Tisotumab Vedotin Shows Favorable Activity in Recurrent or Metastatic Cervical Cancer

The antibody-drug conjugate (ADC) tisotumab vedotin induced clinically meaningful and durable responses in patients who have relapsed or progressed on or after previous treatment for recurrent or metastatic cervical cancer, according to topline results from the phase 2 innovaTV 204 trial.¹

Results showed that treatment with the agent resulted in a confirmed objective response rate (ORR) of 24% per independent central review (95% CI, 15.9%-33.3%), with a median duration of response (DOR) of 8.3 months. Additionally, the most commonly reported treatment-related adverse events reported with the ADC were alopecia, epistaxis, nausea, conjunctivitis, fatigue, and dry eye. The full data from the trial will be presented at an upcoming medical meeting, according to Seattle Genetics, Inc, co-developer of the drug.

“Available therapies upon progression after first line chemotherapy in recurrent or metastatic cervical cancer are limited, and there is a significant unmet need for new treatment options,” Roger Dansey, MD, chief medical officer at Seattle Genetics, said in a press release.¹ “Tisotumab vedotin has demonstrated clinically meaningful and durable objective responses with a manageable safety profile, and we look forward to discussing with the FDA the potential submission of a biologics license application to support an accelerated approval.”

Tisotumab vedotin is a first-of-its-kind investigational ADC that is composed of a human antibody that is targeted to tissue factor, which is expressed on cervical cancer and is known to encourage tumor growth, angiogenesis, and metastases.^2,3 The agent is also comprised of ADC technology that uses a protease-cleavable linker and the microtubule-disrupting agent monomethyl auristatin E. The agent is being developed in collaboration with Genmab.

Standard treatment options for an all-comers population of patients with previously treated recurrent and/or metastatic cervical cancer generally lead to limited ORRs of less than 15% with median overall survival ranging from 6.0 months to 9.4 months, according to the biotechnology company.

The ongoing, single-arm, international, multicenter innovaTV 204 trial is examining tisotumab vedotin in patients with recurrent or metastatic cervical cancer who received previous treatment with doublet chemotherapy with bevacizumab (Avastin) if eligible in accordance with local standards.⁴ Patients were eligible for the trial if they had received up to 2 prior lines of therapy in the metastatic setting. A total of 101 patients have been treated with the ADC across multiple centers in the United States and Europe.

The primary endpoint of the trial is confirmed ORR per RECIST v1.1 criteria, as assessed by independent central review. Key secondary endpoints of the trial include DOR, progression-free survival, overall survival, safety, and tolerability.

Previously, the agent was examined in the open-label, dose-escalation and dose-expansion, phase 1/2 innovaTV 201 trial, which was conducted at 21 centers across the United States and Europe.5 Patients aged ≥18 years who had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, esophagus, squamous cell carcinoma of the head and neck or non–small cell lung cancer were eligible for enrollment. Patients also had to have an ECOG performance status of 0 or 1 and relapsed on or were ineligible for standard-of-care treatment.

In the dose-escalation phase of the trial, patients received the ADC at doses ranging from 0.3 and 2.2 mg/kg, delivered intravenously, once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were given the recommended phase 2 dose of the agent. The primary end point of the trial was incidence of AEs, including serious AEs, infusion-related, treatment-related, grade 3 or higher, and study drug–related AEs assessed in all patients who were given at least 1 dose of the drug.

Participants were enrolled to the dose-escalation phase of the trial between December 9, 2013, and May 18, 2015. Results revealed dose-limiting toxicities, such as grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever in patients who received the 2.2 mg/kg dose of the ADC. As such, the recommended phase 2 dose was established to be 2.0 mg/kg of intravenous tisotumab vedotin once every 3 weeks.

A total of 147 patients were then enrolled to the dose-expansion phase of the trial between October 8, 2015 and April 26, 2018. Here, the most commonly reported treatment-emergent AEs of any grade included epistaxis (69%), fatigue (56%), nausea (52%), alopecia (44%), conjunctivitis (43%), reduced appetite (36%), constipation (35%), diarrhea (30%), vomiting (29%), peripheral neuropathy (22%), dry eye (22%), and abdominal pain (20%).

The most common AEs that were of grade 3 or higher included fatigue (10%), anemia (5%), abdominal pain (4%), hypokalemia (4%), conjunctivitis (3%), hyponatremia (3%), and vomiting (3%).

Just under half of the patients, or 46%, had a treatment-emergent serious AE that was determined to be related to the study drug. Additionally, infusion-related toxicities were reported in 12% of the patients evaluated.

Additionally, the confirmed proportion of patients who achieved objective responses with the ADC, across tumor types, was 15.6% (95% CI, 10.2-22.5). Nine deaths were reported across all phases of the trial, with 3 occurring in the dose-escalation phase and 6 occurring in the dose-expansion phase. However, only 1 case of pneumonia observed in the dose-expansion phase of the trial was considered to potentially be associated with the study treatment.

Tisotumab vedotin is currently under investigation in several ongoing clinical trials. For example, the agent is being examined in combination with pembrolizumab (Keytruda), carboplatin or bevacizumab, and with a weekly dosing schedule in patients with locally advanced or metastatic cervical cancer. The ADC is also being assessed in other tissue factor–expressing tumors, such as ovarian cancer and other solid tumors.⁶

References

1. Seattle Genetics announces positive topline results from phase 2 clinical trial of tisotumab vedotin in recurrent or metastatic cervical cancer. News release. Seattle Genetics, Inc. June 29, 2020. Accessed June 30, 2020. bit.ly/2YMX1Rb.
2. Tisotumab vedotin. Seattle Genetics. Accessed June 30, 2020. bit.ly/2YJerhB.
3. van den Berg YW, Osanto S, Reitsma PH, et al. The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood. 2012;119(4):924-932. doi:10.1182/blood-2011-06-317685
4. A trial of tisotumab vedotin in cervical cancer. ClinicalTrials.gov. Updated May 24, 2019. Accessed June 30, 2020. https://clinicaltrials.gov/ct2/show/NCT03438396.
5. de Bono JS, Concin N, Hong DS, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(3):383-393. doi:10.1016/S1470-2045(18)30859-3
6. Genmab announces very favorable topline results from phase 2 clinical trial of tisotumab vedotin in recurrent or metastatic cervical cancer. News release. Genmab. June 29, 2020. Accessed June 30, 2020. bit.ly/2NDMZLU.