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Novel Agents in HER2-Positive Breast Cancer

Written by Maeve A. Hennessy, Kate Rafferty, Catherine M. Kelly Dept. of Medical Oncology, Mater Misericordiae University Hospital

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“Two new and exciting clinical trials for HER2-positive breast cancer are now open and recruiting in Ireland, providing access to novel therapies for Irish patients, and aiming to address important unanswered questions in both early (Destiny-Breast05) and advanced (Destiny-Breast12) HER2- positive breast cancer”

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15-20% of breast cancers. This subset of breast cancer has historically been characterised by high rates of recurrence and a more aggressive biology. HER2- targeted therapies have altered the clinical course of both early and metastatic HER2-positive breast cancer, reducing the risk of recurrence in the adjuvant setting and prolonging survival in those with advanced disease. 1,2

Trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of HER2 receptors, was the first anti-HER2 monoclonal antibody to demonstrate improved outcomes when added to chemotherapy, for both patients with metastatic and early HER2-positive breast cancer. 1,2 Since then, we have seen the development of an array of novel HER2-targeted agents which have changed the treatment paradigm. We review the evidence and discuss recent key advances in the management of HER2- positive breast cancer.

Anti-HER2 therapies in metastatic HER2 – positive breast cancer

The standard of care for the first line management of HER2-positive metastatic breast cancer was established in the CLEOPATRA trial, which demonstrated significant improvements in overall survival (OS), up to 57 months, for dual anti-HER2 blockade with the monoclonal antibodies trastuzumab, pertuzumab in combination with taxane-based chemotherapy. 3 The antibody drug conjugate (ADC) trastuzumab emtansine (T-DM1) has been the preferred agent in the second line on the basis of the EMILIA study, where it demonstrated improved progression free survival (PFS) and OS as compared with lapatinib/capecitabine, with less toxicity. 4

Following on from the development of T-DM1, improvements in drug engineering led to the development of a second-generation ADC, trastuzumab deruxtecan (T-DXd). 5 This contains an identical humanised monoclonal HER antibody sequence to T-DM1, however is conjugated to a different cytotoxic agent, a novel topoisomerase 1 inhibitor. T-DXd has a higher drug-to-antibody ratio (8 versus 3.5) allowing higher potency and increased drug delivery. In addition, the highly permeable payload membrane allows a ‘bystander effect’, which means that the drug can be released by tumour cells on neighbouring heterogenous non- HER2 tumour cells. 5,6

Trastuzumab deruxtecan has recently shown durable activity in heavily pre-treated patients with HER2-positive metastatic breast cancer and has since shown improved outcomes over T-DM1 in the second line for patients with HER2-positive metastatic breast cancer in the phase III Destiny-Breast03 trial. 7,8 Destiny- Breast03 was an international phase III trial which compared T-DXd versus T-DM1 in patients with HER2-positive metastatic breast cancer who were initially treated with trastuzumab and a taxane. Five-hundred and twentyfour patients were included and were randomised to either T-DXd at 5.4mg/kg or T-DM1 at 3.6mg/ kg every 3 weeks.

Progression free survival was the primary endpoint. At a median followup of 16 months, median PFS was not reached with T-DXd and was 6.8 months with T-DM1 (HR 0.28, p<0.001). The response rate was 79.7% for T-DXd versus 34.2% for T-DM1 (p<0.0001). Importantly, a benefit was noted across all subgroups including patients with brain metastases. 8 An updated subgroup analysis presented at San Antonio Breast Cancer Symposium 2021, showed that 82 patients with stable brain metastases at baseline had an improvement in median PFS, 15 months with T-DXd versus 3 months with T-DM1 (HR 0.25, 95% CI 0.31-0.45). 9

Previous trials of T-DXd had documented interstitial lung disease (ILD) as a significant adverse event, however the rate of ILD in Destiny-Breast03 was less than what was reported in the earlier studies where patients had been more heavily pre-treated, (10.5%, with 9.7% being grade 1 or 2) and no grade 4 or 5 ILD reported. These impressive results were seen as practice changing and T-DXd is now the preferred second-line treatment based on this study, and in particular in the case of central nervous system (CNS) involvement. 8 T-DXd with or without pertuzumab is now being evaluated in the first line against the CLEOPATRA regimen. 10

The inclusion of patients with CNS involvement in clinical trials evaluating novel therapies for metastatic HER2 is vital, especially given that approximately one third of patients with HER2- positive metastatic breast cancer will ultimately develop brain metastases. 11 Further clinical trials are ongoing to assess treatment options in this important cohort of patients and are active and recruiting in Ireland. Destiny- Breast12 is an open-label international phase IIIb/IV study assessing the safety and efficacy of T-DXd in patients with or without brain metastasis.

