Sacituzumab tirumotecan (sac-TMT/MK-2870/SKB264): a novel antibody-drug conjugate in breast cancer.

Background Tucatinib is an oral, reversible, small-molecule tyrosine kinase inhibitor highly selective for HER2 with minimal inhibition of the human epidermal growth factor receptor. Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in patients with HER2+ metastatic breast cancer, with and without brain metastases, who have received 1 or more prior anti-HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is approved in the US for patients with HER2+ metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. In HER2+ breast cancer xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian, et al. (2019). Abstract P1-18-09. Proceedings of San Antonio Breast Cancer Symposium, December 10-14, 2019). While significant advances have been made in the treatment of patients with HER2+ breast cancer, treatment of metastatic disease remains a clinical challenge for which options are limited, particularly in patients with brain metastases. The HER2CLIMB-04 study is evaluating the efficacy and safety of tucatinib in combination with T-DXd in patients with HER2+ metastatic breast cancer following progression on 2 or more HER2-directed regimens in the metastatic setting. Trial Design HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study of tucatinib in combination with T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic HER2+ breast cancer. Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study will enroll 10 patients who will be followed for at least 1 cycle. If tucatinib combined with T-DXd has a manageable safety profile, the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), approximately evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) by investigator assessment per RECIST 1.1, OS, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DoR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes using the European Quality of Life 5-Dimension 5-Level instrument. Efficacy and safety will be summarized with descriptive endpoints to describe continuous variables. For response rates, the 2-sided exact confidence interval using the Clopper-Pearson method will be calculated. Enrollment began in late 2020 at approximately 30 study sites in the US. Citation Format: Erika Hamilton, Lisa Carey, Jorge Ramos, Yiyi Chen, Ian Krop. HER2CLIMB-04: phase 2 trial of tucatinib + trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (trial in progress) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-13-01.

Background: Antibody-drug conjugates (ADCs), including trastuzumab deruxtecan (T-DXd; targeting HER2) and sacituzumab govitecan (SG; targeting TROP2), have transformed the management of metastatic breast cancer, with additional ADCs approved in other solid tumors or in late-stage development. To date, expression of ADC target alone has been poorly predictive of objective response rates (ORRs) in both breast cancer and other tumors. Hence, there is an urgent need to develop better predictive biomarkers to guide ADC vs. other treatments, T-DXd vs. SG treatment, and optimized predictive medicine opportunities involving other ADCs. Additionally, whether ADCs are similarly effective in less common breast cancer subtypes—such as invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC), is unclear. Given the limited availability of trial tissue samples and cohorts with long-term follow-up, herein we sought to determine whether a tissue based, pan-solid tumor, multivariate biomarker algorithm could predict observed ORRs across ADCs and tumor types, as has been used previously to associate tumor mutation burden with immunotherapy ORRs. Methods: From 15,032 FFPE tumor tissue samples (from 21 tumor types) tested by clinical comprehensive genomic profiling plus RNA based quantitative transcriptional profiling (qTP) as part of the observational Strata Trial (NCT03061305), the ADC treatment response score (TRS) was discovered and validated to predict published ORRs across tumor types and approved/late-stage ADCs (n=16 observed ORRs [from 7 tumor types and 8 ADCs; SG not included]). The best performing 3-factor algorithm (by Pearson correlation coefficient of observed ORRs vs. tumor type and ADC specific predicted biomarker positivity rates) included only qTP components and combined ADC target expression, cell proliferation, and extracellular matrix adhesion (the latter being negatively associated with ORRs). Importantly, predictive biomarker positivity rates of TRS was more correlated vs. observed ORRs (n=16, r=0.81, p=0.0001) than target expression alone (n=16, r=0.54, p=0.03). TRS was then validated using held out SG ORRs from nine tumor types in the IMMU-132-01 basket trial and two ADC ORRs from ASCO 2023 abstracts (enfortumab vedotin [EV; targeting NECTIN-4] in head and neck cancer and patritumab vedotin [targeting HER3] in breast cancer), with TRS predictive biomarker positivity rates again being more significantly correlated vs. observed ORRs than target expression alone (n=11, TRS r=0.91, p=0.0001; target expression alone r=44, p=0.17). Lastly, the locked TRS model was then applied to the DESTINY-PanTumor02 T-DXd dataset presented at ASCO 2023 (n=21 tumor type/HER2 expression groups matched to the trial groups), with TRS predictive biomarker positivity rates again being highly correlated vs. observed ORRs (n=21, TRS r=0.80, p< 0.0001). Across the 21 tumor types in the Strata Trial dataset, breast cancer had the highest percentage (76%) of patients predicted positive for at least one ADC, with 23% and 55% positive for the approved ADCs mirvetuximab soravtansine (targeting FOLR1) and EV, respectively. Lastly, patients with ILC vs. IDC had significantly greater TRS positivity rates for T-DXd (61% vs. 47%) and SG (57% vs. 48%) due to significantly decreased extracellular matrix adhesion in ILC vs. IDC. Clinical outcomes data for patients treated with ADCs and available TRS enrolled in the Strata Trial are maturing and will be presented at the meeting. Conclusion: We have developed and validated TRS, a multivariate RNA based tumor tissue algorithm that predicts observed ORRs across tumor types and approved/late-stage ADCs. More than 75% of all patients with metastatic breast cancer are predicted to be responsive to one or more ADCs, including those approved in other tumor types. Citation Format: Laura Lamb, Jonathan Mowers, Azadeh Nasrazadani, Mark Burkard, Nickolay Khazanov, Daniel Hovelson, Kat Kwiatkowski, Scott Tomlins, D. Bryan Johnson, Daniel Rhodes. A multivariate biomarker to guide antibody-drug conjugate selection and provide insight on response differences across breast cancer subtypes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-04.

