What treatment options are available for a patient with recurrent or metastatic cervical cancer who has failed platinum-based therapy, specifically considering cemiplimab (libtayo) and recommendations from international clinical guidelines such as NCCN (National Comprehensive Cancer Network) or ESMO (European Society for Medical Oncology)?

Cemiplimab for Recurrent or Metastatic Cervical Cancer After Platinum Failure

Cemiplimab is recommended by NCCN (2024) as a second-line or subsequent therapy option for recurrent or metastatic cervical cancer after failure of platinum-based therapy, based on the phase III EMPOWER-Cervical 1 trial demonstrating superior overall survival (12.0 vs 8.5 months; HR 0.69, P<0.001) compared to chemotherapy. 1

International Guideline Recommendations

NCCN Guidelines (2024)

• NCCN explicitly includes cemiplimab as a second-line or subsequent therapy option under "other recommended regimens" for recurrent/metastatic cervical cancer after platinum failure. 1
• The recommendation is extrapolated from efficacy demonstrated in the EMPOWER-Cervical 1 trial in cervical cancer and from advanced cutaneous squamous cell carcinoma data. 1
• NCCN does not restrict cemiplimab use based on PD-L1 status, as the trial enrolled patients regardless of PD-L1 expression. 1

SITC Guidelines (2023)

• The Society for Immunotherapy of Cancer (SITC) guidelines recommend pembrolizumab (not cemiplimab) for patients with recurrent or metastatic cervical cancer that is PD-L1-positive (CPS≥1) and has progressed on or after chemotherapy. 1
• SITC does not specifically mention cemiplimab in their 2023 guidelines, as these were published before cemiplimab's widespread adoption for cervical cancer. 1

ESMO Guidelines

• The 2012 ESMO guidelines predate immunotherapy for cervical cancer and only discuss platinum-based chemotherapy options. 1
• No current ESMO guidelines specifically addressing cemiplimab for cervical cancer were identified in the provided evidence.

High-Level Evidence Supporting Cemiplimab

EMPOWER-Cervical 1 Trial (Phase III, 2022-2025)

• Overall Survival Benefit: Median OS was 12.0 months with cemiplimab versus 8.5 months with chemotherapy (HR 0.69; 95% CI 0.56-0.84; P<0.001) in the overall population of 608 patients. 2
• Final Analysis (2025): At 47.3 months median follow-up, median OS remained 11.7 vs 8.5 months (HR 0.67; 95% CI 0.56-0.80; P<0.00001), confirming durable survival benefit. 3
• Progression-Free Survival: Median PFS was 2.8 months with cemiplimab versus 2.9 months with chemotherapy (HR 0.75; 95% CI 0.63-0.89; P<0.001). 1
• Objective Response Rate: 16.4% with cemiplimab versus 6.3% with chemotherapy in the overall population. 2

PD-L1 Status and Treatment Efficacy

• PD-L1-Positive (≥1%): ORR of 18% with cemiplimab. 2
• PD-L1-Negative (<1%): ORR of 11% with cemiplimab, demonstrating benefit regardless of PD-L1 expression. 2
• The final analysis confirmed OS benefit in both PD-L1-positive and PD-L1-negative populations, even with more poor performance status patients in the cemiplimab arm. 3

Histologic Subtype Efficacy

• Overall survival benefit was consistent in both squamous cell carcinoma and adenocarcinoma (including adenosquamous) histologic subgroups. 2

Treatment Algorithm for Recurrent/Metastatic Cervical Cancer After Platinum Failure

Second-Line Treatment Selection

1. Cemiplimab 350 mg IV every 3 weeks is an appropriate option regardless of PD-L1 status, based on NCCN recommendations and phase III evidence. 1, 2
2. Alternative second-line options per NCCN include:
   • Single-agent paclitaxel (ORR 14%, PFS 2.6 months) 1
   • Erlotinib (category 2B) 1
   • Cisplatin/gemcitabine (category 2B) 1

Competing Immunotherapy Option

• Pembrolizumab is recommended by SITC for PD-L1-positive (CPS≥1) recurrent cervical cancer after chemotherapy progression, but this is based on different trial data (KEYNOTE-826 for first-line, KEYNOTE-158 for later lines). 1, 4

Safety Profile

Cemiplimab Toxicity

• Grade ≥3 adverse events: 45.0% with cemiplimab versus 53.4% with chemotherapy, demonstrating a more favorable toxicity profile than chemotherapy. 2
• Overall treatment-emergent adverse events occurred in 79.3% with cemiplimab versus 100% with chemotherapy in the Japanese subgroup analysis. 5
• The safety profile was consistent across analyses, with similar incidences of adverse events between cemiplimab and chemotherapy groups. 3

Immune-Related Adverse Events

• Rare but severe immune-related adverse events can occur, including cardiovascular toxicity and hepatotoxicity, requiring immediate discontinuation. 6
• Despite early discontinuation due to severe irAEs, durable complete responses have been documented. 6

Clinical Considerations

Duration of Treatment

• Cemiplimab can be administered for up to 96 weeks (approximately 2 years). 5

Performance Status

• The trial included patients with varying performance status, and benefit was maintained even in populations with higher proportions of poor performance status. 3

Geographic Applicability

• A Japanese subgroup analysis (n=56) showed an emerging survival benefit (HR 0.86) despite shorter follow-up, supporting global applicability. 5

Key Caveats

• NCCN is currently the only major international guideline explicitly recommending cemiplimab for this indication as of 2024. 1
• The modest PFS benefit (2.8 vs 2.9 months) contrasts with the substantial OS benefit, suggesting potential delayed treatment effects or post-progression survival advantages. 1, 2
• While PD-L1 testing is not required for cemiplimab use per NCCN, response rates are higher in PD-L1-positive patients (18% vs 11%). 2