PD-L1 Testing in Relapsed NSCLC: Not Strictly Required, But Highly Recommended
PD-L1 testing is not absolutely required for all patients with relapsed NSCLC, but it is strongly recommended because it provides valuable information for treatment selection and can guide optimal immunotherapy choices. 1
The Nuanced Reality of PD-L1 Testing Requirements
The answer depends critically on which immunotherapy agent you're considering:
Companion vs. Complementary Diagnostics
- Pembrolizumab requires PD-L1 testing (TPS ≥1%) as a companion diagnostic for second-line use after platinum-based chemotherapy progression 1
- Nivolumab and atezolizumab do NOT require PD-L1 testing - these are approved with complementary diagnostics, meaning testing may aid in patient selection but is not mandatory 1
Clinical Practice Recommendations
The Society for Immunotherapy of Cancer Task Force unanimously agreed that all newly diagnosed patients should receive PD-L1 testing 1. For relapsed disease specifically:
- Patients with squamous or non-squamous NSCLC who progressed on platinum-containing chemotherapy and have not previously received a checkpoint inhibitor should be considered for atezolizumab, nivolumab, or pembrolizumab 1
- PD-L1 testing is routinely recommended at diagnosis to inform immunotherapy use in both first-line and second-line settings 2
Why Test Even When Not Required?
PD-L1 expression correlates with improved outcomes across multiple checkpoint inhibitors 1:
- Higher PD-L1 expression (≥1%, ≥5%, ≥10%) associates with longer OS and PFS with nivolumab compared to chemotherapy 1
- Even PD-L1-negative patients can benefit from nivolumab and atezolizumab, which is why testing isn't mandatory for these agents 1
- 71% of the expert Task Force felt PD-L1 expression was predictive of checkpoint inhibitor response 1
Practical Algorithm for Relapsed NSCLC
If pembrolizumab is being considered: PD-L1 testing is mandatory (companion diagnostic requirement) 1
If nivolumab or atezolizumab is being considered: Testing is optional but recommended to:
- Identify patients most likely to benefit
- Inform discussions about expected response rates
- Guide treatment sequencing decisions
Testing should ideally use archived tissue from initial diagnosis if available, though the guidelines acknowledge PD-L1 expression can be dynamic 1
Important Caveats
- PD-L1 is neither fully sensitive nor specific as a biomarker - some PD-L1-negative patients respond to immunotherapy, and some PD-L1-positive patients do not 1
- Different assays exist (22C3, 28-8, SP142, SP263) with varying cutoffs and scoring systems 1
- Smoking history (29% of experts) was also considered predictive of checkpoint inhibitor response 1
Bottom line: While you can legally prescribe nivolumab or atezolizumab without PD-L1 testing in relapsed NSCLC, best practice is to test all patients to optimize treatment selection and set appropriate expectations for response.