Tivdak (tisotumab vedotin-tftv)

P2, N=692, Recruiting, Seagen Inc. | Trial primary completion date: Apr 2025 --> Feb 2026

Tissue factor (TF), an initiator of the blood coagulation pathway, has been investigated regarding its relationship with cancer, and several preclinical and clinical studies have presented data on anti-TF ADCs, including tisotumab vedotin, which was approved in 2021...Analysis of a pancreatic cancer tissue array showed weak and heterogeneous TF expression in most TF-positive specimens, indicating that the response rate to pancreatic cancer might be higher for DXd- than MMAE-conjugated anti-TF ADC. Nevertheless, our findings indicated that optimizing the ADC payloads individually in each patient could maximize the potential of ADC therapeutics.

Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively...Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%...Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Pembrolizumab was added to cycle three of her systemic chemotherapy regimen of carboplatin/paclitaxel/bevacizumab. She had progression on this regimen and was transitioned to tisotumab vedotin; however, ultimately opted to proceed with hospice secondary to failure to thrive.Case 2A 36-year-old woman with history of an abnormal pap smear in pregnancy and initial biopsy demonstrating endocervical adenocarcinoma, mucinous type...This is the first case report describing these inconsistencies. Etiologies of and outcomes related to the discrepant expression of PD-L1 should be further studied.

In breast cancer, T-DM1 and T-DXd which is HER2-targeted ADC have been approved and are broadly used in Japan. Sacituzumab govitecan, TROP2-ADC has been approved in US...In gynecological cancers, tisotumab vedotin for cervical cancer and mirvetuximab soravtansine for ovarian cancer have been approved in the US...The current development landscape suggests further enhancement of ADC treatment efficacy through new targets, novel payloads, bispecific ADCs, and combination therapies with immunotherapy. This article outlines the current status of ADCs in breast and gynecological cancers, highlighting ongoing development and challenges emerging in the field.

P3, N=686, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P3, N=568, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting | Trial completion date: Feb 2028 --> Aug 2025

P3, N=686, Not yet recruiting, Merck Sharp & Dohme LLC

However, only the ADC tisotumab vedotin (TV) is approved by the Food and Drug Administration (FDA) for use in cervical cancer... TROP2, TF and NECTIN4 are highly expressed in cervical cancer. Clinical trials evaluating the safety and efficacy of ADCs are highly relevant in cervical cancer.

As such, we reviewed FDA approvals from 2019 to 2013 and identified the following approvals in gynecologic oncology: pembrolizumab plus lenvatinib, pembrolizumab for recurrent endometrial cancer that is MSI-H/dMMR, tisotumab vedotin, dostarlimab as single-agent therapy, and dostarlimab plus chemotherapy. We focused on approvals for endometrial cancer, and conducted a cost-effectiveness analysis for combination options approved in treating recurrent or advanced endometrial cancer (i.e. pembrolizumab plus lenvatinib versus placebo; dostarlimab plus chemotherapy versus placebo), and found neither regimen was cost-effective at a willingness-to-pay of $100,000 per Equal Value of Life Years Gained (evLYG). While these costs may not necessarily be translated to an individual patient, these costs are absorbed by healthcare systems and insurance providers on a larger scale with downstream effects on individuals contributing to healthcare costs a whole.

P1/2, N=214, Active, not recruiting, Seagen Inc. | Phase classification: P1b/2 --> P1/2

The recently approved KRAS mutation-specific inhibitors sotorasib and adagrasib (KRAS-I) represent a promising therapy for KRAS-driven non-small cell lung cancer (NSCLC)...Tissue factor (TF) is overexpressed in KRAS-mutated (KRASmut) NSCLC and is the target of the FDA-approved ADC Tivdak...Thus, we have identified the TF/mTORC2 axis as a critical new mechanism for triggering immunosuppression and KRAS-I resistance. We propose that targeting this axis with HuSC1-39 or MTI-31 will improve KRAS-I response in KRAS-driven NSCLC.