TPS1111 Background: Tucatinib is an oral reversible small-molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in adult patients with HER2+ metastatic breast cancer (MBC), with and without brain metastases, who have received ≥1 prior anti–HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is also approved in the US for patients with HER2+ MBC. In HER2+ breast cancer (BC) xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian et al 2019). While significant advances have been made in the treatment of patients with HER2+ BC, treatment of metastatic disease remains a clinical challenge due to limited treatment options. Methods: HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study evaluating the efficacy and safety of tucatinib plus T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic (LA/M) HER2+ BC. Patients must have prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study with 10 patients who were followed for at least 1 cycle has been completed. This portion of the study demonstrated a manageable safety profile so the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per RECIST 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DOR), disease control rate (DCR) by investigator assessment per RECIST 1.1, overall survival, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DOR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes. Efficacy and safety will be summarized with descriptive statistics. Enrollment in the US began in late 2020. Clinical trial information: NCT04539938.

Background: Ado-trastuzumab emtansine (T-DM1), a HER2-targeted antibody drug conjugate (ADC), is approved for patients with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma S, et al. NEJM. 2012). DS-8201a is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed ORR of 54.5%; April 2018 data cutoff) (Iwata et al, ASCO 2018). The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a vs T-DM1 in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-BREAST03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive DS-8201a (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health related quality of life will also be measured. The primary analysis for PFS will be performed when approximately 331 PFS events have been observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 150 sites851468 including in North America, Europe, and Asia. Citation Format: Verma S, Shahidi J, Lee C, Wang K, Cortes J. Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-03.

