What is the role of immunotherapy, including checkpoint inhibitors like pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of cervical (ca) cancer?

Immunotherapy in Cervical Cancer: Role and Recommendations

Pembrolizumab in combination with platinum-based chemotherapy with or without bevacizumab is the standard of care for patients with persistent, recurrent, or metastatic PD-L1-positive (CPS≥1) cervical cancer. 1

Current FDA-Approved Immunotherapy Options

• PD-1 inhibitor pembrolizumab has two approved indications for cervical cancer: 1

  • As monotherapy for recurrent or metastatic cervical cancer with PD-L1 CPS≥1 that has progressed on or after chemotherapy
  • In combination with platinum-based chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic PD-L1-positive (CPS≥1) cervical cancer

• The KEYNOTE-826 trial established pembrolizumab plus chemotherapy with or without bevacizumab as the new standard of care, demonstrating: 1

  • Improved progression-free survival (PFS): 10.4 months vs 8.2 months (HR 0.62)
  • Improved overall survival (OS) across all populations studied
  • Higher objective response rate (ORR): 68.1% vs 50.2% in PD-L1 CPS≥1 group
  • Longer duration of response: 18.0 months vs 10.4 months

Biomarker Testing Recommendations

• PD-L1 testing is strongly recommended for all patients with advanced/recurrent cervical cancer 1

  • PD-L1 CPS≥1 is the established biomarker for pembrolizumab eligibility

• Additional biomarker testing to consider: 1

  • MMR IHC (mismatch repair immunohistochemistry)
  • NGS for MSI (microsatellite instability) and TMB (tumor mutational burden)
  • TMB-H (≥10 mut/Mb) and MSI-H/dMMR tumors may be eligible for tissue-agnostic pembrolizumab treatment

Treatment Algorithm Based on Disease Status and PD-L1 Expression

For patients with persistent, recurrent, or metastatic cervical cancer: 1

PD-L1 CPS ≥1:

• Treatment-naïve: Pembrolizumab + platinum-based chemotherapy ± bevacizumab 1
• After disease progression on chemotherapy: Pembrolizumab monotherapy 1

PD-L1 CPS <1:

• Standard of care: Chemotherapy ± bevacizumab 1
• Consider clinical trial enrollment 1

Safety Considerations

• Treatment-related adverse events with pembrolizumab combination therapy: 1

  • Grade 3-5 adverse events: 81.8% (pembrolizumab group) vs 75.1% (placebo group)
  • Most common serious adverse events: anemia, neutropenia, decreased neutrophil count, and hypertension
  • Immune-related adverse events: 33.9% (11.4% grade 3-5) in pembrolizumab group vs 15.2% (2.9% grade 3-5) in placebo group

• No significant differences in safety or efficacy observed between elderly and younger patients 2

Emerging Immunotherapy Approaches

• ICI combinations showing promise in early-phase trials: 1

  • Balstilimab (anti-PD-1) + zalifrelimab (anti-CTLA-4): ORR 25.6% in phase II trial
  • Ipilimumab (anti-CTLA-4) + nivolumab (anti-PD-1): positive results regardless of PD-L1 expression
  • Bintrafusp alfa (bifunctional fusion protein targeting PD-L1 and TGF-β): ORR 28.2%, DOR 11.7 months

• Other investigational approaches: 1

  • Therapeutic vaccines targeting HPV antigens
  • Cell therapies including CAR-T and tumor-infiltrating lymphocytes
  • Combination strategies with radiation therapy

Key Clinical Considerations

• HPV infection is the primary etiological factor in cervical cancer and creates a unique immunological environment 1, 3

  • HPV uses multiple mechanisms to avoid immune surveillance
  • HPV infection is associated with upregulation of TGF-β signaling

• The prevalence of biomarkers in cervical cancer: 1

  • TMB-H: 10-20% of cervical cancers
  • MSI-H: 2-12% of cervical cancers
  • PD-L1 CPS≥1: High prevalence

• For patients with anti-PD-(L)1-resistant cervical cancer, there are currently no established data to guide sequencing of therapies or rechallenge with an ICI 1

• Clinical trial enrollment should be encouraged for all patients with cervical cancer, especially those with limited standard treatment options 1