P1/2, N=186, Completed, Seagen Inc. | Active, not recruiting --> Completed | Trial completion date: Jan 2026 --> Sep 2024 | Trial primary completion date: Jan 2026 --> Sep 2024

This narrative review explores key predictive factors influencing the efficacy of ADCs, focusing on HER2-targeted therapies, such as trastuzumab emtansine and trastuzumab deruxtecan, as well as sacituzumab govitecan for triple-negative breast cancer. Finally, future perspectives on the sequential use of ADCs and potential combination therapies are highlighted, along with emerging agents targeting alternative antigens like HER3 and LIV-1. Overall, identifying predictive biomarkers and overcoming resistance mechanisms are essential for optimizing the use of ADCs in metastatic breast cancer, thereby improving patient outcomes.

P1/2, N=186, Active, not recruiting, Seagen Inc. | Trial completion date: Dec 2024 --> Jan 2026 | Trial primary completion date: Mar 2024 --> Jan 2026

P=N/A, N=0, Available, Seagen Inc.

Recently, in the United States of America, FDA approved the use of a new drug targeting LIV1, antibody drug conjugate SGN-LIV1A for treatment of TNBC patients...Finally, TNBC patients with 3+ staining intensity showed poor survival (4.44 year) as compared to patients with 2+ LIV1 expression (5.47 year), emphasizing that LIV1 expression is a poor prognostic factor in TNBC. In conclusion, the study reports elevated expression of LIV1 in a large Indian TNBC cohort; high expression is a poor prognostic factor and correlated with aggressive disease and indicating the need for LIV1 targeted therapies.

This article reviews recent advances in the application of ADCs in the treatment of HER2-low breast cancer. Additionally, this review explores the underlying factors contributing to the impact of target selection on ADC efficacy to provide new insights for optimizing the clinical application of ADCs in individuals with low HER2 expression in advanced breast cancer.

P2, N=205, Terminated, Seagen Inc. | Trial completion date: Jul 2025 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: May 2024 --> Nov 2023; Study closed due to portfolio prioritization

P1/2, N=186, Active, not recruiting, Seagen Inc. | Phase classification: P1b/2 --> P1/2

The ASCENT and TROPiCS-02 trial of Sacituzumab Govitecan, a Trop2 ADC, gained great success in TNBC and HR+ BC... The analysis of clinicopathological findings of LIV-1 protein indicates their values for prognosis markers, especially in HR+ BC and TNBC. Trop2 expression has no prognostic role in line with previous research. Further studies are warranted to explore targetable biomarkers for the development of appropriate ADCs.

Similarly, the addition of pembrolizumab in treating early-stage triple-negative breast cancer has led to exploring other ICIs in this setting. However, it has also raised important scientific questions regarding optimal patient selection, biomarkers that predict the success of ICIs, ideal chemotherapy partners, and the financial implications of bringing newer therapies to the forefront. In this review, we discuss the evolving landscape of ICIs and ADCs in managing early-stage breast cancer and provide an overview of potential future advancement in the field.

Conclusions CD74 and SLAMF7 is highly present in melanoma, correlates with PD-L1 expression and predict response to anti-PD-(L)1 therapies. This finding suggests to explore potential combinations between ADCs against these targets and anti-PD-(L)1 therapies.

P2, N=205, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting | N=414 --> 205

P1b/2, N=186, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting

In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided.

P1b/2, N=211, Recruiting, Seagen Inc. | Trial primary completion date: Apr 2023 --> Mar 2024

P1, N=290, Completed, Seagen Inc. | Active, not recruiting --> Completed | Trial completion date: Jun 2023 --> Feb 2023

P1/2; N=280 --> 133

P2, N=414, Recruiting, Seagen Inc. | N=264 --> 414

P1, N=290, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting | N=448 --> 290 | Trial primary completion date: Dec 2022 --> Mar 2023

Sacituzumab govitecan, an anti-trophoblast cell surface antigen 2 ADC, is the only non-anti-HER2 ADC approved for breast cancer to date, with several novel ADCs directed against novel targets (e.g., HER3, LIV-1) at various stages of preclinical and clinical development. The aim of this review is to provide an overview of clinical trials investigating ADCs targeting novel antigens. We discuss the optimal characteristics of the target to be exploited in ADCs' design and potential future challenges in the evolving field of ADCs such as biomarker assessment, patient selection, and sequencing of ADCs.

