Navigating antibody‒drug conjugates (ADCs): from metastatic to early breast cancer treatment strategies.

Introduction

Chemotherapy has been the cornerstone of cancer treatment for more than 50 years and continues to play a significant role today. However, treatment strategies are evolving toward new agents that engage the immune system or target specific pathways. The goal is to develop effective therapies that precisely target cancer cells, and there is no better approach than utilizing a molecule designed to deliver cytotoxic agents directly to the intended target. Antibody‒drug conjugates (ADCs) consist of three components: an antibody that targets a specific antigen with high specificity, a linker, and a payload that contains the drug [ 1 ]. Although ADCs have been under investigation for years, only a few have received approval, with three currently available for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla®), trastuzumab deruxtecan (T-DXd/Enhertu®), and sacituzumab govitecan (SG/Trodelvy®) [ 2 , 3 ].

The innovative design of ADCs allows for a more targeted approach to cancer therapy, which is especially crucial in BC treatment. By utilizing monoclonal antibodies that specifically bind to tumor-associated antigens, ADCs can deliver cytotoxic agents directly to cancer cells while sparing healthy tissue. This targeted delivery not only enhances the therapeutic index but also minimizes the systemic side effects commonly associated with traditional chemotherapy. These innovative anticancer drugs, referred to as “biological missiles,” are paving the way for a new era of targeted cancer treatment [ 4 ].

Clinical results with trastuzumab emtansine (T-DM1) led to its FDA approval as the first antibody‒drug conjugate (ADC) for metastatic HER2-positive breast cancer (HER2 + mBC) [ 5 ]. On the basis of the results of the KATHERINE trial, T-DM1 has been approved for use in the early-stage setting [ 6 ]. Similarly, favorable results from clinical trials of sacituzumab govitecan (SG) resulted in its FDA approval as the first ADC for metastatic triple-negative breast cancer (mTNBC) [ 3 ] and, recently, in hormone receptor-positive (HR +) patients [ 7 ]. For trastuzumab deruxtecan (T-DXd), a series of clinical trials designated DESTINY-Breast studies were initiated, and others are still ongoing. These studies demonstrated the efficacy and safety of this drug and its superiority over T-DM1, as highlighted in DESTINY-Breast03. Recently, in 2024, trastuzumab emtansine (T-DM1) received approval for use in all solid tumors [ 8 , 9 ].

Researchers are committed to ongoing investigations to ensure that long-term treatment with ADCs continues to provide therapeutic benefits to patients while minimizing additional adverse effects. In general, FDA-approved drugs typically begin their clinical journey in metastatic phases before progressing to studies in earlier settings.

In this study, we review the three approved ADCs for BC and present an overview of their ongoing trials, with a focus on early-stage settings to assess their potential role in reducing recurrence rates, enhancing overall survival and providing a more tailored approach to later-line treatment options. Additionally, we will complete the overview by including the ongoing trials for investigational ADCs that have not yet received approval in both metastatic and early-stage settings.

Methods

We initiated our search by listing the FDA's approvals of antibody‒drug conjugates (ADCs) for both hematological and solid tumors, as summarized in Table 1 . Next, we focused specifically on ongoing trials involving ADCs in BC. In the subsequent tables, we focused our search on trials involving the three approved drugs in BC: T-DM1, T-DXd, and SG. To ensure comprehensive coverage, we also incorporated information on investigational ADCs and their ongoing trials. Our review primarily utilized electronic databases such as PubMed and MEDLINE, with a significant portion of the search conducted through ClinicalTrials.gov. Key clinical trials that led to the approval of ADCs, as well as ongoing trials in both the metastatic and early settings of BC, were organized into tables. The preliminary results of these trials were reviewed from the recent presentations of ESMO and ASCO. In our search, we excluded ongoing trials that had been terminated or had an unknown status. We also did not include studies involving all solid tumors to maintain our focus specifically on BC. The sequence of our research process is illustrated in Fig. 1 below. Fig. 1 Research process chart

Results

As of October 2023, the FDA has granted approval to several ADCs for the treatment of both solid tumors and hematological malignancies, underscoring their growing importance. These drugs are summarized in Table 1 , which includes their year of approval and corresponding indications for use.

Among these FDA approvals, only three drugs are approved for the treatment of breast cancer: ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). Table 1 FDA-approved antibody‒drug conjugates: indications and years of approval [ 10 ] Drug Indication for use Approval year Brentuximab vedotin Adult patients with primary cutaneous ALCL or CD30-expressing MF who have received prior systemic therapy 2017 Adult patients with previously untreated systemic ALCL or other CD30‐expressing PTCL 2018 Pediatric patients with previously untreated classical HL in combination with chemotherapy 2022 Trastuzumab emtansine As a single agent for HER2 + mBC who previously received trastuzumab and a taxane 2013 As adjuvant treatment of patients with HER2 + eBC who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment 2019 Gemtuzumab ozogamicin R/R CD33‐positive AML in patients 2 years of age and older 2017 Inotuzumab ozogamicin Adult patients with R/R B-cell precursor ALL 2017 Pediatric patients with R/R CD22-positive B-cell precursor ALL 2024 Moxetumomab pasudotox R/R HCL with at least two prior systemic therapies including at least one purine nucleoside analog 2018 Polatuzumab vedotin-piiq In combination with BR for adult patients with R/R DLBCL with at least two prior therapies 2019 Enfortumab vedotin Locally advanced or metastatic urothelial cancer who have received a PD- 1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting 2019 Trastuzumab deruxtecan Adult patients with unresectable or mHER2 + BC who have received two or more prior anti-HER2-based regimens in the metastatic setting 2019 Adult patients with unresectable or mHER2 + solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options 2024 Sacituzumab govitecan Unresectable locally advanced or mTNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease 2020 Unresectable locally advanced or mHR +, HER2− BC who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting 2023 Belantamab mafodotin-blmf Adult patients with R/R MM who have received at least 4 prior therapies including an anti-CD38 mAb, a PI, and an IMID 2020 Cetuximab saratolacan Unresectable locally advanced or recurrent head and neck cancer 2020 Loncastuximab tesirine-lpyl Adult patients with R/R large B-cell lymphoma after two or more lines of systemic therapy 2021 Disitamab vedotin HER2 + locally advanced or metastatic gastric cancer who have received at least two systemic chemotherapy regimens 2021 Tistotumab vedotin-tftv Adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy 2021 Mirvetuximab soravtansine-gyxn Adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies 2022 R/R relapsed or refractory; AML acute myeloid leukemia; HL Hodgkin lymphoma; ALCL systemic anaplastic large-cell lymphoma; PTCL peripheral T‐cell lymphoma; MF mycosis fungoid, HL; hairy cell leukemia; HER2 human epidermal growth factor receptor 2; eBC early breast cancer; mBC metastatic breast cancer; ALL acute lymphoid leukemia; DLBCL diffuse large B-cell lymphoma; BR bendamustine, Rituximab; TNBC triple-negative breast cancer; MM multiple myeloma; mAB monoclonal antibody; PI proteasome inhibitor; IMID immunomodulatory agent; FRα folate receptor-α; HR hormone receptor

Trastuzumab emtansine (T-DM1/emtansine)

The structure of T-DM1 includes trastuzumab, which targets the HER2 protein and is conjugated to emtansine, a drug that inhibits cell growth by disrupting the cytoskeleton.

Clinical results with T-DM1 have generated significant enthusiasm within the breast cancer research community, culminating in its FDA approval as the first antibody‒drug conjugate (ADC) for the treatment of metastatic HER2 + BC. The two most important studies were EMILIA and KATHERINE.

The EMILIA study in 2013 was a phase III trial that assessed the effectiveness of T-DM1 versus lapatinib plus capecitabine in patients with previously treated HER2 + mBC. The results showed that T-DM1 provided better overall survival and progression-free survival than combination therapy did, highlighting its role as a preferred treatment option in this setting [ 11 ].

The KATHERINE study was a phase III trial that evaluated the efficacy of adjuvant T-DM1 compared with trastuzumab alone in patients with HER2 + early BC who had residual disease after neoadjuvant therapy. The study granted approval for this population in 2019, as T-DM1 significantly improved disease-free survival, establishing it as a new standard of care for this population [ 12 ].

A summary of FDA approvals for T-DM1 is provided in Table 2 . Table 2 Key clinical trials for trastuzumab emtansine (T-DM1) approval in the breast Key clinical trial Phase Population Arms Results EMILIA Study (2013) [ 11 ] III HER2 + advanced BC previously treated with Trastuzumab and Taxane T-DM1 mPFS months (HR0.65) T-DM1: 9.6 Lapatinib + capecitabine: 6.2 Lapatinib + capecitabine mOS % (HR 0.68) T-DM1: 30.9% Lapatinib + capecitabine: 25.1% KATHERINE Study (2019) [ 12 ] III Adjuvant setting for residual invasive HER2 + early BC after neoadjuvant chemotherapy and HER2-targeted therapy T-DM1 OS rate %: (HR 0.66) T-DM1: 89.1% Trastuzumab 84.4% Trastuzumab IDFS % (HR 0.54) T-DM1: 80.8% Trastuzumab: 67.1% T-DM1 trastuzumab emtansine, HER2 human epidermal growth factor receptor 2, PFS progression-free survival, OS overall survival, HR hazard ratio, BC breast cancer, IDFS invasive disease-free survival

Trastuzumab deruxtecan (T-Dxd/Enhertu)

This ADC uses the same antibody as T-DM1- trastuzumab, which targets HER2, but it is linked to a different drug, deruxtecan. This drug is a topoisomerase I inhibitor that disrupts tumor cell DNA repair, delivering the treatment directly to cancer cells.

Following the development of trastuzumab deruxtecan (T-DXd), a series of trials known as DESTINY-Breast studies were initiated to evaluate its efficacy and safety profile. Notably, DESTINY-Breast03 conducted a direct comparison of T-DXd with T-DM1, revealing significant advantages for T-DXd.