Background: Chemotherapy is the main treatment in patients with pre-treated endocrine-resistant HR+/HER2– metastatic breast cancer, but has limited efficacy and substantial toxicities. The antibody-drug conjugate Dato-DXd consists of a humanized IgG1 mAb targeting TROP2 attached via a stable cleavable linker to a topoisomerase I (TopI) inhibitor payload. Heavily pre-treated patients with metastatic triple-negative breast cancer in the TROPION-PanTumor01 (NCT03401385) study of Dato-DXd showed a manageable safety profile and highly encouraging objective response rates (ORR by blinded independent central review [BICR]: 34% in all patients; 52% in patients treatment-naïve to TopI inhibitor-based therapies). The metastatic HR+/HER2– breast cancer cohort of TROPION-PanTumor01 has completed enrollment (n=41); data are currently maturing. Trial design: TROPION-Breast01 (NCT05104866) is an ongoing, global, phase 3, open-label, randomized trial evaluating efficacy and safety of Dato-DXd vs investigators’ choice of chemotherapy (ICC) in patients with inoperable or metastatic HR+/HER2– breast cancer. Patients (n≈700) are randomized 1:1 to Dato-DXd 6 mg/kg IV Q3W or ICC (eribulin, capecitabine, vinorelbine, or gemcitabine) until progression. Adults with an ECOG performance status of 0–1, who experienced progression on or are unsuitable for endocrine therapy, and received 1–2 prior lines of standard-of-care chemotherapy in the inoperable or metastatic setting are eligible. Monotherapy treatment with inhibitors of mTOR, PD-[L]1, CDK4/6 and PARP do not count as prior chemotherapy lines. Patients must have ≥1 measurable lesion per RECIST 1.1 and an archival or fresh formalin-fixed and paraffin-embedded tumor sample. Clinically inactive brain metastases are permitted. Dual primary endpoints are progression-free survival (PFS) by BICR, and overall survival. Secondary endpoints include PFS per investigator, ORR, disease control rate, patient-reported outcomes, and Dato-DXd pharmacokinetics and immunogenicity. Exploratory endpoints include TROP2 expression and exposure–efficacy relationship. Patients are stratified by number of prior chemotherapy lines, prior CDK4/6 inhibitor use, and region. At the time of writing 236 patients have been enrolled across 19 countries. Citation Format: Aditya Bardia, Kevin Kalinsky, Junji Tsurutani, Erika Hamilton, Joo Hyuk Sohn, Kyong Hwa Park, Yeon Hee Park, Seock-Ah Im, Keun Seok Lee, Daisy Dastur, Vincent Haddad, Sabrina Khan, Binghe Xu, Barbara Pistilli, Hope Rugo. Datopotamab deruxtecan (Dato-DXd), a TROP2 antibody-drug conjugate, vs investigators’ choice of chemotherapy in previously-treated, inoperable or metastatic HR+/HER2– breast cancer: TROPION-Breast01 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-04.

Background: BL-B01D1 is a potentially first-in-class novel antibody drug conjugate (ADC) consisting of an EGFRxHER3 bispecific antibody bounded to a novel topoisomerase I inhibitor payload via a cleavable linker. We now present updated safety/efficacy data from phase I study of BL-B01D1 in breast cancer (BL-B01D1-104). Methods: This study included Chinese patients (pts) with locally advanced or metastatic breast cancer (BC) and other solid tumors. BC pts were enrolled in dose-expansion (D-EXP) at 2.5mg/kg D1D8 Q3W regimen regardless of EGFR/HER3 and HER2 expression levels. Results: As of May 31, 2024, a total of 158 BC pts (156 were previously treated) have been treated with at least one dose of BL-B01D1. Among the 158 pts, 44 pts had triple negative breast cancer (TNBC) including 27 HER2 0 pts; 77 pts had HR+HER2- BC including 28 HER2 0 pts; 37 pts had HER2 positive BC. The most common TRAEs (>25%, all grade/≥G3) were anemia (90.5%/39.9%), leukopenia (88.0%/42.4%), neutropenia (85.4%/51.3%), thrombocytopenia (67.7%/25.3%), nausea (58.2%/3.8%), stomatitis (48.7%/3.8%), aspartate aminotransferase increased (45.6%/0%), alanine aminotransferase increased (42.4%/0%), asthenia (42.4%/8.9%), vomiting (40.5%/0.6%), hypertriglyceridemia (36.7%/0.6%), alopecia (32.9%/0%), hypokalemia (31.6%/3.8%), decreased appetite (31.0%/0.6%), hyperglycemia (30.4%/0%), constipation (27.2%/0.6%), hyponatremia (25.9%/1.3%). Among 158 BC pts, 1 patient was dead due to febrile neutropenia that was assessed to be related to BL-B01D1. No ILD was observed. Among the 158 pts, 147 pts were efficacy evaluable (shown in the table). Note: 1. 1 pt with HER2+ BC and 1pt with HR+HER2- BC who didn’t receive standard treatment because of poor economic condition were enrolled. 2. NE, Not evaluable. Including pts who had no post-baseline scan and already off treatment. 3. The median follow up time of PFS is 8.5 months, and the mOS of all sub-group pts are not reached. 4. NR, Not reached. Conclusions: BL-B01D1 has demonstrated encouraging efficacy in previously treated patients with metastatic and locally advanced breast cancer subtypes, particularly in earlier lines of therapy. The safety and tolerability of BL-B01D1 are consistent with previously published data. Clinical trial information: NCT05470348. Citation Format: Jiong Wu, Jian Zhang, Yiqun Du, Yanchun Meng, Sa Xiao, Hai Zhu, Yi Zhu. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with Locally Advanced or Metastatic Breast Cancer and other Solid Tumor: Updated results from a phase 1 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-07-27.

