Recent clinical trials and regulatory actions are reshaping the treatment landscape for locally advanced cervical cancer, offering new hope for improved patient outcomes. These advances include novel combinations of immunotherapy and chemotherapy, as well as targeted therapies that have demonstrated significant benefits in survival rates and disease progression.
Pembrolizumab Plus Chemoradiotherapy in KEYNOTE-A18
The phase 3 KEYNOTE-A18 trial (ENGOT-cx11/GOG-3047) evaluated the addition of pembrolizumab to chemoradiotherapy (CRT) in patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer. The study revealed statistically significant and clinically meaningful improvements in overall survival (OS) compared to CRT alone.
At a median follow-up of 29.9 months, the 36-month OS rate was 82.6% with pembrolizumab plus CRT versus 74.8% with CRT alone (HR, 0.67; 95% CI, 0.50-0.90; 1-sided P = .0040). These benefits were observed when pembrolizumab was continued as monotherapy. Domenica Lorusso, MD, PhD, emphasized the importance of quality radiotherapy, with over 80% of patients receiving modern, image-guided radiotherapy.
The toxicity profile of the combination was manageable, with grade 3 or higher adverse events (AEs) occurring in 78% of patients in the pembrolizumab-CRT group and 70% in the placebo-CRT group. The most common AEs were anemia, decreased white blood cell count, and decreased neutrophil count. Immune-mediated AEs were more frequent in the pembrolizumab arm (39%) compared to the placebo arm (17%).
Based on these results, the FDA approved pembrolizumab with CRT for FIGO 2014 stage III to IVA cervical cancer. However, Lorusso noted that patients with earlier-stage disease also benefited from the combination, expressing hope that regulatory authorities might reconsider their decision based on the final analysis expected in 2025.
Induction Chemotherapy Before CRT in INTERLACE
The phase 3 INTERLACE trial assessed whether adding a short course of induction chemotherapy before CRT is more effective than CRT alone in patients with locally advanced cervical cancer. The study randomized 500 patients to receive either induction chemotherapy with CRT or CRT alone.
The results demonstrated a significant improvement in survival rates for patients receiving induction chemotherapy (carboplatin and paclitaxel) before CRT. With a median follow-up of 67 months, the induction chemotherapy group experienced a 35% relative reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.46-0.91, P = .013). Five-year progression-free survival (PFS) rates were 72% in the induction chemotherapy group and 64% in the CRT alone group.
This regimen also led to a 40% relative reduction in the risk of death (HR, 0.60; 95% CI, 0.40-0.91; P = .015). Five-year overall survival (OS) rates were 80% for the induction chemotherapy group and 72% for the CRT alone group. This translates to an 11 percentage point improvement in 5-year PFS and a 10 percentage point improvement in 5-year OS.
While the new regimen proved effective across all subgroups analyzed, investigators acknowledged the limited representation of patients with FIGO 2008 stage IIIB and IVA disease (14%) and the exclusion of those with para-aortic nodal involvement. Hematological toxicity, primarily neutropenia, was more frequent in the induction chemotherapy group, particularly during CRT.
Atezolizumab Plus Bevacizumab in BEATcc
In the metastatic setting, the phase 3 BEATcc trial evaluated the addition of atezolizumab to bevacizumab and chemotherapy in patients with metastatic, recurrent, or persistent cervical cancer. The study enrolled 410 patients who were randomly assigned to receive either standard therapy (cisplatin, paclitaxel, and bevacizumab) with or without atezolizumab.
Investigators reported a median PFS of 13.7 months for the treatment arm versus 10.4 months in the control arm (HR, 0.62; 95% CI, 0.49-0.78; P < .0001). At the interim OS analysis, the median OS was 32.1 months for the treatment arm versus 22.8 months for the control arm (HR, 0.68; 95% CI, 0.52-0.88; P = .0046).
Tisotumab Vedotin Approval
Tisotumab vedotin-tftv (Tivdak) received full FDA approval based on findings from the phase 3 innovaTV 301 trial in patients with recurrent or metastatic cervical cancer. Treatment with tisotumab led to a 30% reduction in the risk of death versus investigator’s choice of chemotherapy as a second- or third-line treatment.
The median OS was 11.5 months with tisotumab compared with 9.5 months with chemotherapy (HR, 0.70, 95% CI, 0.54-0.89; P = .0038). The median PFS was 4.2 months compared with 2.9 months with chemotherapy (HR, 0.67; 95% CI, 0.54-0.82; P < .0001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (OR, 4.0; 95% CI, 2.1-7.6; 2-sided P < .001).
While these advances are encouraging, experts emphasize the importance of prevention through HPV vaccination and screening to reduce the incidence of cervical cancer.