Table 3 summarizes key findings from several pivotal clinical trials involving HER2 + and HER2-low mBC treatments. DESTINY- 01 (Phase 2) focused on HER2 + mBC patients who had previously been treated with T-DM1. The trial reported a median duration of response (mDOR) of 14.8 months and a median progression-free survival (mPFS) of 16.4 months [ 13 ]. DESTINY-BREAST- 02 (Phase 3) evaluated HER2 +, unresectable, and/or mBC patients previously treated with T-DM1 and compared the experimental treatment to a physician’s choice of therapy (trastuzumab plus capecitabine or lapatinib plus capecitabine). The results revealed a significant improvement in mPFS, with 17.8 months for the ADC group versus 6.9 months for the control group (hazard ratio [HR] 0.36), with no adverse effects [ 14 ]. DESTINY-BREAST- 03 (Phase 3) included patients with HER2 + mBC who had received prior trastuzumab and taxane therapy for early or metastatic disease in comparison to T-DM1 patients. The trial demonstrated improved progression-free survival (PFS) and overall survival (OS), with a 36-month PFS rate of 45.7% compared with 12.4% and a median OS of 52.6 months versus 42.7 months (HR 0.73). This study led to the FDA approval of the agent as a second-line therapy in HER + mBC [ 15 ]. DESTINY-BREAST- 04 (Phase 3) focused on patients with HER2-low unresectable disease and/or mBC and compared the ADC to a physician’s choice of single-agent chemotherapy. Both PFS (9.9 vs. 5.1 months; HR 0.50) and median OS (mOS) (23.4 vs. 16.8 months; HR 0.64) improved. An extended analysis of patients from the DESTINY-Breast- 04 cohort confirmed that T-DXd offers longer-term benefits in patients with HER2-low BC, with no additional adverse effects. T-DXd received FDA approval in HER2-low BC on the basis of the results of this study and set a new standard for the paradigm of HER- 2-low BC [ 16 ]. DESTINY-BREAST- 06 (Phase 3) is evaluating HER2-low and HER2-ultralow mBC patients. In this trial, T-DXd demonstrated median PFS of 13.2 months, compared to 8.1 months in patients receiving chemotherapy. This resulted in a 36% reduction in the risk of disease progression or death (HR 0.64) in the overall population of chemotherapy-naive HER2-low or HER2-ultralow metastatic breast cancer patients. The FDA has recently granted approval for this treatment in this setting [ 17 ]. Table 3 Completed DESTINY trials for deruxtecan in breast cancer Destiny trial Phase Population Arms Results Destiny- 01 [ 13 ] II HER2 + mBC previously treated with T-DM1 mDOR months : 14.8 mPFS months :16.4 Destiny-breast- 02 [ 14 ] III HER2 + unresectable and/or mBC previously treated with T-DM1 T-DXd mPFS months (HR 0·36): T-DXd:17.8 months TPC: 6.9 months TPC: trastuzumab + capecitabine or lapatinib + capecitabine mOS months (HR 0.66): T-DXd: 39.2 months TPC: 26.5 months Destiny-breast- 03 [ 9 , 15 ] III HER2 + mBC with prior trastuzumab + taxane for early and mBC T-DXd mPFS months (HR 0.3): T-DXd: 9.0 months T-DM1: 7.2 months T-DM1 mOS months (HR 0.73): T-DXd: 52.6 months T-DM1: 42.7 months DESTINY-BREAST- 04 [ 16 ] III HER2-low unresectable and/or mBC T-DXd mPFS months (HR 0.50): T-DXd: 9.9 months TPC: 5.1 months TPC: chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel) mOS months (HR 0.64): T-DXd: 23.4 months TPC: 16.8 months HER2 human epidermal growth factor receptor 2, T-DM1 trastuzumab emtansine, mBC metastatic breast cancer, T-DXD trastuzumab deruxtecan, TPC treatment of physician’s choice, mDOR median duration of response, PFS progression-free survival, OS overall survival, mOS median OS, vs versus, HR hazard ratio

Sacituzumab govitecan (SG/Trodelvy)

Within this drug, the antibody sacituzumab binds to the TROP- 2 protein and is linked to the drug SN- 38, which is another topoisomerase I inhibitor.

The approval of sacituzumab govitecan (SG) in 2021 was based on strong evidence that ASCENT showed significant benefits in survival for patients with limited treatment options in patients with relapsed or refractory metastatic triple-negative breast cancer (mTNBC)

[ 18 ]. With the TROPICS- 02 trial, SG provided a progression-free survival (PFS) advantage (5.5 vs. 4.0 months) and improved overall survival (OS) (14.4 vs. 11.2 months) compared with chemotherapy in patients with HR + and HER2− mBC who had previously received endocrine therapy, CDK inhibitors, and at least two lines of systemic chemotherapy [ 19 ]. Post hoc analyses from the TROPICS- 02 and ASCENT trials confirmed that SG also demonstrated consistent benefits in terms of PFS, OS, and overall response rates in patients with HER2-low and HER2 IHC scores of 0 mBC. These two major trials leading to the approval of SG in BC are presented in Table 4 . Table 4 Key clinical trial for sacituzumab govitecan (SG) approval in breast cancer Key clinical trial Phase Population Arms Results Ascent study [ 18 ] III Unresectable, locally advanced or mTNBC who have received ≥ 2prior systemic therapies, at least one of them for metastatic disease SG mPFS months (HR 0.41): SG: 5.6 months TPC: 1.7 months TPC: eribuline, capecitabine, gemcitabine, vinorelbine mOS months (HR 0.48): SG: 12.1 months TPC: 6.7 months Tropics- 02 [ 19 ] III Unresectable locally advanced or mHR +, HER2− BC who have received endocrine-based therapy and ≥ 2 systemic therapies in the metastatic setting SG mPFS months (HR 0.66) SG: 5.5 months TPC: 4.0 months TPC: eribuline, capecitabine, gemcitabine, vinorelbine mOS months (HR 0.79) SG: 14.4 months TPC: 11.2 months SG sacituzumab govitecan, mTNBC metastatic triple-negative breast cancer, TPC treatment of physician’s choice, mPFS median progression-free survival, mOS median overall survival, HR hazard ratio, HR hormone receptor positive, HER2 human epidermal growth factor receptor 2

Ongoing trials for trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan

Trastuzumab emtansine (T-DM1)

Metastatic setting

The efficacy and safety of T-DM1 are being investigated both as a monotherapy and in combination for advanced HER2 + BC following treatment with TKIs or HP therapy [ 20 ]. In a Chinese population, T-DM1 is under investigation as a second- or later-line therapy with prior treatment with taxane and trastuzumab [ 21 ]. The first-stage interim analysis of a trial presented at the 2024 ASCO meeting demonstrated the acceptable efficacy and toxicity of T-DM1 combined with pyrotinib, with an ORR of 30% reported and no grade 3 or 4 toxicities observed [ 22 , 23 ]. The BRIDGET trial is currently evaluating the addition of tucatinib to T-DM1-tucatinib in the first or second isolated intracranial event [ 24 ]. The ATOP trial is not yet recruiting patients but will test older patients with HER2 + mBC [ 25 ]. Furthermore, T-DM1 has been studied in solid tumors other than BC harboring HER2 amplification [ 26 ]. TUCATEMEB, for example, is assessing the intracranial antitumor activity of T-DM1 in patients with HER2 + metastatic solid tumors with metastases to the brain [ 27 ].

Early setting

Adjuvant T-DM1

Many trials are evaluating the tolerability and effectiveness of T-DM1 in the early breast cancer setting. In a real world retrospective-prospective trial, the tolerability and efficacy of adjuvant T-DM1 were studied in patients with HER2 + BC after incomplete pathological response to neoadjuvant chemotherapy [ 28 , 29 ]. The CompassHER2 pCR (comprehensive use of pathologic response assessment to escalate and de-escalate therapy in HER2 + BC) and the CompassHER2 RD trials are designed to address this objective. In the Compass HER2- pCR, the objective is to de-escalate systemic therapy for those who achieve a pCR (pathological complete response) after neoadjuvant chemotherapy, whereas in the Compass HER2-RD the objective is to assess the benefit of adding tucatinib to T-DM1 to prevent relapses after neoadjuvant therapy [ 30 , 31 ].

Adjuvant combinations with T-DM1

As for the ASTEFANIA trial, the adjuvant combination of T-DM1 with atezolizumab for patients at high risk of recurrence following preoperative therapy is being tested [ 32 ]. This combination (T-DM1 plus atezolizumab) had already been studied in the phase II KATE2 trial for locally advanced or metastatic BC. While the overall study did not meet its primary end point in the intention-to-treat population, exploratory analyses in subgroups of patients with PD-L1-positive disease demonstrated that the addition of atezolizumab to T-DM1 resulted in longer median progression-free survival (8.5 vs 4.1 months; HR: 0.60; 95% CI: 0.32–1.11) [ 33 ]. Similarly, another trial aims to evaluate the dynamic changes in minimal residual disease (MRD) following treatment with T-DM1 and Neratinib in resected stage I to stage III HER2 + BC with MRD + [ 34 ]. Finally building on the findings of the ATTEMPT trial, which demonstrated outstanding results of adjuvant T-DM1 versus HP in preventing recurrences of stage I HER2 + BC with a 5-year recurrence-free interval (RFI) of 98.3%, the ATTEMPT 2.0 trial continues to assess longer-term outcomes [ 35 , 36 ].

In terms of cardiotoxicity of T-DM1, the SCHOLAR- 2 is evaluating the safety and efficacy of T-DM1 in early-stage HER2 + BC cancer patients despite mild or asymptomatic left ventricular dysfunction [ 36 , 37 ].

Trastuzumab deruxtecan (T-DXd)

Metastatic setting

HER +/HER2 low/HER2- expression

Several studies are exploring T-DXd in HER2 + patients in the metastatic setting to determine the predictive cut-point for response and the effect of HER2 biomarker on the outcomes [ 38 , 39 ]. In the DAISY trial, the efficacity of T-DXd according to HER2 level of expression have been reported; ORR was 70.6% (95% confidence interval (CI) 58.3–81) in HER2 +, 37.5% (95% CI 26.4–49.7) in HER2 low and 29.7% (95% CI 15.9–47) in HER2 negative [ 40 , 41 ]. HEROIC trial will also address this issue [ 42 ]. Moreover, REFRESH and PROVIDENCE trials aim both to evaluate the real-world effectiveness, health-related quality of life (HRQoL), treatment patterns, and safety of T-DXd in patients with and HER2-low mBC [ 43 , 44 ]. The feasibility of sequential therapy with T-DXd is even being studied in HER2-negative patients [ 45 ].

I n 2023, the DESTINY-Breast04 clinical trial showed that T-DXd was more effective than current standard chemotherapies in HER2 low mBC patients who had received one or two previous lines of chemotherapy [ 16 ]. In ASCO 2024, the primary results from DESTINY- 06 demonstrated statistically meaningful PFS benefit vs TPC (chemotherapy) in HER2-low mBC with prior endocrine therapy but no chemotherapy [ 17 ]. Based on these results, the FDA granted approval for this drug in this setting in 2024 but data for the overall survival are still immature. Additional DESTINY trials are underway such as a DESTINY-Breast15 and DESTINY-Breast Respond HER2-low which will gather more information about how effective T-DXd treatment is in the real world [ 16 , 46 ]. The TRANSCENDER trial evaluates T-DXd as a first line in metastatic setting [ 47 ], and T-DXd is also being evaluated in a basket study for its effects in the HER2 + oligometastatic setting [ 48 ].

