What is the recommended immunotherapy approach for metastatic squamous cell carcinoma of the neck?

Immunotherapy for Metastatic Squamous Cell Carcinoma of the Neck

For first-line treatment of metastatic head and neck squamous cell carcinoma, pembrolizumab combined with platinum and 5-FU should be offered to patients with PD-L1 CPS ≥1, while pembrolizumab monotherapy is an alternative for those with CPS ≥20 who do not require rapid tumor reduction. 1

First-Line Treatment Algorithm Based on PD-L1 Status

For PD-L1 CPS ≥20:

• Pembrolizumab monotherapy (240 mg every 2 weeks or 480 mg every 4 weeks) provides median OS of 14.9 months versus 10.7 months with cetuximab-chemotherapy (HR 0.61, P=0.0007) 1
• This option is preferred when rapid tumor reduction is not clinically urgent, as response rates remain approximately 20% 1
• Pembrolizumab + platinum + 5-FU is the alternative when faster response is needed 1

For PD-L1 CPS 1-19:

• Pembrolizumab + platinum + 5-FU is the primary recommendation, achieving median OS of 12.3 months versus 10.3 months with cetuximab-chemotherapy (HR 0.78, P=0.0086) 1
• Pembrolizumab monotherapy is less effective in this subgroup and should be reserved for patients unable to tolerate chemotherapy 1

For PD-L1 CPS <1:

• Pembrolizumab + platinum + 5-FU may be offered, though the benefit is less pronounced (median OS 11.3 vs 10.7 months, HR 1.12) 1
• Cetuximab + platinum + 5-FU remains a reasonable alternative in this subgroup given the limited data supporting immunotherapy 1

Platinum-Refractory Disease (Second-Line Treatment)

For patients progressing within 6 months of platinum-based chemotherapy, pembrolizumab or nivolumab should be offered as single agents, regardless of PD-L1 status. 1

Evidence for Second-Line Immunotherapy:

• Nivolumab (240 mg every 2 weeks) achieved median OS of 7.5 months versus 5.1 months with standard therapy (HR 0.70, P=0.01) in CheckMate 141 1
• Pembrolizumab (200 mg every 3 weeks) demonstrated median OS of 8.4 months in KEYNOTE-040 1
• Both agents show significantly lower grade 3-4 adverse events (13.1% for nivolumab, 9% for pembrolizumab) compared to standard chemotherapy (35.1%) 1
• The OS benefit is independent of HPV status and PD-L1 expression 1
• Nivolumab is FDA-approved with Category 1 evidence, while pembrolizumab has Category 2A evidence 1, 2

Critical Clinical Decision Points

When to Choose Chemoimmunotherapy vs. Immunotherapy Alone:

• Choose pembrolizumab + chemotherapy when rapid tumor reduction is clinically necessary (e.g., symptomatic disease, impending airway compromise, significant pain) 1
• Choose pembrolizumab monotherapy for CPS ≥20 patients who can tolerate a slower response, prioritizing quality of life and avoiding chemotherapy toxicity 1

Biomarker Testing Requirements:

• PD-L1 CPS testing should be performed using the combined positive score (tumor cells + immune cells), with CPS ≥1 considered positive 1
• If PD-L1 testing is unavailable, tumor mutational burden (TMB) ≥10 mutations/megabase correlates with benefit from PD-1 inhibitors and may guide treatment 1
• HPV status does not alter immunotherapy recommendations, though HPV-negative patients may show greater efficacy 1

Common Pitfalls and Caveats

Avoid These Errors:

• Do not withhold immunotherapy based solely on low PD-L1 in platinum-refractory disease—both pembrolizumab and nivolumab show OS benefit regardless of PD-L1 status in second-line treatment 1
• Do not use combination anti-PD-1 + anti-CTLA-4 (durvalumab + tremelimumab) in platinum-refractory disease—the EAGLE trial showed no OS benefit 1
• Do not routinely combine pembrolizumab with cetuximab outside clinical trials—while phase II data show promise (45% response rate), randomized data are lacking 1

Safety Monitoring:

• Immune-related adverse events occur more frequently with immunotherapy but are generally manageable 1
• Grade 3-4 treatment-related adverse events are substantially lower with immunotherapy (9-13%) versus chemotherapy (35%) 1
• Treatment discontinuation rates due to adverse events are similar between immunotherapy and chemotherapy (7.5% vs 4.9%) 1

Special Consideration: Nasopharyngeal Carcinoma

If the neck squamous cell carcinoma is nasopharyngeal in origin, the treatment paradigm differs:

• Toripalimab, camrelizumab, or tislelizumab + gemcitabine + cisplatin should be offered as first-line treatment, regardless of PD-L1 status 1, 3
• Toripalimab achieved median PFS of 11.7 months versus 8.0 months with chemotherapy alone (HR 0.52) 1, 3
• If these agents are unavailable, pembrolizumab or nivolumab with gemcitabine-cisplatin may be substituted 3