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A research team led by Professor Johann de Bono at the Institute of Cancer Research, London has successfully tested a new drug that has infiltrated different forms of cancer in an ongoing human trial [1].

The drug is called tisotumab vedotin (TV) and works like a ‘Trojan Horse’ by hiding a cancer-killing payload inside an antibody, which allows it to infiltrate the tumor and attack it from the inside.

The antibody seeks out a surface receptor on tumor cells known as ‘tissue factor’ (TF). TF is expressed by many tumor cells and contributes to a variety of pathological processes, including thrombosis, metastasis, tumor growth, and tumor angiogenesis. Once the antibody has located the TF receptor, it binds to it, and the cancer-killing payload is able to enter the tumor cell and destroy it from the inside.

The trial, which included 147 patients from the UK, the US, Belgium, Denmark, and Sweden, aimed to establish the safety, tolerability, pharmacokinetic profile, and anti-tumor activity of the TV drug. Most of the patients in the trial had advanced-stage cancer that had spread either around the body or locally and had developed resistance to an average of three other cancer treatments.

The drug was delivered intravenously to the patients during the trial and appears to work against a number of types of cancer, including cervical, bladder, ovarian, lung, throat, and womb.

The researchers observed that there was a small but significant number of patients who experienced a halt in tumor growth or even shrinkage: 27% for bladder cancer, 26.5% for cervical cancer, 14% for ovarian cancer, 13% for throat and non-small cell lung cancers, and 7% for endometrial cancer. It had no effect on prostate cancer in this particular study.

The effects of TV treatment were also persistent, with responses lasting an average of around six months and, in some cases, up to nine and a half months. This initial phase was focused on determining if the drug was reaching the correct target and what effect it would have on tumors. These smaller initial trials also generally establish the optimal dose and frequency and help to pave the way for larger-scale studies.

The promising initial results have led to an ongoing larger-scale trial, which includes hundreds of patients with other types of solid-tumor cancers, including pancreatic, bowel, brain, and neck. The researchers believe that their early results suggest that TV has the potential to address many different kinds of cancers, including cancers with low survival rates.

Findings

Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.

Interpretations

Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.

Conclusion

Cancer therapies have made great progress in the last few years in particular, and we are seeing some very novel approaches that significantly differ from the traditional approaches that have largely failed to bring a solution. There is a reasonable chance that many common targets and mechanisms may be identified in most cancers, and so the hope of generic therapies that can treat multiple cancer types is increasing along with our knowledge. We welcome the arrival of new drugs such as this Trojan Horse, and we eagerly await the ongoing study results.

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Literature

[1] de Bono, J. S., Concin, N., Hong, D. S., Thistlethwaite, F. C., Machiels, J. P., Arkenau, H. T., … & Ghatta, S. (2019). Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1–2 trial. The Lancet Oncology.

CategoryNews, Research
About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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