Intracranial efficacy trials

Following the substantial and durable intracranial efficacy demonstrated by T-DXd in previously treated patients with HER2 + mBC in DESTINY-Breast12 presented in ESMO 2024, its use is supported regardless of stable or active baseline brain metastases(BMs): the 12-month PFS in the BMs cohort was 61.6% (95% CI 54.9–67.6), and the ORR in the non-BM cohort was 62.7% (95% CI 56.5–68.8) [ 49 , 50 ]. The final results of the TUXEDO- 1 trial also revealed the benefit of T-DXd in prolonged intra- and extracranial disease control in patients with active HER2 + BC BMs with a median PFS of 21 months (95% CI: 13.3–n.r.) [ 51 ]. Furthermore, the ongoing TUXEDO- 4 trial might lead to a shift in the paradigm on treating central nervous system involvement in this population in the next few years [ 52 , 53 ]. The efficacy of T-DXd on brain metastases is being evaluated also with the combination of pyrotinib [ 54 ].

Combinations involving T-DXd

On the other hand, many combinations are being explored in the metastatic setting and include T-DXd with evorpacept, valemetostat, anlotinib, or hydroxychloroquine [ 55 – 58 ]. The most important study is the PRE-ISPY trial, an open-label Phase IB platform study, that evaluated the safety for promising single-agent or combination regimens, with the goal of advancing effective drug regimens into the I-SPY2 [ 58 ].The I-SPY2 trial is a phase II study that aimed at enhancing personalized treatment of stage II and III BC who are at high risk for early recurrence by assessing whether the addition of experimental agents to standard neoadjuvant therapies improves the likelihood of achieving a pCR compared to standard neoadjuvant chemotherapy for each biomarker signature identified at the trial’s outset. Twenty-two agents or combinations and several novel ADCs were included and till now twelve agents have completed accrual and seven have “graduated” in at least one tumor subtype indicating a 85% probability that the agent will be successful in a confirmatory phase III trial [ 59 ]. The preliminary results from the T-DXd + pertuzumab module of DESTINY-Breast- 07 part 1 (data cutoff: Oct 15, 2021), T-DXd + anastrozole and T-DXd + fulvestrant modules of DESTINY-Breast08 part 1 (data cutoff: Sep 27, 2021) [ 60 – 62 ] showed no dose-limiting toxicity. Moreover the safety and effectiveness of T-DXd in combination with immunotherapy is under investigation specifically with pembrolizumab (Pembro) in HER2 + mBC and metastatic non-small cell lung cancer (mNSCLC) [ 63 ].

Early setting

Neoadjuvant T-DXd

In the early-stage breast cancer population, several trials have evaluated the clinical efficacy and safety of neoadjuvant T-DXd. The phase 2 TALENT trial provided preliminary evidence of clinical activity of neoadjuvant T-DXd in patients with HR +/HER2-low early BC: from the 37 patients who were enrolled as of January 2022, 24 completed treatment and 14 have had surgery [ 64 , 65 ]. Currently, the ARIADNE trial is assessing T-DXd in conjunction with a biology-driven selection of neoadjuvant treatments for HER2 + BC [ 66 ], and the TRUDI trial is assessing T-DXd with immunotherapy as a neoadjuvant treatment for stage III HER + BC [ 67 ]. Similarly, the DESTINY-B11, SHAMROCK, and ADAPT-HER2-IV studies are evaluating the efficacy and safety of T-DXd in the neoadjuvant setting for HER + BC exploration strategies for therapy escalation and de-escalation [ 68 – 70 ]. Previous ADAPT HER2 + subtrials demonstrated that T-DXd and T-DM1 are excellent candidates for de-escalation approaches in HER2 + early BC because of their high efficacy and low toxicity [ 71 ] .

Sacituzumab govitecan (SG)

Real-world trials in TNBC

Sacituzumab govitecan (SG) treatment has shown efficacy in the setting of TNBC, and other biological BC and ongoing treatment strategies have been implemented recently.

A real-world phase I study of SG is currently active, with a focus on patients with mBC in China [ 72 ]. The effectiveness of SG is also being studied in a real-world context for research on predictive biomarkers of efficacy/tolerability in the BIO-PROSA trial [ 73 ].

HR +/HER2− BC

The CelTIL score is used as a surrogate of treatment response after one dose of SG in HR +/HER2− BC in the ACROSS-TROP2 trial [ 74 ]. The SERIES trial is also examining HR +/HER2− advanced/mBC patients who have been previously treated with T-DXd [ 75 ].

Combination including SG

Additional studies include phase II trials examining SG alone or with pembrolizumab for PD-L1-TNBC or for HR +/HER2− BC [ 76 , 77 ]. The addition of pembrolizumab to SG showed a nonsignificant trend toward improved PFS in HR +/HER2− MBC patients at the preliminary time point (2024) and OS data are still immature [ 78 ]. However, with the addition of talazoparib to SG in a single-arm phase II study, talazoparib was acceptable and demonstrated till march 2023 there was preliminary evidence of efficacy in mTNBC with 6 of 26 patients remaining on treatment at time of data cutoff [ 79 , 80 ]. Other combination trials of SG with trastuzumab, avelumab, or alpelisib are awaiting promising results [ 81 – 83 ].

Intracranial efficacy

On the other hand, the evaluation of intracranial efficacy enrollment is currently ongoing for the phase 2 SWOG S2007 trial, which tested SG in patients with HER2− BC with brain metastasis [ 84 ].

Ongoing ASCENT trials

Otherwise, a list of phase III trials called “ASCENT trials” is comparing the SG to the physician’s choice in TNBC. The clinical benefit of SG over chemotherapy has been established in patients with mTNBC as second-line therapy or later on the basis of the final analysis of the ASCENT T trial, which revealed improvements in mPFS of 4.8 v 1.7 months (hazard ratio (HR), 0.41 [95% CI, 0.33–0.52]) and mOS of 11.8 v 6.9 months (HR, 0.51 [95% CI, 0.42–0.63]) over [ 85 ]. Currently, the ASCENT- 03 trial focuses on patients who are PD-L1 negative or PD-L1 + in treatment-naïve mTNBC. Similarly, the ASCENT- 04 trial evaluated the combination of SG plus pembrolizumab against TPC as a first-line treatment in PD-L1 + TNBC patients [ 86 , 87 ].

Early setting

Neoadjuvant treatment

For early-stage BC, the NEOSTAR trial assessed SG as an upfront treatment for 50 patients with localized TNBC, revealing a 30% pathological complete response (pCR) and a 64% response rate (RR) postsurgery. This first neoadjuvant trial with an ADC in patients with localized TNBC demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation [ 87 ]. The ADAPT-TN-III raises the question of whether 12–18 weeks of neoadjuvant treatment with SG alone or in combination with pembrolizumab can be associated with comparable pCR rates after chemotherapy as neoadjuvant therapy [ 88 ].

Adjuvant treatment

The ongoing SASCIA trial randomly assigns patients with residual invasive disease after taxane-based neoadjuvant chemotherapy to receive either SG or treatment of physician’s choice (TPC) for eight cycles, focusing on invasive disease-free survival (iDFS) [ 89 ], and the results from the interim analysis of this trial presented at ESMO Breast Cancer 2022 suggested that the safety profile of SG was manageable [ 90 ]. The early-stage setting has been explored in the ASCENT- 05 trial for TNBC patients following surgery and neoadjuvant therapy, while additional studies are investigating the combination of SG with pembrolizumab in this population for residual disease [ 91 – 93 ].

