What is the role of immunotherapy, such as pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in a patient with stage IVB cervical cancer and multiple pulmonary metastases who has failed first-line platinum-based combination chemotherapy?

Immunotherapy in Platinum-Refractory Stage IVB Cervical Cancer

Pembrolizumab combined with chemotherapy (with or without bevacizumab) should be offered as first-line treatment for stage IVB cervical cancer with PD-L1 combined positive score (CPS) ≥1, and pembrolizumab or nivolumab monotherapy should be offered as second-line treatment after platinum-based chemotherapy failure. 1

First-Line Setting: Pembrolizumab + Chemotherapy

For patients with newly diagnosed stage IVB cervical cancer who have not yet received first-line platinum-based chemotherapy:

• Pembrolizumab 200 mg every 3 weeks plus platinum-based chemotherapy (with or without bevacizumab) is the preferred regimen for patients with PD-L1 CPS ≥1. 1
• This combination demonstrated superior outcomes compared to chemotherapy alone: median progression-free survival of 10.4 months versus 8.2 months (HR 0.62, P<0.001), and 24-month overall survival of 53.0% versus 41.7% (HR 0.64, P<0.001). 1
• The benefit extends across all PD-L1 expression levels in patients with CPS ≥1, with even greater benefit in those with CPS ≥10 (HR for death 0.61, P=0.001). 1
• PD-L1 testing using the combined positive score is essential before treatment initiation, as approximately 77% of cervical cancer patients express PD-L1 at CPS ≥1. 2

Second-Line Setting: After Platinum Failure

For patients who have already failed first-line platinum-based chemotherapy (the scenario in your question):

Pembrolizumab Monotherapy

• Pembrolizumab monotherapy is FDA-approved for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy in patients with PD-L1 CPS ≥1. 3, 4
• Single-agent pembrolizumab shows limited but meaningful activity in this heavily pretreated population, with durable responses observed specifically in PD-L1-expressing tumors. 3
• The accelerated FDA approval was based on response rates and durability of response in PD-L1-positive patients, though overall response rates remain modest in unselected populations. 3, 4

Nivolumab Monotherapy

• Nivolumab 3 mg/kg every 2 weeks is an alternative immunotherapy option after platinum failure, though it demonstrates lower activity than pembrolizumab. 2
• In the NRG-GY002 trial, nivolumab achieved only a 4% confirmed partial response rate (90% CI, 0.4%-22.9%) with 36% stable disease. 2
• Median progression-free survival was limited, with only 16% of patients progression-free at 6 months. 2
• Despite modest efficacy, nivolumab demonstrated an acceptable safety profile with predominantly grade 1-2 adverse events (84% of patients) and only 24% experiencing grade 3 toxicities. 2

Treatment Selection Algorithm

Step 1: Determine treatment line and prior therapy

• If first-line treatment → pembrolizumab + chemotherapy ± bevacizumab 1
• If post-platinum failure → single-agent immunotherapy 2, 3

Step 2: Obtain PD-L1 testing

• PD-L1 CPS ≥1 → pembrolizumab is preferred (FDA-approved indication) 3, 4
• PD-L1 CPS <1 → pembrolizumab has limited efficacy; consider alternative options 3
• Note: Nivolumab showed activity regardless of PD-L1 status, though overall response rates were low 2

Step 3: Assess performance status

• ECOG PS 0-1 → all immunotherapy options appropriate 2
• ECOG PS ≥2 → consider best supportive care or clinical trial, as immunotherapy trials excluded these patients 2

Step 4: Choose specific agent

• Pembrolizumab is preferred over nivolumab in the second-line setting based on FDA approval and stronger supporting evidence 3, 4
• Nivolumab may be considered if pembrolizumab is unavailable or contraindicated 2

Safety Considerations

Common adverse events with pembrolizumab + chemotherapy:

• Anemia (30.3% grade 3-5) and neutropenia (12.4% grade 3-5) are most frequent. 1
• Immune-related adverse events occur but are manageable with standard protocols. 1

Common adverse events with nivolumab monotherapy:

• Most toxicities are grade 1-2 (84% of patients). 2
• Grade 3 toxicities occur in 24% of patients, with hepatic toxicity being a notable concern requiring treatment discontinuation in some cases. 2
• No grade 5 treatment-related adverse events were reported in the NRG-GY002 trial. 2

Critical Pitfalls to Avoid

• Do not use single-agent immunotherapy in the first-line setting when combination therapy is appropriate – the KEYNOTE-826 trial clearly demonstrated superior outcomes with pembrolizumab + chemotherapy compared to historical controls. 1
• Do not omit PD-L1 testing – while nivolumab may be given regardless of PD-L1 status, pembrolizumab's FDA approval is restricted to PD-L1 CPS ≥1 patients. 2, 3
• Recognize that response rates with single-agent immunotherapy after platinum failure are modest – set realistic expectations with patients, as objective response rates range from 4% (nivolumab) to slightly higher with pembrolizumab in selected populations. 2, 3
• Monitor for immune-related adverse events even in patients with good performance status, as these can occur at any time during treatment. 2, 1