Antibody drug conjugates in recurrent or metastatic cervical cancer: a focus on tisotumab vedotin state of art

Abstract

Cervical cancer (CC) is still characterized by a poor prognosis despite the progress made in its treatment in recent years. Although immunotherapy has improved outcomes for advanced/recurrent disease, there is a significant gap in addressing patients' needs when they progress after platinum and immunotherapy treatments. In this setting, traditional chemotherapy showed limited effectiveness. In this context, antibody-drug conjugates (ADCs) emerged as a promising tool within targeted cancer therapies. Tisotumab vedotin (TV), an ADC targeting tissue factor, represents the first ADC approved by the US Food and Drug Administration for the treatment of recurrent or metastatic CC with disease progression on or after chemotherapy. In phase I-III published trials, TV has already demonstrated an advantage in terms of objective response rate (17.8%-54.4%) and progression-free survival (3.1-6.9 months) in patients who progressed to the first-line standard therapy. Data concerning the addition of TV to platinum/pembrolizumab first-line chemotherapy are still under analysis and strongly expected. However, several questions are still unresolved: (1) the identification of the most suitable timing for ADCs administration in the treatment sequence of advanced/recurrent CC; (2) the evaluation of combination therapies as a tool to minimize the emergence of resistant clones and to enhance overall effectiveness; and (3) the assessment of tolerability and correct management of special toxicities (e.g. ocular and neurological adverse events). In the near future, an improvement in patient selection via biomarker-driven strategies should be crucial for optimizing both treatment benefits and maintaining an acceptable toxicity profile.

Keywords: antibody–drug conjugates < targeted therapy; cervical cancer; systemic treatment; targeted therapy; tisotumab vedotin.

Figure 1.

ADCs’ mechanism of action: a magnifying glass on TV is composed of a human monoclonal antibody against TF linked to the MMAE, a microtubule-disrupting agent. TF, also called platelet tissue factor, is expressed in 90%–95% of cancer cells in cervical cancer. TV mechanisms of action consist of three phases: (1) recognition of the target and internalization; (2) linker’s lysosomal degradation; and (3) release of payload. Besides the direct cytotoxic effect, TV is characterized by a bystander effect on neighboring cancer cells, which enhances its efficacy. ADCs, antibody–drug conjugates; MMAE, monomethyl auristatin E; TF, tissue factor; TV, tisotumab vedotin.

Figure 2.

Antibody drug conjugates in cervical cancer: mechanism of action and current drugs under investigation. (a) The binding between antibodies and cervical cancer cells’ receptors is highly specific. In detail in a clockwise direction: trastuzumab recognizes ERBB2, tisotumab and sacituzumab recognize the corresponding antigens (TF and TROP-2) on cell’s surface. (b) On the left ADC mechanism of action and anti-TF, anti-HER2, anti-TROP-2 specific components. ADC, antibody–drug conjugates; HER2, human epidermal growth factor receptor 2; TF, tissue factor; TROP-2, trophoblast antigen 2.