The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.

P2, N=692, Recruiting, Seagen Inc. | Trial primary completion date: Nov 2023 --> Apr 2025

P1, N=19, Completed, Zai Lab (Shanghai) Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Nov 2023

P1, N=20, Active, not recruiting, Zai Lab (Shanghai) Co., Ltd. | Not yet recruiting --> Active, not recruiting | Initiation date: Oct 2023 --> Jun 2023

In this review, we discuss prevention measures and the outcomes of recent trials in all stages of cervical cancer. As therapies continue to evolve, ongoing trials and new areas of exploration will continue to identify opportunities to improve survival in cervical cancer.

P1b/2, N=214, Active, not recruiting, Seagen Inc. | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024

The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.

We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care-such as bevacizumab and the immune CPIs-and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.

In summary, our study opens the door for further evaluation of ADCs in several indications not explored before.

The relationship between ADC and MMAE exposure and safety end points suggests increased exposure was associated with increased AE risk. These results align with clinical findings showing TV 2 mg/kg (≤200 mg for patients ≥100 kg) every 3 weeks is efficacious and tolerable for patients with r/mCC.

TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

The combination of immunotherapies and biologics have significantly increased overall survival, but with associated higher costs, primarily related to drug costs.

Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

Also, other unique side effects are specific to the tissue antigen that is targeted for, such as the cardiac toxicity with Her-2 targeting ADCs, and the hemorrhagic side effects with the tissue factor (TF) targeting Tisotumab vedotin. Further exciting developments are centered in the strategies to improve the tolerability and efficacy of the ADCs to improve the therapeutic window; as well as the development of novel payloads including (1) peptide-drug conjugates (PDCs), with the peptide replacing the monoclonal antibody, rendering greater tumor penetration; (2) immune-stimulating antibody conjugates (ISACs), which upon conjugation of the antigen, cause an influx of pro-inflammatory cytokines to activate dendritic cells and harness an anti-tumor T-cell response; and (3) the use of radioactive isotopes as a payload to enhance cytotoxic activity.

For many years, the standard of care was the combination of platinum-based drug and paclitaxel with the possible addition of bevacizumab. The most recent years have seen the development of the use of immune checkpoint inhibitors (ICIs) (pembrolizumab, cemiplimab and others) in patients with CC...Another emerging drug is tisotumab vedotin, an antibody-drug conjugate targeting tissue factor...Today, there is a growing consensus that combining RT with ICIs may boost abscopal response or cure rates for various cancers. Here we will review the potential abscopal effect of immune-radiation therapy in metastatic cervical cancer.

P1, N=20, Recruiting, Zai Lab (Shanghai) Co., Ltd. | Not yet recruiting --> Recruiting

P2, N=692, Recruiting, Seagen Inc. | N=532 --> 692 | Trial completion date: Dec 2024 --> Nov 2026

Although there are still many challenges, TF could possibly be a potential molecule to be used for further cancer therapy as some TF-targeted therapies like Seagen and Genmab's tisotumab vedotin have gained FDA approval for treatment of cervical cancer. Overall, based on the overviewed studies, this review article provides an in-depth overview of the crucial role that TF plays in cancer development and progression, and emphasizes the potential of TF-targeted and re-targeted therapies as potential approaches for the treatment of cancer.

Tissue factor (TF) is the target of the FDA-approved ADC Tivdak. HuSC1-39 is the parent antibody of MRG004A, a clinical stage TF-ADC (NCT04843709)...Treatment of TF-high TNBC cells with anti-TF or TF-knockout all stimulated CXCL9/10/11 production, promoted T cell migration and effector function. Thus, we have identified a new mechanism of TF in TNBC tumor progression and therapy resistance.

