Tisotumab Vedotin Regimens Have Significant Antitumor Activity Across Settings in Metastatic Cervical Cancer

Adding tisotumab vedotin to carboplatin for frontline metastatic cervical cancer or combining it with pembrolizumab (Keytruda) as second- or third-line therapy in patients with recurrent disease elicits significant responses without prohibitive toxicity, according to interim findings from 2 expansion cohorts of the phase 1/2 innovaTV 205 trial (NCT03786081) that were presented during the 2021 European Society for Medical Oncology Congress.¹

At a median follow-up of 7.9 months in the tisotumab vedotin/carboplatin cohort (n = 33), the objective response rate (ORR) was 55% (n = 18; 95% CI, 36%-72%), comprising 4 complete responses (12%; CRs) and 14 partial responses (42%; PRs); there were 12 cases of stable disease (36%; SD).

At a median follow-up of 13.0 months in the tisotumab vedotin/pembrolizumab cohort (n = 34), the ORR was 38% (n = 13; 95% CI, 22%-56%), comprising 2 CRs (6%) and 11 PRs (32%); there were 12 cases of SD (35%).

“Acknowledging the limited sample size, both first-line tisotumab vedotin plus carboplatin and second- and third-line tisotumab vedotin plus pembrolizumab showed encouraging and durable antitumor activity in patients with recurrent or metastatic cervical cancer,” said lead study author Ignace B. Vergote, MD, PhD, head of the Department of Obstetrics and Gynecology and Gynecologic Oncology, Catholic University of Leuven, in Belgium, in a virtual presentation of the data.

Frontline platinum and taxane chemotherapy plus bevacizumab (Avastin), if eligible, has improved survival for patients with recurrent or metastatic cervical cancer, but more effective and safer treatments are needed.

Tisotumab vedotin, an antibody-drug conjugate (ADC) that targets tissue factor, is under study for the treatment of several solid tumors, including cervical cancer.

On April 9, 2021, the FDA granted a priority review to the biologics license application (BLA) for tisotumab vedotin as a potential treatment for patients with recurrent or metastatic cervical cancer with progressive disease on, or following, chemotherapy.²

The application was based on findings from the phase 2 innovaTV 204 trial (NCT03438396), which showed that 2 mg/kg of intravenous (IV) treatment with the ADC given every 3 weeks led to an ORR of 24% and a median duration of response (DOR) of 8.3 months in previously treated patients with recurrent or metastatic cervical cancer.³ Additionally, the agent had a manageable safety profile.

The recommended phase 2 dose for tisotumab vedotin in combination with pembrolizumab, carboplatin, and bevacizumab in patients with recurrent or metastatic cervical cancer enrolled in innovaTV 205 was recently reported at the 2021 International Gynecologic Cancer Society Annual Global Meeting.⁴

The focus of the present analysis is on the carboplatin and pembrolizumab cohorts. In the carboplatin cohort, patients with no prior systemic therapy for recurrent or metastatic cervical cancer received 2 mg/kg of IV tisotumab vedotin every 3 weeks plus IV carboplatin at an area under the curve of 5 every 3 weeks. In the pembrolizumab cohort, patients with recurrent or metastatic cervical cancer with disease progression on or after 1 or 2 prior systemic treatments received 2 mg/kg of IV tisotumab vedotin every 3 weeks plus 200 mg of IV pembrolizumab every 3 weeks.

ORR per RECIST v1.1 criteria served as the primary end point; secondary end points included adverse effects (AEs) and laboratory parameters, DOR, time to response, progression-free survival (PFS), overall survival (OS), and pharmacokinetic concentrations and anti-drug antibodies associated with tisotumab vedotin.

The baseline demographics and clinical characteristics indicated that in the carboplatin and pembrolizumab cohorts, the median age was 51.0 vs 47.0 years, respectively. The majority of patients in both cohorts had an ECOG performance status of 0, squamous histology, and prior chemoradiation.

