Tisotumab vedotin versus chemotherapy in Chinese patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy

To the Editor: Treatment modalities remain limited for recurrent or metastatic cervical cancer (r/mCC) in second-line or later settings.[1] Tisotumab vedotin is a novel antibody–drug conjugate directed at tissue factor, which is highly expressed in cervical cancer.[2–4] It selectively delivers the potent cytotoxic agent monomethyl auristatin E into target cells, triggering programmed cell death and arresting tumour cell proliferation.[5] In the global portion of the open-label, randomised, phase 3 innovaTV 301 trial, tisotumab vedotin significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus chemotherapy in patients with r/mCC who progressed on or after first-line chemotherapy.[4] This article reports the prespecified analysis of all patients enrolled in Chinese mainland within innovaTV 301, aiming to evaluate the efficacy and safety of tisotumab vedotin versus chemotherapy in Chinese patients. The innovaTV 301 trial (ClinicalTrials.gov, NCT04697628) was conducted globally, with 23 sites in Chinese mainland. The trial was done in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local laws and regulations. Written informed consent was obtained from all patients, and the study was approved by the ethics committee of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (approval number: 22/153-3354). Eligible patients were adults (≥18 years or as per local regulations) diagnosed with r/mCC. They had experienced disease progression during or after treatment with a standard of care systemic doublet chemotherapy, with bevacizumab and an inhibitor of programmed death-ligand 1 or programmed cell death protein 1 (PD-[L]1), if eligible and available, and received one or two prior lines of systemic therapy. They had measurable disease according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a life expectancy of ≥3 months. The study planned to enrol approximately 482 patients globally, with 74 in Chinese mainland (15% of the target sample size). By the time the global enrolment target was met (502 patients randomised for the global portion), 8 patients had been enrolled from Chinese mainland, and the remaining 66 Chinese patients continued to enrol, forming the China extension portion as described in the protocol. Between 12 February 2023 and 4 February 2024, 74 patients in Chinese mainland, across the global and China extension portions, were randomised (1:1) to receive intravenously either tisotumab vedotin (Zai Lab [Shanghai] Co., Ltd, Shanghai, China) at 2.0 mg/kg every three weeks (n = 35) or investigator’s choice chemotherapy (n = 39), until unacceptable toxicities, disease progression, death, withdrawal of consent, study termination, or patient/investigator request to discontinue study treatment, whichever occurred first. Tumour assessments were conducted using computed tomography, or magnetic resonance imaging when computed tomography was contradicted. The primary endpoint was OS. More methodology details are provided in Supplementary Material, https://links.lww.com/CM9/C870. The data cut-off date for the current analysis was 15 November, 2024. In the tisotumab vedotin arm, 35 (100%) patients received at least one dose of study treatment; among them, 34 (97%) discontinued study treatment and 22 (63%) remained in the study. In the chemotherapy arm, four (10%) patients did not receive any study treatment (3 due to patient withdrawal, 1 due to worsening of pre-existing pneumonia), 35 patients (90%) received at least one dose of study treatment, all of whom discontinued study treatment, and 19 (49%) remained in the study (Supplementary Figure S1, https://links.lww.com/CM9/C870). In both arms, disease progression was the primary reason for treatment discontinuations. Baseline characteristics and demographics were largely comparable across the two arms [Supplementary Table S1, https://links.lww.com/CM9/C870]. In the China subpopulation, 40 (54%) patients previously received anti-PD-(L)1 therapy and 54 (73%) had received one previous line of systemic therapy. In the China intention-to-treat analysis set (n = 74), comprising all randomised patients in Chinese mainland, median follow-up for OS was 11.5 months (95% confidence interval [CI], 10.7–12.2 months), and 13 (37%) and 20 (51%) OS events occurred in the tisotumab vedotin and chemotherapy arms, respectively. Median (95% CI) OS was not reached (9.7 months–not evaluable [NE]) in the tisotumab vedotin arm and 10.7 months (6.0–NE) in the chemotherapy arm [Figure 1], corresponding to a 45% lower risk of death with tisotumab vedotin versus chemotherapy (hazard ratio [HR], 0.55; 95% CI, 0.27–1.15). The 12-month OS rate was 62% (95% CI, 43%–76%) in the tisotumab vedotin arm and 47% (95% CI, 30%–62%) in the chemotherapy arm. The OS benefit observed with tisotumab vedotin versus chemotherapy was generally consistent across pre-specified subgroups, independent of ECOG performance status, prior use of anti–PD-(L)1 therapy, or histological subtype [Supplementary Table S2, https://links.lww.com/CM9/C870].Figure 1: Overall survival (intention-to-treat population) in the China subpopulation. CI: Confidence interval; NE: Not evaluable; NR: Not reached; OS: Overall survival.A total of 27 (77%) and 27 (69%) PFS events occurred in the tisotumab vedotin and chemotherapy arms, respectively. Median PFS (95% CI) was 4.4 months (3.0–5.0) in the tisotumab vedotin arm and 2.8 months (1.5–4.2) in the chemotherapy arm [Supplementary Figure S2, https://links.lww.com/CM9/C870], corresponding to a 48% lower risk of disease progression or death with tisotumab vedotin versus chemotherapy (HR, 0.52; 95% CI, 0.27–1.03). The confirmed ORR (95% CI) was 14.3% (4.8%–30.3%) in the tisotumab vedotin arm and 5.1% (0.6%–17.3%) in the chemotherapy arm (odds ratio, 3.2; 95% CI, 0.6–16.9) [Supplementary Table S3, https://links.lww.com/CM9/C870]. Disease control rate (95% CI) was 82.9% (66.4%–93.4%) in the tisotumab vedotin arm and 48.7% (32.4%–65.2%) in the chemotherapy arm. In the China safety analysis set (n = 70), comprising all randomised patients in Chinese mainland who received at least one dose of study treatment, all patients experienced at least one treatment-emergent adverse event (TEAE) of any cause [Supplementary Table S4, https://links.lww.com/CM9/C870]. Grade ≥3 TEAEs of any cause were reported in 49% (17/35) in the tisotumab vedotim arm and 51% (18/35) in the chemotherapy arm. Serious TEAEs of any cause occurred in 7 (20%) patients in the tisotumab vedotin arm and 12 (34%) patients in the chemotherapy arm. No fatal adverse events occurred in the tisotumab vedotin arm. The proportion of patients who discontinued treatment due to TEAEs of any cause was 26% (9/35) in the tisotumab vedotin arm and 14% (5/35) in the chemotherapy arm. More details are provided in Supplementary Table S5, https://links.lww.com/CM9/C870 on TEAEs leading to treatment discontinuation. The most common TEAEs of any grade and grade ≥3 are summarised in Supplementary Tables S6 and S7, https://links.lww.com/CM9/C870, respectively. The pre-specified adverse events of special interest (AESIs) (all-causality) for tisotumab vedotin included ocular adverse events, peripheral neuropathy, and bleeding. AESIs in the China subpopulation are summarised in Supplementary Table S8, https://links.lww.com/CM9/C870. AESIs were mostly of grade 1 or 2 in both arms and manageable with dose modifications. No AESIs of grade 4 or 5 were observed in either arm. Most patients who experienced AESIs saw all or some of their AESIs resolved or improved by the data cut-off date. In conclusion, the China subpopulation analysis of the innovaTV 301 trial demonstrated that tisotumab vedotin improved OS, PFS, and tumour response compared to chemotherapy in Chinese patients with r/m CC with disease progression on or after systemic therapy, regardless of prior use of anti-PD-(L)1 therapy, consistent with the findings in the global population. Meanwhile, tisotumab vedotin showed a manageable safety profile in Chinese patients, with no new safety signals detected. Collectively, these findings support tisotumab vedotin as an effective treatment option for Chinese patients with r/mCC who progress on or after chemotherapy. Conflicts of interest This study was sponsored by Zai Lab (Shanghai) Co., Ltd. Third-party writing assistance for this article, provided by Jinlong Guo, PhD (Costello Medical), was also funded by Zai Lab (Shanghai) Co., Ltd., in compliance with the Good Publication Practice 2022 guidelines. Sonia Deutsch is an employee of Pfizer. Ibrahima Soumaoro is an employee of Genmab and has stock or ownership in Genmab. Zhao Huang, Ning Wang, and Jianmei Hou are employees of Zai Lab and have stock and/or stock options in Zai Lab. No disclosures were reported by the other authors.