Which molecular and immunologic biomarkers should be tested to identify non‑chemotherapy treatment options for a patient with metastatic head and neck cancer?

Biomarker Testing to Identify Non-Chemotherapy Options in Metastatic Head and Neck Cancer

Test PD-L1 expression by Combined Positive Score (CPS) to determine eligibility for pembrolizumab or nivolumab monotherapy, which can replace chemotherapy in platinum-refractory disease regardless of PD-L1 status, and guide first-line treatment decisions where pembrolizumab monotherapy is appropriate for CPS ≥1 tumors. 1

Essential Biomarkers for Treatment Selection

PD-L1 Testing (Primary Biomarker)

PD-L1 CPS testing is the single most important biomarker to identify patients who can avoid chemotherapy in metastatic head and neck squamous cell carcinoma (HNSCC). 1

• First-line setting: Pembrolizumab monotherapy is appropriate for patients with CPS ≥1, avoiding the need for chemotherapy entirely 1
• Platinum-refractory setting: Both pembrolizumab and nivolumab should be offered regardless of CPS status, providing a non-chemotherapy option after platinum failure 1
• The OS benefit with anti-PD-1 therapy is independent of PD-L1 expression in the platinum-refractory setting, with median OS of 8.4 months (pembrolizumab) and 7.5 months (nivolumab) versus standard chemotherapy 1

Critical caveat: For patients with CPS <1 in the first-line setting, the KEYNOTE-048 data suggest cetuximab with chemotherapy may be considered, though the subgroup was small (39-43 patients) and underpowered 1

HPV/p16 Testing (Secondary Biomarker)

HPV status should be determined but does not exclude patients from immunotherapy. 2

• For oropharyngeal primaries: Perform p16 immunohistochemistry (IHC) as surrogate marker for high-risk HPV, with ≥70% nuclear and cytoplasmic expression at moderate-to-strong intensity defining positivity 2
• For unknown primary with cervical lymph node metastases: Routinely perform p16 IHC on upper/mid-jugular chain nodes 2
• Clinical significance: The OS benefit with anti-PD-1 therapy is independent of HPV status, so HPV-negative patients remain candidates for immunotherapy 1
• HPV testing helps with prognostication and clinical trial eligibility but does not determine immunotherapy candidacy

Testing NOT Routinely Recommended

Do not routinely test for:

• Low-risk HPV 2
• Repeat HPV testing on recurrent/persistent tumors if primary tumor status already established 2
• HPV in non-oropharyngeal primaries (unless poorly differentiated with diagnostic uncertainty) 2

Algorithmic Approach to Biomarker-Guided Treatment

Step 1: Establish Disease Context

• Platinum-refractory (progressed within 6 months of platinum): Proceed directly to pembrolizumab or nivolumab monotherapy without PD-L1 testing required 1
• Treatment-naïve metastatic disease: PD-L1 CPS testing is essential

Step 2: PD-L1 CPS Testing for First-Line Treatment

• CPS ≥1: Pembrolizumab monotherapy (chemotherapy-free option) 1
• CPS <1: Consider cetuximab-based chemotherapy, though data limited 1

Step 3: HPV/p16 Testing

• Perform on all oropharyngeal primaries and unknown primaries with cervical nodes 2
• Use for prognostic information and clinical trial stratification
• Does not alter immunotherapy eligibility

Important Clinical Pitfalls

Avoid these common errors:

1. Withholding immunotherapy based on PD-L1 negativity in platinum-refractory disease: The strong recommendation is to offer pembrolizumab or nivolumab regardless of CPS status after platinum failure 1

2. Using p16 alone without proper validation: A small fraction of oropharyngeal tumors overexpress p16 without HPV etiology; pathologists should have confirmatory HPV testing available 2

3. Incorrect p16 interpretation: The threshold is ≥70% nuclear and cytoplasmic staining with moderate-to-strong intensity—lower percentages do not qualify as positive 2

4. Testing non-oropharyngeal primaries routinely for HPV: This is not recommended and wastes resources 2

Emerging Biomarkers (Not Yet Standard)

While tumor mutational burden (TMB), microsatellite instability, and tumor microenvironment markers are under investigation 3, 4, 5, 6, these are not currently recommended for routine clinical decision-making outside of clinical trials. The 2023 ASCO guideline focuses exclusively on PD-L1 as the validated predictive biomarker 1.

Special Population: Nasopharyngeal Carcinoma

For recurrent/metastatic nasopharyngeal carcinoma specifically, toripalimab, camrelizumab, or tislelizumab with gemcitabine-cisplatin should be offered first-line, though this represents immunotherapy plus chemotherapy rather than a chemotherapy-avoidance strategy 1.