Breast cancer is the most common cancer and the most important cause of cancer-related death in females worldwide. Antibody-drug conjugates (ADCs) represent a novel class of targeted therapies that combine the precision of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. This review highlights recent mechanistic, technological, and clinical developments of ADCs in breast cancer, including next-generation ADCs beyond those that target HER2 (human epidermal growth factor receptor 2). Authors performed a systematic literature study for ADCs and their structural features, including their components (antibody, linker, and payload) and their therapeutic efficacy. A frame of preclinical research findings and clinical evidence integration of HER2-targeted therapy outcomes in HER2-positive, HER2-low, and triple-negative breast cancer (TNBC) subtypes were presented. Clinical studies of antibody-drug conjugates such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have demonstrated significant improvements in progression-free survival and overall survival across diverse breast cancer patient populations. ADCs offer unique advantages in breast cancer therapy by combining the precision of targeted antibodies with the potency of chemotherapy drugs. This allows them to selectively kill cancer cells, overcome resistance, reduce toxicity to healthy tissues, and expand treatment options for difficult subtypes like HER2-low and triple-negative breast cancer. Unlike previous reviews focusing on HER2-targeted ADCs, herein we review exciting ADCs targeting HER3 HER3 (human epidermal growth factor receptor 3) and Nectin-4, as well as the implications of bispecific and immune-stimulatory ADCs in the clinic. Additionally, it features mechanism-based innovations and novel trial data that revolutionize ADC applications in the HER2-low as well as the triple-negative breast cancer subtypes. The advent of ADC is changing precision oncology in breast cancer. With a new design and indications evolving, they are an attractive avenue for bypassing resistance and reducing toxicity and ultimately improving patient outcomes in the molecular subtypes. The present review summarizes recent advancements in antibody-drug conjugates (ADCs) and emerging targeted therapeutic strategies for breast cancer. It covers mechanistic insights, linker-payload innovations, receptor-based targeting approaches, clinical trial progress, and next-generation modalities that extend beyond HER2-directed ADCs. Current challenges, safety profiles, and future opportunities in engineering more selective and effective ADC platforms are also discussed.

Background- Hormone Receptor-Positive/HER2-low (HR+/HER2-low) and Triple Negative Breast Cancer (TNBC) represent distinct subtypes of breast cancer with varying treatment approaches and clinical outcomes. Trastuzumab Deruxtecan (T-Dxd) and Sacituzumab Govitecan (SG), the two ADCs, have emerged as promising therapeutic options for both subtypes. However, there is a lack of real-world data comparing the effectiveness of these agents in different treatment sequences. This retrospective study aims to compare the sequencing of T-Dxd and SG in HR+/ HER2-low and TNBC patients at Henry Ford Cancer Institute(HFCI), with a primary focus on median progression-free survival (mPFS). Methods- The electronic medical records of patients at HFCI from January 2020 to August 2024 were searched to identify patients diagnosed with metastatic HR+/HER2-low and TNBC who had received both SG and T-Dxd. Patients with incomplete medical records were excluded. Based on the tumor type and sequencing of treatment, patients were divided into four groups: 1) HR+/HER2-low who received T-Dxd followed by SG, 2) HR+/HER2-low who received SG followed by T-Dxd, 3) TNBC who received SG followed by T-Dxd, and 4) TNBC who received T-Dxd followed by SG. The mPFS, median overall survival (mOS), overall response rate (ORR), and disease control rate (DCR) for each of these four groups were plotted using the Kaplan-Meier Method. Results- A total of 33 patients were initially identified. Of these, 14 patients were HR+/HER2 low (median OS = 18 months, 95% CI 13.737 - 22.263), 14 were TNBC (median OS was 17 months, 95% CI 12.16 - 21.84), and 5 were excluded. Amongst Group 1 patients (n=12), mPFS after receiving T-Dxd was 7.09 months, mOS was 18.07 months, ORR was 33%, and DCR was 75%. On progression, they received SG with mPFS of 3.08 months, mOS of 5.61 months, and DCR of 40%. Amongst Group 2 patients (n=2), mPFS after receiving SG was 1.15 months, and mPFS after receiving sequential T-Dxd was 2.07 months. Amongst Group 3 patients (n=11), the mPFS after receiving SG was 5.06 months, mOS was 15.08 months, ORR was 22.2%, and DCR was 66.7%. Those who progressed and received T-Dxd had an mPFS of 2.16 months, an mOS of 6.3 months, and a DCR of 22.2%. Amongst Group 4 patients (n=3), mPFS after receiving T-Dxd was 7.95 months, mOS was 17.97 months, ORR was 33.3% and DCR was 100%. Those who progressed and received SG had mPFS of 3.08 months, mOS of 5.61 months, and DCR of 40%. Conclusion- Our retrospective study presents real-world data on the effect of sequencing the ADCs. The overall benefit observed is lesser when a second ADC is used after the first ADC. Contrary to common practice, using T-Dxd followed by SG sequencing, regardless of receptor status, appears more effective in our patient population than the reverse. Further studies analyzing the sequencing of ADCs prospectively with larger cohort populations and identifying biomarkers to aid patient selection can be conducted. Citation Format: Dhairya Gor, Maria Jamil, Sunita Ghosh, Vrushali Dabak. Sequencing of antibody drug conjugates (ADCs) in metastatic breast cancer: A real-world analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5948.

