PD-L1 and TMB Testing of Patients With Lung Cancer for Immunooncology Therapies

The guideline’s key questions aimed to address the role for biomarkers for immunooncology in both early and late-stage patients with non-small cell lung cancer (NSCLC). However, at the time of the literature review and refresh, there were no peer-reviewed published studies supporting the role for immunooncology in the early-stage setting. Studies related to the use of PD-L1 and related biomarkers in early-stage setting were published after guideline manuscript was drafted. The guideline discussion addressed this omission accordingly.

If feasible, pathologists should use regulatory-approved assays as intended, which are clinically validated. However, most laboratories may be relying on laboratory developed tests (LDTs) because of limited access to a full suite of approved clones and platforms, as well as the increased cost of running companion diagnostic-labeled assays. To ensure patient access to PD-L1 testing, particularly at the local level, the expert panel also endorses the use of LDTs and validated PD-L1 IHC (LDTs) following technical validation against one or more of the approved companion diagnostic PD-L1 assays. The panel acknowledges the potential cost barriers to implementation of one or more FDA-approved assays and recommends use of laboratory developed assays to ensure broader access to testing. The panel does not endorse tumor mutation burden (TMB) testing for NSCLC and as such does not comment on test type.

Based on the available evidence, the guideline does not recommend a specific PD-L1 antibody clone. If a laboratory has access to a clinically validated assay, use of this testing is encouraged. If a laboratory cannot access this type of assay due to equipment or cost restrictions, then the use of a laboratory developed assay may be considered following careful validation according to the CAP immunohistochemistry validation guidelines.

Each of the four PD-L1 immunohistochemistry regulatory-approved assays (22C3 Dako/Agilent pharmDx, PD-L1 IHC 28-8 Dako/Agilent pharmDx, VENTANA PD-L1 SP142 and SP263) were co-developed with a specific anti-PD-1/PD-L1 agent used in clinical trials and have been approved by the FDA and/or other regulatory agencies as companion diagnostics (CDx) for the use of those agents (for intended use) in NSCLC. The laboratory director should be familiar with these testing indications and approvals when determining which assays to validate for clinical use. It is important to note that while data suggest that 22C3, 28-8 and SP263 CDx may be interchangeable, information about predictive performance of those CDx for anti-PD-1/PD-L1 agents outside of their given indication or that of LDTs is limited. Therefore, if feasible, pathologists should use CDx assays as intended, until larger cohort studies confirm the comparability of those CDx from both technical and clinical standpoints.

CAP expert panels now employ a well-organized and standardized tool, GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision Framework. In this system, level of evidence is an important factor in the determination of strength of recommendation, but it is not the only factor. Other contributing factors include balance of benefits and harms and considered judgments by the expert panel around values and preferences in relation to outcomes, resources, health equity, accessibility, and feasibility.

As with any clinical evidence-based guideline, following the recommendations is not mandatory. Recommendations may be incorporated into future versions of the CAP Laboratory Accreditation Program (LAP) checklists; however, they are not currently required by LAP or any regulatory or accrediting agency. It is only highly encouraged that clinicians and laboratories adopt these recommendations, as appropriate for their clinical settings.