What is the rationale for using cetuximab (epidermal growth factor receptor (EGFR) inhibitor) and pembrolizumab (programmed death-1 (PD-1) inhibitor) in a patient with stage IV tongue cancer, and what are the potential side effects?

Cetuximab and Pembrolizumab for Stage IV Tongue Cancer

Treatment Rationale

For stage IV tongue cancer (squamous cell carcinoma of the oral cavity), the combination of pembrolizumab with platinum-based chemotherapy plus 5-fluorouracil represents the current first-line standard of care, while cetuximab combined with platinum/5-FU (EXTREME regimen) serves as an alternative for patients with contraindications to immunotherapy or PD-L1-negative tumors. 1

First-Line Treatment Selection Algorithm

The choice between these regimens depends on several key factors:

For PD-L1-positive tumors (CPS ≥1):

• Pembrolizumab plus platinum/5-FU is the preferred first-line option, demonstrating superior overall survival of 13.0 months versus 10.7 months with cetuximab-based therapy (EXTREME regimen) 1
• In patients with high PD-L1 expression (CPS ≥20), pembrolizumab monotherapy can be considered when rapid tumor shrinkage is not required, achieving median overall survival of 14.9 months 1

For PD-L1-negative tumors (CPS <1):

• The EXTREME regimen (cetuximab plus platinum/5-FU) remains standard of care 1
• Current evidence does not definitively establish whether pembrolizumab/chemotherapy improves survival compared with cetuximab/chemotherapy in PD-L1-negative patients 1, 2
• The FDA has approved pembrolizumab plus chemotherapy regardless of PD-L1 status, though the benefit in CPS 0 patients remains unproven 2

For symptomatic patients requiring rapid tumor response:

• Pembrolizumab plus platinum/5-FU is appropriate regardless of PD-L1 status, as objective response rates (36.3%) and progression-free survival (5.1 months) are similar to cetuximab-based therapy 1, 2

Mechanisms of Action

Cetuximab (EGFR Inhibitor)

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR), which is constitutively expressed in many head and neck cancers including oral cavity tumors 3:

• Blocks EGFR ligand binding: Competitively inhibits binding of epidermal growth factor and transforming growth factor-alpha to EGFR 3
• Inhibits downstream signaling: Blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinases and vascular endothelial growth factor 3
• Mediates immune response: Can trigger antibody-dependent cellular cytotoxicity (ADCC) against tumor cells expressing EGFR 3
• Pharmacokinetics: Reaches steady-state by the third weekly infusion with a mean half-life of approximately 112 hours 3

Pembrolizumab (PD-1 Inhibitor)

Pembrolizumab is a monoclonal antibody targeting programmed cell death protein 1 (PD-1), restoring anti-tumor immune responses 1:

• Blocks immune checkpoint: Prevents PD-1 from binding to its ligands (PD-L1 and PD-L2), thereby releasing the brake on T-cell activation 1
• Enhances tumor immunity: Allows cytotoxic T-cells to recognize and destroy cancer cells that would otherwise evade immune surveillance 4
• Synergistic potential: The KEYNOTE-048 trial demonstrated that pembrolizumab plus chemotherapy improved overall survival to 13.0 months versus 10.7 months with cetuximab-based therapy in the total population 4

Why Not Both Together?

The combination of pembrolizumab plus cetuximab (without chemotherapy) showed promising activity in a phase 2 trial with a 45% overall response rate, but this regimen is not currently standard of care and requires further investigation. 5 Current guidelines recommend either pembrolizumab-based or cetuximab-based regimens combined with chemotherapy, not both immunotherapy and EGFR inhibition together as first-line treatment 1.

Side Effects Profile

Cetuximab-Specific Toxicities

Grade 3-5 adverse events occur in 85.1% of patients receiving cetuximab with platinum/5-FU: 1

• Dermatologic toxicity (most characteristic):

  • Acneiform rash affecting face, upper chest, and back 1
  • Radiodermatitis when combined with radiation therapy 6
  • Skin fissures and paronychia

• Infusion reactions: Can occur during or after administration, requiring premedication and monitoring 3

• Mucositis: Severe oral mucositis occurs in approximately 9% of patients 5

• Electrolyte abnormalities: Hypomagnesemia requiring monitoring and supplementation 3

Pembrolizumab-Specific Toxicities

Grade 3-5 adverse events occur in 83.3% of patients receiving pembrolizumab with platinum/5-FU, but only 54.7% with pembrolizumab monotherapy: 1, 4

• Immune-related adverse events (irAEs):

  • Pneumonitis
  • Colitis and diarrhea
  • Hepatitis with elevated liver enzymes
  • Endocrinopathies (thyroid dysfunction, hypophysitis, adrenal insufficiency)
  • Nephritis
  • Dermatologic reactions (distinct from cetuximab's acneiform rash)

• Infusion reactions: Less common than with cetuximab 4

Comparative Toxicity

Pembrolizumab monotherapy demonstrates significantly better tolerability than cetuximab-based chemotherapy (54.7% versus 83.3% grade 3-5 adverse events), though this comes at the cost of lower response rates in unselected populations. 1 When combined with chemotherapy, toxicity profiles are similar between pembrolizumab and cetuximab regimens (83.3% versus 85.1% grade 3-5 events) 1, 4.

A critical distinction: pembrolizumab concurrent with radiation therapy (without chemotherapy) showed lower toxicity than cetuximab-RT in locally advanced disease (74% versus 92% grade 3+ adverse events), primarily due to reduced mucositis and radiodermatitis, though this did not translate to improved tumor control. 6

Treatment-Related Deaths

• Pembrolizumab monotherapy: 8% treatment-related deaths 4
• Pembrolizumab plus chemotherapy: 12% treatment-related deaths 4
• Cetuximab plus chemotherapy: 10% treatment-related deaths 4

Critical Clinical Caveats

PD-L1 testing is mandatory before initiating pembrolizumab monotherapy, as the EMA restricts approval to CPS ≥1 tumors, while the FDA allows broader use. 1 The combined positive score (CPS) measures PD-L1 expression on both tumor cells and immune cells, with thresholds at CPS 1 and CPS 20 determining treatment eligibility and expected benefit 1.

For patients progressing on pembrolizumab-based therapy, cetuximab plus platinum/5-FU can be considered as second-line treatment in fit patients eligible for platinum-based chemotherapy. 1 Conversely, after progression on cetuximab, pembrolizumab has limited evidence as salvage therapy 1.

The survival benefit of pembrolizumab in patients with CPS 1-19 (intermediate PD-L1 expression) remains unclear and requires further clarification. 1 In this population, the decision between pembrolizumab-based and cetuximab-based therapy should weigh the need for rapid tumor response, patient fitness for chemotherapy, and tolerance for immune-related adverse events 1, 2.