Antibody-Drug Conjugates in HER2-Positive Breast Cancer

Breast cancer is a significant global health concern, and HER2-positive breast cancer is a subtype that has unique characteristics and treatment challenges. Antibody-drug conjugates (ADCs) have emerged as a promising treatment option for HER2-positive breast cancer. In this article, we will explore the composition, mechanism, and clinical progress of ADCs in HER2-positive breast cancer.

Introduction

Breast cancer is the most common cancer among women worldwide. HER2-positive breast cancer accounts for approximately 15% to 20% of all breast cancers. HER2 is a receptor tyrosine kinase that is overexpressed in HER2-positive breast cancer, and it plays a crucial role in tumor growth, invasion, and metastasis.

ADCs are a class of targeted therapies that combine the specificity of monoclonal antibodies with the cytotoxicity of small-molecule drugs. ADCs consist of three components: a monoclonal antibody, a linker, and a cytotoxic payload. The monoclonal antibody binds to a specific antigen on the surface of tumor cells, and the linker releases the cytotoxic payload inside the tumor cells.

Composition and Mechanism of ADCs

Target Antigen and Monoclonal Antibody

The targeted antigen should be highly expressed in tumor tissues but not expressed or expressed at low levels in normal tissues. Currently, the approved ADCs for breast cancer target HER2 and human trophoblast cell-surface antigen 2 (TROP2). All ADCs currently approved for breast cancer use humanized immunoglobulin G (IgG) 1 as a monoclonal antibody.

Linker

The linker conjugates the payload with the monoclonal antibody and is a key factor in delivering the payload to tumor cells. It must have good stability in the blood circulation. Depending on whether the linker is lysed in the cell, it can be classified as cleavable and non-cleavable.

Payload

The most commonly used payloads in ADCs are tubulin inhibitors and topoisomerase inhibitors. The number of small-molecule cytotoxic payloads that ADCs can carry is limited. To achieve an effective therapeutic concentration, it is necessary to choose cytotoxic drugs with a low half-maximal inhibitory concentration (IC50).

Mechanism of ADCs

The main anti-tumor mechanism of ADCs targeting HER2 is shown in Figure 1. The monoclonal antibody in the ADCs serves as a carrier to transport payloads to target tumor cells. Trastuzumab in ADCs binds to the extracellular domain IV of HER2 and inhibits HER2 homodimerization, thereby blocking HER2-mediated signaling pathways. ADCs with the cleavable linkers directly release the payloads in the tumor microenvironment or in the target cell, whereas ADCs with non-cleavable linkers enter the tumor cell and are degraded in the lysosome to release the payloads. The highly membrane-permeable payloads can penetrate the cell membrane to kill adjacent HER2-negative tumor cells, known as the bystander effect. In addition, ADCs can inhibit the shedding of the extracellular domain of HER2 and induce tumor cell apoptosis through cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Comparison of Features and Pharmacokinetic Parameters between T-DM1 and DS-8201a

Table 1 shows the comparison between T-DM1 and DS-8201a in terms of their features and pharmacokinetic parameters. Both DS-8201a and T-DM1 use IgG1 as a monoclonal antibody. The average DAR of T-DM1 is 3.5, which is also within the recommended DAR range, whereas DS-8201A has a high DAR of 8. The IC50 of payloads in T-DM1 and DS-8201a was higher than that of conventional chemotherapeutic agents. However, the anti-tumor mechanisms of payloads in DS-8201a and T-DM1 are different. The former is a topoisomerase I inhibitor, whereas the latter is a tubulin polymerization inhibitor. Moreover, DS-8201a has a highly membrane-permeable payload and kills adjacent HER2-negative tumor cells through the bystander effect.

New Advances in Clinical Research

ADCs in Advanced HER2-Positive Breast Cancer

ADCs revised the treatment guidelines for HER2-positive breast cancer and provided patients with promising treatment options. Compared with capecitabine plus lapatinib, T-DM1 significantly improved the median progression-free survival (PFS) and median overall survival (OS) in the phase III EMILIA study. Based on the results of the EMILIA study, T-DM1 was approved by the Food and Drug Administration in 2013 for the treatment of patients with HER2-positive metastatic breast cancer (mBC) who previously received trastuzumab and taxane, separately or in combination. TH3RESA further confirmed the efficacy and safety of T-DM1 in HER2-positive advanced breast cancer.

