Evolving standards and future directions for systemic therapies in cervical cancer

Abstract

Several groundbreaking clinical trials with the potential to transform the management paradigm of both locally advanced and persistent, recurrent, or metastatic cervical cancers have been presented in 2023. This review describes the reported data from INTERLACE and KEYNOTE-A18 in the locally advanced setting, as well as BEATcc, innovaTV 301 and DESTINY-PanTumor02 for advanced disease. The practice implications of their positive results are interpreted in the context of global health considerations, and updated treatment algorithms are proposed. Furthermore, emerging trends in drug development for cervical cancer are discussed. As the routine use of immune checkpoint inhibitors (ICIs) for curative and palliative indications increases in the foreseeable future, patients whose cervical cancers which persist, relapse or progress after prior ICI exposure will represent an area of unmet clinical need and form the key target population for next-generation trials. Future research will help shape oncologists' approaches in the optimal selection, sequencing and re-treatment or rechallenge of immuno-oncology agents and/or antibody-drug conjugates in women with cervical cancer.

Keywords: Adoptive Immunotherapy; Cervical Cancer; Chemoradiotherapy; Immune Checkpoint Inhibitors; Immunoconjugates.

Fig. 1. Proposed changes to treatment algorithms for advanced cervical cancer after 2023.

Changes are necessitated by the introduction of new treatment options in first line (atezolizumab) and late-line (trastuzumab deruxtecan). Furthermore, results of the confirmatory phase III trial for second- to third-line tisotumab vedotin versus chemotherapy were announced in 2023. CPS, combined positive score; HER2, human epidermal growth factor 2; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; PD-L1, programmed death-ligand 1.

Fig. 2. The sequencing of immune checkpoint inhibitors with relation to concurrent chemoradiation or RH in clinical trials of locally advanced cervical cancers.

A number of Phase I–III trials investigate anti-PD-(L)1 alone or together with anti-CTLA-4 ICIs timed before, during and/or after CCRT. Postulated mechanisms of action of ICIs and synergism with CCRT are presented in the topmost panel. Separately, the single-arm phase II NACI trial [41] explored the neoadjuvant application of an anti-PD-1 (camrelizumab) with carboplatin; responders were considered for radical surgery. To our knowledge, no trial has been designed yet for adjuvant ICI therapy after definitive surgery for LACC. CCRT, concurrent chemoradiation; ChT, cytotoxic chemotherapy; CR, complete remission; ICI, immune checkpoint inhibitor; CTLA-4, cytotoxic T-lymphocyte associated protein 4; LACC, locally advanced cervical cancers; PD, progressive disease; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PR, partial response; RH, radical hysterectomy; RT, radiation therapy; SD, stable disease; TME, tumor microenvironment. ^*Bars are not drawn to scale according to the duration of per-protocol ICI therapy but are intended to illustrate the sequencing of ICI vis-à-vis CCRT. Studies which investigated ICI in the same phase are grouped together.

Fig. 3. Prospective evolution of the clinical development of immunotherapies and antibody-drug conjugates in cervical cancer.

After successes in later lines in aCC, immunotherapies, mainly ICIs, have moved forward to the first line and for curative indications. Autologous TILs, a type of adoptive T cell therapy, has also made headway from metastatic disease into the LACC setting [42]. ADCs are likely to follow this path of drug development. There is potential for combination trials across the disease spectrum as ICI resistance emerges with increasing routine clinical use for aCC and soon, LACC. aCC, advanced cervical cancers; ADCs, antibody-drug conjugates; ICI, immune checkpoint inhibitor; IO, immuno-oncology agents; LACC, locally advanced cervical cancers; RH, radical hysterectomy; RT, radiation therapy; TILs, tumor infiltrating lymphocytes.