Tisotumab Vedotin Earns Japanese Approval in Advanced Cervical Cancer

Tisotumab vedotin elicited a median OS of 11.5 months vs 9.5 months with chemotherapy in advanced cervical cancer in the phase 3 innovaTV 301 trial.

Japan’s Ministry of Health, Labour and Welfare has approved tisotumab vedotin-tftv (Tivdak) for the treatment of patients with advanced or recurrent cervical cancer who progressed on or after chemotherapy, according to a press release from the developer, Genmab.¹

Supporting data for the approval came from the phase 3 innovaTV 301 trial (NCT04697628), which evaluated the efficacy and safety of tisotumab vedotin compared with investigator’s choice of chemotherapy.

The median overall survival (OS) was 11.5 months (95% CI, 9.8-14.9) with tisotumab vedotin compared with 9.5 months (95% CI, 7.9-10.7) with chemotherapy, ultimately demonstrating a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.89; two-sided P = .004).² The median progression-free survival (PFS) was 4.2 months (95% CI, 4.0-4.4) vs 2.9 months (95% CI, 2.6-3.1), respectively.

The confirmed objective response rate (ORR) was 17.8% (95% CI, 13.3%-23.1%) with tisotumab vedotin vs 5.2% (95% CI, 2.8%-8.8%) with chemotherapy (OR, 4.0; 95% CI, 2.1-7.6; P <.001). A confirmed complete or partial response (CR/PR) or stable disease lasting 5 weeks or more after randomization occurred in 75.9% (95% CI, 70.1%-81.0%) of the tisotumab vedotin arm and 58.2% (95% CI, 51.8%-64.4%) of the chemotherapy arm. The median duration of response (DOR) per investigator assessment was 5.3 months (95% CI, 4.2-8.3) and 5.7 months (95% CI, 2.8-not reached [NR]), respectively; the median time to response was 1.6 months vs 1.7 months.

Previously, in April 2024, the FDA approved tisotumab vedotin in the indicated population.³ In Japan, tisotumab vedotin is the only antibody-drug conjugate approved for patients with cervical cancer.

“Patients with advanced or recurrent cervical cancer, in general, have a poor prognosis. The advent of new treatment options, especially for second-line or later treatment, is much needed,” Aikou Okamoto, MD, PhD, chief professor in the Department of Obstetrics and Gynecology at The Jikei University School of Medicine, stated in the press release.¹ “Cervical cancer treatment has advanced in recent years, but it is very meaningful that the approval of tisotumab vedotin as an [antibody-drug conjugate] has increased the number of treatment options with a new mechanism of action that is expected to prolong [OS]. This is good news for patients and healthcare professionals.”

innovaTV 301 is an open-label, randomized trial that enrolled a total of 502 patients who were randomly assigned, in a 1:1 ratio, to receive either 2.0 mg/kg of tisotumab vedotin every 3 weeks (n = 253) or investigator’s choice of chemotherapy (n = 249) of either topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed. In the trial, 101 patients were Japanese.

Eligible patients had recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology who had disease progression during or after prior standard-of-care systemic doublet chemotherapy with bevacizumab (Avastin) and an anti–PD-1/L1 agent. Additionally, patients had an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and a life expectancy of at least 3 months.

Those with primary neuroendocrine, lymphoid, sarcomatoid, or other histologic features and patients with significant bleeding, cardiovascular issues, or risks were excluded from participating in the trial.

The median age of patients was 50 years (range, 26-80); the majority of patients had an ECOG performance status of 0 (54.4%), 1 prior line of systemic therapy (61.4%), extrapelvic metastatic disease at trial entry (89.8%), and squamous cell carcinoma histology (63.1%). Also, 35.9% of patients were Asian.

The trial’s primary end point was OS. Secondary end points included PFS, confirmed ORR, DOR, time to response, and safety.

The median duration of treatment exposure was 3.7 months with tisotumab vedotin and 2.8 months with chemotherapy. Any-grade adverse events (AEs) occurred in 98.4% and 99.2% of patients, respectively, and grade 3 or higher AEs occurred in 52.0% and 62.3%. Common AEs of any grade included nausea (33.2% vs 40.2%, respectively), conjunctivitis (31.2% vs 0.4%), peripheral sensory neuropathy (28.4% vs 2.5%), and constipation (24.8% vs 16.3%); of grade 3 or higher, AEs included anemia (8.4% vs 27.6%), urinary tract infection (4.4% vs 7.1%), and abdominal pain (4.0% vs 1.7%).

In January 2025, findings from a Chinese subpopulation in the trial were published and showed that, in patients from China, the study treatment reduced the risk of death vs chemotherapy by 45% (HR, 0.55; 95% CI, 0.27-1.15); the median OS was NR with tisotumab vedotin vs 10.7 months with chemotherapy.⁴

References

1. TIVDAK® (tisotumab vedotin) approved by Japan Ministry of Health, Labour and Welfare for the treatment of advanced or recurrent cervical cancer that has progressed on or after chemotherapy. News release. Genmab. March 27, 2025. Accessed March 28, 2025. https://tinyurl.com/bdzn3hax
2. Vergote I, González-Martín A, Fujiwara K, et al. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. N Engl J Med. 2024;391(1):44-55. doi:10.1056/NEJMoa2313811
3. FDA approves tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. News release. FDA. April 29, 2024. Accessed March 28, 2025. https://tinyurl.com/ets4ma4b
4. Zai Lab announces positive topline results for TIVDAK in the China subpopulation of the global phase 3 innovaTV 301 trial in patients with recurrent or metastatic cervical cancer. News release. Zai Lab Limited. January 15, 2025. Accessed March 28, 2025. https://tinyurl.com/y2yyvjew