Is PDL1 (Programmed Death-Ligand 1) testing compulsory in metastatic Squamous Cell Carcinoma (SCC)?

PD-L1 Testing in Metastatic Squamous Cell Carcinoma

PD-L1 testing is not compulsory but is strongly recommended in metastatic squamous cell carcinoma (SCC) of the lung, as it provides critical information for treatment selection, particularly when considering immunotherapy monotherapy versus chemoimmunotherapy combinations. 1

Context-Specific Recommendations by Site

Metastatic Lung SCC (Squamous NSCLC)

PD-L1 testing should be performed routinely before first-line treatment to guide optimal therapy selection, though it is not an absolute requirement for all treatment options. 1

First-Line Treatment Decision Algorithm:

• If PD-L1 ≥50%: Pembrolizumab monotherapy is a category 1 option, offering superior survival (OS rate 80.2% vs 72.4% at 6 months) with fewer severe adverse events (26.6% vs 53.3%) compared to chemotherapy. 1

• If PD-L1 status unknown or any level: Platinum-based chemotherapy plus immunotherapy (pembrolizumab, cemiplimab, nivolumab/ipilimumab, or durvalumab/tremelimumab) can be administered regardless of PD-L1 status, as these combinations show benefit across all PD-L1 levels. 1

• Second-line setting: Nivolumab is approved (category 1) for metastatic squamous NSCLC after platinum-based chemotherapy without requiring PD-L1 testing, as PD-L1 expression was not associated with response in squamous histology (median OS 9.2 vs 6.0 months with docetaxel). 1

Key Clinical Nuances:

The NCCN guidelines explicitly state that PD-L1 testing is a category 2A recommendation (meaning high-level evidence with uniform consensus) before first-line treatment in metastatic NSCLC. 1 However, the 2023 ESMO guidelines demonstrate that combination chemoimmunotherapy can be given regardless of PD-L1 status, making testing technically optional if combination therapy is planned. 1

Critical distinction: While nivolumab does not require PD-L1 testing for prescription in squamous NSCLC, the FDA approved a complementary diagnostic test because it "may provide useful information" for patient counseling, even though PD-L1 was not predictive in the CheckMate-017 trial. 1

Metastatic Head and Neck SCC

PD-L1 testing is required for pembrolizumab monotherapy in first-line recurrent/metastatic HNSCC (CPS ≥1 required for approval), but not required for nivolumab. 1, 2

Treatment Algorithm:

• First-line with PD-L1 CPS ≥1: Pembrolizumab monotherapy or pembrolizumab plus platinum/5-FU are approved options. 1, 2

• First-line with PD-L1 CPS <1 or unknown: Platinum/5-FU/cetuximab remains standard therapy. 1

• Second-line after platinum failure: Nivolumab is approved without PD-L1 testing requirement, though higher PD-L1 expression correlates with better outcomes (22% response rate in PD-L1 ≥1% vs 4% in PD-L1 negative, p=0.021). 1, 2

Practical Testing Considerations

Common Pitfalls to Avoid:

1. Specimen selection matters: PD-L1 expression shows significant heterogeneity, with biopsies potentially underestimating expression compared to resection specimens, and metastatic lymph nodes showing higher positivity than primary tumors in HNSCC. 3

2. Timing of testing: The most recent tumor material relative to disease progression is most reliable, as prior therapy can alter PD-L1 expression unpredictably. 3

3. Multiple biopsies preferred: PD-L1 expression is "continuously variable and dynamic," so single-site testing may not capture true tumor status. 1, 4

4. Assay-specific cutoffs: Different immunotherapy agents use different PD-L1 assays and cutoff definitions—pembrolizumab uses CPS (combined positive score) while nivolumab trials used tumor proportion score. 1

When Testing Can Be Deferred:

• If urgent treatment initiation is needed and combination chemoimmunotherapy is planned (works regardless of PD-L1 status). 1

• In second-line squamous lung cancer when nivolumab is the intended agent (PD-L1 not predictive). 1

Evidence Quality Assessment

The strongest evidence comes from the 2023 ESMO guidelines 1 and 2024 NCCN guidelines 1, which represent the most current consensus. These supersede the 2017 NCCN recommendations 1 in terms of treatment algorithms, though the fundamental biology regarding PD-L1's predictive value remains consistent.

Bottom line: While not absolutely compulsory for all treatment decisions in metastatic SCC, PD-L1 testing should be performed whenever feasible to optimize treatment selection, particularly when considering immunotherapy monotherapy or when patients may benefit from avoiding chemotherapy toxicity. 1, 2