All these trials for T-DM1, T-DXd and SG are summarized in Tables 5 , 6 , and 7 , respectively, organized by their focus on either the metastatic or early-stage settings. Table 5 Ongoing trials of trastuzumab emtansine ADC Trial Phase Population/setting Arms/combinations Primary outcome Secondary outcomes Preliminary results Advanced/metastatic setting T-DM1 NCT06125834 [ 20 ] II HER2 + advanced BC after progression after TKIs or HP ORR PFS OS AEs Antitumor immunity Tumor heterogeneity N/A NCT05945927 [ 21 ] I Second- or later-line therapy in Chinese HER2 + advanced unresectable BC after treatment with taxane and trastuzumab % AEs rwPFS TTD % of T-DM1 (line of therapy + dosage + dose intensity + duration) N/A NCT05560308 [ 23 ] II HER2 + mBC after progression on TKI therapy ORR safety DCR PFS OS ORR % : 30% > 3 AEs % : 20% PFS months : 7.77 months (95% CI 3.30–NA) [ 21 ] BRIDGET NCT05323955 [ 24 ] II HER2 + BC on maintenance HP or T-DM1 with 1 st or 2nd intracranial disease event HP + tucatinib T-DM1 + tucatinib PFS PFS Site of first progression OS AEs N/A ATOP NCT03587740 [ 25 ] II Older (age ≥ 60 years) HER2 + BC 5-year DFS RFS OS Sites of recurrence Toxicity Cardiac AES N/A Early setting NCT05754502 [ 28 ] I HER2 + BC with residual disease after neoadjuvant chemotherapy and anti-HER2 CR effectiveness N/A NCT06272799 [ 29 ] I HER2 + BC with incomplete PR to Neoadjuvant Chemotherapy and Anti-HER2 Tolerability Effectiveness N/A CompassHER2 RD NCT04457596 [ 30 ] III High-risk HER2 + BC with residual disease after neoadjuvant chemotherapy T-DM1 T-DM1 + Tucatinib IDFS Idfs DFS DRFS BM-free survival OS Incidence of BMs QoL N/A CompassHER- 2 Pcr NCT04266249 [ 31 ] II Stage II-IIIa HER2 + BC with residual disease after neoadjuvant chemotherapy and anti HER2 RFS IDFS DDFS DRFS RFI OS EFS AEs N/A Astefania NCT04873362 [ 32 ] III HER2 + (Ct4/anyN/M0, any Ct/N2 - 3/M0, or Ct1 - 3/N0 - 1/M0) who have received preoperative chemotherapy and anti-HER2 Placebo + T-DM1 Atezo + T-DM1 Idfs IDFS IDFS in the PD-L1-positive and the PD-L1-negative Population DFS OS DRFI GHS/QoL Cmax Cmin Atezo, Trastuzumab and T-DM1 AEs N/A KAN-HER-MRD NCT05388149 [ 34 ] II Resected Stage I-III HER2 + BC with MRD + after standard neoadjuvant T-DM1 + neratinib Rate of ctDNA clearance Clinical outcomes (IBCFS) Toxicities Dynamic changes and kinetics in ctDNA MRD N/A ATEMPT 2.0 NCT04893109 [ 35 ] II Adjuvant Stage I HER2 + invasive BC T-DM1 ➔ trastuzumab SC Paclitaxel + Trastuzumab SC ➔ trastuzumab SC Clinically relevant toxicities DFS AEs QoL Gene profiling OS Toxicity of radiation therapy N/A SCHOLAR- 2 NCT04680442 [ 37 ] II Stage I-III HER- 2 + BC with left ventricular dysfunction % of patients continuing treatment LVEF at the close-out visit Composite of NYHA class III or IV heart failure or CV death BC relapses All-cause mortality N/A Table 6 Ongoing trials for trastuzumab deruxtecan Trial Phase Population/setting Arms/combinations Primary outcome Secondary outcomes Preliminary results Metastatic setting T-DXd DIAMOND NCT05919212 [ 38 ] II HER2 + BC with T-Dxd used as second line treatment Alterations associated with resistance to T-Dxd Molecular stratification Lead time assessment by liquid biopsy association between HER2 and outcomes N/A HER2-PREDICT NCT04257162 [ 39 ] I HER2 + mBC ERBB2 mRNA cut-point predictive of T-DXd response N/A DAISY NCT04132960 [ 40 ] II mBC with different HER2 level of expression HER2 + ORR Safety ORR % HER2 + 70.6% (95% CI 58.3–81) HER2-low 37.5% (95% CI 26.4–49.7) HER2- negative 29.7% (95% CI 15.9–47) [ 39 , 41 ] HER2 low HER2 negative HEROIC NCT06551220 [ 42 ] II HER2 + mBC with different HER2 expressions PFS OS N/A PROVIDENCE NCT05573893 [ 44 ] II HER2 +/HER2 low unresectable or mBC previously treated rwTTNT N/A REFRESH NCT06210776 [ 43 ] I HER2 +/HER2 low unresectable or mBC previously treated or progressed after adjuvant therapy rwTTNT Change in T-DXd TTP Dosing rwTTD AEs N/A NCT06409390 /MCC- 22617 [ 45 ] I HR + HER2− mBC previously treated Cytoxan/taxotere Feasibility of sequential therapy Safety No evidence of disease N/A SG or T-DXd Capecitabine Fulvestrant + CDK 4/6 inhibitor DESTINY-BREAST- 06 NCT04494425 [ 17 ] III HR + or HER2 low or HER2 ultralow mBC with ≥ 1 prior endocrine-based therapy (ET) T-DXd PFS OS PFS2 ORR DoR QoL AEs PFS months (HR, 0.62 95% CI 0.51–0.74): T-DXd: 13.2 months TPC: 8.1 months TPC paclitaxel, nab-paclitaxel) DESTINY-Breast Respond HER2-low Europe NCT05945732 [ 16 ] I Unresectable or HER2-low mBC with prior chemotherapy or recurrence within 6 months after adjuvant Rw TTNT RwTTD, Safety events, AEs PGI-TT N/A DESTINY-Breast15 NCT05950945 [ 46 ] IIIb HER2− or low/HR + or HR -unresectable and/or mBC with one or 2 prior lines of therapy HR-/HER2-low TTNT PFS, TTT Time From Start to discontinuation of T-DXd or death (TTD) ORR Number of patients with AEs, QoL N/A HR-/HER2− HR + HER2-low HR +/HER2− TRANSCENDER NCT05744375 [ 47 ] II HER2 + advanced or mBC with no prior chemotherapy or HER2 targeted therapy ORR PFS, OS DOR Number of participants with AEs GHS score TTD in QoL N/A ANISE NCT05982678 [ 48 ] II HER2 + BC and 1–3 distant metastatic lesions (oligometastatic) CRR PFS OS pCR Metabolic response AEs N/A DESTINY-Breast12 NCT04739761 [ 50 ] IIIB/ IV HER2 + advanced or mBC stable or active (untreated/previously treated and progressing) BMs ORR without BM PFS with BM CNS PFS, ORR TTSP CNS ORR New BMs TTP DOR OS ILD Time and site of next progression, QoL ORR % Without BM: 62.7% (95% CI 56.5–68.8) PFS 12 months 61.6% (95% CI 54.9–67.6) [ 49 ] TUXEDO- 4 NCT06048718 [ 52 ] II HER2-low BC with BMs ORR-CNS ORR for extracranial lesions Bi-CBR Bi-DCR TTR % of change in tumor burden DOR OS PFS Aes QoL N/A NCT06135194 [ 54 ] II HER2 + BC with BM after prior pyrotinib CNS-PFS ORR/CBR for intra/extracranial lesions OS N/A T-DXd or SG NCT06328387 [ 55 ] I/II HER2 + inoperable cancer SG DLT AEs ORR PFS OS CBR DCR QoL Correlation between biomarkers and ORR N/A HCQ + SG T-DXd HCQ + T-DXd ALTER-BC-Ib- 01 NCT06331169 [ 56 ] Ib HER2 low unresectable and/or mBC with ≥ 1 prior lines of chemotherapy T-DXd + anlotinib RP2D ORR DOR DCR PFS OS Aes N/A NCT05633979 [ 57 ] Ib HER2 low/ultralow/null locally progressive or mBC with prior one line of treatment T-DXd + valemetostat MTD/RDE of valemetostat ORR DOR PFS OS CBR N/A PRE-I-SPY/I-SPY-P1 NCT05868226 [ 58 ] I/Ib HER2 + mBC PRE1 ALX148 + T-DXd AEs DLTs MTD RP2D ORR DOR PFS CBR N/A PRE2 zanidatamab (ZW25, zani) + tucatinib (TUKYSA®) DESTINY-BREAST- 08 NCT04556773 [ 60 ] Ib HER2 low advanced or mBC T-DXd + capecitabine AEs ORR OS PFS No DLTs for T-DXd + anastrozole or T-DXd + fulvestrant [ 61 ] T-DXd + Durva + Pac T-DXd + capivasertib T-DXd + anastrozole T-DXd + fulvestrant DESTINY- BREAST − 07 NCT04538742 [ 61 ] I/II T-DXd AEs ORR PFS PFS2 OS RP2D Immunogenicity No DLTs for Durva + pertuzumab [ 61 ] T-DXd + Durva T-DXd + pertuzumab T-DXd + paclitaxel T-DXd + Durva + paclitaxel T-DXd + Tucatinib NCT04042701 [ 63 ] Ib HER2 +/HER2 low advanced/mBC and HER2 locally advanced/mNSCLC ± prior treatment with T-DM1 T-DXd + Pembro DLTs ORR N/A Early setting TRIO-US B- 12 TALENT trial NCT04553770 [ 65 ] II HR +/HER2-low cT2 or if cN1/N2 the tumor must be considered operable Neo Adjuvant T-DXd pCR Molecular changes in tumor biomarkers COR AEs Biomarkers analysis 24/27 patients enrolled completed treatment, 14 had surgery [ 64 ] Neoadjuvant T-DXd + Anastrosole ARIADNE NCT05900206 [ 66 ] III HER2 + BC stage cT2-cT4 with any cN, or cN1-cN3 with any Ct T-DXd (cycles 1–3) pCR EFS Distant RFS, OS ORR Residual cancer burden Breast conserving surgery De-escalation of breast surgery SLND De-escalation of axillary surgery N/A TCHP or PCHP (cycles 1–3) TRUDI NCT05795101 [ 67 ] II HER2 +/HER2-low inflammatory BC with no prior treatment T-DXd + Durva pCR Residual cancer burden EFS DP DDFS N/A ADAPTHER2-IV NCT05704829 [ 68 ] II HER2 + patients with a low-intermediate risk profile (e.g., node-negative patients with cT1 - 2 tumors) T-DXd × 12 weeks in low-intermediate risk PFS DDFS CR DDFS iDFS OS LRFS BCFS DRFI QoL N/A T-DXd × 18 weeks in intermediate-high risk T HP in low-intermediate risk × 12 weeks [P or T] + C + HP × 18 weeks in intermediate-high risk SHAMROCK NCT05710666 [ 69 ] II Neoadjuvant setting stage II/III HER2 + BC pCR EFS OS Molecular evolution of tumors N/A DESTINY- 011 NCT05113251 [ 70 ] III Neoadjuvant setting, high-risk, HER2 + cT0 - 4 and N1 - 3; or > cT3/N0/M0 T-DXd pCR EFS IDFS OS N/A T-DXd➔ THP ddAC ➔THP Table 7 Ongoing trials of sacituzumab govitecan ADC Trial name Phase Population/setting Arms/combinations Primary outcome Secondary outcomes Preliminary results Metastatic setting SG Real-word Chinese trial NCT06356519 [ 72 ] I Chinese mBC PFS OS ORR Safety N/A BIO-PROSA NCT06240195 [ 73 ] I mTNBC Biomolecular investigations PFS Tolerability N/A ACROSS TROP2 NCT06236269 [ 74 ] II HR +/HER2− advanced or mBC CelTIL score ORR CBR PFS DPR TTR AEs Correlation and clinical benefit between TROP2 mRNA expression with TROP2 IHC expression Safety and tolerability N/A SERIES NCT06263543 [ 75 ] II HR +/HER2- low BC previously treated with (T-DXd) ORR CBR DOR PFS OS Growth factor support Global QoL AEs N/A Saci-IO HR + NCT04448886 [ 76 ] II HR +/HER2− BC after previous endocrine therapy SG + Pembro PFS CBR DOR ORR OS TTP safety PFS months (HR 0.76, 95% CI 0.47–1.23): SG + Pembro: 8.4 months SG: 6.2 months [ 77 ] SG Saci- IO TNBC NCT04468061 [ 77 ] II Treatment naïve (first line) mTNBC PDL1 negative SG + Pembro PFS OS ORR DOR TTOR CBR Safety N/A SG NCT04039230 [ 79 ] I/II mTNBC SG + Talazoparib ORR DLT PFS OS TTR DOR 6/26 still on treatment at time of data cutoff mPFS months : 6.2 months (95% CI, 3.7–12.8) mOS months : 18 months (95% CI, 10.7–NA) [ 79 ] ASSET NCT05143229 [ 81 ] I Locally recurrent or mHER2 negative BC SG + alpelisib dose (RP2D) of alpelisib + SG Pharmacokinetics ORR N/A SATEEN NCT06100874 [ 82 ] II HER2 + mBC SG + trastuzumab ORR PFS CBR OS DOR TTR N/A InCITe NCT03971409 [ 83 ] II Unresectable, locally advanced or mTNBC Avelumab, binimetinib, liposomal doxorubicin BORR ORR CBR PFS OS Safety QoL AEs N/A avelumab, SG Avelumab, liposomal doxorubicin SWOG S2007 NCT04647916 [ 84 ] II HER2 + BC with BMs ORR OS PFS AEs N/A ASCENT- 03 NCT05382299 [ 87 ] III Unresectable, locally advanced or metastatic treatment naïve TNBC, PD-L1—and PD-L1 + SG PFS OS ORR DOR TTR Safety QoL N/A TPC Paclitaxel/nabpaclitaxel gemcitabine/carboplatin + Pembro ASCENT- 04 NCT05382286 [ 86 ] III Unresectable, locally advanced or metastatic treatment naïve TNBC, PD-L1 + SG + Pembro PFS OS ORR DOR TTR Safety N/A TPC Paclitaxel/nabpaclitaxel gemcitabine/carboplatin + Pembro Early setting NeoSTAR NCT04230109 [ 94 ] II Neoadjuvant for early or locally advanced treatment naïve TNBC SG pCR DFS OS BCR AE QoL pCR %: 30% (95% CI 18 to 45%) ORR %: 64% (95% CI 77 to 98%) [ 94 ] SG + Pembro ADAPT-TN-III NCT06081244 [ 88 ] II Neoadjuvant low-risk early TNBC SG pCR iDFS OS dDFS dDFI BCFI QoL N/A SG + Pembro SASCIA NCT04595565 [ 89 ] III Postneoadjuvant (residual disease) TNBC HR +/HER- SG iDFS OS DDFS iBCFS LRRFI Safety PROs Occurrence of AEs % SG: 100% TPC: 86% [ 89 ] TPC: capecitabine, carboplatin or cisplatin ASPRIA NCT04434040 [ 91 ] II Early TNBC SG + Atezo Undetectable cfDNA Undetectable cfDNA AEs IDFS DMFS OS RR N/A ASCENT- 05 NCT05633654 [ 92 ] III Postneoadjuvant and surgery (residual disease) of invasive TNBC SG + Pembro iDFS OS dDFS RFS AEs QoL N/A Pembro or Pembro + capecitabine NCT05675579 [ 93 ] II Immunochemotherapy-resistant early-stage TNBC SG + Pembro AEs N/A The following are abbreviations for Tables 5 , 6 , and 7 : BC breast cancer; mBC metastatic breast cancer; mTNBC metastatic triple-negative breast cancer; RD residual disease; BMs brain metastasis; BORR best overall response rate; CBR clinical benefit rate; CT chemotherapy; DP distant progression; DDFS distant disease-free survival; DDFI distant disease-free interval; CRR complete radiological response; CV cardiovascular; RFS recurrence-free survival; LRFS local recurrence-free survival; DFS disease-free survival; DMFS distant metastasis-free survival; DLT dose-limiting toxicity; ddAC dose-dense doxorubicin and cyclophosphamide; DOR duration of response; ET endocrine therapy; EXP experimental; HER2 human epidermal growth factor receptor 2; HR hormone receptor; TN triple negative; NTC national clinical trial; ORR objective response rate; OS overall survival; pCR pathologic complete response; PD-L1 programmed death-ligand 1; PFS progression-free survival; QoL quality of life; RCT randomized clinical trial; rRR radiological response rate; SG Sacituzumab govitecan; TNBC triple negative breast cancer; TPC Treatment of Physician’s Choice; TTD time to deterioration; TTOR time-to-objective response; TTR time to response; TTNT Time From the Start of T-DXd to Initiation of Subsequent Anticancer Treatment; PGI-TT Patient’s Global Impression of Treatment Tolerability; rw real word; EFS event free survival; RFS relapse free survival; Pembro pembrolizumab; Atezo atezolizumab; Durva durvalumab; HCQ hydroxychloroquine; HP trastuzumab, PAC paclitaxel, DOC docetaxel; TCHP docetaxel, carboplatin, trastuzumab, pertuzumab; PCHP paclitaxel, carboplatin, trastuzumab, pertuzumab; MTD maximum tolerated dose; RDE recommended dose escalation; RP2D recommended phase 2 dose; Bi bicompartmental; iBCSF invasive breast cancer-free survival; LRRFI locoregional recurrence-free interval; LRFS local recurrence-free survival; BCFI breast cancer-free interval; BCFS breast cancer-free survival; PROs patient-reported outcomes; cFDNA circulation-free DNA

