The Roche VENTANA PD-L1 (SP263) Assay is a CE-IVD immunohistochemistry test used to detect programmed death ligand 1, or PD-L1, in formalin-fixed, paraffin-embedded tumour tissue.
In non-small cell lung cancer, the assay can support treatment selection for several immunotherapies. Its companion diagnostic indications include Libtayo, or cemiplimab, with the applicable PD-L1 threshold determined by the medicinal product indication and current local labelling.
The October 2022 milestone added Libtayo to the assay’s CE-IVD indications for non-small cell lung cancer. Since then, the assay and the Libtayo label have continued to evolve. This article explains the original milestone, the current indication and the clinical bridging evidence that connected SP263 with the Libtayo clinical programme.
Key point: The VENTANA PD-L1 (SP263) Assay does not provide a general positive or negative answer for every immunotherapy. The relevant tumour type, scoring method, threshold, treatment and approved product label must be considered together.
What is the VENTANA PD-L1 (SP263) Assay?
VENTANA PD-L1 (SP263) is a qualitative immunohistochemistry assay based on a rabbit monoclonal antibody against PD-L1.
According to the current Roche product information, the assay is used with the OptiView DAB IHC Detection Kit on compatible BenchMark IHC/ISH instruments. For non-small cell lung cancer, PD-L1 expression is determined by assessing tumour-cell membrane staining.
The result must be interpreted by a qualified pathologist together with the histological examination, relevant clinical information and appropriate controls. The applicable instructions for use and medicinal product label should always take precedence over a general product summary.
What did the 2022 CE-IVD milestone mean?
The October 2022 announcement concerned the use of VENTANA PD-L1 (SP263) as a companion diagnostic to help identify patients with locally advanced or metastatic non-small cell lung cancer who could be eligible for treatment with Libtayo.
For Libtayo monotherapy, the current European medicinal product information identifies adults with locally advanced or metastatic NSCLC whose tumours express PD-L1 in at least 50% of tumour cells and do not have EGFR, ALK or ROS1 aberrations.
The current label also includes Libtayo in combination with platinum-based chemotherapy for eligible patients whose tumours express PD-L1 in at least 1% of tumour cells. The complete indications, limitations and treatment requirements are available in the current EMA product information for Libtayo.
The diagnostic result is therefore only one element of treatment eligibility. Tumour type, disease stage, molecular alterations, treatment regimen and the current medicinal product label remain relevant.
Why clinical bridging was necessary
It is incomplete to say that SP263 was simply validated by the Phase III EMPOWER-Lung 1 study, also known as Study 1624.
The pivotal clinical study used the PD-L1 IHC 22C3 pharmDx assay to determine PD-L1 status. Roche therefore needed evidence connecting results generated with VENTANA PD-L1 (SP263) to the clinical evidence generated with 22C3.
The current VENTANA SP263 instructions for use describe a clinical bridging study using archived samples from Study 1624. Among 768 specimens with evaluable paired results at the 50% threshold, Roche reported:
| Agreement measure | Result |
|---|---|
| Positive percentage agreement | 82.7% |
| Negative percentage agreement | 93.6% |
| Overall percentage agreement | 88.0% |
The subsequent efficacy analyses supported the conclusion that the clinical benefit of Libtayo was maintained in the population identified as PD-L1 positive by SP263.
These results support the specific product claim. They should not be interpreted as evidence that SP263 and 22C3 are universally interchangeable across every tumour type, threshold, treatment or laboratory setting.
What the case demonstrates about companion diagnostic development
The VENTANA SP263 and Libtayo case illustrates several recurring requirements in companion diagnostic development.
The clinical-trial assay and commercial assay must be connected
A drug trial may use an assay that is different from the diagnostic eventually placed on the market. When that happens, a bridging strategy must show that the commercial assay identifies an appropriate population for the corresponding medicinal product.
Analytical agreement is important, but it may not be sufficient on its own. The programme may also need clinical bridging, efficacy analyses, missing-data assessments and justification of the selected cut-off.
The cut-off is part of the clinical claim
A PD-L1 result cannot be separated from the scoring method and threshold used to generate it.
For NSCLC, the current SP263 label includes different tumour-cell thresholds depending on the associated therapy and treatment context. A manufacturer cannot assume that evidence supporting one threshold automatically supports another.
Diagnostic and medicinal product labels must remain aligned
The intended purpose, instructions for use, Summary of Safety and Performance and medicinal product information should describe compatible populations, specimen requirements, thresholds and clinical applications.
A change to a treatment indication, biomarker population or regimen can create corresponding diagnostic labelling and evidence requirements.
Implementation conditions matter
The assay is validated as part of a defined system that includes the antibody, detection chemistry, instrument platform, specimen preparation, controls, scoring method and trained interpretation.
Changing one of these elements can affect performance and may require additional validation rather than a simple administrative label update.
How the IVDR applies to companion diagnostics
Under the EU In Vitro Diagnostic Medical Devices Regulation, companion diagnostics are generally classified as Class C devices.
Their conformity assessment requires a Notified Body. The companion diagnostic procedure also includes consultation with the competent medicinal products authority or, where applicable, the European Medicines Agency regarding the device’s suitability for use with the corresponding medicinal product.
The EMA companion diagnostic guidance explains the consultation procedure between the Notified Body and the medicines regulator.
CE marking is therefore the result of an applicable conformity assessment route. It is not a general European Commission approval of every possible use of the assay, nor does it establish that different PD-L1 assays are interchangeable.
For a broader explanation, see MDx CRO’s guide to the IVDR companion diagnostic certification pathway.
Frequently asked questions
The Roche VENTANA PD-L1 (SP263) Assay is an immunohistochemistry test that detects PD-L1 protein in formalin-fixed, paraffin-embedded tumour tissue. Its clinical application and scoring method depend on the tumour type, associated therapy and applicable product label.
SP263 identifies the antibody clone used by the assay to bind to PD-L1. The assay is part of a defined staining and interpretation system and should not be treated as an antibody reagent that can be transferred to any platform without validation.
The current European labels include different thresholds for different Libtayo treatment contexts. Libtayo monotherapy in the relevant first-line NSCLC population uses a threshold of at least 50% tumour cells. The combination with platinum-based chemotherapy includes a threshold of at least 1% tumour cells.
The current medicinal product and diagnostic labels should be checked before applying either threshold.
Not as a general rule. Clinical bridging supported defined SP263 indications using evidence connected to studies that employed 22C3. This does not prove universal interchangeability across all clinical applications, cut-offs or laboratory settings.
No. Roche’s current CE-IVD product information describes a broader portfolio of NSCLC therapy indications than the four mentioned in the original 2022 announcement. The exact companion diagnostic and non-companion diagnostic claims should be taken from the current instructions for use and local product approvals.
No. The European CE-IVD and United States FDA pathways are separate. The FDA approved the VENTANA PD-L1 (SP263) Assay as a companion diagnostic for Libtayo in NSCLC on 1 March 2023. The FDA approval summary applies to the US indication and should not be used as a substitute for European labelling.
Regulatory implications for CDx developers
The most important lesson from this case is not the addition of another therapy to a PD-L1 assay. It is the need to connect the clinical-trial assay, commercial diagnostic, biomarker cut-off, medicinal product indication and final labelling through a defensible evidence strategy.
MDx CRO supports companion diagnostic programmes with performance strategy, clinical bridging, technical documentation and preparation for Notified Body and medicines-authority consultation. Explore our Precision Medicine and Companion Diagnostics services.
