ladiratuzumab vedotin (SGN-LIV1A)

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.

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

P1/2; Active, not recruiting --> Recruiting

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

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

P1/2; N=133 --> 242 | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

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

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

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

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | N=1920 --> 4000

P2, N=1920, Recruiting, QuantumLeap Healthcare Collaborative | Trial primary completion date: Dec 2020 --> Dec 2025

P2, N=180, Recruiting, Seattle Genetics, Inc. | Trial completion date: Nov 2020 --> Apr 2021