Some of these trials are currently underway to evaluate sequential therapies, including ADCs such as T-DXd and SG, to find more effective treatments for mBC [ 95 ]. Additionally, umbrella studies are ongoing and include a range of FDA-approved and non-FDA-approved ADCs for mBC, one of which is the Morpheus pan-BC study [ 96 , 97 ]. The data presented in the ESMO 2024 trial of Morpheus were immature but showed a trend toward benefit with the combination of atezolizumab and SG versus atezolizumab and nabpaclitaxel of 12.2 vs. 5.9 months in patients with mTNBC [ 98 ].

Ongoing trials of investigational antibody‒drug conjugates (ADCs)

Most ADCs have not yet received approval for use, but many are currently being evaluated in clinical trials for their use in BC. In Table 8 , we present a list of ongoing studies examining investigational ADCs, focusing on their application in both early-stage and locally advanced/mBC, and present preliminary results if they exist. Table 8 Ongoing trials of investigational antibody‒drug conjugates (ADCs) ADC Target Trial Name Phase Combinations Population/Setting Primary Outcomes Preliminary results Ladiratuzumab vedotin (SGN-LIV1 A) LIV- 1 KEYNOTE 721 NCT03310957 [ 99 ] I/II Pembro Advanced TNBC ORR N/A I-SPY2 Trial NCT01042379 [ 100 ] II 22 agents of combinations Early-stage, locally advanced HR +/HER2− HER2 + and TNBC BC pCR Twelve agents have completed accrual and seven have “graduated” in at least one tumor subtype [ 59 ] Disitamab vedotin (RC48-ADC) HER2 NCT04400695 [ 101 ] III HER2 low BC previous use of anthracyclines, and one or two prior systemic chemotherapy PFS N/A NCT05831878 [ 102 ] II HER2 low advanced previously treated BC ORR N/A ROSY NCT05904964 [ 103 ] III RC48 1 st-line endocrine resistant HER2-low mBC PFS N/A Endocrine therapy Jixin Yang et al. [ 104 ] II Neoadjuvant for early stage HER2 + BC pCR 11.8% (2/17) HR-/HER2 + patients achieved pCR [ 103 ] Patritumab deruxtecan (U3 - 1402) HER3 NCT04699630 [ 105 ] II mBC ORR PFS 6 months ORR % : 35% [95% CIs 23.1, 48.1] PFS 6 months: 60% ICARUS-BREAST- 01 NCT06298084 [ 106 , 107 ] II HR + and HER2- Advanced BC unselected for HER3 expression, who progressed on multiple lines ORR RR 3 months% : 28.6% (95% CI: 18.4–41.5) SOLTI TOT-HER3 NCT04610528 [ 108 ] II Early-stage treatment naïve HR +/HER2- and TNBC Change from baseline in CelTIL score Part A results: Biogical and clinical activity: increase in CelTIL from baseline of 3.5 Part B results: Significant change in CelTIL; P = 0.046) ORR 32% VALENTINE NCT05569811 [ 109 ] II Endocrine therapy Neoadjuvant high-risk HR +/HER2- early stage BC pCR N/A ARX- 788 HER2 ACE-Breast- 02 CTR20201708 [ 110 ] III ARX788 HER2 + advanced mBC PFS mPFS months (HR 0.64): ARX 788: 11.33 months LC: 8.25 months Lapatinib + Capecitabine ACE-Breast- 03 NCT04829604 [ 111 ] II HER2 + mBC previously treated with T-DXd NA ISPY- 2.2 [ 112 ] II Cemiplimab Neoadjuvant early stage I–III HER2 + BC pCR N/A NCT04983121 [ 113 ] II Pyrotinib (HER2 TKI) Neoadjuvant early stage II–III HER2 + BC RCB N/A Datopotamab deruxtecan (Dato-DXd, DS- 1062a) Trop 2 TROPION Breast 01 NCT05104866 [ 114 ] III Dato-DXd Inoperable or mHR +/HER2− PFS OS mPFS months (HR 0.63) Dato-DXd: 6.9 months ICC: 4.9 months [ 115 ] ICC Capecitabine Gemcitabine Eribulin mesylate Vinorelbine TROPION Breast 02 NCT05374512 [ 116 ] III Dato-DXd Locally recurrent inoperable or mTNBC who are not candidates for PD- 1/PD-L1 inhibitor therapy PFS OS NA ICC TROPION Breast 03 NCT05629585 [ 117 ] III Dato-DXd + Durva Postneoadjuvant early (stage I–III) TNBC with residual disease iDFS NA Dato-DXd ICC ISPY- 2.2 [ 100 ] II Dato-DXd + Durva Neoadjuvant early stage I–III TNBC pCR rate pCR % : 72% [ 118 ] NCT03742102 [ 119 , 120 ] Ib/II Durva + T-DXd First-line mTNBC AEs Grade 3/4 AEs Durva + paclitaxel: 44% Durva + T-DXd: 36% SAEs Durva + paclitaxel: 9% Durva + T-DXd: 4% [] Durva paclitaxel + capivasertib Durva + paclitaxel + oleclumab Durva + Paclitaxel Durva + Dato-DXd TROPION-Breast05 NCT06103864 [ 121 ] III Dato-DXd + Durva PD-L1 positive locally recurrent inoperable or mTNBC PFS NA ICC + Pembro (paclitaxel/nabpaclitaxel/or gemcitabine + carboplatin) COMPASS-TNBC NCT06508216 [ 122 ] Ib/II Early Relapsed mTNBC ORR NA DATO-BASE NCT06176261 [ 123 ] II mBC with BMs IC RR NA TUXEDO-II NCT05866432 [ 105 ] II mTNBC with BMs IC RR IC- RR % : 83.3% enrolled in the first stage The trial progressed to the second stage Trastuzumab rezetecan (SHR-A1811) HER 2 NCT06411457 [ 124 ] II SHR + adebrelimab HER2 low mBC, with prior treatment with ≥ 1 line of therapy or localized recurrence or metastatic disease ORR NA NCT05814354 [ 125 ] III SHR-A1811 HER2 low recurrent/mBC PFS NA ICC Capecitabine/eribulin/gemcitabine/paclitaxel/Nab-paclitaxel NCT05845138 [ 126 ] I/II Capecitabine Unresectable or mBC with low HER2 expression DLT AEs ORR NA SHR-A1811 injection NCT05353361 [ 127 ] Ib/II SHR + pyrotinib or pertuzumab or adebrelimab or paclitaxel for injection mBC Safety DLT AE NA NCT05769010 [ 128 ] II SHR ± Pyrotinib or Bevacizumab HER2-expression Advanced BC with BMs CNS ORR (ORR-IC) ORR-IC: 84% NCT05635487 [ 129 ] II SHR + pyrotinib maleate Neoadjuvant early stage HER2 + BC pCR RR % : 78.6% (95% CI, 59.1–91.7) [ 130 ] NCT05911958 [ 131 ] II Neoadjuvant early HR +/HER2 low BC ORR NA Sacituzumab Tirumotecan (SKB264/MK- 2870) Trop 2 OptiTROP-Breast01 NCT05347134 [ 132 ] III SKB264 Locally recurrent or mTNBC who had received ≥ 2 prior therapies including at least one for metastatic setting PFS PFS months (HR 0.31; 95% CI, 0.22–0.45) SKB264: 5.7 months TPC: 2.3 months [ 133 ] ICC Eribulin/capecitabine/gemcitabine/vinorelbine NCT06312176 [ 134 ] III SG HR +/HER2− unresectable, locally advanced or mBC PFS OS ORR Change from baseline TTD AEs NA Pembro + SKB264 ICC MORAb- 202 FRα NCT04300556 [ 135 ] I/II mTNBC previously treated ORR RP2D DLT AEs CR: 5% PR: 41% Stable disease: 46% [ 135 ] BC breast cancer; TNBC triple-negative breast cancer; mBC metastatic BC; mTNBC metastatic triple-negative breast cancer; HR + hormone receptor positive; HER2 + HER2 positive; HER2− HER2 negative; Pembro pembrolizumab; Durva durvalumab; ORR overall response rate; OS overall survival; PFS progression-free survival; AEs adverse effects; SAEs serious adverse effects; RR response rate; ICRR intracranial response rate DLT TTD time to deterioration; RP2D recommended phase 2 dose; pCR pathological complete response; CR complete response; PR partial response; DLT dose-limiting toxicity; RCB residual cancer burden; CNS ORR central nervous system overall response rate; ICC investigators’ choice of chemotherapy; NA not applicable

