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;14:461-71.

22. Phillips GD, Fields CT, Li G, et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res. 2013 Nov 22. [Epub ahead of print]

23. US Food and Drug Administration. Kadcyla (ado-trastuzumab emtansine) label. Available from: http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm340913.htm. Accessed January 4, 2013.

24. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2013;13:25-32.

25. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24:2278-84.

26. US Food and Drug Administration. Perjeta (pertuzumab) label. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125409s051lbl.pdf. Accessed February 13, 2014.

27. A randomized multicenter, double-blind, placebo-controlled comparison of chemotherapy plus trastuzumab plus placebo versus chemotherapy plus trastuzumab plus pertuzumab as adjuvant therapy in patients with operable HER2-positive primary breast cancer. APHINITY trial. www.clinicaltrials.gov identifier: NCT01358877.

28. US Food and Drug Administration. 2013 meeting materials, Oncologic Drugs Advisory Committee. Available from: http://www.fda.gov/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsadvisorycommittee.ucm341089.htm. Accessed January 4, 2014.

29. Prowell T. US Food and Drug Administration. Draft guidance for industry. Pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/UCM305501.pdf. Accessed January 4, 2014.

30. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997-4013.

31. Baselga J, Cortes J, Im S-A, et al. Biomarker analysis in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer. [oral presentation] Presented at: The 35th San Antonio Breast Cancer Symposium, San Antonio, Texas. December 4-8, 2012.

32. Baselga J, Majewski I, Nuciforo PG, et al. PIK3CA mutations and correlation with pCR in the NeoALTTO trial (BIG 01-06). Presented at: The European Cancer Congress, Amsterdam, The Netherlands, Sept 27–Oct 1, 2013. Abstr 1859.

33. Gianni L, Bianchini G, Valagussa P, et al. Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study. Cancer Res. 2012;72(24 Suppl): Abstr S6-7.

34. Perez EA, Eckel-Passow JE, Ballman KV, et al. Predictive genomic markers to chemotherapy and adjuvant trastuzumab via whole genome expression DASL profiling in the NSABP N9831 adjuvant study. Presented at: The 35th San Antonio Breast Cancer Symposium, San Antonio, Texas. December 4-8, 2012.

35. NCCN Guidelines, breast cancer; version 01.2014. Available from: http://www.nccn.org/profressionals/physician_gls/pdf. Accessed January 4, 2014.

36. Ray L. Perjeta approved as pre-surgery breast cancer treatment. Available from: http://www.curetoday.com/index.cfm/fuseaction/blog.showindex/lindsayray/2013/ Accessed January 4, 2014.