Can pembrolizumab (pembrolizumab) plus cisplatin (cisplatin)/5-fluorouracil (5-FU) be used in a patient with recurrent sinonasal squamous cell carcinoma and a PD-L1 (Programmed Death-Ligand 1) expression of 0?

Pembrolizumab Plus Cisplatin/5-FU in PD-L1 CPS 0 Recurrent Sinonasal Squamous Cell Carcinoma

Yes, pembrolizumab plus cisplatin/5-FU can be used in patients with PD-L1 CPS 0, as the FDA has approved this combination regardless of PD-L1 expression status, though the evidence for survival benefit specifically in PD-L1-negative patients remains uncertain. 1

Regulatory Approval and Evidence Base

FDA vs EMA Divergence

• The FDA approved pembrolizumab combined with platinum/5-FU as first-line treatment regardless of PD-L1 expression, making it a valid option for your patient with CPS 0. 1
• In contrast, the EMA has only approved pembrolizumab (with or without chemotherapy) for patients with CPS ≥1, reflecting more conservative interpretation of the KEYNOTE-048 data. 1
• ASCO guidelines support pembrolizumab plus platinum/5-FU for CPS <1 patients with moderate evidence quality and strong recommendation strength. 1

Evidence Limitations in PD-L1-Negative Disease

• The KEYNOTE-048 trial showed improved overall survival with pembrolizumab plus chemotherapy versus cetuximab plus chemotherapy in the total population (13.0 vs 10.7 months, HR 0.77, p=0.0034). 1, 2
• However, in the CPS <1 subgroup specifically, median OS was 11.3 months with pembrolizumab/chemotherapy versus 10.7 months with cetuximab/chemotherapy (HR 1.12,95% CI 0.76-1.94, p=0.78932), showing no statistically significant benefit. 1
• This subgroup included only 39 and 43 patients respectively, and the study was not powered to evaluate efficacy in PD-L1-negative patients. 1
• Current evidence does not definitively establish whether platinum/5-FU/pembrolizumab improves survival compared with platinum/5-FU/cetuximab in patients not expressing PD-L1. 1

Clinical Decision Algorithm for CPS 0 Patients

When to Use Pembrolizumab Plus Chemotherapy (CPS 0)

Use pembrolizumab/cisplatin/5-FU when:

• Patient requires rapid tumor shrinkage due to symptomatic disease burden 1
• Patient has good performance status and can tolerate combination therapy 3
• No contraindications to anti-PD-1 inhibitors exist 1
• Operating under FDA jurisdiction where this is approved 1

When to Consider EXTREME Regimen Instead

Consider cetuximab/platinum/5-FU (EXTREME) when:

• Patient has PD-L1-negative tumor (CPS <1) and you prioritize evidence-based benefit over regulatory approval 1
• Operating under EMA jurisdiction where pembrolizumab is not approved for CPS <1 1
• Patient has contraindications to immunotherapy 1
• EXTREME remains standard of care for PD-L1-negative tumors with Level I, Grade A evidence (ESMO-MCBS score: 3) 1

Special Considerations for Sinonasal Squamous Cell Carcinoma

Limited Evidence Base

• Sinonasal squamous cell carcinoma was specifically excluded from the KEYNOTE-048 and KEYNOTE-040 trials, meaning the evidence base is extrapolated from other head and neck sites. 4
• A recent prospective phase II study (2025) evaluated pembrolizumab with nab-paclitaxel and platinum in recurrent/metastatic sinonasal SCC, showing 60% ORR and median PFS of 12.2 months, though this used nab-paclitaxel rather than 5-FU. 5
• Case reports demonstrate pembrolizumab can induce remission in recurrent/metastatic sinonasal SCC, though data remain sparse. 4

Practical Implementation

Treatment Selection Based on Clinical Scenario

For symptomatic patients requiring rapid response:

• Pembrolizumab plus cisplatin/5-FU is appropriate despite CPS 0, as response rates (35.6-36.3%) and PFS (4.9-5.1 months) were similar between pembrolizumab/chemotherapy and cetuximab/chemotherapy arms regardless of PD-L1 status. 1

For less symptomatic patients:

• EXTREME regimen may be preferred given the lack of proven survival benefit with pembrolizumab in CPS <1 subgroup and established Level I evidence for EXTREME. 1

Toxicity Considerations

• Grade 3-5 adverse events are similar between pembrolizumab/chemotherapy (83.3%) and cetuximab/chemotherapy (85.1%). 1
• Treatment-related deaths occurred in 12% with pembrolizumab/chemotherapy versus 10% with cetuximab/chemotherapy. 2

Critical Caveat

The survival benefit of adding pembrolizumab to platinum/5-FU in PD-L1-negative patients remains unproven, and the decision to use this combination in CPS 0 patients relies on FDA approval and extrapolation from total population data rather than subgroup-specific evidence. 1