Ladiratuzumab vedotin (SGN-LIV1 A)

An example of these ADCS is ladiratuzumab vedotin, which is composed of a humanized anti-LIV- 1 monoclonal antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable linker. SGN-LIV1 A has already been demonstrated to be safe alone and with trastuzumab in HER2 + BC [ 97 ]. Other ongoing studies are investigating LV in combination with pembrolizumab as a first-line treatment and atezolizumab as a second-line treatment for TNBC in the Morpheus trial mentioned above [ 96 , 99 ]. In the early-stage setting, LV was included as a neoadjuvant treatment in the I-SPY2 trial.

Disitamab vedotin (RC48)

Disitamab vedotin (RC48) is a novel ADC that targets HER2 with improved affinity. It is currently being studied in populations with low HER2 expression [ 101 , 102 ]. Wang et al. (2021) reviewed data from two prior studies demonstrating the effectiveness of RC48 in both HER2 + and HER2 low populations with advanced or mBC, and the results showed consistent efficacy in both subgroups [ 136 ]. In the ongoing Rosy trial, we intend to explore the efficacy and safety of RC48 in the treatment of HER2‐low patients with endocrine resistance [ 103 ].

In the early setting, the interim analysis of a trial suggested that the safety and efficacy of RC48 as a neoadjuvant therapy in HR-/HER2 + patients are promising, with 11.8% (2 out of 17 patients) achieving a pathological complete response (pCR) [ 104 ].

Patritumab deruxtecan (HER3-DXd)

Patritumab deruxtecan (HER3-DXd) is an antibody‒drug conjugate that combines a fully human anti-HER3 IgG1 monoclonal antibody, patritumab, with a topoisomerase 1 inhibitor. In a phase II interim analysis presented in ASCO 2023, HER3-DXd demonstrated an acceptable safety profile, and the data further confirmed the clinical activity in the metastatic setting across the broad range of HER3 expression levels, with an ORR of 35% (95% CIs 23.1, 48.1) and PFS 6 months of 60% for all patients [ 105 ]. Moreover, the ICARUS-BREAST01 assessment of HER3-DXd in HR +/HER2− mBC patients who progressed on multiple lines of treatment, including CDK4/6 inhibitors and chemotherapy, demonstrated a 3-month response rate of 28.6% [ 106 , 107 ]. Dose expansion of HER3 is under investigation in ICARUS-BREAST02 [ 137 ].

In early HR +/HER2− early BC, a window-of-opportunity trial evaluated the use of P-DXd within a 21-day preoperative window in treatment-naïve patients [ 108 ]. This study revealed an association between P-DXd and clinical response, enhanced immune infiltration, and cell growth suppression. Finally, in this same population, the VALENTINE trial assessed P-DXd in combination with endocrine therapy [ 109 ].

ARX- 788

ARX- 788 is an antibody‒drug conjugate (ADC) that targets HER2 and is characterized by its ability to conjugate a wide variety of payloads. In the preliminary results of the phase III ACE-Breast- 02 trial’s preliminary results, ARX788 significantly prolonged PFS compared with lapatinib combined with capecitabine (LC) in HER2 + mBC: the median PFS was 11.33 months with ARX788 versus 8.25 months with LC [ 110 ]. The ongoing ACE-Breast- 03 study is assessing ARX- 788 in HER2 + mBC patients previously treated with trastuzumab deruxtecan (T-DXd) [ 111 ]. Additionally, this ADC is included in the I-SPY2 trial exploring the combination of ARX- 788 with the PD- 1 inhibitor cemiplimab as neoadjuvant therapy in early-stage HER2 + BC [ 111 ]. Other combinations are also under investigation [ 112 ].

Datopotamab deruxtecan (Dato-DXd)

Datopotamab deruxtecan (Dato-DXd) is another notable ADC that consists of a Trop- 2 directed MoAb, a tetrapeptide-based linker and a topoisomerase 1 inhibitor. Compared with the investigator chemotherapy choice (ICC) (HR, 0.63), Dato-DXd was associated with a 37% reduction in the risk of progression or death compared to the investigators chemotherapy choice (ICC) (HR, 0.63) in HR +/HER2− mBC as shown in TROPION – Breast01 trial. The median PFS as assessed was 6.9 months (95% CI, 5.7 to 7.4) for Dato-DXd, compared to 4.9 months (95% CI, 4.2 to 5.5) for ICC. Although OS data is not definitive, there was a trend in the interim OS results that favored the Dato-DXd arm [ 114 ]. After the favorable preliminary results of phase III TROPION-Breast01 in inoperable or mHR + BC [ 115 ], the TROPION-Breast02 trial evaluated Dato-DXd versus ICC in patients as a first-line therapy for locally recurrent inoperable or mTNBC patients who cannot receive PD- 1/PD-L1 inhibitors [ 116 ]. Moreover, the TROPION-Breast05 trial will assess this combination compared to the investigator’s choice of chemotherapy plus pembrolizumab in patients who are PD-L1-positive [ 121 ], and the TROPION-BREAST03 will shift the focus to the combination or Dato-DXd with durvalumab or Dato-DXd plus durvalumab in the early stage setting [ 117 ].

On the basis of the results from the SPY2.2 trial presented in ASCO 2024, the combination of Dato-Dxd and durvalumab achieved the graduation threshold, with an estimated pCR rate of 72% [ 100 , 118 ], and on the basis of the phase Ib/II BEGONIA study, this combination demonstrated durable responses in unresectable advanced TNBC patients [ 119 ]. The phase IB/II Compass- TNBC trial focused on addressing Dato-Dxd in early relapse [ 122 ].

Finally, the DATO-based trial focuses on Dato in brain metastases. This study is based on clinically significant preliminary activity demonstrated in TUXEDO- 1 among HER2 + BC patients with BM, where an intracranial response rate of 83.3% was observed [ 123 , 138 , 139 ].

Trastuzumab rezetecan (SHR-A1811)

SHR-A1811 is a novel ADC composed of trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. Previously, in a phase I trial that enrolled 77 patients with HER2-low mBC, SHR-A1811 demonstrated an ORR of 49.4% and a 6-month PFS rate of 63.8% [ 140 ]. SHR-A1811 is currently undergoing trials alone and in combination with adebrelimab to target mBC with low HER2 expression [ 124 ]. In this context, two ongoing phase III trials are comparing the activity of the conjugate with that of conventional chemotherapy among patients who are chemotherapy refractory or chemotherapy naïve, assessing dose-limiting toxicities, adverse events, and the ORR [ 125 , 126 ].

Additionally, SHR-A1811 as an injection is being examined for safety and tolerability in mBC in combination with pyrotinib, pertuzumab, adebrelimab, or paclitaxel [ 127 ]. Another trial is currently evaluating the efficacy of this treatment in HER2-expressing advanced BC patients with BMs. At the ASCO 2024 meeting, 25 patients with HER2 + BC with BM were enrolled. All participants had previously received HER2-targeted therapies, with a median of two prior systemic treatments in the advanced setting. As of January 30 2024, 21 patients achieved intracranial responses, resulting in an ORR in the central nervous system (ORR-IC) of 84% [ 130 ].

In the early setting, SHR-A1811 was combined with pyrotinib maleate as a neoadjuvant therapy in HER2 + BC patients. As of November 14 2023, 29 patients were enrolled and the overall tpCR rate was 78.6% (22/28, 95% CI, 59.1–91.7) [ 129 , 130 ]. Another neoadjuvant trial is ongoing and will target HR+/HER2-low BC, assessing the overall response rate (ORR) [ 131 ].

Sacituzumab tirumotecan (SKB264/MK- 2870)

Another ADC that targets the trop- 2 protein is sacituzumab tirumotecan (MK- 2870), which was evaluated in the OptiTROP-Breast01 trial for mTNBC [ 132 ]. The primary results of this trial are presented in ASCO 2024: the primary end point was met as of the data cutoff in 2023, with a 69% reduction in the risk of progression or death (PFS of 5.7 vs 2.3 months (HR 0.31)). The median OS was not reached, but the planned interim analysis for OS was in favor of SKB264 (HR.053) [ 133 ]. SKB264 is currently undergoing a phase III trial ( NCT06312176 ) for HR +/HER2− unresectable locally advanced or mBC, which compared three treatment arms with or without pembrolizumab [ 134 ].

Farletuzumab ecteribulin (MORAb- 202)

Currently, MORAb- 202, a new ADC, is under investigation. MORAb- 202 consists of farletuzumab, a humanized IgG1 MoAb that targets FRα. After promising in vitro outcomes were reported, a phase I/II clinical trial of various tumor types, including breast, endometrial, NSCLC, ovarian, and fallopian tube cancer, was conducted [ 135 ]. As of November 2019, 22 patients were enrolled. The best response was a complete response (5%), a partial response (41%) and stable disease (36%). A tumor response in a triple-negative breast cancer patient was observed at a dose of 0.68 mg/kg [ 141 ].