P1/2; Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> May 2024 | Trial primary completion date: Sep 2023 --> May 2024

The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents (eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders-trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs)...Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics.

P1, N=448, Recruiting, Seagen Inc. | Trial primary completion date: Jul 2022 --> Dec 2022

P2, N=264, Recruiting, Seagen Inc. | Trial completion date: Jul 2023 --> Jul 2025 | Trial primary completion date: Aug 2022 --> May 2024

P1/2; Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Mar 2023 --> Sep 2023

Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla, Enhertu, Trodelvy, and Abraxane)...In TNBC these conjugates (Trodelvy, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody-drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed.

P1b/2, N=211, Recruiting, Seagen Inc. | N=161 --> 211 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Feb 2022 --> Apr 2023

P2; Trial completion date: Dec 2026 --> Dec 2031 | Trial primary completion date: Dec 2025 --> Dec 2030

P1, N=508, Recruiting, Seagen Inc. | Trial completion date: Mar 2022 --> Jun 2023 | Trial primary completion date: Apr 2021 --> Jul 2022

P1b/2, N=161, Recruiting, Seagen Inc. | N=122 --> 161 | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Aug 2021 --> Feb 2022

Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P1 --> P2

P1, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P2 --> P1

P2, N=264, Recruiting, Seattle Genetics, Inc. | Trial completion date: Jan 2023 --> Jul 2023 | Trial primary completion date: Jul 2021 --> Aug 2022

Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing.

P1b/2, N=122, Recruiting, Seattle Genetics, Inc. | Trial completion date: Mar 2023 --> Jun 2023 | Trial primary completion date: Dec 2020 --> Aug 2021

We analyzed 44 TNBC and HER2 NAICT pts from 4 distinct Trx protocols including: (1) 14 TNBC pts treated with intratumoral Talimogene laherparepvec (TVEC) in combination with weekly paclitaxel (T) followed by dose dense Adriamycin and Cytoxan (ddAC); (2) 13 ER+HER2+ pts treated with subcutaneous interferon gamma (IFN-) in combination with weekly T with trastuzumab and pertuzumab (HP); (3), 6 ER-HER2+ pts treated with 3 weeks of HER2 pulsed dendritic cell vaccines (DC1) followed by Taxotere, Carboplatin, and HP; and (4), 11 pts on ISPY2 trial; 8 pts randomized to Trx with pembrolizumab with weekly T followed by ddAC, 1 pt treated with SGN-LIV1A followed by ddAC, and 2 pts treated with durvalumab, and T, followed by ddAC. The addition of IT with standard CT regimens in TNBC and HER2 BC has improved pCR but reduced the predictive capacity of MRI suggesting MRI may not be accurate enough to make further surgical decisions.

P1/2, N=280, Recruiting, Hoffmann-La Roche | Trial completion date: May 2023 --> Jan 2023 | Trial primary completion date: May 2023 --> Jan 2023

Treatment protocols included (1) 14 TNBC patients treated with intratumoral Talimogene laherparepvec (TVEC) in combination with weekly Paclitaxel followed by dose dense Adriamycin and Cytoxan (ddAC); (2) 13 ER+HER2+ patients treated with subcutaneous interferon gamma (IFN-γ) in combination with weekly paclitaxel with Trastuzumab and Pertuzumab ; (3), 6 ER-HER2+ patients treated with 3 weeks of HER2 pulsed dendritic cell vaccines (DC1) followed by Taxotere, Carboplatin, and Pertuzumab; and (4), 10 patients on ISPY2 trial; 7 patients randomized to treatment with Pembrolizumab with weekly T followed by ddAC, 1 patient treated with SGN-LIV1A followed by ddAC, and 2 patients treated with Durvalumab, and Paclitaxel, followed by ddAC. Patients with biopsy-proven nodal HER2-positive and triple-negative breast cancer treated with NAICT had an overall 65% axillary pCR (68% in N1 group and 50% in N2/N3 groups). NAICT does not interfere with accuracy of MRI in assessment of node-negative disease. The accuracy and sensitivity of MRI increases with greater nodal burden.

Legal entity responsible for the study Seattle Genetics, Inc. Funding Seattle Genetics, Inc.

Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Research Funding: Seattle Genetics Inc.

P1b/2, N=122, Recruiting, Seattle Genetics, Inc. | Trial completion date: May 2022 --> Mar 2023 | Trial primary completion date: May 2020 --> Dec 2020