DESTINY-Breast01 aimed to evaluate the safety and efficacy of DS-8201a in HER2-positive advanced breast cancer patients who previously received T-DM1. The results showed that the objective response rate (ORR) reached 60.9%, of which 6.0% were complete responses and 54.9% were partial responses. Therefore, DS-8201a is significantly superior to other anti-HER2 therapies. It was approved in 2019 for the treatment of adult patients with HER2-positive, unresectable, or mBC who had received two or more anti-HER2 therapies.

The European Society for Medical Oncology Congress 2021 and American Society of Clinical Oncology Annual Meeting 2021 also announced the progress of ADCs in HER2-positive breast cancer. The results of the phase III DESTINY-Breast03 study showed that DS-8201a had better PFS and ORR than T-DM1 in patients previously treated with trastuzumab and taxane whereas the rates of adverse events were similar. In the phase I study of ARX788, the ORR of the 1.5 mg/kg dose group reached 74%, and the disease control rate reached 100%. It has obtained the fast-track qualification granted by the Food and Drug Administration. A166 is an ADC composed of a novel cytotoxic drug (Duo-5, anti-microtubule agent) and trastuzumab. In the phase I study of A166, the ORR of the 6 mg/kg dose group also reached 59.1%. The application of ADCs in HER2-positive breast cancer will become more and more common.

ADCs in Adjuvant and Neoadjuvant Therapy

As the first optimized treatment study for residual lesions after neoadjuvant treatment of HER2-positive breast cancer, the KATHERINE study achieved breakthrough results. Compared with trastuzumab, T-DM1 treatment significantly improved the invasive disease-free survival (88.3% vs. 77.0%), with an absolute value benefit of 11.3%. However, it is still unclear whether patients who have not received neoadjuvant therapy can benefit from T-DM1 adjuvant therapy. Dual HER2-targeted neoadjuvant therapy with pertuzumab plus trastuzumab significantly reduced the risk of HER2-positive breast cancer recurrence. The efficacy and safety of neoadjuvant T-DM1 plus pertuzumab were also assessed in the phase III KRISTINE study but did not reach the primary clinical endpoint. There have been no clinical studies of DS-8201a exploring adjuvant and neoadjuvant therapy in breast cancer, but due to its high incidence rate of serious AEs, caution should be taken while conducting clinical trials.

ADCs in HER2 Low-Expressing Breast Cancer

Monoclonal antibodies are only effective for HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with fluorescence in situ hybridization [FISH] amplification) breast cancers and do not exert significant anti-tumor activity against low-expression HER2 (IHC1+ or IHC2+/FISH negative) breast cancers. In fact, only 15% to 20% of breast cancers are HER2-positive, and most breast cancers have low HER2 expression. Furthermore, several studies have confirmed that HER2 amplification is lost or downregulated in metastatic tumors. DS-8201a showed satisfactory efficacy in patients with HER2 low-expressing mBC. The ORR of DS-8201a in HER2 low-expressing breast cancer reached 37%, and the median PFS was 11.1 months. There have been no prospective clinical studies on T-DM1 in breast cancer with low HER2 expression, but exploratory analyses have shown limited efficacy. Novel ADCs, such as trastuzumab duocarmazine and ARX788, have also shown potential anti-tumor activity against breast cancer with low HER2 expression in preclinical models or clinical trials. This suggests that there may be a need to redefine HER2-positive breast cancer and identify optimal candidates who would benefit from anti-HER2 therapy.

ADCs in HER2-Positive Breast Cancer with Brain Metastases (BMs)

Most chemotherapeutic and targeted agents have difficulty passing through the blood–brain barrier; therefore, patients with BMs tend to have a poor prognosis. Patients with HER2-positive breast cancer have the most frequent BMs. As a novel anti-HER2 ADC, T-DM1 exhibits favorable efficacy in patients with BMs. In the BMs subgroup of the EMILIA study, the median OS of T-DM1 was more than twice that of lapatinib plus capecitabine (26.8 months vs. 12.9 months). Montemurro et al analyzed 126 patients with measurable BMs in the KAMILLA study. The results showed that 67% of patients had target lesion reduction, and the clinical benefit rate reached 43%. Moreover, the median PFS was 18.1 months among the 24 patients with asymptomatic BMs in the DESTINY-Breast01 study. The efficacy of the secondary prevention effect of T-DM1 combined with temozolomide rhythm chemotherapy on locally treated HER2-positive breast cancer with BMs was evaluated in a phase I/II study.