Many other antibody‒drug conjugates (ADCs) are under development, but few ongoing trials are investigating them. Notable examples presented in Table 9 include XMT- 1522 (TAK- 522) [ 142 ], XMT- 2056 [ 143 ], ZW49 [ 144 ], BB- 1701 [ 145 ], B003 [ 146 ], GQ1001 [ 147 , 148 ], HS630 [ 149 ], GB251 [ 150 ], DHES0815 A [ 151 ], SHR-A1201, trastuzumab duocarmazine, SYD- 985 [ 100 ], and DX126 - 262 [ 152 ]. Some of these trials are phase III trials comparing novel agents with other approved ADCs in HER2 + BC, such as T-DM1. These include DP- 303 and BL-M07D1 [ 153 – 155 ], MRG- 002 [ 156 ], ZRC- 3256 [ 157 ], FS- 1502 [ 158 ], and DB- 1303/BNT323, an ADC that is granted the FDA therapy designation in advanced endometrial cancer [ 159 ]. Finally, TAA013 is a phase III trial comparing TAA013 with lapatinib combined with capecitabine in HER2 + BC [ 160 ]. Table 9 Emerging antigen-targeted drugs ADC Trial phase XMT- 1522 (TAK- 522) [ 142 ] Phase Ib XMT- 2056 [ 143 ] Phase I ZW49 [ 144 ] Phase I BB- 1701 [ 145 ] Phase I B003 [ 146 ] Phase I GQ1001 [ 147 , 148 ] Phase I/II HS630 [ 149 ] Phase I GB251 [ 150 ] Phase I DHES0815 A [ 151 ] Phase I SHR-A1201 [ 161 ] Phase I Trastuzumab duocarmazine [ 100 ] Phase II (I-SPY) SYD- 985 [ 100 ] Phase II (I-SPY) DX126 - 262 [ 152 ] Phase II DPC 303c [ 153 , 154 ] Phase II- Phase III BL-M07D1 [ 155 ] Phase III MRG- 002 [ 156 ] Phase II/III ZRC- 3256 (T-DM1 biosimilar) [ 157 ] Phase III FS- 1502 [ 158 ] Phase III DB- 1303/BNT323 [ 159 ] Phase III TAA013 [ 160 ] Phase III

Discussion

Differences in the results between the phase trials

Our results indicate that most clinical trials for investigational ADCs in Tables 8 and 9 are predominantly in Phases I and II. Phase I trials focus primarily on assessing safety, whereas phase II trials expand on this by evaluating efficacy in a larger patient cohort; however, they often still lack the rigorous comparative designs seen in later phases. In contrast, once an ADC receives FDA approval, we see a proliferation of phase III trials, as shown in Tables 5 , 6 , and 7 . These trials, such as the ASCENT trials for sacituzumab govitecan, often involve comparisons with standard treatment arms, providing robust evidence of the effectiveness of ADCs in a more definitive setting [ 85 , 86 , 91 ]. Approval generates greater confidence among researchers, leading to more comprehensive trials that support FDA labeling and define the ADC’s clinical role. This distinction between trial phases for approved versus not yet approved ADCs highlights the progression of evidence generation as data accumulate and the potential biases of investigational ADCs trials, as conclusions from these studies may lack reliability associated with FDA-approved treatments.

Conclusions drawn from reviewing trials

In reviewing the studies for T-DM1 , incorporating this ADC in the HER2 + population is essential. Current trials are investigating its efficacy in various combinations and settings, including as a second-line therapy for metastatic cases and in adjuvant regimens after neoadjuvant treatment. Key studies, such as the CompassHER2 trials and ATTEMPT 2.0 trial, aim to refine treatment strategies for this patient group [ 30 , 31 , 35 ].

T-DXd is being investigated in HER2 + patients progressively extending to HER2-low populations through trials such as REFRESH and PROVIDENCE and potentially even HER2-negative cases, as observed in ongoing studies [ 42 , 44 ]. A key consideration with this ADC is its incorporation into neoadjuvant early-stage treatment, with numerous trials underway, including ARIADNE and TRUDI [ 66 , 67 ].

Over the past two decades, polychemotherapy combined with trastuzumab has become the standard neoadjuvant treatment for HER2 + BC. Trials assessing dual or sequential HER2-targeted therapies have shown better oncologic outcomes [ 162 ]. As a result, recent studies have explored “de-escalated” systemic therapies, which have yielded excellent results for patients with HER2 + early BC [ 163 ]. However, for patients at high risk, treatment escalation is important, as reported in the KATHERINE adjuvant trial [ 12 ]. Many ongoing trials, such as ADAPT HER2 +, have shown that TDM1 and T-DXd are excellent candidates for de-escalation [ 71 ].

In the context of TNBC, it is important to consider SG as a therapeutic option and to focus on its potential in combination with immunotherapy. Preliminary results from clinical trials, such as MORPHEUS-pan BC and BEGONIA, indicate that combining immune checkpoint inhibitors (ICIs) with novel ADCs can significantly increase overall response rates in TNBC patients [ 97 , 118 , 119 ]. This could be explained by enhancing the immune-activating properties of ICIs alongside the targeted cytotoxic effects of ADCs. This dual approach not only inhibits tumor growth but also stimulates the immune system to more effectively attack cancer cells. As shown in this review, numerous clinical trials are underway to further investigate these strategies [ 81 – 83 ]. SG is currently also being investigated for potential use in HR + HER2− patients, as shown in the SERIES trial [ 75 ].

Currently, numerous ongoing studies are rigorously exploring combinations of ADCs with various anticancer agents, including chemotherapy, targeted therapies, and immunotherapies, in both [ 33 , 34 , 55 , 56 , 64 , 80 ]. These trials are mostly early-phase to assess the associated risks, as these combinations do not always ensure a synergistic or additive effect and may lead to overlapping toxicities.

Importance of including ADCs in the management of early BC

ADCs are transforming cancer treatment by offering new options for patients with limited responses to traditional therapies, especially in challenging cancers such as HER2 +/low and TNBC. The incorporation of ADCs into the management of early-stage BC is crucial for several reasons. The ability of these agents to deliver potent cytotoxic drugs directly to cancer cells minimizes systemic exposure and reduces side effects. In fact, the structure of ADCs employs monoclonal antibodies (mAbs) that specifically target tumor-associated antigens. The synergistic effect arises from the conjugation of mAbs with small-molecule chemotherapeutics via a chemical linker [ 164 ].

In Figs. 2 , 3 , 4 , and 5 , we present the structures and mechanisms of action of three FDA-approved drugs: trastuzumab emtansine (T-DM1), fam-trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG). Each of these ADCs has unique structural features that enhance their efficacy. Fig. 2 Comparison of components in antibody‒drug conjugates: T-DM1, T-DXd, and sacituzumab govitecan Fig. 3 Mechanism of action of T-DXd, an overview. (1) HER2 targeting and binding: the trastuzumab antibody component binds to HER2 receptors on the surface of HER2- overexpressing tumor cells. (2) Internalization via endocytosis: the HER2-antibody complex undergoes receptor-mediated endocytosis, entering the cell inside a vesicle. (3) Payload release: inside the cell, the linker is cleaved by lysosomal enzymes, releasing the drug deruxtecan a potent topoisomerase I inhibitor, into the cytoplasm. (4) Cytotoxic action and bystander effects: the released deruxtecan can induce DNA damage, leading to the apoptosis of tumor cells. The cytotoxic payload also diffuses to nearby HER2-negative or HER2-low-expressing cells, known as the bystander effect Fig. 4 Mechanism of action of the SG; an overview. (1) Targeting and binding: the antibody component binds to Trop2 on the surface of tumor cells. (2) Internalization via endocytosis: the antibody-Trop2 complex is internalized into the cell via receptor-mediated endocytosis. (3) Payload release: the linker in SG is a hydrophilic cleavable linker that is hydrolyzed intracellularly by enzymes, releasing SN- 38 and causing DNA damage by inhibiting topoisomerase I, leading to apoptosis in the cell Fig. 5 Mechanism of action of T-DM1; an overview. (1) HER2 targeting and binding: the trastuzumab antibody component of T-DM1 binds to HER2 receptors on the surface of HER2-overexpressing tumor cells. (2) Internalization via endocytosis: the HER2-antibody complex is internalized through receptor-mediated endocytosis and entrapped in an intracellular vesicle. (3) Payload release: inside the cell, the MCC linker is cleaved, and emtansine, a potent microtubule inhibitor, is released into the cytoplasm. (4) Cytotoxic action: DM1 binds to microtubules, disrupting their assembly and causing cell cycle arrest and apoptosis. Unlike T-DXd, T-DM1 has limited bystander effects

Another significant advantage of antibody‒drug conjugates (ADCs) in the early setting is their ability to maintain their ability to aid even after disease progression. This characteristic allows ADCs to provide continued therapeutic benefits after progression in early lines of treatment by targeting residual disease more effectively after neoadjuvant therapy. This was demonstrated in the postprogression therapy outcomes in patients from the phase 3 ASCENT study, with remarkably improved median OS [ 72 , 164 ]. In this review, many trials in the early BC setting focused on residual disease after neoadjuvant therapy [ 28 – 30 , 69 , 70 , 92 ]. Residual disease after neoadjuvant systemic therapy is associated with a poorer prognosis, emphasizing the need to incorporate residual disease for higher-risk patients.

