Next-Generation Antibody-Drug Conjugates Make Their Mark in Breast Cancer

In 2013, ado-trastuzumab emtansine (T-DM1; Kadcyla) gained FDA approval for the treatment of patients with HER2-positive metastatic breast cancer (MBC), making it the first antibody-drug conjugate (ADC) with an indication for a solid tumor. Since then, ADCs have become one of the fastest-growing classes of oncology drug therapy.^1,2 In breast cancer, ADCs continue to evolve, with advancements in indications, targets, and drug designs (Figure).³

Figure. Timeline of FDA Approvals of ADCs for Breast Cancer³

Recent developments in the field include full regulatory approval for sacituzumab govitecan-hziy (Trodelvy), a first-in-class Trop-2–targeted ADC for patients with metastatic triple-negative breast cancer (TNBC).^4,5 Meanwhile, fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-targeted ADC initially approved in 2019,⁶ recently demonstrated superior efficacy to T-DM1 in previously treated patients with HER2-positive MBC, according to topline data from the DESTINY-Breast03 t rial (NCT03529110).^7,8

The honing of ADC design also may open new therapeutic doors. Because of their ability to deliver a membrane-permeable payload, sacituzumab govitecan and trastuzumab deruxtecan are able to kill nearby target antigen–negative tumor cells via the “bystander effect.”^9-11 Partly because of this effect, investigators hypothesize that trastuzumab deruxtecan and other novel HER2-targeted ADCs may also prove effective in patients with breast cancer that is classified as HER2 low, for whom HER2-targeted therapy is not currently indicated.^3,12

A growing number of ADCs are now in development in breast cancer, with a variety of novel designs, including several that are in late-stage clinical trials (Table). If these drugs continue to deliver on the promise they have demonstrated in earlier trials, then ADCs appear poised to further shape the breast cancer treatment landscape in coming years.

Table. ADCs With Targets Under Development in Breast Cancer

Breast Cancer Success

Sometimes described as the “Trojan horses” of the cancer therapy armamentarium, ADCs have been in development for decades, with initial indications in hematologic malignancies.^2,12-14 These drugs are composed of 3 major components: a monoclonal antibody (mAb) targeting a tumor-associated antigen, a cytotoxic drug (the “payload”), and a linker that connects them.^3,12-14

T-DM1 is composed of the HER2-targeted mAb trastuzumab conjugated to emtansine, a potent inhibitor of tubulin polymerization, via a noncleavable linker. T-DM1 has a drug-to-antibody ratio (DAR) of 3.5, meaning that an average of 3.5 emtansine molecules are carried by each molecule of trastuzumab.^3,15

The initial T-DM1 approval, for the treatment of HER2-positive MBC, was based on results from the phase 3 EMILIA trial (NCT00829166).¹ T-DM1 significantly improved median progression-free (PFS) and overall survival (OS) compared with the combination of lapatinib (Tykerb), a HER2/EGFR inhibitor, plus capecitabine (Xeloda), which inhibits DNA synthesis by reducing thymidine. Median PFS was 9.6 months with T-DM1 vs 6.4 months with lapatinib/capecitabine (HR, 0.65; 95% CI, 0.55-0.77; P < .001); median OS was 30.9 months with T-DM1 vs 25.1 months with lapatinib/capecitabine (HR, 0.68; 95% CI, 0.55-0.85; P < .001).¹⁶

In the frontline setting, the MARIANNE trial (NCT01120184) demonstrated that T-DM1, either alone or combined with pertuzumab (Perjeta), also a HER2-targeted mAb, was noninferior to the combination of trastuzumab (Herceptin) and a taxane for the treatment of HER2-positive MBC. Noninferiority was based on median PFS data of 14.1 months with T-DM1 monotherapy, 15.2 months with T-DM1 plus pertuzumab, and 13.7 months with trastuzumab plus a taxane. Although superiority was not established, the novel combination generally was less toxic and provided a better quality of life.¹⁷

Although the combination of pertuzumab, trastuzumab, and a taxane is the preferred regimen in this setting according to National Comprehensive Cancer Network Guidelines, T-DM1 provides a treatment option for patients for whom taxane therapy is unsuitable.¹⁸

In 2019, T-DM1 was approved for the adjuvant treatment of patients with HER2-positive early breast cancer following the KATHERINE trial (NCT01772472), in which T-DM1 improved invasive disease–free survival by 50% compared with trastuzumab (HR for invasive disease or death, 0.50; 95% CI, 0.39-0.64; P < .001) in patients with residual invasive disease after neoadjuvant treatment with trastuzumab and a taxane.^1,19

Growing Options Available

Investigators are working on creating ADCs with greater efficacy and reduced toxicity. Trastuzumab deruxtecan consists of a humanized immunoglobulin G1 HER2-targeted mAb that shares the same sequence as trastuzumab conjugated to the topoisomerase I inhibitor deruxtecan via a linker that is selectively cleaved by lysosomal cathepsins.^3,15

