Cervical cancer - Emerging treatments

Induction chemotherapy

Induction chemotherapy (carboplatin and paclitaxel) significantly improved both progression-free survival and overall survival in a phase 3 trial of patients with locally advanced cervical cancer.[183][184] The trial, which randomized patients with stages IB1 node positive, IB2, II, IIIB, and IVA cervical cancer to induction chemotherapy (carboplatin and paclitaxel) followed by chemoradiation or to chemoradiation alone, reported 5-year progression-free survival of 72% versus 64% and 5-year overall survival of 80% and 72% favoring induction chemotherapy.[184]

Novel agents targeted against PIK3CA mutations

PIK3CA mutations are present in up to 36% of advanced or recurrent tumors.[185] In a first-in-human phase Ia study, alpelisib, an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor, demonstrated a tolerable safety profile and preliminary activity in patients with PIK3CA-altered solid tumors, including cervical cancer.[186]

Axalimogene filolisbac

Axalimogene filolisbac (a live attenuated Listeria monocytogenes-based immunotherapy that generates T cells against human papillomavirus E7-transformed cells) has shown promise in early clinical trials in patients with persistent, recurrent, or metastatic cervical cancer.[187][188][189][190] The Food and Drug Administration (FDA) has granted fast-track designation to axalimogene filolisbac for adjuvant therapy of high-risk, locally advanced cervical cancer. A European marketing application for axalimogene filolisbac for cervical cancer was withdrawn in July 2018 due to a lack of adequate data to support the application, rather than for safety reasons.

Immune checkpoint inhibition: programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4)

Combination therapy, targeting both PD-1 and CTLA-4, has the potential to augment treatment effect. The PD-1/CTLA-4 bi-specific antibody, cadonilimab, has been approved for use in patients with relapsed or metastatic cervical cancer in China.[191] One phase 3 trial of cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer demonstrated improved progression-free survival and overall survival compared with platinum-based chemotherapy with or without bevacizumab. The median progression-free survival for the cadonilimab group was 12.7 months versus 8.1 months for the placebo group. The median overall survival was not reached for the cadonilimab group (median follow-up of 25.6 months) compared with 22.8 months for the placebo group.[192]

VGX-3100

VGX-3100 (a synthetic DNA vaccine targeting the human papillomavirus E1 and E7 proteins) has shown efficacy against high-grade dysplasia (cervical intraepithelial neoplasia 2/3) in an early clinical trial.[193] Response durability of up to 1.5 years following dosing has been reported.[194]

Adoptive T-cell therapy with tumor-infiltrating lymphocytes

Preliminary results from a phase 2 study suggest that adoptive T-cell therapy with tumor-infiltrating lymphocytes (TIL) selected for human papillomavirus E6- and E7-oncogene reactivity (HPV-TIL) can induce durable, complete regression of metastatic cervical cancer.[195] The FDA has granted breakthrough therapy designation to autologous TIL immunotherapy LN-145 for the treatment of recurrent, metastatic, or persistent cervical cancer.

Neoadjuvant and adjuvant chemotherapy

Meta-analysis suggests that intensive neoadjuvant chemotherapy plus surgery is associated with some impact on survival compared with surgery alone. However, methodologic challenges to the analysis and the lack of clinical codification has prevented it becoming a standard approach.[196] Neoadjuvant chemotherapy plus surgery does not appear to offer a survival advantage over chemoradiation therapy for patients with stage IB2-IIB cervical cancer.[197][198] Adjuvant chemotherapy is being investigated in international clinical trials for patients with high-risk or advanced stage disease. [ ]