ADCs Combined with Other Treatments

NSABP FB-10 initially explored the efficacy of T-DM1 plus lenvatinib in patients with disease progression after previous trastuzumab plus pertuzumab treatment, with an ORR of 63%. The combination of ADC with other targeted therapies and the combination of ADC with bispecific antibodies is worthy of further exploration. T-DM1 combined immunotherapy has shown promising efficacy against breast cancer. ADCs can mediate ADCC, induce lymphocyte infiltration in the tumor microenvironment, upregulate the expression of immune checkpoint receptors of CTLA4, PD-1, and PD-L1, and enhance the immune response. Phase II of the KATE2 study compared the efficacy and safety of T-DM1 plus atezolizumab with T-DM1 monotherapy for trastuzumab- and taxane-treated HER2-positive advanced breast cancer. There were no significant benefits from PFS in the intention to treat the population. However, in the PD-L1 positive subgroup, the median PFS (8.5 months vs. 4.1 months) and 1-year OS rate (94.3% vs. 87.9%) of T-DM1 plus atezolizumab were significantly improved. For HER2 and PD-L1 “double positive” patients, targeted therapy combined with immunotherapy was hopeful to further improve the prognosis.

The WSG ADAPT study explored the efficacy of T-DM1 combined with endocrine therapy in neoadjuvant therapy. The pathological complete response rate of the two regimens containing T-DM1 was >40%, while that of the trastuzumab regimen was 15% (P < 0.001). T-DM1 combined with endocrine therapy is expected to replace targeted therapy combined with chemotherapy in the future, as well as become a new adjuvant treatment option for HER2-positive and hormone receptor (HR)-positive breast cancer. The study also suggested that early breast cancer patients who are both HER2- and HR-positive have unique biological characteristics, and future studies should evaluate the efficacy of patients with different HR statuses separately.

Adverse Events of ADCs Approved in HER2-Positive Breast Cancer

The toxicity of ADCs can be caused by multiple mechanisms, including monoclonal antibodies, payloads, off-target effects, ADCC, and CDC. Therefore, the AEs of ADCs are diverse [Figure 2], and clinicians should pay close attention to their toxicity. The most common AEs were nausea, fatigue, alopecia, and thrombocytopenia. The most commonly reported grade 3–5 AEs with T-DM1 were thrombocytopenia, anemia, and elevated serum concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Compared with T-DM1, DS-8201a had a higher frequency of grade 3 or higher AEs (52.2% vs. 47.6%). Grade 3 or 4 increased AST or ALT with DS-8201a was relatively rare, but hematologic toxicity (except thrombocytopenia), such as neutropenia, anemia, and leukopenia, was more serious. Thrombocytopenia is a special AE of T-DM1, and the incidence of any grade events was 8.7% to 30.6% (incidence of grade 3–5 events is 2.7%–14.0%). Compared with DS-8201a, peripheral neuropathy caused by T-DM1 was more serious. Most AEs were grade 1 or 2 and did not require dose reduction or discontinuation of therapy. Approximately 10% to 15% of all patients discontinued therapy due to AEs. Notably, the AEs related to the discontinuation of DS-8201a were mainly due to pneumonitis and interstitial lung disease.

Conclusions

Till August 30, 2021, there have been >1000 clinical trials on ADCs registered on the website (https://clinicaltrials.gov). The excellent efficacy and controllable safety of T-DM1 and DS-8201a in HER2-positive breast cancer have been confirmed, but ADCs, such as A166, RC48, and ARX788, are still in phase I or II clinical trials. Relevant studies on predicting efficacy, drug resistance biomarkers, and other evaluation methods are also actively carried out, which will further promote and optimize the clinical application of ADCs. Additionally, clinical trials of ADC in other malignant solid tumors, such as lung cancer and gastric cancer, are also ongoing. The potential anti-tumor activity of ADC will provide more promising treatment options for patients with malignant tumors in the future.

doi:10.1097/CM9.0000000000001932

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