Sequencing ADCs

The use of these ADCs in the early treatment setting raises the question of how to sequence these agents effectively. The sequences of treatment incorporating available ADCs for mBC are resumed in Fig. 6 . Evidence suggests that the benefit from ADC2 after ADC1 is generally lower. In Hupper’s report, the ORR and PFS were higher for ADC1 (SG and T-DXd) compared to ADC2 [ 165 ]. However, the DESTINY-Breast 02 trial showed that ADCs can still be effective sequentially, with T-DXd proving superior to physician’s choice. DESTINY-Breast 03 and the TUXEDO trial also demonstrated that sequencing T-DXd and T-DM1 did not negatively impact outcomes and may even benefit patients with brain metastases [ 13 , 50 , 166 ]. However, due to the short FDA approval timeline of T-DXd and SG, limited data is available on their sequencing. Poumeaud’s study, which included 179 MBC patients treated sequentially with T-DXd and SG or vice versa, reported a median PFS2 of 2.7 months [ 167 ]. Future research should focus on understanding how the efficacy of ADC sequencing is influenced by changes in monoclonal antibodies (TROP2 vs. HER2) or payloads (e.g., topoI inhibitor vs. SN- 38). It is logical to assume that ADCs with similar payloads, such as T-DXd and SG, might experience more resistance compared to ADCs with different payloads, like T-DXd and T-DM1, but came the A3 study indicating that PFS is similar when ADCs with different payloads are sequenced, but resistance is higher when the second ADC targets the same antibody [ 168 ]. Another retrospective analysis further supported that resistance increases when using the same antibody target in sequential ADC therapy: the PFS for ADC2 was 3.25 months with a target change, compared to 2.30 months without a target change ( p = 0.16) [ 169 ]. Fig. 6 The sequence of therapy including ADCs in mBC

Importance of the ADC in brain metastases

As we observed in our results, many ADCs are being investigated in the context of BMs owing to the unique challenges posed by the blood‒brain barrier and the limited treatment options currently available. The intracranial antitumor activity is under evaluation in many trials, such as the TUCATEMEB trial for T-DM1, the DESTINY- 012 trial and the TUXEDO trials for T-DXd, and the SWOG trial for SG [ 27 , 52 , 53 , 84 ]. Despite therapeutic advancements, the prognosis for patients with BMs from breast cancer remains poor. The median survival varies, ranging from 7 to 9 months for hormone receptor-positive (HR +/HER2− BC), 16 to 19 months for HR +/HER2 + BC, 11 to 13 months for hormone receptor-negative (HR-/HER2 + BC), and less than 5 months for TNBC [ 170 – 173 ]. Preliminary clinical trials have shown promising results with ADCs in BMs, and ongoing research is exploring biomarkers that may help predict patient responses to these therapies [ 15 , 16 ]. Despite their relatively large size, ADC molecules can reach the brain. Awaiting these results, the potential for improved patient intracranial outcomes becomes increasingly promising.

Limitations to the adoption of ADC trials

Lack of activity predictors on the basis of biomarkers

Currently, the approval of many ADCs used in clinical practice has not been consistently guided by biomarker evidence. There remains a significant unmet need for reliable predictors of ADC activity based on specific biomarkers, thus complicating the understanding of the precise mechanisms underlying ADCs and limiting their efficacy.

In our study, we cited many ongoing trials examining the impact of various markers on the efficacy of ADCs, such as the BIOPROSA trial [ 73 ]. In studies such as the Compass trials for T-DXd, the SASCIA trial for SG and the Tropion Breast- 03 trial for Dato-DXd, which investigate antibody‒drug conjugates (ADCs) as adjuvant therapy, the primary predictor of outcomes remains the pathological response following neoadjuvant therapy and surgery [ 30 , 31 , 91 – 93 , 118 ].

F urthermore, it is still unclear whether target antigen expression significantly influences the primary activity of ADCs, and many trials have focused on this topic, such as DAISY and HEROIC, which aim to elucidate the impact of HER2 expression levels on treatment responses, and ICARUS-BREAST- 01, which focuses on the influence of HER3 levels on U3 - 1403 [ 40 , 42 , 137 ].

Toxicity

The toxicity associated with ADCs can significantly limit their therapeutic effectiveness, and many ADCs have faced clinical development failure due to unacceptable toxicity profiles called “target toxicity” [ 174 ]. Our review revealed that most of the ongoing trials have included safety and adverse effects as primary or secondary outcome measures in their analyses, such as the BRIDGET trial of T-DM1, the DESTINY trials of T-DXd and the ASCENT trials of SG [ 18 , 85 – 87 ]. This issue of safety and tolerability is particularly significant in real-world trials and in those involving older patients, such as the ATOP trial [ 25 ]. A key indicator of a safety trial is the pre-SPY phase, which assesses the safety of drugs before they advance to the next SPY 2.2 trial [ 58 , 112 ].

Clinical data analysis reveals that dose-limiting toxicities (DLTs) are often shared among ADCs that use the same cytotoxic payload, regardless of the targeted antigen or type of cancer. A review by Masters et al. of clinical ADC data from 2010–2014 revealed that the most common grade 3/4 toxicities were consistent with the specific class of payload use. This suggests that much of the off-site toxicity stems from off-target delivery of the cytotoxic agent, indicating that this off-target distribution is a key factor affecting the tolerability of ADCs [ 175 ].

The main toxicities of these ADCs and suggested management strategies are summarized in Table 10 . Table 10 Summary of the main adverse effects of ADCs and management strategies Side effects SG T-DXd TDM- 1 Management Gastrointestinal toxicity Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea Nausea, vomiting and diarrhea less common Hepatotoxicity Hold for grades 3–4 Hematological adverse events Neutropenia Febrile neutropenia Neutropenia Febrile neutropenia Thrombocytopenia Monitor blood cell counts periodically Interrupt until resolve to grade 1 Reduce dose by one level if grade 4 Ocular toxicity Not mentioned Dry eye Dry eye conjunctivitis, keratitis, cataract, and tear duct stenosis Topical lubricants, antibiotics, steroids, and diuretics Delay or stop the administration Dermatological adverse events Cutaneous rash Alopecia Cutaneous rash not mentioned Alopecia Cutaneous rash Alopecia less common Reducing the temperature of the scalp Cardiotoxicity QT prolongation, myocardial ischemia, hypertension, left ventricular dysfunction (LVD), heart failure (HF) QT prolongation, myocardial ischemia, hypertension, left ventricular dysfunction (LVD), heart failure (HF) Low risk of left ventricular dysfunction Interrupt for symptomatic-moderate/severe and asymptomatic-severe Continue with cardioprotective therapy for asymptomatic-mild and moderate Neuropathy Peripheral sensory and motor neuropathy Not mentioned Peripheral sensory and motor neuropathy Reduce pain (duloxetine, anticonvulsivants, topical agents) Pneumotoxicity Interstitial lung disease (ILD) Steroid initiation and discontinue T-DXd for grade ≥ 2

Gastrointestinal adverse events, particularly nausea and diarrhea, were commonly reported in mBC patients treated with newer-generation ADCs (SG and T-DXd) in clinical trials and less commonly with T-DM1. Management suggests holding SG treatment for grades 3–4 gastrointestinal toxicities, restarting only when toxicity returns to grade 1, with a possible 25% dose reduction. If grade 3–4 toxicities persist for more than three weeks, treatment should be discontinued [ 176 , 177 ].

Adverse effects such as hematological neutropenia and anemia may lead to dose modifications or interruptions, ultimately impacting patient adherence. Thrombocytopenia was more commonly associated with T-DM1, whereas neutropenia was more frequently observed with T-DXd and SG [ 176 ].

Ocular toxicities, particularly affecting the cornea, conjunctiva, and epithelium, are a significant concern with T-DM1 [ 178 ]. It is important to note that ocular toxicity is also important with the new ADC SYD985 [ 99 ]. The ocular toxicity is typically reversible and manageable with proper ocular care. Treatment often includes the use of artificial tears, topical steroids, or antibiotics, and in some cases, interventions may be necessary for issues like lacrimal duct stenosis or cataracts.

Alopecia is significantly more common in patients treated with T-DXd compared to T-DM1, as shown in the DESTINY-Breast03 trial, and is also more prevalent in SG-treated patients while alopecia is less common with T-DXd. We suggest that other anti-Trop- 2 therapies, such as Dato-DXd, may also have a similar effect. Oral antihistamines can be beneficial, and topical steroids are effective for maculopapular rashes, while managing skin eruptions can include cleansing with warm water and mild soap, avoiding sun exposure, and using sunscreen with SPF 30 or higher [ 179 ]. Cooling the skin scalp may be effective in alopecia [ 180 ].

The cardiotoxicity of ADCs includes dysfunction, arrhythmias, and ischemia. The threshold for cardiac toxicity associated with trastuzumab emtansine is still under investigation [ 37 ].The European Society of Cardiology (ESC) Guidelines recommend interrupting or continuing treatment with cardioprotective therapy (ACE-I/ARB and beta-blocker) based on the severity of the dysfunction [ 181 ].

Peripheral neuropathy is a common adverse event associated with T-DM1, as reported in the KATHERINE trial, and with SG, as noted in the ASCENT trial [ 86 ]. The primary treatment for this adverse effect focuses on pain management [ 6 , 182 ].

Stomatitis is most common with Dato-DXd, and management includes improving oral hygiene, using steroid-containing mouthwashes, topical antifungals, and pain relief options like lidocaine or morphine mouthwash. The TROPION-PanTumor01 and BEGONIA trials report rates ranging from 50 to 70% [ 116 , 120 ].

Finally, pneumonitis/interstitial lung disease (ILD) has been reported in 10.5% of patients with T-DXd in the DESTINY-Breast03 and can impact treatment outcomes [ 9 ]. Current guidelines for T-DXd-induced ILD/pneumonitis suggest considering steroids for grade 1 and rechallenge if resolved, recommend steroid initiation for grade ≥ 2 and permanently discontinuing the drug for grade 2 or higher [ 183 ].

Cost

Finally, we believe that the cost-effectiveness of ADCs significantly impacts their utilization in clinical practice. While ADCs can offer targeted treatment options, the financial burden associated with ADCs can pose a significant challenge.

Conclusion

In this study, we provide a comprehensive review of ongoing trials for FDA-approved ADCs in the context of breast cancer, with a particular emphasis on early-stage settings. By detailing the current landscape of these approved therapies, we aimed to highlight their potential integration into early management strategies. Additionally, we explored ongoing trials for investigational ADCs, recognizing the need to understand the evolving landscape while being attentive to the biases in evaluating these non-approved agents.

Incorporating ADCs into the management of early-stage BC is essential, given their capacity to deliver potent cytotoxic agents directly to cancer cells while minimizing systemic exposure. The unique mechanisms of action and structures of approved ADCs, such as T-DM1, T-DXd, and SG, support their therapeutic benefits in early lines, with benefit even after disease progression and after multiple lines of therapy. However, the challenges associated with biomarker identification, target toxicity, and cost-effectiveness remain significant barriers to the widespread adoption of ADCs. The ongoing trials addressing these issues are crucial for optimizing patient selection and improving treatment tolerability.

While the understanding of tumor biology evolves, ADCs offer the potential to address specific tumor characteristics, such as HER2 positivity, providing a tailored therapeutic approach that aligns with the growing trend toward personalized medicine. Preliminary results of these ongoing trials studies have shown that early use of ADCs can lead to improved disease-free survival rates, making them a valuable option in the treatment landscape. As we continue to gather data and refine our understanding of ADCs, we anticipate that these innovative therapies will play an increasingly vital role in the management of BC, offering hope for improved outcomes in this patient population.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author contribution

The primary and author of the review: Dr Tala Najdi. Data Collection and Assembly: Dr. T. N, Dr. L. A, Dr A.C and Dr C. S. Tables Constructions: Dr. T. N, Dr. L. A and Dr H.K. Images Construction: Dr A.C. Manuscript Writing: Dr T. N, Dr L.A, Dr C. S and Dr H. K. Final approval of manuscript: All authors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and informed consent

Not applicable.

Competing interests

The authors declare no competing interests.

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