What Exactly Are Antibody Drug Conjugates, and Why Are They Important in Metastatic Breast Cancer?

Presentation by Sramila Aithal, MD, Alliance Cancer Specialists at ESMO22 Pennsylvania.

Chemotherapy drugs have been used for decades in cancer treatment, particularly for patients with more advanced, or metastatic disease once it has spread from the primary site. By combining a cancer-specific antibody molecule with a chemotherapy drug, however, it is now possible to deliver the chemotherapy more selectively, and greatly improve the tumor cell killing, while at the same time reducing the toxic effects of chemotherapy to the rest of the body. At this year’s third ESMO US review session in Philadelphia, PA, Dr Sramila Aithal from Alliance Cancer Specialists discussed the use of these therapies, known as antibody-drug conjugates, or ADCs, in the setting of metastatic breast cancer, while highlighting some recent developments from the ESMO 2022 Congress.

ADC Technology: A Brief Overview

Simply put, ADCs are composed of a cancer-specific antibody molecule that is fused to a chemotherapy drug (called the ‘payload’) using a linker molecule. The antibody part of the ADC is usually designed to recognize and bind to a cell surface molecule, or receptor, that is very highly expressed on the cancer cells relative to normal cells. Once the antibody molecule ‘finds’ the cancer in the body, it attaches to the cell and becomes internalized. Only then is the molecule broken down and the cytotoxic payload is released, killing the cancer cell. Because the ADC carries the payload through the bloodstream while it is still attached to the linker molecule, the payload does not cause harm to other normal cells. Some ADCs also exhibit what is known as a ‘bystander effect’, whereby the ADC kills not only the tumor cell to which it attaches, but also the surrounding tumor cells, after the payload is released. There are now several ADCs which have been approved for use in the setting of metastatic breast cancer (mBC).

Triple-Negative Breast Cancer (TNBC)

Sacituzumab govitecan (SG) is an ADC directed against a molecule known as TROP2, which is expressed on a wide variety of epithelial cell cancers, including about 80% - 90% of breast cancers, and its expression has been associated with a poor prognosis. In the ASCENT trial, SG was compared with treatment of physician’s choice (TPC) in patients with metastatic triple-negative breast cancer (mTNBC). In this trial, SG improved progression-free survival (PFS) by 60% relative to TPC (median PFS, 5.6 vs. 1.7 months; P<0.0001), and overall survival (OS) was significantly longer with SG relative to TPC (12.1 vs. 6.7 mo.; P<0.0001). While these results are encouraging, Dr Aithal believes it will be possible to advance survival even further for mTNBC patients by combining ADCs such as SG with immunotherapy drugs like pembrolizumab as well as other targeted therapies for mTNBC such as PARP inhibitors, and she noted trials currently underway to investigate these novel treatment combinations.

HR+/HER2- mBC

For patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) mBC, Dr Aithal noted the TROPiCS-02 trial of SG versus TPC in HR+/HER2- mBC. The initial results of this trial showed a significant improvement in PFS (5.5 vs. 4.0 mo., P=0.0003), and SG was better in relevant patient subgroups including those with 3 or more prior treatment regimens, and those 65 and older. At ESMO 2022, results for the key secondary endpoint of OS were presented, which showed a significant benefit of SG over TPC (14.4 vs. 11.2 mo.; P=0.020). Also presented at this year’s ESMO was a further analysis from TROPiCS-02 for the newly defined “HER2-Low” patient subgroup, which also showed a significant benefit of SG over TPC in these patients (6.4 vs. 4.2 mo.; P<0.001). Dr Aithal also noted the TROPION-01 trial of another ADC, datopotamab deruxtecan versus TPC in HR+/HER2- mBC, which was also described at ESMO 2022. This trial is underway and will have the dual primary endpoints of PFS and OS.

HER2+ mBC

In the setting of mBC that is positive for HER2, Dr Aithal reviewed results from the DESTINY BR-03 trial, which examined the efficacy of the anti-HER2 ADC trastuzumab deruxtecan (T-DXd) versus another anti-HER2 ADC called T-DM1. The results showed T-DXd was significantly better in prolonging PFS (75.8 vs. 34.1 months). Notably, for the subset of patients who had treated brain metastases in DESTINY BR-03, there were more intracranial (CNS) complete responses with T-DXd as compared with T-DM1 (27.8% vs. 2.8%) and partial responses in the CNS were also higher with T-DXd (36.1% vs. 30.6%). The promising CNS responses seen in the study were also consistent with other trials which have shown CNS responses of 44% to 83% for patients on T-DXd. She also noted a range of other ADCs targeting HER2 that are currently under development which have different payloads and promising activity, although ocular toxicities have been observed with some.

HER3+ mBC

Dr Aithal also briefly noted results from the U3-1402 trial of another ADC, patritumab deruxtecan in hormone receptor positive HER2- mBC, which were presented at ESMO 2022. This ADC targets the HER3 molecule which is expressed in 30% to 50% of breast cancers. Results from the trial showed an overall response rate of 30.1%, a duration of response of 7.2 months, and median PFS and OS of 7.4 and 14.6 months, respectively. Antitumor responses were also observed across a range of HER3 expression levels in the trial. The most common treatment emergent adverse events (AEs) were GI and hematologic toxicities.

ADCs – Unanswered Questions

Dr Aithal noted that while results with ADCs in mBC have been remarkable and, in some cases, practice changing, there are several unanswered questions that remain and will require further study. These questions include what is the optimal order or sequence in which ADCs should be used, what is the role of novel ADC combination therapies, and what are the main mechanisms of resistance to ADC treatments. In addition, there remains a need for biomarkers to select which patients will benefit the most from ADC therapy, and better procedures to manage ADC-related toxicities such as interstitial lung disease (ILD).

See more from the 2022 ESMO Pennsylvania Conference here.

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