In a prespecified interim analysis of the phase III, multinational innovaTV 301/ENGOT-cx12/GOG-3057 study involving patients with recurrent cervical cancer, tisotumab vedotin as second- or third-line treatment resulted in significantly better overall survival (OS) outcomes than the investigator’s choice of chemotherapy, with a 30% lower risk of death and a median OS that was 2 months longer. The OS curves separated early and the separation was maintained throughout the follow-up period.
Progression-free survival (PFS) and the objective response rate (ORR) as assessed by the investigator, which were the key secondary efficacy endpoints, were also significantly better in patients treated with tisotumab vedotin than in patients treated with chemotherapy according to Dr. Ignace Vergote of the University Hospitals Leuven in Leuven, Belgium, and colleagues, who reported the findings on 3 July 2024 in The New England Journal of Medicine.
The authors wrote in the background that prognosis for patients with cervical cancer is poor, with 5-year OS less than 19% among patients with distant disease. Anti-PD1 or anti-PD-L1 therapy (pembrolizumab or atezolizumab) in combination with the previous standard-of-care (a doublet of platinum and paclitaxel with or without bevacizumab) has shown an OS benefit in two phase III studies. Cemiplimab monotherapy has also shown an OS benefit superior to that with chemotherapy for second-line or later treatment for recurrent cervical cancer, although patients who had previously received anti-PD1 or anti-PD-L1 therapy were excluded. Despite these advances, patient outcomes remain poor and additional treatment options are needed.
Tisotumab vedotin is an investigational antibody-drug conjugate composed of a tissue factor–directed human monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E. Tissue factor is elevated in several solid tumours, including recurrent cervical cancer. Tisotumab vedotin showed encouraging and durable responses as a second- and third-line treatment in patients with recurrent cervical cancer in a phase II innovaTV 204/ENGOT-cx6/GOG-3023 study. In addition, tisotumab vedotin in combination with pembrolizumab has shown encouraging antitumour activity in patients with recurrent cervical cancer who have not previously received treatment and in patients with previously treated recurrent cervical cancer who have not previously received immunotherapy.
The innovaTV 301/ENGOT-cx12/GOG-3057 team conducted this phase III, multinational, open-label study of tisotumab vedotin as second- or third-line treatment in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy or the investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary endpoint was OS.
A total of 502 patients underwent randomisation, from whom 253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group. The groups were similar with respect to demographic and disease characteristics. The median OS was significantly longer in the tisotumab vedotin group than in the chemotherapy group with 11.5 months (95% confidence interval [CI] 9.8 to 14.9] versus 9.5 months (95% CI 7.9 to 10.7), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio [HR] 0.70, 95% CI 0.54 to 0.89; two-sided p = 0.004).
The median PFS was 4.2 months (95% CI 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI 2.6 to 3.1) with chemotherapy (HR 0.67, 95% CI 0.54 to 0.82; two-sided p < 0.001). The confirmed ORR was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio 4.0, 95% CI 2.1 to 7.6; two-sided p < 0.001).
The authors commented that although the subgroup analyses were helpful for assessing consistency in the treatment effect in the intention-to-treat (ITT) population, the results should be interpreted with caution, as OS and PFS trends in the prespecified subgroups resulted in CIs that overlapped with those in the ITT population.
No biologic reason is known for the different outcomes of subsequent treatment between patients who have received bevacizumab previously and those who have not. In innovaTV 204 study, the subgroup of patients who had not received previous bevacizumab had a higher ORR than patients who had received previous bevacizumab. Given the evolving role of immunotherapy in earlier lines of treatment, innovaTV 301 showed the benefit of tisotumab vedotin over chemotherapy in patients with recurrent cervical cancer regardless of previous receipt of an anti-PD-1 or anti-PD-L1 agent. Tissue factor expression was similar in the two groups regardless of best overall response.
A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period, defined as the period from day 1 of dose 1 until 30 days after the last dose. Grade 3 or greater adverse events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of side effects.
This study was conducted in collaboration with the European Network of Gynaecological Oncological Trial (ENGOT) and the Gynecologic Oncology Group Foundation (GOG-F). The authors also acknowledged the Latin American Cooperative Oncology Group, the Gynecologic Oncology Trial and Investigation Consortium, and the Korean Gynecologic Oncology Group for their involvement in the study.
The study was supported by Genmab and Seagen, which was acquired by Pfizer in December 2023. Tisotumab vedotin was codeveloped by Genmab and Pfizer.
Reference
Vergote I, González-Martín A, Fujiwara K, et al. for the innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med2024;391:44-55.