In ovarian cancer, mirvetuximab soravtansine, an ADC targeting alpha-folate receptor (FRα), received US Food and Drug Administration (FDA) accelerated approval in November 2022 after data from the single-arm phase III SORAYA trial. A second ADC targeting FRα, STRO-002, received FDA fast track designation in August 2021. Multiple studies with upifitamab rilsodotin, an ADC comprising a NaPi2B-binding antibody, are underway. In cervical cancer, tisotumab vedotin, an ADC-targeting tissue factor, received FDA accelerated approval in September 2021 after the phase II innovaTV 204 trial...Trastuzumab-deruxtecan (T-DXd), an ADC targeting human epidermal growth factor receptor 2 (HER2), is currently approved for HER2-positive and HER2-low breast cancer and shows promise in endometrial cancer. Like all anticancer treatments, the decision for a patient to undergo therapy with an ADC is a personal choice that balances the potential benefits with the side effects and requires thorough and compassionate support of their physician and care team and shared decision making.

P1, N=20, Not yet recruiting, Zai Lab (Shanghai) Co., Ltd.

The first-line standard of care for R/M CC now benefits from the addition of the immune checkpoint inhibitor, pembrolizumab, to platinum-based chemotherapy with paclitaxel and bevacizumab. We searched clinicaltrials.gov for ongoing trials and pubmed.ncbi.nih.gov for recently published trial data, as well as recent years' proceedings from the annual conferences of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO) and the International Gynecologic Cancer Society (IGCS). Therapeutics currently attracting attention include novel immune checkpoint inhibitors, therapeutic vaccination, antibody-drug conjugates, such as tisotumab vedotin, tyrosine kinase inhibitors targeting HER2 and multitarget synergistic combinations.

The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor...In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens...We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination therapies, including chemotherapy, anti-angiogenic and immunotherapeutic agents.

In urological cancer, olaparib + abiraterone was demonstrated thru the PROpel trial to benefit in first-line treatment mCRPC regardless of the HRR stratification factor, along with the adjuvant therapy everolimus, for fully resected RCC in the EVEREST trial. In gynecological cancer, tisotumab vedotin demonstrated a potential role in improving clinical outcomes in 1st line r/mCC thru InnovaTV-205. In breast cancer, trastuzumab deruxtecan showed significant benefit for redefined human epidermal growth factors receptor 2 status in HER2 low BC patients, where current targeted-HER2 therapies are ineffective in the DESTINY-BREAST 04 study...research papers. In this article, we resumed the different renowned and what we considered intriguing to review studies presented during these three long sessions at the ASCO 2022 meeting.

Current evidence strongly supports the use of ADCs and ongoing clinical trials will provide further information into the potential of making these drugs part of current standard practice allowing patients to be treated with a higher level of personalized cancer care.

This vedotin drug linker system has been clinically validated in multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. Moreover, SGN-B7H4V in combination with an anti-PD1 agent led to improved antitumor activity and elicited durable immune memory. Altogether, these nonclinical data further support the evaluation of SGN-B7H4V as a monotherapy in the ongoing Phase 1 Study of SGN-B7H4V in Advanced Solid Tumors ( NCT05194072 ) and potential future clinical combinations with immunotherapies.

Moreover, we reviewed the effectiveness of candidate drugs targeting hypercoagulation, such as tissue factor- or interleukin-6-targeting drugs, anti-inflammatory drugs, anti-hypoxia signaling drugs, anticoagulants, and combined immunotherapy with these drugs for OCCC. This review is expected to contribute to novel basic research and clinical trials for the prevention, early detection, and treatment of OCCC focused on hypercoagulation.

In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated.

This vedotin drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, tisotumab vedotin, and polatuzumab vedotin. Finally, SGN-B7H4V drove robust, curative activity in an immunocompetent tumor model as a monotherapy and paired well with an anti-PD1 agent. Altogether, these data support the evaluation of SGN-B7H4V as a monotherapy in a first-in-human phase 1 clinical study and potential future clinical combinations with immunotherapies.