Antibody–drug conjugates (ADCs) have emerged as a transformative class of targeted therapies, offering new hope in the management of advanced breast cancer and other solid tumors. Among the most impactful developments are fam-trastuzumab deruxtecan-nxki (T-DXd) and datopotamab deruxtecan (Dato-DXd, also known as Datroway), both of which integrate precise tumor targeting with potent cytotoxic activity. T-DXd, a HER2-directed ADC, has significantly advanced the treatment paradigm for HER2-positive and HER2-low metastatic breast cancer. Results from the DESTINY-Breast01, DESTINY-Breast03, and DESTINY-Breast04 trials demonstrated exceptional objective response rates (ORR) and substantial improvements in progression-free survival (PFS). The molecule’s design—featuring a high drug-to-antibody ratio and a cleavable linker that allows for a bystander effect—enables it to effectively eliminate heterogeneous tumor populations and overcome resistance to prior HER2-targeted therapies. These findings have positioned T-DXd as a breakthrough option that extends the benefits of HER2-directed treatment beyond traditional HER2-positive disease categories. Similarly, Dato-DXd, a novel ADC targeting TROP2, has shown considerable promise in hormone receptor (HR)-positive, HER2-negative breast cancer and non–small cell lung cancer (NSCLC). In the TROPION-Breast01 trial, Dato-DXd achieved a 37% reduction in the risk of disease progression, establishing its clinical potential as a new therapeutic standard. Like T-DXd, it employs a topoisomerase I inhibitor (DXd) payload, which, combined with its bystander killing capacity, ensures strong activity even in tumors with heterogeneous or low antigen expression. Despite their remarkable efficacy, both agents face challenges that require careful management. The most significant among these are interstitial lung disease (ILD), a potentially serious adverse event, as well as the issues of acquired resistance and treatment cost. Ongoing research efforts are focused on improving patient selection criteria, developing combination strategies with other targeted or immune-based therapies, and enhancing safety monitoring to mitigate toxicity.

