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.

Immuno-Molecular Targeted Therapy Use and Survival Benefit in Patients with Stage IVB Cervical Carcinoma in Commission on Cancer®-Accredited Facilities in the United States

“…The incremental survival benefit in patients with stage IVB with the addition of IMT after applying propensity score analysis extends to prior retrospective studies [ 5 , 10 , 16 , 20 , 21 , 23 ] and is consistent with results from phase II and phase III clinical trials [ 23 , 24 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 44 , 45 ]. Outside of clinical trials, Perkins et al [ 25 ] reported a 24-month improvement in overall survival following CT + EBRT (whole pelvic radiation) vs. CT in a small multi-site retrospective cohort study with a median follow-up of 9 months.…”

“…Our study included patients who were diagnosed through 2019 and found that patients who were treated with CT + EBRT + ICBT ± IMT had a 5-year survival rate between 40 and 55%. This doubling in 5-year survival likely reflects improvements associated with the use of intensity-modulated RT, stereotactic body RT, and high-dose ICBT [ 14 , 20 , 21 , 22 , 30 , 46 , 47 ] and the addition of bevacizumab, pembrolizumab, antibody drug conjugates, biologic response modifiers, and immune checkpoint inhibitors in the treatment of metastatic, recurrent, and persistent cervical cancer [ 23 , 24 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 48 ]. The study by Musa et al [ 39 ] showed that immunotherapy use has been increasing, but only a small subset of patients stayed on immunotherapy for prolonged periods, suggesting a need for more therapeutic options for first-line and second-plus-line treatments for metastatic, recurrent, or persistent cervical cancer.…”

“…Additional survival improvements have also been achieved with advances in radiation techniques, as well as the addition of immunotherapy and antibody drug conjugates [ 14 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. This includes the randomized phase III BEATcc (GOG-3030/ENGOT cx10/GEICO 68-C/JGOG-1084) trial [ 26 ] showing the benefit of Atezolizumab with CT and Bevacizumab in metastatic and recurrent cervical cancer, with a median survival of 32.1 vs. 22.8 months.…”

“…The addition of Bevacizumab to CT for the treatment of advanced-stage cervical cancer further increased the median survival to 17.0 months [23,24]. Additional survival improvements have also been achieved with advances in radiation techniques, as well as the addition of immunotherapy and antibody drug conjugates [14,[25][26][27][28][29][30][31][32][33][34][35][36][37][38]. This includes the randomized phase III BEATcc (GOG-3030/ENGOT cx10/GEICO 68-C/JGOG-1084) trial [26] showing the benefit of Atezolizumab with CT and Bevacizumab in metastatic and recurrent cervical cancer, with a median survival of 32.1 vs. 22.8 months.…”

Efficacy and Safety of Atezolizumab as a PD-L1 Inhibitor in the Treatment of Cervical Cancer: A Systematic Review

“…This suggests that ICIs remain a viable option even after initial failure. Daniel Jia Ming Ang’s review [ 39 ] discusses ongoing clinical trials such as INTERLACE and KEYNOTE-A18, which are pivotal in shaping future treatment paradigms by integrating ICIs with other therapeutic modalities for both advanced and locally advanced cervical cancer. Further insights from Wutao Chen’s meta-analysis [ 40 ] indicate that in cervical cancer patients with low PD-L1 expression, ICI monotherapy was associated with adverse survival outcomes compared to ICI combination therapy or non-ICI treatments, with significant differences in OS (HR = 2.60) and PFS (HR = 7.59).…”