EMA Validates MAA for Tisotumab Vedotin in Recurrent or Metastatic Cervical Cancer

The European Medicines Agency has validated the marketing authorization application (MAA) seeking the approval of tisotumab vedotin-tftv in adult patients with recurrent or metastatic cervical cancer with disease progression on or following systemic treatment.¹

The MAA is supported, in part, by findings from the phase 3 innovaTV 301 trial (NCT04697628), in which the antibody-drug conjugate (ADC; n = 253) improved median overall survival (OS) over investigator’s choice of chemotherapy (n = 249), at a median of 11.5 months (95% CI, 9.8-14.9) and 9.5 months (95% CI, 7.9-10.7), respectively (HR, 0.70; 95% CI, 0.54-0.89; P = .0038).²

The 12-month OS rates were 48.7% and 35.3%, respectively. Moreover, the median investigator-assessed progression-free survival (PFS) with tisotumab vedotin was 4.2 months (95% CI, 4.0-4.4) vs 2.9 months (95% CI, 2.6-3.1) with chemotherapy (HR, 0.67; 95% CI, 0.54-0.82; P < .0001). The 6-month PFS rates were 30.4% and 18.9%, respectively.

Tisotumab vedotin elicited an objective response rate (ORR) of 17.8% (95% CI, 13.3%-23.1%) vs 5.2% (95% CI, 2.8%-8.8%) with chemotherapy (OR, 4.0; 95% CI, 2.1-7.6; P < .0001). Among those who responded to the ADC, 2.4% had a complete response (CR) and 15.4% experienced a partial response (PR); 58.1% had stable disease, 18.2% experienced disease progression, and 5.9% were not evaluable for response. The disease control rate (DCR) with the ADC was 75.9% (95% CI, 70.1%-81.0%) vs 58.2% (95% CI, 51.8%-64.4%) with chemotherapy. The median duration of response (DOR) was 5.3 months (95% CI, 3.2-8.3) with tisotumab vedotin vs 5.7 months (95% CI, 2.8-not reached) with chemotherapy.

The application was also supported by data from the phase 2 innovaTV 204 study (NCT03438396).³ At a median follow-up of 10.0 months (interquartile range, 6.1-13.0), the ADC elicited a confirmed ORR of 24% (95% CI, 16%-33%), which was comprised of a CR rate of 7% and a PR rate of 17%.

“The validation of our application is an important milestone supporting our commitment to bringing a new therapeutic option for recurring or metastatic cervical cancer to more patients,” Jan van de Winkel, PhD, chief executive officer of Genmab, stated in a press release.¹ “There continues to be a need for therapeutic options for these patients, and we’re dedicated to delivering potentially improved outcomes to women diagnosed with this devastating disease.”

The open-label, randomized, phase 3 innovaTV 301 study enrolled patients with recurrent or metastatic cervical cancer whose disease had progressed on or following a chemotherapy doublet with or without bevacizumab (Avastin) and an anti–PD-(L)1 agent if eligible and available.2 Patients must have received at least 2 previous lines of therapy, measurable disease by RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.

A total of 502 patients were randomly assigned 1:1 to receive intravenous tisotumab vedotin at 2.0 mg/kg every 3 weeks or investigator’s choice of chemotherapy, which could have been topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed. Randomization was stratified by performance status (0 vs 1), previous receipt of bevacizumab (yes vs no), prior anti–PD-(L)1 therapy (yes vs no), and geographic region (United States vs Europe vs other).

OS served as the trial’s primary end point, and key secondary end points comprised PFS, ORR, and safety.

The median patient age was 51 years (range, 26-80) with tisotumab vedotin vs 50 years (range, 27-78) with chemotherapy. Slightly more than half of patients had an ECOG performance status of 0 (54.2% vs 54.6%) and just under half of patients were from Europe (41.9% vs 41.8%). Most had squamous cell carcinoma (63.2% vs 63.1%) and pelvic recurrent–only disease (89.3% vs 90.4%).

In the ADC arm, 62.8% received 1 prior systemic regimen, 36.8% received 2 prior regimens, and this information was unknown in 0.4% of patients; in the chemotherapy arm, these respective rates were 59.8%, 40.2%, and 0%, respectively. In the tisotumab vedotin arm, 64.8% of patients previously received bevacizumab, 28.1% had prior exposure to immunotherapy, and 81.0% had prior radiation therapy; these respective rates were 63.1%, 26.9%, and 81.5%, respectively, in the chemotherapy arm.

Grade 1 or 2 treatment-related adverse effects (TRAEs) occurred in 58.4% of patients in the ADC arm vs 40.2% in the chemotherapy arm; grade 3 or higher TRAEs were reported in 29.2% vs 45.2% of patients, respectively. The most common TRAEs to occur in the tisotumab vedotin and chemotherapy arms, respectively, were anemia (12.8% vs 43.9%), nausea (29.2% vs 36.0%), conjunctivitis (30.4% vs 0%), peripheral sensory neuropathy (26.8% vs 2.1%), alopecia (24.4% vs 2.9%), epistaxis (22.8% vs 2.1%), neutropenia (6.4% vs 21.8%), decreased appetite (18.0% vs 10.0%), diarrhea (16.0% vs 8.8%), and keratitis (15.6% vs 0%).

No grade 4 or 5 AEs of special interest were reported with tisotumab vedotin. Treatment discontinuation because of ocular and peripheral neuropathy events occurred in 5.6% of patients in each arm.

In January 2024, the FDA granted priority review to a supplemental biologics license application seeking to convert the accelerated approval of tisotumab vedotin (Tivdak) to a full approval for patients with recurrent or metastatic cervical cancer who disease progresses on or after first-line therapy.⁴ The application is supported by innovaTV 301 findings.

References

1. Tisotumab vedotin marketing authorization application validated by European Medicines Agency for treatment of recurrent or metastatic cervical cancer. News release. February 2, 2024. Accessed February 2, 2024. https://ir.genmab.com/news-releases/news-release-details/tisotumab-vedotin-marketing-authorization-application-validated
2. Fujiwara K, Slomovitz BM, Gonzalez Martin A, et al. InnovaTV 301/ENGOT-cx12/GOG-3057: a global, randomized, open-label, phase III study of tisotumab vedoyin vs investigator’s choice of chemotherapy in 2L or 3L recurrent or metastatic cervical cancer. Ann Oncol. 2023;34(suppl 4):S1586. doi:10.1016/j.annonc.2023.10.410
3. Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5
4. Tivdak supplemental biologics license application accepted for priority review by FDA for patients with recurrent or metastatic cervical cancer. News release. Pfizer. January 9, 2024. Accessed February 2, 2024. https://www.pfizer.com/news/press-release/press-release-detail/tivdakr-supplemental-biologics-license-application-accepted