TPS1137 Background: Antibody-drug conjugates (ADCs) have demonstrated substantial improvement in progression free survival (PFS) and overall survival (OS) in phase III clinical trials in patients with metastatic triple negative breast cancer (mTNBC) and hormone receptor positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC), offering an effective new treatment strategy. Several outstanding questions impact the use of these drugs clinically, and prospective real-world data is needed. First, it is important to understand the safety and efficacy of these agents in a real-world population with diverse patient characteristics. Second, it is critical to understand the safety and efficacy of these ADCs in sequence. Third, it is essential to identify biomarkers that can help clarify mechanisms of response and resistance to ADCs, which may inform future sequencing and treatment strategies. Methods: This is a multicenter prospective registry study of patients with HER2-negative MBC who are treated with sequential ADCs per standard of care (SOC) with the goal to understand the safety and efficacy of sequential ADCs in a real-world setting (NCT06774027). A total of 100 participants with HER2-negative MBC will be enrolled in this study, either prior to starting their first ADC per SOC (cohort 1 = HR+/HER2-; cohort 2 = mTNBC) or prior to starting their second ADC per SOC (cohort 3 = HR+/HER2-; cohort 4 = mTNBC). The dual primary endpoints are real-world progression free survival (rwPFS) of ADC1 and rwPFS of ADC2. Secondary endpoints include overall response rate (ORR), duration of response (DOR), best overall response (BOR), disease control rate (DCR), and real-world overall survival (rwOS), and safety for each ADC. Exploratory endpoints include translational correlates of response/resistance to ADCs (e.g., circulating tumor DNA, circulating tumor cells, and tissue spatial correlates) and patient-reported outcomes (PROs). rwPFS and rwOS will be estimated by the Kaplan-Meier method. Statistics will be descriptive. Enrollment to start in the first quarter of 2025. Clinical trial information: NCT06774027 .

Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). DS-8201a is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a drug-to-antibody ratio of 7 to 8. It is designed with the goal of improving critical attributes of an ADC. In an ongoing phase 1 trial, DS-8201a showed promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff; Iwata et al, ASCO 2018). Based on preliminary results from the phase 1 trial, DS-8201a received FDA breakthrough therapy and fast track designations for metastatic BC that progressed after prior treatment with T-DM1. The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-BREAST02). Approximately 600 subjects will be randomized (2:1) to DS-8201a or investigator's choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. DS-8201a (5.4 mg/kg) will be administered IV once every 3 weeks. Progression free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. The primary analysis for PFS will occur when approximately 372 PFS events have been observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator's choice to 4.7 months with DS-8201a) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of the PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 160 sites including in North and South America, Europe, and Asia. For further information on this trial, contact Fabrice André at FABRICE.ANDRE@gustaveroussy.fr or visit clinicaltrials.gov. Citation Format: André F, Shahidi J, Lee C, Wang K, Krop IE. Trastuzumab deruxtecan (DS-8201a) vs investigator's choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-02.

Antibody drug conjugates (ADCs) are transforming the treatment of breast cancer as well as lung, ovarian, and several other cancer indications. ADCs targeting HER2 and TROP2 are currently approved in breast and lung cancer subgroups. Some HER2-targeted therapies are efficacious in breast cancer in newly defined HER2-low and -ultralow subgroups. There has been recent interest and some successes combining ADC’s with immune checkpoint inhibitors. Despite these successes, tumors still develop resistance through both target-dependent and independent mechanisms. Previously we investigated which ADC’s may be expressed in HER2-positive versus negative breast cancers and adeno versus squamous NSCLC histological subtypes. We have now extended these analyses to explore which ADC’s show the highest relative expression levels in these cancers, co-expression with PD-L1 and expression in HER2-low and -ultralow breast cancer subgroups. Optimized IHC assays for B7-H3, B7-H4, Nectin-4, TROP2, PD-L1 and HER2 on Ventana or Dako automated staining platforms were applied to treatment naïve tumor samples from ER+ BC (n=60), TNBC (n=52) and NSCLC (n=134; adeno and squamous) in tissue microarray format (1mm cores). ADC targets were scored by pathologist-assisted digital image analysis to deliver H-Scores and frequencies of positivity at high, moderate, low and negative expression levels. Diagnostic visual scoring methods were employed for analysis of PD-L1 and HER2 (including addition of ultra-low score for HER2). We demonstrate that immune positivity for PD-L1 (CPS >10) was most frequent in HER2-low TNBC compared with HER2-ultralow or negative samples, and that B7-H3 and Nectin-4 H-Scores were higher in TNBC compared with ER+ BC, regardless of PD-L1+ status suggesting potential for immunotherapy combinations in TNBC and especially HER2-low subtype. Furthermore, B7-H4 H-Scores were higher in HER2-low, ultralow and negative ER+ BC compared with HER2 positive samples, while the inverse was observed for B7-H3 revealing potential opportunities for therapies that may overcome resistance to HER2-targeted therapies in this cancer subtype. Squamous NSCLC displayed higher B7-H3 and B7-H4 H-Scores and percent positive cells compared with adeno subtype, and B7-H3 and B7-H4 H-Scores were higher in PD-L1 positive samples (TPS≥1%) supporting ADC therapy for these targets in combination with PD-1/PD-L1 immunotherapies. Taken together, these data may aid the future selection of targets for upcoming therapeutics that can overcome target-independent resistance and provide rationale for immunotherapy combinations. Citation Format: Marie Cumberbatch, Woo Ho Kim, Milan Bhagat, John Cogswell. Expression profiles of antibody drug conjugate (ADC) targets in breast and lung cancer subtypes and in new HER2 subgroups with their PD-L1 status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2690.