The trial aims to recruit a total of 500 eligible participants across 19 countries, and is currently open in three sites in Ireland: Cork University Hospital, St Vincent’s University Hospital, and the Mater Misericordiae University Hospital. Eligible participants must be at least 18 years of age, have unresectable/ advanced or metastatic HER2-positive breast cancer and evidence of disease progression on trastuzumab, pertuzumab, or T-DM1 (≤ 2 lines/regimens of therapy in the metastatic setting). Participants will be stratified according to presence or absence of brain metastasis at baseline and will receive intravenous T-DXd at 5.4 mg/kg every 3 weeks until progressive disease or development of unacceptable toxicity.

Small molecules such as tucatinib, an oral anti-HER2 tyrosine kinase inhibitor (TKI), are another class of drug being explored in the treatment of HER2-positive breast cancer. Tucatinib has been shown to effectively cross the blood brain barrier and has demonstrated activity in patients with CNS metastases, as seen in the HER2CLIMB trial. 12 In this international trial, 612 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1, with or without brain metastases, were randomised to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. 291 patients (47.5%) had brain metastases at baseline.

The tucatinib plus trastuzumab/capecitabine arm had more than double the response rate as compared with the control arm (47% vs 20%, p=0.03). There was also an impressive intracranial response with intracranial PFS 9.9 months versus 4.2 months p<0.001). 12 Therefore, tucatinib may be a valid option in the second line if patients have brain metastases and this novel TKI is now being examined in earlier settings to prevent CNS relapse.


Anti-HER2 therapy In early stage HER2 – positive breast cancer

For patients with early stage HER2-positive breast cancer, a neoadjuvant approach is standard of care for HER2-positive tumours greater than 2cm and/ or lymph node involvement. 13 Upfront systemic therapy has the advantage of assessing response to treatment and allowing further personalisation of treatment in the adjuvant setting. Currently, this takes the form of anthracycline/ taxane-based chemotherapy plus dual anti-HER2 blockade with trastuzumab and pertuzumab. However, increasingly the role of anthracyclines in contemporary dual anti-HER2 treatment regimens is limited and non-anthracycline regimens are now the most frequently administered (neo) adjuvant regimens.

Neoadjuvant therapy is followed by surgical resection, plus or minus adjuvant radiotherapy, completion of anti-HER2 therapy and endocrine therapy depending on the tumour hormone status. The introduction of a dual HER2 blockade neoadjuvantly has resulted in improved rates of pathologic complete response (up to 60%), which has been shown to translate to better long-term outcomes for patients. 14,15

Patients with residual invasive breast cancer post neoadjuvant chemotherapy plus HER2-targeted therapy have a worse prognosis than those who have no residual cancer. The management of patients with residual disease following neoadjuvant therapy has been informed by the landmark KATHERINE study, which was published in the New England Journal of Medicine (NEJM) in 2019. 16 In this randomised phase III trial, 1468 patients with HER2- positive breast cancer who had residual disease post neoadjuvant taxane-based chemotherapy and anti-HER2 therapy were randomly assigned to either trastuzumab or T-DM1 for 14 cycles. The T-DM1 arm had an improved invasive disease-free survival (IDFS) compared to the trastuzumab arm, (88 vs. 77%; HR = 0.50; 95% CI 0.39–0.64), and T-DM1 was approved by the FDA and EMA in this setting as a result. 16 Trastuzumab emtansine has only recently (January 2022) been funded in Ireland for this indication.

Destiny-Breast05 is an exciting phase III international, multicentre, randomised, open-label trial that is studying this cohort of patients, i.e., those with HER2- positive breast cancer who have residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy, and will examine treatment with T-DXd versus T-DM1. The primary objective of the trial is to compare the invasive disease-free survival (IDFS) between T-DXd and T-DM1. This trial is open in Ireland and is being run in the following institutions: Mater Misericordiae University Hospital, Cork University Hospital, St James’s Hospital, St Vincent’s University Hospital and University Hospital Limerick. This study will help to provide further evidence to inform treatment selection for this group of patients who are at a higher risk of disease recurrence.

Significant progress has been made in recent years in the management of HER2-positive breast cancer, with many patients with advanced disease now experiencing longterm responses. The spectrum of active therapies means that treatment is becoming increasingly effective and individualised. Two new and exciting clinical trials for HER2-positive breast cancer are now open and recruiting in Ireland, providing access to novel therapies for Irish patients, and aiming to address important unanswered questions in both early (Destiny- Breast05) and advanced (Destiny- Breast12) HER2-positive breast cancer.

Finding effective drugs to treat patients with brain metastases has been a long term challenge, and there are now some excellent options for patients, many of whom have stable extracranial disease, but progressive disease in the CNS. It is likely that in the coming years the current anti-HER2 therapies being used in the neoadjuvant and metastatic setting will be replaced by new highly active antibody drug conjugates and combinations of potent small molecule tyrosine kinase inhibitors.

Additionally, treatments approved for other breast cancer subtypes associated with improvements in survival, such as immunotherapies in triple negative breast cancer and CDK4/6 inhibitors in hormone receptorpositive breast cancer, are also being explored in HER2-positive breast cancer. In summary, the recent advances in the treatment of HER2-positive breast cancer have been impressive, resulting in significantly improved outcomes and the future is promising for patients with this diagnosis.

References available on request

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