With an average of 8 deruxtecan molecules per antibody molecule, trastuzumab deruxtecan has a higher DAR than T-DM1. Historically, increasing the DAR of a drug has negatively affected its pharmacokinetic profile,^{3,11, 20,21} but this was not the case for trastuzumab deruxtecan because of its novel linker design.^10,11,22 The deruxtecan payload of this agent is also much more membrane permeable than that of T-DM1; as a result, the potent bystander killing that trastuzumab deruxtecan demonstrates is absent from T-DM1.^9,10

Trastuzumab deruxtecan was granted accelerated approval in December 2019 based on the phase 2 DESTINY-Breast01 study (NCT03248492) for the treatment of patients with HER2-positive MBC who have received 2 or more prior HER2-targeted therapies in the metastatic setting.⁶ The novel agent demonstrated an objective response rate (ORR) of 60.9% (95% CI, 53.4%68.0%) and a median duration of response (DOR) of 14.8 months (95% CI, 13.8-16.9).²²

Numerous clinical trials evaluating trastuzumab deruxtecan are ongoing, including a head-to-head comparison with T-DM1 in DESTINY-Breast03. Results from the primary analysis were first presented at the 2021 European Society for Medical Oncology Congress. Among the 524 patients randomized at data cutoff, trastuzumab deruxtecan significantly improved median PFS compared with T-DM1 (not reached vs 6.8 months, respectively; HR, 0.2840; P = 7.8 × 10^-22). Although the 12-month OS rate was numerically higher in the trastuzumab deruxtecan arm (94.1% vs 85.9%), this was not statistically significant. Similar rates of treatment-emergent adverse events (TEAEs) were observed with both drugs.⁷

In results of an exploratory analysis of DESTINY-Breast03 presented at the 2021 San Antonio Breast Cancer Symposium (2021 SABCS), a consistent median PFS benefit was observed with trastuzumab deruxtecan across numerous subgroups, including in patients with baseline brain metastases (n = 82), among whom PFS was 15 months compared with 3 months for T-DM1 (HR, 0.25; 95% CI, 0.13-0.45).⁸

Several other HER2-targeted ADCs are in clinical development, including vic-trastuzumab duocarmazine (SYD985), in which a cleavable linker connects trastuzumab to a prodrug of the DNA alkylating agent duocarmycin-hydroxybenzamide-azaindole.^15,23

Despite its DAR (2.8) being lower than that of T-DM1 (3.5), SYD985 has demonstrated higher antitumor activity in preclinical models.^3,23 In the phase 3 TULIP trial (NCT03262935), SYD985 was compared against physician’s choice of therapy in patients with previously treated HER2-positive MBC. SYD985 significantly improved median PFS (7.0 months vs 4.9 months; HR, 0.64; 95% CI, 0.490.84; P = .002). The most common adverse effects (AEs) in the SYD985 arm were conjunctivitis, keratitis, and fatigue.²⁴

Other notable HER2-targeted ADCs in development are ARX788, which has a tubulin inhibitor payload²⁵; ZW49, a bispecific ADC that employs an antibody targeting both the trastuzumab- and pertuzumab-binding sites on HER2 simultaneously²⁶; and BDC-1001, which uses a Toll-like receptor agonist as its payload and is designed to stimulate an antitumor immune response rather than directly kill tumor cells.²⁷ ZW49 and BDC-1001 also both recently displayed promising preliminary activity in ongoing phase 1/2 clinical trials, according to the companies developing the drugs.^26,27

ARX788 was highlighted in a presentation at 2021 SABCS; in the ACE-Breast-01 study (CTR20171162) in patients with heavily pretreated HER2-positive MBC, among 29 patients who received a dose of 1.5 mg/kg every 3 weeks, the ORR was 66% (95% CI, 45.7%-82.1%), the median DOR was 14.4 months (95% CI, 9.0 months-not reached), and the disease control rate (DCR) was 100%. Notably, the ORR was 80% among 5 patients previously treated with HER2-targeted ADCs. ARX788 was well tolerated, with mostly grade 1 or 2 AEs.²⁸ ARX788 has been granted fast-track designation by the FDA in this setting.²⁹

Expanding Beyond HER2

An estimated 15% to 20% of breast cancers are classified as HER2 positive, with high levels of HER2 protein expression, defined as an immunohistochemistry (IHC) score of 3+, and/or HER2 gene amplification by in situ hybridization. Up to 50% are classified as HER2 low (IHC1+ or 2+, without gene amplification).^3,10,15

In terms of treatment decision-making, HER2-low breast cancers are currently grouped with those that are HER2 negative and thus are ineligible for HER2-targeted therapies. That could be set to change, however, as novel ADCs with an increased capacity for bystander killing may have clinical activity in this patient population.^3,10,15

Both trastuzumab deruxtecan and SYD985 are being evaluated in ongoing clinical trials in patients with HER2-low breast cancer, and preliminary data are emerging. In a phase 1b trial evaluating trastuzumab deruxtecan in solid tumors (NCT02564900), a cohort of 54 patients with heavily pretreated, advanced HER2-low breast cancer received a dose of 5.4 or 6.4 mg/kg. The resulting ORR was 37.0% (95% CI, 24.3%51.3%), with a median DOR of 10.4 months (95% CI, 8.8 months-not evaluable).³⁰

Two phase 3 trials comparing trastuzumab deruxtecan against investigator’s choice of chemotherapy in patients with HER2-low MBC are ongoing. In the DESTINY-Breast04 trial (NCT03734029), for which recruitment is now complete, patients were previously treated with 1 or 2 prior lines of chemotherapy and could be hormone receptor positive or negative, whereas in DESTINY-Breast06 (NCT04494425), patients have received at least 2 prior lines of endocrine therapy and were hormone receptor positive.