e13174 Background: Historically, HER2-targeted therapies failed to improve survival of patients with HER2-low-expressing tumors. Recently, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), demonstrated superior outcomes compared with treatment of physician´s choice (TPC) in this population. Other ADCs have also shown encouraging results, including sacituzumab govitecan (SG), MRG002, and RC48-ADC. Hence, we performed a systematic review and meta-analysis to assess the effectiveness of ADCs in patients with HER2-low advanced/metastatic (a/m) breast cancer (BC). Methods: We searched PubMed, Embase, and Cochrane databases and ASCO, ESMO, and SABCS websites for studies evaluating ADCs on patients with HER2-low a/mBC. Outcomes of interest were objective response rate (ORR); disease control rate (DCR); clinical benefit rate (CBR); progression-free survival (PFS); and overall survival (OS). We used R software (v.4.2.2) and random effects models for all analyses. Heterogeneity was assessed using I2 test. Results: Overall, 12 studies were included (3 real-world studies and 9 clinical trials), with 1,292 HER2-low a/mBC patients, 378 received TPC, and 914 received ADCs. Most were treated with T-DXd (63%, n=572), SG (29%, n=268), MRG002 (6%, n=56), and RC48-ADC (2%, n=18). Median age ranged from 48.1 to 58 years, and follow-up from 9.5 to 18.4 months. Patients treated with T-DXd achieved a significantly higher ORR and DCR compared to those who received SG, RC48-ADC, and MRG002 (Table). CBR was numerically higher in patients on T-DXd than those on SG but did not reach a significant difference. Patients with HR-positive tumors treated with SG had an ORR of 45% (95% CI 23 – 67%), and patients with pure HER2-low treated with any ADC, had an ORR of 38% (95% CI 30 – 45%). In the pooled analysis of 3 RCTs, ADCs significantly prolonged PFS compared with TPC (n=963, HR: 0.44, 95% CI 0.32 – 0.61, I2 = 66%, p<0.001), and OS (n= 680, HR: 0.56, 95% CI 0.36 – 0.89, I2 = 73%, p=0.015). Patients on ADCs also achieved a greater anti-tumor response than TPC, including better ORR (OR: 4.18, 95% CI 2.40 - 7.28, I2 = 52%, p<0.001), DCR (OR: 2.82, 95% CI 2.06 - 3.85, I2 = 7%, p<0.001), and CBR (OR: 3.41, 95% CI 2.36 - 4.93, I2 = 25%, p<0.001). Conclusions: Our systematic review and meta-analysis supports the efficacy of ADCs in HER2-low a/mBC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population.Anti-tumor activity of ADCs presented as overall % (95% CI). [Table: see text]