In the pembrolizumab cohort, 81.5% of patients (n = 22) were PD-L1 positive, and the majority of patients had received 1 line of prior treatment (n = 26; 74.3%) and prior bevacizumab (n = 18; 51.4%).

Additional results showed in the tisotumab vedotin/carboplatin cohort, the median PFS was 9.5 months (95% CI, 4.0-not reached [NR]), and the median OS was NR (range, 0.8+ to 14.1+). The median DOR was 8.3 months (95% CI, 4.2-NR). The median time to response was 1.4 months (range, 1.1-4.4).

The median duration of exposure was 4.9 months (range, 1-9) with tisotumab vedotin vs 4.1 months (range 1-9) with carboplatin. The median number of cycles initiated was 6.0 (range, 1-12) with tisotumab vedotin and carboplatin.

In the tisotumab vedotin/pembrolizumab cohort, the median PFS was 5.6 months (95% CI, 2.7-13.7), and the median OS was NR (range, 1.3-17.5+). The median DOR was 13.8 months (95% CI, 2.8-NR). The median time to response was 1.4 months (range, 1.3-5.8).

The median duration of exposure was 4.1 months (range, 1-16) with tisotumab vedotin vs 4.3 months (range 1-17) with pembrolizumab. The median number of cycles initiated was 6.0 (range, 1-21) with tisotumab vedotin and 6.0 months (range, 1-25) with pembrolizumab.

In terms of safety, in the tisotumab vedotin/carboplatin cohort, all patients had at least 1 treatment-emergent AE (TEAE); 97% (n = 32) of these events were related to tisotumab vedotin. Grade 3 or greater AEs occurred in 78.8% (n = 26) of patients; 57.6% (n = 19) of these events were related to tisotumab vedotin.

Serious AEs occurred in 42.4% of patients (n = 14); 15.2% (n = 5) of these events were related to tisotumab vedotin. No patients in the cohort had a fatal event.

In the tisotumab vedotin/pembrolizumab cohort, all patients had at least 1 TEAE; 97.1% (n = 34) of these events were related to tisotumab vedotin. Grade 3 or greater AEs occurred in 74.3% (n = 26) of patients; 45.7% (n = 16) of these events were related to tisotumab vedotin.

Serious AEs occurred in 51.4% of patients (n = 18); 14.3% (n = 5) of these events were related to tisotumab vedotin. One fatal event was reported in the cohort but was not determined to be related to tisotumab vedotin.

AEs that occurred in approximately half of patients in both cohorts included ocular events, bleeding events, and peripheral neuropathy.

“These data support further research to evaluate additional tisotumab vedotin combinations as interventions in recurrent or metastatic cervical cancer. The dose expansion cohort of tisotumab vedotin and pembrolizumab in first-line recurrent or metastatic cervical cancer in this study is being evaluated and will be reported at a future medical meeting,” concluded Vergote.

References

1. Vergote IB, Monk BJ, O’Cearbhaill RE, et al. Tisotumab vedotin (TV) + carboplatin (carbo) in first-line (1L) or + pembrolizumab (pembro) in previously treated (2L/3L) recurrent or metastatic cervical cancer (r/mCC): interim results of ENGOT-Cx8/GOG-3024/innovaTV 205 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 723MO.
2. Seagen and Genmab announce US FDA filing acceptance for priority review of tisotumab vedotin biologics license application for patients with recurrent or metastatic cervical cancer. News release. April 9, 2021. Accessed September 19, 2021. https://bit.ly/3s6I7AL
3. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020;31(suppl 4):S1162-S1163. doi:10.1016/j.annonc.2020.08.2262
4. Monk BJ, Van Gorp T, Lorusso D, et al. Tisotumab vedotin + bevacizumab or pembrolizumab or carboplatin in recurrent/metastatic cervical cancer: phase 1b/2 ENGOT-Cx8/GOG-3024/innovaTV 205 study dose-escalation results. Presented at: 2021 IGCS Annual Global Meeting; August 30-September 2, 2021; virtual. Plenary 5.