A first-in-human study of SYD985 conducted in patients with metastatic solid tumors (NCT02277717) included 95 evaluable patients with MBC in dose-expansion cohorts. Results showed ORRs of 33% (95% CI, 20.4%-48.4%) in the HER2-positive cohort (n = 48); 28% (95% CI, 13.8%-46.8%) in the HER2-low, hormone receptor–positive cohort (n = 32); and 40% (95% CI, 16.3%-67.6%) in the HER2-low, hormone receptor–negative cohort (n = 15). All were partial responses (PRs).²³

Trop-2 in TNBC and Beyond

TNBCs do not express HER2; thus, alternative antigen targets are under investigation. Studies exploring Trop-2, a transmembrane glycoprotein that is overexpressed in breast cancer, have yielded sacituzumab govitecan.¹⁰

Sacituzumab govitecan is a first-in-class Trop-2-targeted ADC, in which a Trop-2 mAb is conjugated to SN-38, a topoisomerase I inhibitor, via a cleavable linker. Sacituzumab govitecan has a high DAR (7.6) and has been shown to display bystander killing in preclinical studies.^10,15

The FDA granted an accelerated approval to sacituzumab govitecan in April 2020 for patients with TNBC previously treated with at least 2 regimens in the metastatic setting.³¹ The decision was based on results of the phase 1/2 IMMU-132-01 study (NCT01631552) in patients with advanced epithelial tumors, which enrolled 108 patients with previously treated metastatic TNBC. The ORR was 33.3% (95% CI, 24.6%-43.1%), the median DOR was 7.7 months (95% CI, 4.9-10.8), and the therapy was well tolerated.³²

One year later, sacituzumab govitecan received full FDA approval based on recently published results from the confirmatory phase 3 ASCENT trial (NCT02574455).⁴ These data demonstrated that sacituzumab govitecan significantly prolonged median PFS (5.6 months vs 1.7 months; HR, 0.41; 95% CI, 0.32-0.52; P < .001) and median OS (12.1 months vs 6.7 months; HR, 0.48; 95% CI, 0.38-0.59; P < .001) compared with chemotherapy in patients with metastatic TNBC who had received at least 2 prior standard chemotherapy regimens in the advanced or metastatic setting, including at least 1 taxane.⁵

High Trop-2 expression is frequently seen in multiple breast cancer subtypes,¹⁰ and the IMMU132-01 study included a cohort of 54 patients with hormone receptor–positive/HER2-negative MBC who were treated with sacituzumab govitecan. The ORR was 31.5% (95% CI, 19.5%-45.6%), and the median DOR was 8.7 months (95% CI, 3.7-12.7).³³ The phase 3 TROPiCS-02 study (NCT03901339) is comparing sacituzumab govitecan to chemotherapy in this breast cancer subtype.³³

A second Trop-2-targeted ADC, datopotamab deruxtecan, is also in clinical development. Results from the metastatic TNBC cohort of the ongoing phase 1 TROPION-PanTumor01 trial (NCT03401385), in which most participants have received 2 or more prior lines of therapy including sacituzumab govitecan (16%), were presented at 2021 SABCS. Among 38 response-evaluable patients, the ORR was 39%, all PRs, and the DCR was 84%. TEAEs included nausea, stomatitis, alopecia, vomiting, and fatigue.³⁴

Alternative Targets

Another member of the HER family of tyrosine kinase receptors, HER3, promotes the oncogenic activity of HER2. HER3 is overexpressed in breast cancers and is associated with poor prognosis and resistance to HER2-targeted and endocrine therapies.^35-37

Patritumab deruxtecan (HER3-DXd) is a HER3-targeted ADC composed of the mAb patritumab conjugated to deruxtecan via a novel cleavable linker that allows a high DAR (8) without compromising the drug’s physiochemical properties.³⁸

HER3-DXd demonstrated promising antitumor activity in an ongoing phase 1/2 study (NCT02980341) in patients with heavily pretreated hormone receptor–positive, HER2-negative MBC, regardless of whether HER3 expression was low or high, and was well tolerated.³⁹

Meanwhile, results of an interim analysis of TOT-HER3 (NCT04610528), a window-of-opportunity study, revealed that a single dose of HER3-DXd (6.4 mg/kg) was associated with clinical response in patients with treatment-naïve hormone receptor–positive, HER2-negative, primary operable breast cancer.⁴⁰

Several other antigen targets are being explored for ADCs in breast cancer, including the LIV-1 protein and folate receptor-α, both of which are highly expressed in this cancer type. Ladiratuzumab vedotin, which targets the former, and MORAb-202, which targets the latter, are both in the early stages of clinical development.^41,42

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