**Background:** Cervical cancer remains the fourth most frequent cancer in women worldwide, with an estimated 14,100 new cases in 2022 in the US and 4,280 deaths. While early-stage disease has a 5-year overall survival of approximately 92%, metastatic disease has only 17%. After first-line platinum-based chemotherapy with or without bevacizumab, no effective standard second-line therapy exists, with response rates around 10% and progression-free survival of 3-6 months. Tisotumab vedotin (TV) is a first-in-class antibody-drug conjugate targeting tissue factor (TF), a transmembrane glycoprotein expressed in 94-100% of cervical cancer cells but with limited expression in healthy tissues. TV is conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent, via a protease-cleavable linker. Upon binding to TF-expressing cells, TV is internalized and releases MMAE, causing direct cytotoxicity and bystander killing of adjacent cells. Additionally, TV induces immunogenic cell death and engages immune effector functions including antibody-dependent cellular cytotoxicity and phagocytosis.
**Methods:** This narrative review selected studies from PubMed, Google Scholar, and ScienceDirect databases using terms including 'Cervical Cancer', 'Metastatic Cervical Cancer', 'Tisotumab Vedotin', and 'Second-line Chemotherapy'. Inclusion criteria comprised clinical trials, review articles, guidelines, and conference abstracts focusing on patients with advanced or recurrent cervical cancer, with no limitation on publication year. Exclusion criteria were duplicate papers and non-English articles. Key studies reviewed include the phase I/II innovaTV 201 trial, the pivotal phase II innovaTV 204 trial, the ongoing phase Ib/II innovaTV 205 combination trial, and the phase III innovaTV 301 trial.
**Key Results:** In the dose-escalation phase of innovaTV 201 (27 patients), the recommended phase II dose of 2.0 mg/kg every 3 weeks was established. In the expansion phase (147 patients across multiple tumor types), the objective response rate (ORR) for all patients was 15.6%, with cervical cancer patients showing 26.5% ORR. The pivotal innovaTV 204 trial enrolled 101 patients with recurrent or advanced cervical cancer progressing after platinum-based chemotherapy. After a median follow-up of 4.2 months, the confirmed ORR was 24% (95% CI: 15.9-33.3%), including 7% complete responses and 17% partial responses. Median duration of response was 8.3 months (95% CI: 4.2, not reached), median progression-free survival was 4.2 months (95% CI: 3.0-4.4), and median overall survival was 12.1 months (95% CI: 9.6-13.9). Responses were rapid, with median time to response of 1.4 months, and 79% of patients had tumor size reduction from baseline. TF expression was detected in 77 of 80 evaluable patients (96%), but responses occurred regardless of membrane TF expression level. Adverse events occurred in 92% of patients (65% grade 1-2, 25% grade 3). Common grade 1-2 events included alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), and dry eye (23%). Grade 3 events included peripheral neuropathies (8%), neutropenia (3%), fatigue (2%), and ulcerative keratitis (2%). Implementation of an eye care plan (steroid eye drops, vasoconstrictor drops, lubricating drops, and cooling pads) reduced ocular events from 80% to 25% in innovaTV 201. The ongoing innovaTV 205 trial (phase Ib/II) is evaluating TV combinations. Interim results showed ORR of 54.5% for first-line TV plus carboplatin, 40.6% for first-line TV plus pembrolizumab, and 38.3% for second/third-line TV plus pembrolizumab. The phase III innovaTV 301 trial comparing TV versus investigator's choice chemotherapy has completed recruitment with primary endpoint readout expected in Q2 2024.
**Clinical Implications:** TV received FDA accelerated approval on September 20, 2021, for recurrent or metastatic cervical cancer progressing after platinum-based chemotherapy, based on innovaTV 204 results. This addresses a critical unmet need, as no standard second-line therapy exists after platinum failure. The manageable safety profile, particularly with implemented mitigation strategies for ocular and bleeding events, supports its clinical use. The high TF expression in cervical cancer (94-100%) suggests broad applicability. Ongoing trials exploring TV combinations with immunotherapy and chemotherapy may further expand its role, potentially moving into first-line treatment. The results of innovaTV 301 will be crucial for European registration and confirmatory evidence. TV represents a novel therapeutic option with a distinct mechanism of action in a disease where effective second-line treatments are urgently needed.