Metastatic Breast Cancer Awareness Day: Assessing the Role of ADCs

Muhammad Imam, MD

If systemic treatments in breast oncology in 2021 were defined by the FDA approvals of neoadjuvant pembrolizumab (Keytruda) and adjuvant abemaciclib (Verzenio), then 2022 is most defined by the resurgence of next-generation antibody-drug conjugates (ADCs) and their wider use beyond the intended subtype of metastatic breast cancer (mBC).

Background of ADCs in mBC

Breast cancer oncologists have been familiar with ADCs since the approval of trastuzumab emtansine (Kadcyla; TDM-1) in 2013, which had been used in the second-line setting of metastatic HER2-positive (HER2+) breast cancer until recently. ADCs are defined by these components: an antibody (usually an IgG1) targeting an antigen, a linker molecule, and a toxin/payload.¹ The concept of delivering toxins only to cancer cells overexpressing targeted antigens seems at once elegant and obvious and has been proposed since the early 1900s but was limited by the technology behind antibodies and linker molecules.

The linker molecule has to be stable in circulation, so as to not let go of its payload prematurely. Once arriving at the target, the payload has to be efficiently released. The mechanism of this release could be through proteolysis of the entire IgG1/linker/toxin complex (known as non-cleavable) versus releasing separately soon after internalization by lysozymes (known as cleavable). More powerful linkers will allow the transport of an increasing number of toxin molecules (known as increased drug-antibody ratio).

TDM-1 was the prototypical ADC in breast cancer. The toxin being delivered was DM1, an anti-microtubule linked to Immunoglobulin G1 (IgG1) targeting the HER2 receptor with a drug-to-antibody ratio (DAR) of 3.5 and the linker was non-cleavable. Two more recently approved ADCs in breast cancer, sacituzumab govitecan (Trodelvy) and trastuzumab deruxtecan (Enhertu; T-Dxd), have several distinct advantages. Cleavable linkers allow the release of the toxin earlier. The DAR is considerably higher, close to 8 for both. The toxins being delivered in these 2 ADCs are topoisomerase I inhibitors and have the advantage of being membrane permeable—crossing cell membranes causing adjacent cells that may not have bound the antibody to also undergo apoptosis.

The Role of Sacituzumab Govitecan in mBC

Sacituzumab govitecan had already been given accelerated approval in April 2020, and subsequently regular approval 1 year later in April 2021 for triple-negative breast cancer (TNBC) based on the phase 3 ASCENT trial (NCT02574455). It is an IgG1 antibody directed against Trop-2, tumor-associated calcium signal transducer that is expressed in TNBC in up to 85% of cases. The payload being delivered is SN-38, an active, more potent metabolite of irinotecan. An early phase 1/2 basket trial (NCT01631552) of sacituzumab govitecan demonstrated an objective response rate (ORR) of 33.3% in patients with TNBC.²

In the same trial of sacituzumab govitecan, patients with hormone-positive, HER2-negative (HR+/HER2-) breast cancers—who have similar rates of Trop-2 expression as TNBC—had similar a ORR to TNBC as well (31.5%).³ Therefore, it wasn’t surprising when the positive results of phase 3 TROPiCS-02 trial (NCT03901339) in patients with metastatic HR+/HER2- randomly assigned to sacituzumab govitecan vs chemotherapy were presented at the American Society of Clinical Oncology 2022 annual meeting and then published 1 month later.⁴ A total of 543 patients were enrolled, all of them exposed to CDK4/6 inhibitors, a median of 3 lines of chemotherapy, and had a median of 4 years after their initial diagnosis of metastatic disease, suggesting a fairly modern and heavily pretreated population.

The median progression-free survival (PFS) was 5.5 months vs 4.0 months (HR, 0.66; 95% CI, 0.53-0.83; P = .0003), with a 12-month PFS rate of 21% vs 7%, for sacituzumab vs chemotherapy, respectively. Toxicities remained mild with most common grade 3 adverse events being hematologic and with only few patients (9% vs 1%) with grade 3 diarrhea.

