Tisotumab Vedotin Shows Clinical Benefit and Ongoing Responses in Cervical Cancer

A first-in-human study showed that the antibody drug conjugate (ADC) tisotumab vedotin (HuMax^®-TF-ADC) was well-tolerated and provided promising anti-tumor activity in patients with relapsed, recurrent, and/or metastatic cervical cancer, according to findings presented in a poster at the European Society of Gynaecological Oncology (ESGO) 2017 Congress.

Tisotumab vedotin is composed of a human monoclonal antibody that is specific for human tissue factor (TF) and is covalently coupled via a protease-cleavable peptide linker to monomethyl auristatin E (MMAE). MMAE is a potent microtubule disrupting agent that results in cell cycle arrest at the G2/M phase and apoptosis. TF is a transmembrane protein involved in angiogenesis, cell adhesion, motility, and cell survival, and is aberrantly over-expressed across a broad range of solid tumors, including cervical cancer, according to the poster authors.

“TF expression has been associated with a poor prognosis in cervical cancer; tisotumab vedotin selectively targets TF to deliver a clinically validated toxic payload to tumor cells, said Nicole Concin, MD, of the oncology department at the University Hospital Leuven in Leuven, Belgium, during a poster discussion session.

Tisotumab vedotin was evaluated in the cervical cancer expansion cohort of the open label, single arm, phase IIa GEN701 trial (NCT02001623). Thirty-four patients with relapsed, recurrent, and/or metastatic cervical cancer received tisotumab vedotin at 2.0 mg/kg administered by IV every 3 weeks. The primary objectives were safety and tolerability while secondary objectives included preliminary antitumour activity according to RECIST v1.1 as evaluated by CT scans done every 6 weeks.

The patients had a median age of 43 years and 21% of patients had an ECOG performance status of 0, and 76% had 1. The majority (44% each) of patients had adenocarcinoma or squamous cell cancer, 3 (9%) patients had adeno-squamous, and the cancer type was missing for 1 (3%) patient. Overall, 91% of patients had received prior treatment with a platinum- and/or taxane-based chemotherapy regimen, and 71% had received prior bevacizumab (Avastin).

The safety analysis showed compound-specific conjunctival toxicity that could be resolved with prophylactic steroid lubricating eye drops and cooling eye masks worn during treatment infusion. Prior to mitigation, 73% of patients experienced conjunctivitis of any grade. After mitigation, 32% of patients experienced any grade conjunctivitis and 5% of patients reported grade ≥3 conjunctivitis.

“Compound-specific conjunctival events were observed; however, mitigation measures substantially the reduced rates of toxicity,” she remarked.

Other frequently occurring treatment emergent adverse events (TEAEs) of any grade included epistaxis, fatigue, and alopecia, each in 47% of patients, and nausea in 44% of patients.

Grade 3 TEAEs were reported in 16 (47%) patients, and included vomiting in 15% of patients, while 9% of patients each reported grade 3 abdominal pain, nausea, and fatigue. There were no grade 4/5 events

“The safety profile of tisotumab vedotin in recurrent cervical cancer was generally consistent with other MMAE-based ADCs,” she pointed out.

Study discontinuation was reported for 27 (79%) patients. Five patients withdrew due to an AE, 16 due to disease progression, and 6 patients for other reasons.

Efficacy results after 12 weeks of treatment revealed 50% of patients showed clinical benefit. Eleven patients showed tumor reduction for an overall response rate of 32% including 8 confirmed and 3 unconfirmed partial responses. Tumor reduction from baseline was 40% or greater in all 11 responding patients, 3 patients showed tumor size reduction over 60%, and 80% tumor reduction was observed in 1 patient.

Stable disease was achieved by 6 patients, yielding a disease control rate (DCR) of 50%.

In responding patients, the median duration of confirmed responses was 8.3 months. Seven (21%) patients remain on treatment.

“Tisotumab vedotin demonstrated robust efficacy and a manageable safety profile in the cervical cancer expansion cohort,” Concin said. “The substantial efficacy and the manageable safety profile warrant further development of tisotumab vedotin in previously treated recurrent/advanced cervical cancer.”

The authors noted that an additional dosing schedule is being evaluated in a cervical cancer expansion cohort in the GEN702 study (NCT02552121).

Concin N, Vergote I, Dean E, et al. A phase IIa study of tisotumab vedotin (HuMax®-TF-ADC) in patients with relapsed, recurrent and/or metastatic cervical cancer: updated safety and efficacy. Poster presented at: 2017 ESGO Congress; November 4-7, 2017; Vienna, Austria.