Introduction: HER2 is overexpressed on 15-20% of breast cancers and is a clinically important cancer driver. In spite of the HER2 targeted therapy’s success, most patients in the metastatic setting will eventually experience disease progression. ARX788 is an antibody drug conjugate (ADC) that consists of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269, that is site-specifically conjugated to the antibody via a non-natural amino acid incorporated into antibody by using a proprietary EuCODE technology platform. The phase 1 study ACE-Breast-01 (ZMC-ARX788-111 [CTR20171162]) evaluates the safety, pharmacokinetics, and efficacy of ARX788 in patients in China with metastatic HER2-positive breast cancer. Methods: ACE-Breast-01 is an open label, single site, dose escalation study using a 3+3 study design in 69 heavily pretreated patients (median of 6 prior lines of therapy, range: 2-17) with metastatic HER2-positive breast cancer who received intravenous ARX788. While the ARX788 MTD has not been determined, the 1.5 mg/kg of ARX788 dose is reported herein. Eligible patients had histologically documented, incurable, locally advanced or metastatic HER2+ (IHC 3+ and/or FISH positive) breast cancer whose disease had failed prior anti-HER2 treatments in the advanced disease setting; ECOG performance ≤1; adequate organ function; no history of interstitial lung disease or other significant lung disease; no radiotherapy for pulmonary diseases including lung parenchyma; no history of keratitis, corneal disease, or active ocular infection; no unstable brain or spinal cord metastasis; and no history of hypersensitivity to trastuzumab or any component of ARX788. The DLT assessment period was 84 days for pulmonary toxicity and one cycle of duration for all other toxicities. Investigators assessed efficacy using RECIST 1.1 and evaluated safety using NCI-CTCAE V.4.1. Results: Nineteen patients showed clinical response in the 1.5 mg/kg Q3W cohort, with the confirmed objective response rate of 66% (19/29, exact 95% CI, 45.7% to 82.1%), with median duration of response of 14.4 months [95% CI (9.0, NA)]. The disease control rate (CR + PR + SD) among the 29 patients treated was 100%. All patients (29/29, 100%) received prior trastuzumab in addition to other anti-HER2 treatments. Patients were heavily treated with prior HER2-targeted therapies and demonstrated robust ORR ranging from 65-80% (Table 1). ARX788 was generally well tolerated with most adverse events being grade 1 or 2 and were manageable. Low systemic toxicity (low incidence and low grade of neutropenia, thrombocytopenia, anemia, decrease WBC counts, nausea, vomiting, constipation, fatigue, etc.) was observed. No DLT or drug-related deaths occurred, as of data cut-off of 30-Jun-2021. Conclusion: At the 1.5 mg/kg dose level, ARX788 had robust anti-tumor activity in patients whose disease was resistant/refractory to other HER2 targeted therapies and was generally well tolerated with low systemic toxicity. Table 1.Summary of ACE-Breast-01 Confirmed ORR in patients whose disease is resistant or refractory to prior HER2 treatment (trastuzumab, ADCs, TKIs, and bispecific antibodies) at ARX788 1.5 mg/kg Q3WPrior anti-HER2 therapy*Confirmed ORRTrastuzumab containing regimens*19/29 (66%)HER2 ADCs (T-DM1, DX126-262, A166, BAT8001, and HS630) regimens**4/5 (80%)​HER2 TKIs (lapatinib, pyrotinib, neratinib, AST-1306, and Hemay-022) regimens15/23 (65%)​Both HER2 ADC and HER2 TKI regimens3/4 (75%)Bispecific antibodies (KN026 and M802) containing regimens3/4 (75%)*All patients (29/29) received prior trastuzumab-containing regimens.**One patient who received prior pertuzumab also achieved confirmed PR. Citation Format: Jiang Zhang, Dongmei Ji, Weina Shen, Qin Xiao, Yajia Gu, Joyce O’Shaughnessy, Gang Xia, Yanping Ji, Gaozhun Xiong, Matt Li, Dong Xu, Robert Cartmell, Cynthia Song, Jinchun Yan, Xichun Hu. Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-04.

TPS1112 Background: The overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. This HER2 subtype confers aggressive tumor behavior and the HER2 receptor remains a valuable target for antibodies, bi-specifics, and antibody drug conjugates (ADC). With advances in targeted therapy, patients with HER2-positive breast cancer (HER2+ BC) may experience an improved prognosis, including survival. Novel HER2-targeted therapies are being investigated to overcome drug resistance and to help mitigate adverse events (e.g., cardiotoxicity). ARX788 is a next-generation ADC using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Clinical activity has been seen in Phase I HER2 breast and pan-tumor studies. Methods: Trial Design: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function. Any brain metastases must be radiographically stable without steroid dependence. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by imaging every 6 weeks on study. Endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), and time to response (TTR). The safety and tolerability profile will be evaluated. Blood samples will be collected at specified time points to determine serum concentrations of ARX788, total antibody, and metabolite pAF-AS269. Potential predictive and/or prognostic biomarkers at baseline and on-treatment will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Clinical trial information: NCT04829604.