At the European Society for Medical Oncology (EMSO) Congress 2022, overall survival (OS) data were presented, showing a median of 14.4 months vs 11.2, and an ORR of 21% vs 14%.⁵ Sacituzumab govitecan is now listed as an approved regimen for HR+/HER2- disease in National Comprehensive Cancer Network guidelines, and may gain FDA approval in the near future.⁶

T-Dxd in the mBC Landscape

Trastuzumab deruxtecan (T-Dxd), another ADC, had similarly achieved accelerated FDA approvals for HER2+ breast cancer in 2019 for third-line treatment. Trastuzumab is an IgG1 antibody against HER2 that is cleavably linked to another topoisomerase I inhibitor camptothecin analogue known as deruxtecan. This newer generation ADC was compared directly with TDM-1 and proven to have higher efficacy in DESTINY-Breast03 (NCT03529110) with median PFS not reached vs 6.8 months, and an HR of 0.28 (95% CI, 0.22-0.37; P < .001), validating the improvements in design of the ADCs.⁷

In 2022, a development that impacted a larger number of patients with mBC even more significantly was the DESTINY-Breast04 trial (NCT03734029). In this study, the increased DAR and the bystander effect of membrane-permeable toxin of T-Dxd were tested in patients with HER2-low breast cancer, with the hypothesis that the target antigen did not have to be strongly expressed for the ADC to be effective.

A total of 557 patients were enrolled with either HER2 immunohistochemistry (IHC) of 1+ or HER2 IHC of 2+ with a negative HER2 fluorescence in situ hybridization; patients had at least 1 line of chemotherapy and, if HR+, had previously received endocrine treatment.⁸ This trial enrolled a largely HR+ subset (88.7%) randomly assigned 2:1 to T-Dxd vs chemotherapy. The results were convincing, almost doubling the median PFS with T-Dxd at 10.1 months vs 5.4 (HR, 0.51; P < .001). Most importantly, OS was significantly longer at 23.9 months vs 17.5 months (HR, 0.64; P = .003). Toxicities remained consistent with previous studies, primarily resulting in grade 3 hematologic toxicities with rare, but present, risk of death (0.8%). Many oncologists are now retroactively testing patients with metastatic HR+/HER2- with HER2 IHC in order to incorporate T-Dxd soon after progression on 1 line of chemotherapy in the metastatic setting.

Sequencing and the Future of ADCs as mBC Treatment

The almost simultaneous presentations and publications of these 2 newer ADCs led to questions of sequencing of which ADC to use first in HR+/HER2-low mBC. Cross-trial comparisons are difficult as DESTINY-Breast04 and TROPiCS-02 had slightly different populations, with TROPiCS-02 involving a more heavily-pretreated population. Still, the PFS and OS data from DESTINY-Breast04 are striking, so at this time, I lean towards using T-Dxd. In the subset of patients with HR-/HER2-low mBC, my preference is for sacituzumab govitecan, given that patients with HR- disease were only a small subset of DESTINY-Breast04.

There are numerous ADCs in development in breast cancer with different targets and payloads. In terms of targeting HER2, the furthest in development is trastuzumab duocarmazine (SYD-985). For this drug, the payload is unique—an alkylator. The phase 3 TULIP study (NCT03262935) presented at ESMO 2021 showed improvement in median PFS (7.0 months vs 4.9 months with trastuzumab duocarmazine vs physician’s choice chemotherapy, respectively) and the initial read out indicated a numerical but not significant improvement in OS (HR, 0.83; 95% CI, 0.62-1.09; P = .153).⁹ The FDA accepted a Biologics License Application for HER2+ mBC earlier this year.

In terms of targeting Trop-2, phase 3 trials of datopotamab deruxtecan begun after the phase 1 TROPION-Breast02 study (NCT03401385) showed activity with an ORR of 34% in metastatic TNBC.¹⁰ Other targets being explored include HER3 and folate receptor α, which are in various stages of development.

The future remains bright for ADCs in breast cancer. The focus seems to be shifting from the broad approach of traditional chemotherapeutic agents towards delivering the same toxins in a more targeted fashion via ADCs. The magic bullet that German Nobel laureate Paul Ehrlich envisioned over 100 years ago may finally be hitting its target.

_References:

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_{2. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213}

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_{6. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 4.2022. Accessed October 5, 2022. https://bit.ly/3Cgj9Gb}

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_{8. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated her2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

_{9. Manich CS, O’Shaughnessy J, Aftimos PG, et al. LBA15 - Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741}

_{10. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05.}