Pembrolizumab Plus Chemotherapy is Superior to Bevacizumab Plus Chemotherapy for Stage IVB Cervical Cancer
For patients with stage IVB cervical cancer and pulmonary metastases who have failed first-line platinum-based chemotherapy, pembrolizumab plus chemotherapy (with or without bevacizumab) is the preferred treatment over bevacizumab plus chemotherapy alone, provided the tumor expresses PD-L1 with a combined positive score (CPS) ≥1. This recommendation is based on the landmark KEYNOTE-826 trial, which demonstrated superior survival outcomes with the addition of pembrolizumab to standard chemotherapy regimens 1, 2.
Evidence Supporting Pembrolizumab Plus Chemotherapy
Survival Benefits from KEYNOTE-826
The phase III KEYNOTE-826 trial (N=617) established pembrolizumab plus chemotherapy (with or without bevacizumab) as the new standard of care for persistent, recurrent, or metastatic cervical cancer 1, 2:
- Overall Survival at 24 months: 50.4% with pembrolizumab versus 40.4% with placebo (HR 0.67; 95% CI 0.54-0.84; P<0.001) in the intention-to-treat population 2
- Progression-Free Survival: 10.4 months with pembrolizumab versus 8.2 months with placebo (HR 0.65; 95% CI 0.53-0.79; P<0.001) 2
- Benefit across PD-L1 expression levels: In patients with PD-L1 CPS ≥1 (N=548), median PFS was 10.4 versus 8.2 months (HR 0.62; 95% CI 0.50-0.77; P<0.001) 2
FDA Approval and Guideline Recommendations
Pembrolizumab received FDA approval in October 2021 for combination with platinum-based chemotherapy (paclitaxel plus cisplatin or carboplatin) with or without bevacizumab for persistent, recurrent, or metastatic PD-L1-positive (CPS≥1) cervical cancer 1, 3. The Society for Immunotherapy of Cancer (SITC) 2023 guidelines specifically recommend this combination as first-line therapy 1.
Why Bevacizumab Alone is Insufficient
While bevacizumab plus chemotherapy was previously the standard of care, it provides inferior outcomes compared to pembrolizumab-containing regimens:
- Historical bevacizumab data: Bevacizumab plus chemotherapy achieved median OS of 16.8 months versus 13.3 months with chemotherapy alone (HR 0.765; 95% CI 0.62-0.95) 4
- Direct comparison limitation: The KEYNOTE-826 trial allowed bevacizumab use in both arms at investigator discretion, demonstrating that pembrolizumab adds benefit regardless of bevacizumab use 1, 2
- Failed combination attempt: A phase II study (NCT02921269) of atezolizumab (another PD-L1 inhibitor) plus bevacizumab showed 0% objective response rate and median PFS of only 2.9 months, suggesting anti-VEGF therapy alone does not enhance immunotherapy efficacy sufficiently 5
Critical Patient Selection Criteria
PD-L1 Testing is Mandatory
- PD-L1 CPS ≥1 required: Pembrolizumab is only FDA-approved and recommended for tumors expressing PD-L1 with CPS ≥1 1, 3, 2
- Testing recommendation: SITC guidelines recommend PD-L1 testing for all patients with advanced/recurrent cervical cancer (Level of Evidence: 2) 1
- CPS definition: Combined positive score = (number of PD-L1-staining cells / total viable tumor cells) × 100 2
Additional Biomarker Considerations
- MSI-H/dMMR testing: Can be considered as pembrolizumab has tumor-agnostic approval for MSI-H/dMMR tumors, though prevalence in cervical cancer is low (2-12%) 1
- TMB testing: Can be considered, though median TMB in cervical cancer is moderate (1-10 mut/Mb) with only 10-20% being TMB-high 1
Recommended Treatment Algorithm
For PD-L1 CPS ≥1 (Your Patient's Scenario)
- First choice: Pembrolizumab 200 mg IV every 3 weeks + carboplatin/paclitaxel + bevacizumab (if no contraindications to bevacizumab) 1, 3, 2
- Alternative if bevacizumab contraindicated: Pembrolizumab 200 mg IV every 3 weeks + carboplatin/paclitaxel 1, 3
- Treatment duration: Up to 35 cycles of pembrolizumab (approximately 2 years) 3
For PD-L1 CPS <1
- Standard therapy: Carboplatin/paclitaxel + bevacizumab (pembrolizumab not indicated) 4, 6
- Evidence limitation: No evidence supports pembrolizumab use in PD-L1 non-expressing cervical tumors 6
Toxicity Profile and Management
Expected Adverse Events
The combination of pembrolizumab with chemotherapy increases toxicity compared to chemotherapy alone 1:
- Most common grade 3-5 events: Anemia (30.3% pembrolizumab arm vs 26.9% placebo), neutropenia (12.4% vs 9.7%) 2
- Immune-related adverse events: Diarrhea (RR 1.19), elevated liver enzymes (RR 1.13), thyroid dysfunction (RR 2.13), rash (RR 1.56), pneumonitis (RR 2.79) 1
- Critical toxicity: Pneumonitis, though rare, is one of the most common treatment-related causes of death with immunotherapy combinations 1
Monitoring Requirements
- Baseline evaluation: Complete blood count, renal function, liver function tests, thyroid-stimulating hormone 7
- During treatment: Clinical and laboratory evaluation every 3 weeks during active treatment 8
- Post-treatment surveillance: Every 3 months during first year, then every 6 months, with vigilant monitoring for delayed immune-related adverse events 8
Common Pitfalls to Avoid
- Do not use pembrolizumab without PD-L1 testing: FDA approval and efficacy data are restricted to CPS ≥1 tumors 1, 3, 6
- Do not withhold bevacizumab unnecessarily: The KEYNOTE-826 trial included bevacizumab use, and the combination of all three agents (pembrolizumab + chemotherapy + bevacizumab) is the optimal regimen when no contraindications exist 1, 2
- Do not assume bevacizumab enhances immunotherapy universally: The atezolizumab-bevacizumab combination failed to show benefit, suggesting the pembrolizumab benefit is independent of anti-VEGF therapy 5
- Monitor for immune-related adverse events beyond treatment completion: Immune toxicities can develop months after pembrolizumab cessation 8
Contraindications to Bevacizumab
If bevacizumab is contraindicated, use pembrolizumab plus chemotherapy alone 1, 4:
- Clinically significant hemoptysis
- Inadequate organ function
- ECOG performance status >1
- Clinically significant cardiovascular disease
- Medically uncontrolled hypertension